Graves' orbitopathy post-SARS-CoV-2 vaccines: report on six patients.

CONTEXT: Autoimmune and inflammatory thyroid diseases (Graves' disease, subacute thyroiditis, chronic autoimmune thyroiditis) have been reported following SARS-CoV-2 vaccines but Graves' orbitopathy (GO) post-COVID-19 vaccination is uncommon. METHODS: We describe six new patients seen in Endocrinology Departments with Outpatient Clinics for GO following SARS-CoV-2 vaccines in France. RESULTS: After COVID-19 vaccination, GO was observed in six patients (three men, three women, mean age 53 ± 6 years) with a personal past history of Graves' disease (5/6) or orbitopathy (4/6). New-onset (n = 2) or recurrence (n = 4) of GO was observed following mRNA vaccines after the first (3/6) or second (3/6) dose, with the mean time from vaccination to GO at 23.8 ± 10.4 days. In one patient, thyrotoxicosis was confirmed by increased free T4 and low TSH concentrations while others had normal TSH levels, during chronic levothyroxine treatment in three patients. Four patients had significant anti-TSH receptor antibodies levels. According to the severity and activity of GO, the patients were treated using selenium (n = 2), intravenous glucocorticoids (n = 2), teprotumumab (n = 1), tocilizumab (n = 2) and orbital decompression (n = 1) with a significant improvement in GO signs and symptoms observed by most patients. CONCLUSION: In this study, we report the main data from six new patients with GO following SARS-CoV-2 vaccines. Clinicians need to be aware of the risk of new-onset or recurrent GO in predisposed patients with autoimmune thyroid diseases after COVID-19 vaccination. This study should not raise any concerns regarding SARS-CoV-2 vaccination since the risk of COVID-19 undoubtedly outweighs the incidence of uncommon GO after SARS-CoV-2 vaccination.

A proactive medical necessity review program reduces revenue loss associated with outpatient medical benefit drugs.

PURPOSE: A common denial trend that occurs with "outpatient medical benefit drugs" (ie, medications covered by a medical benefit plan and administered in an outpatient visit) is payers not requiring or permitting prior authorization (PA) proactively, yet denying the drug after administration for medical necessity. In this situation, a preemptive strategy of complying with payer-mandated requirements is critical for revenue protection. To address this need, our institution incorporated a medical necessity review into its existing closed-loop, pharmacy-managed precertification and denials management program. SUMMARY: Referrals for targeted payers and high-cost medical benefit drugs not eligible for PA and deemed high risk for denial were incorporated into the review. Payer medical policies were evaluated and clinical documentation assessed to confirm alignment. This descriptive report outlines the medical necessity workflow as a component of the larger precertification process, details the decision-making process when performing the review, and delineates the roles and responsibilities for involved team members. A total of 526 drug orders were evaluated from September 2018 to August 2019, with 146 interventions completed. Of the 761 individual claims affected by proactive medical necessity review, 99.2% resulted in payment and less than 1% resulted in revenue loss, safeguarding more than $5.3 million in annual institutional drug reimbursement. At the time of analysis, there were only 3 cases of revenue loss. CONCLUSION: Our institution's pharmacy-managed medical necessity review program for high-cost outpatient drugs safeguards reimbursement for therapies not eligible for payer PA. It is a revenue cycle best practice that can be replicated at other institutions.

Research and innovation as a catalyst for food system transformation.

BACKGROUND: Food systems are associated with severe and persistent problems worldwide. Governance approaches aiming to foster sustainable transformation of food systems face several challenges due to the complex nature of food systems. SCOPE AND APPROACH: In this commentary we argue that addressing these governance challenges requires the development and adoption of novel research and innovation (R&I) approaches that will provide evidence to inform food system transformation and will serve as catalysts for change. We first elaborate on the complexity of food systems (transformation) and stress the need to move beyond traditional linear R&I approaches to be able to respond to persistent problems that affect food systems. Though integrated transdisciplinary approaches are promising, current R&I systems do not sufficiently support such endeavors. As such, we argue, we need strategies that trigger a double transformation - of food systems and of their R&I systems. KEY FINDINGS AND CONCLUSIONS: Seizing the opportunities to transform R&I systems has implications for how research is done - pointing to the need for competence development among researchers, policy makers and society in general - and requires specific governance interventions that stimulate a systemic approach. Such interventions should foster transdisciplinary and transformative research agendas that stimulate portfolios of projects that will reinforce one another, and stimulate innovative experiments to shape conditions for systemic change. In short, a thorough rethinking of the role of R&I as well as how it is funded is a crucial step towards the development of the integrative policies that are necessary to engender systemic change - in the food system and beyond.

Outcomes of orbital decompression using surgical navigation in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy can result in proptosis. In such cases, orbital decompression surgery is often warranted to reduce the adverse impact on patient quality of life. Due to the anatomical complexity of the orbit, navigation can be of considerable assistance during orbital decompression. The objective of this study was to evaluate the benefits of using a surgical navigation device in orbital decompression surgery. A retrospective study was performed based on patients who underwent decompression surgery with (N+) or without (N-) a navigation device between 1997 and 2017. Included patients had undergone unilateral or bilateral orbital decompression by resection of the orbital floor and medial wall of the orbit. Criteria assessed were the presence of debilitating postoperative diplopia, postoperative proptosis reduction, symmetry of protrusion of the eyeballs, and the duration of surgery. Three hundred and fifty eyes were analysed (191 patients): 205 in the N+ group and 145 in the N- group. Use of the surgical navigation system resulted in a greater proptosis reduction, and this result was statistically significant for the right eyeball (P=0.03). The surgical navigation system had no effect on symmetry of protrusion of the eyeballs or on postoperative diplopia. Setting up the navigation device increased the duration of surgery by 40 minutes on average.

[Immune-related adverse events after immune checkpoints inhibitors in 2019: An update]. / Toxicités immunologiques induites par les inhibiteurs de checkpoint en 2019 : mise au point.

Use of checkpoint inhibitors to treat cancer was one of the most important revolution these last years and an increasing number of new types of tumors is currently under investigation with these new treatments. However, immune-related adverse events associated with these agents frequently affect various organs, mimicking auto-immune or inflammatory diseases. Some of these effects can be severe, often requiring hospitalization and specialized treatment (immunosuppression). Most known agents are ipilimumab (anti-CTLA-4 antibody) nivolumab and pembrolizumab (anti-PD-1 antibodies). New molecules are now approved or in development as anti-PD-L1 antibodies, anti-LAG-3 or anti-TIM-3 antibodies, increasing the probability and new description of immune-related adverse events. With his experience in auto-immune diseases, the immunologist/internal medicine specialist has an important role in the management of these toxicities. The goal of this review is to focus on the incidence, diagnostic assessment and recommended management of the most relevant immune-related adverse events.

[Toxicity of immune checkpoints inhibitors]. / Toxicité des inhibiteurs de points de contrôle immunitaires.

INTRODUCTION: Anti-tumoral immunotherapy is currently the basis of a profound modification of therapeutic concepts in oncology, in particular since the arrival of immune checkpoint inhibitors (ICI). In addition to their efficacy profile, these immune-targeted agents also generate adverse events. With the increasing use of ICI for a growing number of tumor types, awareness of immunotherapy-related adverse events is essential to ensure prompt diagnosis and effective management of these potentially serious adverse events. BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (irAEs), which resemble autoimmune disease. Though severe irAEs remain rare, they can be fatal if not diagnosed and treated in an appropriate manner. OUTLOOK AND CONCLUSION: Additional studies are needed to better understand the clinical characteristics and chronology of these adverse effects and to clarify their pathophysiological mechanisms.

L'hypophyse et ses traitements : comment peuvent-ils influer sur le comportement ?: The pituitary and its treatments: how can they influence behaviour?

Behaviour may be influenced by pituitary hormones or treatments. Dopamine agonist (DA) indicated in prolactinomas treatment can cause side effects, and especially impulse control disorders. In the context of prolactinomas treatment, impulse control disorders (ICD) have been reported like gambling, compulsive shopping, but mostly hypersexuality. These ICD can occur with low AD doses, and seem to be independent of type of molecule and psychiatric medical history. The main pathophysiologic hypothesis is a dysregulation of dopaminergic pathway involved in reward system. Given the possible devastating social impact of these ICD, they have to be screened in patients treated with DA. Our social behaviour can also be impacted by oxytocin. This hormone secreted on physiologic state at posterior pituitary, but also by others areas of brain and brainstem, has an impact on attachment in pair partners and in parent-child relationship, but also in empathy behaviour. Oxytocin affects as well eating behaviour with an anorexigenic impact. Studies on small populations assessed the relevance of an oxytocin treatment in several endocrine and nutritional pathologies like post-surgery craniopharyngioma, panhypopituitarism and obesity. Despite promising results, several pitfalls prevent yet the oxytocin use in clinical practice.

Sex steroid hormones in relation to Barrett's esophagus: an analysis of the FINBAR Study.

Previously, we observed strong positive associations between circulating concentrations of free testosterone and free dihydrotestosterone (DHT) in relation to Barrett's esophagus in a US male military population. To replicate these findings, we conducted a second study of sex steroid hormones and Barrett's esophagus in the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study based in Northern Ireland and Ireland. We used mass spectrometry to quantitate EDTA plasma concentrations of nine sex steroid hormones and ELISA to quantitate sex hormone-binding globulin in 177 male Barrett's esophagus cases and 185 male general population controls within the FINBAR Study. Free testosterone, free DHT, and free estradiol were estimated using standard formulas. Multivariable logistic regression estimated odds ratios (OR) and 95% confidence intervals (95%CI) of associations between exposures and Barrett's esophagus. While plasma hormone and sex hormone-binding globulin concentrations were not associated with all cases of Barrett's esophagus, we did observe positive associations with estrogens in younger men (e.g. estrone + estradiol ORcontinuous per ½IQR  = 2.92, 95%CI:1.08, 7.89), and free androgens in men with higher waist-to-hip ratios (e.g. free testosterone ORcontinuous per ½IQR  = 2.71, 95%CI:1.06, 6.92). Stratification by body mass index, antireflux medications, and geographic location did not materially affect the results. This study found evidence for associations between circulating sex steroid hormones and Barrett's esophagus in younger men and men with higher waist-to-hip ratios. Further studies are necessary to elucidate whether sex steroid hormones are consistently associated with esophageal adenocarcinogenesis.

Cabergoline for Cushing's disease: a large retrospective multicenter study.

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

[Genetics of congenital lipodystrophies]. / Génétique des lipodystrophies congénitales.

Congenital lipodystrophies are heterogeneous genetic diseases, leading to the loss of adipose tissue. This loss of adipose tissue can be generalized or partial, thus defining different phenotypes. These lipodystrophies have a major metabolic impact, secondary to lipotoxicity. This lipotoxicity is responsible for insulin resistance, dyslipidemia and hepatic steatosis. The severity of the metabolic impact correlates with the severity of the loss of adipose tissue. Mutations in 15 predisposition genes are currently described; BSCL2 and AGPT2 genes are the major genes in the generalized forms. On the contrary, LMNA and PPARG gene mutations are recovered in partial lipodystrophies forms. These different genes encode for proteins involved in adipocyte physiology, altering adipocyte differentiation, triglycerides synthesis and lysis or playing a major role in the lipid droplet formation. Congenital lipodystrophies treatment is based on the management of metabolic comorbidities but recombinant leptin therapy appears to have promising results. These different points have been recently discussed during the 2015 Endocrine Society Congress, notably by S. O'Rahilly and are highlighted in this review.

[Acromegaly and pregnancy: report of six new cases]. / Acromégalie et grossesse: six nouvelles observations.

INTRODUCTION: Pregnancies in acromegalic women are rare. Data from the literature indicate absence of congenital malformation in newborns, an increase of pituitary adenoma volume rarely clinically symptomatic, an increased risk of gestational diabetes and gravid hypertension in women with non-controlled GH/IGF-1 hypersecretion before gestation. The changes of somatotroph function are rarely described. AIM OF THE STUDY: Report of six new pregnancies in five women with acromegaly. PATIENTS AND METHODS: Before pregnancy three women had incomplete surgical resection of GH-secreting pituitary adenoma, all were treated with somatostatin analogues, and the medical treatment was withdrawal at the diagnosis of gestation. We studied clinical (blood pressure, headaches, visual field), biological (blood glucose concentration) signs, GH and IGF-1 levels were measured during each trimester of pregnancy as well as in post-partum and were compared with pregestational values, MRI of the pituitary performed during the second trimester and in the post-partum were compared with MRI examen before pregnancy. RESULTS: All those pregnancies were normal without gestational diabetes, gravid hypertension and pituitary tumor syndrome. Clinical signs of acromegaly improved in 50 % of the patients, and IGF-1 decreased (22 %) in comparison of pregestational value without significant change in GH levels. No newborn had congenital malformation. CONCLUSION: Pregnancies in those women with acromegaly are uneventful without obstetrical or foetal complication, but a maternal follow-up is necessary in order to diagnose gravid hypertension and gestational diabetes. On the other hand, a clinical monitoring of pituitary tumor syndrome is necessary in women with non-operated GH-secreting macroadenoma before pregnancy. During the first trimester of gestation, an improvement of acromegalic signs can be due to a decrease of IGF-1 levels related to hepatic GH-resistance state secondary to physiological secretion of estrogens during gestation.

[What's new in follicular thyroid cancer management in 2014?]. / Actualités dans la prise en charge des cancers thyroïdiens de souche vésiculaire.

The American Thyroid Association has presented new guidelines for the management of thyroid cancer. These guidelines tend to appreciate more accurately the individual risk of patients, to adapt accordingly the treatment and the follow up. The initial risk stratification has been completed, especially precising the risk of N1 patients, follicular thyroid cancers, and the prognostic impact of molecular markers. Indications, doses and modalities of radioiodine (RAI) have been reevaluated, restricting its utilization in order to avoid overtreatment of low risk patients. Moreover the response to initial treatment allows to restratify the risk of the patients, and to adapt the monitoring and the thyroid hormone therapy management. The risk of suppressive thyroid hormone therapy has also to be considered. Concerning advanced thyroid cancer, prognosis is mainly depending on its RAI sensitivity. The systemic treatment of progressive, threatening refractory cancers is nowadays based on targeted therapy. However none of these treatments has demonstrated an improvement in overall survival, and side effects are frequent. Fagin et al presented promising results concerning short term treatment with selective inhibitors of the MAPK pathway, able to partially restore RAI sensitivity of refractory lesions in murine models, and recently in human patients.

[Diagnosis and treatment of dysthyroid orbitopathy: a multidisciplinary disease]. / Prise en charge diagnostique et thérapeutique d'une orbitopathie dysthyroïdienne: une affection multidisciplinaire.

Graves' disease is a common autoimmune disorder that can be complicated, especially in smokers, by an orbitopathy which can sometimes jeopardize vision and result in functional sequelae affecting quality of life of these patients. Although the diagnosis of dysthyroid orbitopathy is usually obvious, clinical evaluation must specify the stage of progression (clinical activity score) and severity according to the European Group EUGOGO classification. At first, rapid restoration of the euthyroid state, smoking cessation and simple symptomatic ophthalmic treatment are suggested. In the case of severe or active orbitopathy, oral or intravenous corticosteroid therapy with or without orbital radiation therapy (and even emergency orbital surgery in the case of compressive optic neuropathy) should be implemented. Ultimately, orbital surgery (orbital decompression in cases of exophthalmos), oculomotor surgery (diplopia) or eyelid surgery (retraction) may be required depending on the severity of sequelae. A multidisciplinary approach involving ophthalmologist, endocrinologist and orbital surgeon should facilitate an overall diagnosis and treatment plan for these patients.

Profiling serum bile acid glucuronides in humans: gender divergences, genetic determinants, and response to fenofibrate.

Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.

[Treatment of hyperthyroidism due to Graves' disease: what is the recommended antithyroid drug during pregnancy?]. / Traitement d'une hyperthyroïdie secondaire à une maladie de Basedow : quel antithyroïdien de synthèse au cours de la grossesse ?

Clinical hyperthyroidism during the first trimester of pregnancy due to Graves' disease can be associated with maternal, obstetrical and fetal complications, indicating an active treatment to restore normal thyroid function. Antithyroid drugs are the first line treatment in pregnant women with hyperthyroidism. Due to the increased congenital malformations reported in neonates after first-trimester carbimazole/methimazole treatment and propylthiouracil associated hepatotoxicity, the recommended treatment for pregnant women with hyperthyroid Graves' disease is propylthiouracil during the first trimester of pregnancy and following the first trimester, consideration should be given switching to carbimazole/methimazole during the second part of gestation.

[Characteristics of sleep apnea syndrome in a cohort of patients with acromegaly]. / Caractéristiques du syndrome d'apnées du sommeil dans une cohorte de patients acromégales.

INTRODUCTION: Sleep apnoea syndrome (SAS) has a prevalence of between 40 and 80 % in patients with acromegaly. The objective of our study was to focus on the occurrence of SAS and its relation with acromegalic characteristics in this population as well as to study patients' comorbidities. METHODOLOGY: This study was retrospective, monocentric and related to a cohort of 106 acromegalic patients of whom 55 patients had performed ventilatory polygraphic recordings looking for SAS in addition to assessment of comorbidities. RESULTS: Within the screened patients, 42 had sleep apnoea syndrome with a majority of them having severe SAS. In this population, SAS was associated with hypertension, diabetes and a longer duration of acromegaly but acromegaly control was not a risk factor. Patients with severe SAS were older (mean 64 years) than the ones without SAS (47 years) (P=0.01). CONCLUSION: SAS prevalence is twenty times higher in the acromegalic population than for the normal population, even more so if patients are diabetic, hypertensive, older and if acromegaly has had a long evolution. Knowing this high prevalence, systematic screening for SAS may be justified in this population.