The Year in Basic Thyroid Cancer Research.

Background: Every year, the American Thyroid Association (ATA) Annual Meeting opening session features presentations covering the most recent advances in the three major areas of thyroidology: basic, clinical, and surgical. As the ATA did not have an annual meeting in 2020, because of the COVID19 pandemic, the 2021 meeting opened with a special "Two Years in Thyroidology" session. Methods: A PubMed electronic search was conducted to identify original basic science research studies on thyroid cancer published between October 2019 and September 2021. Methodologically rigorous studies that were deemed most likely to influence the field of basic science research in thyroid cancer were grouped into three thematic units: Genetics and Genomics, Molecular Biology and Signaling, and Preclinical and Translational Science. Four publications for each category were chosen for discussion. Results: Selected studies covered topics ranging from the genetics of thyroid cancer predisposition to the genomics of anaplastic thyroid cancer evolution, from novel molecular pathways involved in thyroid cancer pathogenesis to potentially game-changing imaging and therapeutic innovations. Conclusions: The past two years, in the face of unique COVID19 pandemic-associated hurdles, have witnessed a large number of important developments in basic and translational thyroid cancer research. These studies not only have shed novel light on a number of long-standing scientific questions but have also highlighted the major challenges and open questions that still remain to be addressed in the coming years.

Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c < 6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Consensus report: Definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

A practical guide to genetic testing in endocrinology.

Rapid advances in sequencing technology have led to significant improvements in genomic analysis, resulting in increased understanding of the molecular basis of many endocrine conditions. Genomic testing for rare disease is being integrated into everyday clinical practice, as the importance of confirming a genetic diagnosis earlier in a patient's pathway helps direct their clinical care and specialized management. In England, the new nationally commissioned Genomic Medicine Service has started to deliver testing for rare and inherited disease and cancer somatic tissue via seven Genomic Laboratory Hubs. The range of genetic tests, technology employed and eligibility criteria for patient testing are all defined in the National Genomic Test Directory. This review provides practical guidance on how to access genomic testing for endocrine disease, how to interpret and relay results, and details how genetic counselling can help integrate results into ongoing care of the individual and their family. This article discusses general principles as well as specifics related to the process of genomic testing in England. We illustrate mainstream genetic testing with a clinical scenario involving an individual with inherited endocrine neoplasia, followed by a generic description of the different steps involved, including informed consent to proceed to diagnostic testing. Most genetic tests analyse multiple genes simultaneously by next-generation sequencing, and variant interpretation may yield not only pathogenic explanatory results, but also ambiguous outcomes, with variants of unknown significance or incidental findings. Delivery of results and posttest genetic counselling are therefore key components of integrating genetic testing into routine endocrine care.

Metabolic Homeostasis: It's All in the Timing.

Cross-talk between peripheral tissues is essential to ensure the coordination of nutrient intake with disposition during the feeding period, thereby preventing metabolic disease. This mini-review considers the interactions between the key peripheral tissues that constitute the metabolic clock, each of which is considered in a separate mini-review in this collation of articles published in Endocrinology in 2020 and 2021, by Martchenko et al (Circadian rhythms and the gastrointestinal tract: relationship to metabolism and gut hormones); Alvarez et al (The microbiome as a circadian coordinator of metabolism); Seshadri and Doucette (Circadian regulation of the pancreatic beta cell); McCommis et al (The importance of keeping time in the liver); Oosterman et al (The circadian clock, shift work, and tissue-specific insulin resistance); and Heyde et al (Contributions of white and brown adipose tissues to the circadian regulation of energy metabolism). The use of positive- and negative-feedback signals, both hormonal and metabolic, between these tissues ensures that peripheral metabolic pathways are synchronized with the timing of food intake, thus optimizing nutrient disposition and preventing metabolic disease. Collectively, these articles highlight the critical role played by the circadian clock in maintaining metabolic homeostasis.

Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics.

Genetically predicted sex hormone binding globulin and ischemic heart disease in men and women: a univariable and multivariable Mendelian randomization study.

Men are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone. Correspondingly, sex hormone binding globulin (SHBG) which lowers circulating testosterone might protect men against IHD. SHBG may also affect IHD independent of testosterone, which has not previously been examined. To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants to predict SHBG, and examined their association with IHD in the UK Biobank. We also replicated using genetic instruments from Japanese men and applied to Biobank Japan. To assess the role of SHGB independent of testosterone in men, we used multivariable MR controlling for testosterone. Genetically predicted SHBG was associated with lower IHD risk in men [odds ratio (OR) 0.78 per standard deviation, 95% confidence interval (CI) 0.70 to 0.87], and the association was less clear in women. The estimates were similar in Japanese. The inverse association remained after controlling for testosterone in men (OR 0.79, 95% CI 0.71 to 0.88). SHBG might lower the risk of IHD in men, with a role independent of testosterone. Exploring intervention strategies that increase SHBG is important for targeting IHD treatments.

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia.

BACKGROUND: Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid. METHODS: Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia. SUMMARY: Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. CONCLUSIONS: CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Case Report: Medullary Thyroid Cancer Workup Initiated by Unexpectedly High Procalcitonin Level-Endocrine Training Saves Life in the COVID-19 Unit.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that has caused a worldwide pandemic. The majority of medullary thyroid cancers present as a thyroid nodule. At the time of diagnosis, cervical lymph nodes and distant metastases are frequently detected. Case Report: Here, we present a case of a 46-year-old man with coronavirus disease (COVID) pneumonia, who had persistently high serum procalcitonin levels despite normal C-reactive protein levels. The attending infectologist happened to be a colleague who spent some time, as part of her internal medicine rotation, in the Endocrine Ward and recalled that medullary thyroid cancer might be the cause. This led to the timely workup and treatment of the medullary cancer.

From Pituitary Adenoma to Pituitary Neuroendocrine Tumors: How Molecular Pathways may Impact the Therapeutic Management?

The classification of adeno-pituitary tumor was deeply revised over the last 20 years, in order to better describe the variable and complex biological and clinical behavior of these neoplasia and to identify prognostic markers of aggressiveness and poor prognosis. Recently, the International Pituitary Pathology Club proposed to replace the term "pituitary adenoma" with "pituitary neuroendocrine tumour" (PitNET), to reflect similarities of adeno-pituitary tumours with neuroendocrine neoplasia of other organs, underling better the variable behaviour of adeno-pituitary neoplasia. A definitive consensus was not reached on this issue. In this review, we will describe how molecular and biological marker can predict aggressiveness of PitNETs and impact on therapeutic management of PitNETs.

Challenges in the care of transgender and gender-diverse youth: an endocrinologist's view.

An increasing number of transgender and gender-diverse (TGD) youth (early pubertal through to late adolescent, typically 9-10 through to 18 years of age) are seeking medical services to bring their physical sex characteristics into alignment with their gender identity - their inner sense of self as male or female or somewhere on the gender spectrum. Compelling research has demonstrated the clear mental health - even life-saving - benefits of gender-affirming care, but current clinical practice guidelines and standards of care are based on only several short-term and a few medium-term outcomes studies complemented by expert opinion. Nevertheless, although the relative paucity of outcomes data raises concerns, the stance of not intervening until more is known is not a neutral option, and large observational studies evaluating current models of care are necessary and are now underway. This Review highlights key advances in our understanding of transgender and gender-diverse youth, the challenges of providing gender-affirming care, gaps in knowledge and priorities for research.

Composite Cardiovascular Outcomes in Patients With Primary Aldosteronism Undergoing Medical Versus Surgical Treatment: A Meta-Analysis.

Background: Superior outcomes after surgical treatment over medical treatment for primary aldosteronism (PA) has been reported in small-scale clinical studies, but no solid conclusion has been drawn as results of large randomized trials are lacking. Methods: We performed a search of PubMed, MEDLINE, Embase and Cochrane Library for randomized or observational studies that investigated cardiovascular outcomes in patients with PA undergoing medical versus surgical treatment. Meta-analyses of both composite and individual outcomes were conducted. Risks of bias of the included studies were assessed with Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) checklist. Trial sequential analysis (TSA) was performed to control the risk of random errors and assess whether the results in our meta-analysis were conclusive. Results: A total of 12 studies, including a total of 6148 PA patients, were included in the meta-analysis. The results of meta-analyses demonstrated lower incidence of composite cardiovascular outcomes among PA patients who underwent surgical treatment over medical treatment (odds ratio (OR): 0.49). Surgical treatment also led to less incidence of persistence of hypertension (OR of non-cure hypertension: 0.31). Fewer major cardiovascular events and mortality events were observed (OR: 0.60) after surgical treatment. TSA result showed that the required information size was 2151 and the cumulative Z curve crossed the futility boundary and reached the required information size. Conclusion: Superior performance of surgical treatment over medical treatment is confirmed with meta-analyses in terms of lower incidences of composite cardiovascular outcomes and non-cure of hypertension. Hence, adrenalectomy could now be concluded as the treatment of choice for lateralized PA.

What Is an L-Cell and How Do We Study the Secretory Mechanisms of the L-Cell?

Synthetic glucagon-like peptide-1 (GLP-1) analogues are effective anti-obesity and anti-diabetes drugs. The beneficial actions of GLP-1 go far beyond insulin secretion and appetite, and include cardiovascular benefits and possibly also beneficial effects in neurodegenerative diseases. Considerable reserves of GLP-1 are stored in intestinal endocrine cells that potentially might be mobilized by pharmacological means to improve the body's metabolic state. In recognition of this, the interest in understanding basic L-cell physiology and the mechanisms controlling GLP-1 secretion, has increased considerably. With a view to home in on what an L-cell is, we here present an overview of available data on L-cell development, L-cell peptide expression profiles, peptide production and secretory patterns of L-cells from different parts of the gut. We conclude that L-cells differ markedly depending on their anatomical location, and that the traditional definition of L-cells as a homogeneous population of cells that only produce GLP-1, GLP-2, glicentin and oxyntomodulin is no longer tenable. We suggest to sub-classify L-cells based on their differential peptide contents as well as their differential expression of nutrient sensors, which ultimately determine the secretory responses to different stimuli. A second purpose of this review is to describe and discuss the most frequently used experimental models for functional L-cell studies, highlighting their benefits and limitations. We conclude that no experimental model is perfect and that a comprehensive understanding must be built on results from a combination of models.

Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes.

Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.