Autoantibodies reactive to adrenocorticotropic hormone can alter cortisol secretion in both aggressive and nonaggressive humans.

Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11-24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1-13). Purified IgGs from approximately half of the examined sera were able to block ACTH-induced cortisol secretion of human adrenal cells in vitro, irrespective of the source of sample (from a control subject or a violent aggressor). Nevertheless, in the resident-intruder test in mice, i.p. injection of residents with ACTH and IgG from aggressive subjects, but not from control subjects, shortened latency for the first attack against intruders. Immunohistochemical screening of violent aggressors' sera on rat brain and pituitary sections did not show IgG binding to ACTH-producing cells, but 4 of 16 sera revealed selective binding to a nonidentified antigen in vasopressinergic neurons of the hypothalamic paraventricular and supraoptic nuclei. Thus, the data show that ACTH-reactive plasmatic IgGs exhibit differential epitope preference in control and violently aggressive subjects. These IgGs can modulate ACTH-induced cortisol secretion and, hence, are involved in the regulation of the stress response. However, the possible role of ACTH-reactive autoantibodies in aggressive behavior needs further investigation.

Role of Mast Cells in the Control of Aldosterone Secretion.

Mast cells are immune cells present in adrenals from various species. Proliferation and activation of adrenal mast cells seem to be influenced by environment, since they increase during summer and in response to sodium restriction in frogs and mouse, respectively. Although the physiological factors regulating adrenal mast cell activity have not been identified, they might involve neurotransmitters and the renin-angiotensin system. Some data indicate that adrenal mast cells stimulate proliferation of steroidogenic cells in the zona glomerulosa and activate the mineralocorticoid production. In human, mast cell degranulation stimulates aldosterone synthesis through the release of serotonin (5-HT) and activation of 5-HT4 receptors. Increase in mast cell population and upregulation of the 5-HT signaling pathway occur in aldosterone-producing adenomas. In particular, aldosterone-producing adenoma cells overexpress 5-HT4 receptors and are hyper-responsive to 5-HT4 receptor agonists. These data suggest that the intra-adrenal serotonergic regulatory system represents a potential target for development of both adrenal imaging methods to evaluate the lateralization of aldosterone production, and pharmacological treatments of primary aldosteronism.

Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.

A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations.

OBJECTIVE: Disorders of sex development (DSD) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of DSD in two 46,XY sisters from a consanguineous family. DESIGN: We performed a whole-exome sequencing of two 46,XY female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog (DHH) gene. Molecular dynamics simulations were performed to get insights into the impact of the variant on protein structure and on its interaction with the protein partner BOC (brother of CDO/cell adhesion molecule, downregulated by oncogenes). PATIENTS: The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high FSH and LH). She also had an apparent absence of intra-abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation. RESULTS: Whole-exome sequencing revealed a homozygous variant in DHH leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein and potentially alters its interaction with BOC, a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with DHH-intein-mediated auto-processing. CONCLUSIONS: This report increases the number of described homozygous DHH variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants.

WNT/ß-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production.

Primary aldosteronism (PA) is the main cause of secondary hypertension, resulting from adrenal aldosterone-producing adenomas (APA) or bilateral hyperplasia. Here, we show that constitutive activation of WNT/ß-catenin signalling is the most frequent molecular alteration found in 70% of APA. We provide evidence that decreased expression of the WNT inhibitor SFRP2 may be contributing to deregulated WNT signalling and APA development in patients. This is supported by the demonstration that mice with genetic ablation of Sfrp2 have increased aldosterone production and ectopic differentiation of zona glomerulosa cells. We further show that ß-catenin plays an essential role in the control of basal and Angiotensin II-induced aldosterone secretion, by activating AT1R, CYP21 and CYP11B2 transcription. This relies on both LEF/TCF-dependent activation of AT1R and CYP21 regulatory regions and indirect activation of CYP21 and CYP11B2 promoters, through increased expression of the nuclear receptors NURR1 and NUR77. Altogether, these data show that aberrant WNT/ß-catenin activation is associated with APA development and suggest that WNT pathway may be a good therapeutic target in PA.

Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.

BACKGROUND: Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands. METHODS: We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients. RESULTS: The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion. CONCLUSIONS: Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.).

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.

Bilateral Adrenocortical Nodular Disease and Cushing's Syndrome.

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and Bilateral Macronodular Adrenocortical Disease (BMAD) are two forms of Adrenocortical Nodular Diseases causing Cushing's syndrome, but are two very distinct conditions. PPNAD, affecting mostly young patients with an almost constant severe Cushing's syndrome, is characterized by pigmented micronodules, usually less than 1 cm, not always visible on imaging. On the contrary, BMAD is predominantly diagnosed in the fifth and sixth decades, with highly variable degrees of cortisol excess, from mild autonomous cortisol secretion to overt Cushing's syndrome. BMAD presents as large bilateral adrenal macronodules, easily observed on imaging. Both diseases are often genetically determined: frequently PPNAD is observed in a multiple neoplasia syndrome, Carney complex (CNC), and a germline genetic defect is identified in around 80% of index cases, always affecting key actors of the cAMP/PKA pathway: mostly PRKAR1A, encoding the PKA 1-alpha regulatory subunit. On the other hand, BMAD appears mostly isolated, and two predisposing genes are known at present: ARMC5, accounting for around 20% of index cases, and the recently identified KDM1A, causing the rare presentation with food-dependent Cushing's syndrome, mediated by the ectopic expression of the Glucose-dependent Insulinotropic Polypeptide receptor (GIPR) in adrenal nodules. GIPR was the first demonstrated receptor to illegitimately regulate cortisol secretion in nodular adrenocortical diseases, and a myriad of other receptors and paracrine signals were discovered afterward. The last 30 years were pivotal in the understanding of the genetics and pathophysiology of Bilateral Adrenocortical Nodular Diseases, leading to a personalized approach of these fascinating conditions.

Long-term safety of dietary salt: A 5-year ProspEctive rAndomized bliNded and controlled stUdy in healThy aged cats (PEANUT study).

BACKGROUND: High-salt diets promote urine dilution and decrease urolithiasis risk. OBJECTIVE: Prospectively evaluate the safety of chronic high dietary salt intake (randomized controlled trial). ANIMALS: Twenty research colony neutered, healthy aged cats (11.5 years [10.0-11.6], median [interquartile range]). METHODS: Healthy cats were randomized to control or high-salt dry diets (sodium: 1.02 ± 0.16 [mean, SD] and 3.26 ± 0.30 g/Mcal metabolizable energy [ME], respectively; chloride: 2.26 ± 0.33 and 5.71 ± 0.28 g/Mcal ME, respectively), fed for up to 60 months. Assessments included CBC, plasma biochemistry, urinalysis, glomerular filtration rate (GFR), blood pressure, renal and cardiac (conventional Doppler and 2-dimensional color tissue Doppler) imaging, annually. Cats that died or were euthanized underwent necropsy. Diet effects over time were evaluated with linear mixed models. RESULTS: Follow-up duration (median [Interquartile range]) was similar between the control (38.7 months [28.6-48.2]) and high-salt group (51.4 months [45.7-59.0]). Diet had no significant effect on changes in GFR, blood pressure, plasma creatinine concentration, end-diastolic left ventricular (LV) wall thicknesses, LV internal diameters, LV systolic function, left atrial size, or systolic and diastolic Doppler variables. One control cat developed hypertension. One high-salt group cat developed persistent azotemia. Serial plasma biochemistry and urine specific gravity suggested early chronic kidney disease in 4 nonazotemic cats (2 per group), consistent with necropsy findings. CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy aged cats, a commercial veterinary diet containing 3.26 ± 0.30 g/Mcal ME sodium was safe with regard to renal and cardiac function for up to 5 years.

Carney complex predisposes to breast cancer: prospective study of 50 women.

OBJECTIVE: Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors. DESIGN: The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. METHODS: A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings. RESULTS: Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene. CONCLUSIONS: As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT00668291.

Lessons from prospective longitudinal follow-up of a French APECED cohort.

BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.

Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog.

BACKGROUND: Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin-induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model). RESULTS: Analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs.For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD).The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 µg/L for creeping speed, 284 µg/L for the lameness score, 161 µg/L for the ground reaction vertical force and 193 µg/L for the body temperature.To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. CONCLUSIONS: Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg/kg daily was determined for confirmatory clinical trials.

Immunohistochemical characterization of a steroid-secreting oncocytic adrenal carcinoma responsible for paraneoplastic hyperparathyroidism.

We report a unique case of a 44-year-old man with paraneoplastic hyperparathyroidism due to an oncocytic adrenocortical carcinoma (stage pT3N0R0M0, ENSAT 2 with a 4% Ki-67). Paraneoplastic hyperparathyroidism was associated with mild adrenocorticotropic hormone (ACTH)-independent hypercortisolism and increased estradiol secretion responsible for gynecomastia and hypogonadism. Biological investigations performed in blood samples from peripheral and adrenal veins revealed that the tumor secreted parathyroid hormone (PTH) and estradiol. Ectopic PTH secretion was confirmed by abnormally high expression of PTH mRNA and clusters of PTH immunoreactive cells in the tumor tissue. Double-immunochemistry studies and analysis of contiguous slides for the expression of PTH and steroidogenic markers (scavenger receptor class B type 1 [SRB1], 3ß-hydroxysteroid dehydrogenase [3ß-HSD], and aromatase) were performed. The results suggested the presence of two tumor cells subtypes with large cells with voluminous nuclei producing only PTH and that were distinct from steroid-producing cells.

Steroidogenesis and androgen/estrogen signaling pathways are altered in in vitro matured testicular tissues of prepubertal mice.

Children undergoing cancer treatments are at risk for impaired fertility. Cryopreserved prepubertal testicular biopsies could theoretically be later matured in vitro to produce spermatozoa for assisted reproductive technology. A complete in vitro spermatogenesis has been obtained from mouse prepubertal testicular tissue, although with low efficiency. Steroid hormones are essential for the progression of spermatogenesis, the aim of this study was to investigate steroidogenesis and steroid signaling in organotypic cultures. Histological, RT-qPCR, western blot analyses, and steroid hormone measurements were performed on in vitro cultured mouse prepubertal testicular tissues and age-matched in vivo controls. Despite a conserved density of Leydig cells after 30 days of culture (D30), transcript levels of adult Leydig cells and steroidogenic markers were decreased. Increased amounts of progesterone and estradiol and reduced androstenedione levels were observed at D30, together with decreased transcript levels of steroid metabolizing genes and steroid target genes. hCG was insufficient to facilitate Leydig cell differentiation, restore steroidogenesis, and improve sperm yield. In conclusion, this study reports the failure of adult Leydig cell development and altered steroid production and signaling in tissue cultures. The organotypic culture system will need to be further improved before it can be translated into clinics for childhood cancer survivors.

[Retroperitoneal bronchogenic cyst]. / Kyste bronchogénique de localisation rétropéritonéale.

Bronchogenic cysts are benign lesions, which are usually described at the chest level. We present here a case report of a retroperitoneal bronchogenic cyst. A 77-year-old man presented with a left retroperitoneal tumor discovered by scanner. There was no endocrine disruption. Excision of the lesion was performed and final diagnosis was a bronchogenic cyst. Current widespread use of modern radiology enables increased discovery of such "incidentalomes". In the future, pathologists will be routinely faced with this type of diagnosis, which up to now has been described as exceptional.

Cushing's syndrome caused by intra-adrenocortical adrenocorticotropic hormone in a dog.

A 13-year-old Labrador retriever was diagnosed with Cushing's syndrome (CS) caused by primary bilateral nodular adrenocortical hyperplasia with adrenocorticotropic hormone (ACTH) expression. The pituitary origin of CS was ruled out by suppression of plasma ACTH concentration and absence of a proliferative lesion on histological evaluation of the pituitary gland using periodic acid-Schiff (PAS) staining, reticulin staining, and immunostaining for ACTH. A pheochromocytoma also was found at necropsy examination. On histological evaluation of both adrenal glands, at the junction of the fascicular and glomerular zones, multiple cell clusters distributed in both hyperplastic adrenal cortices expressed ACTH, whereas the pheochromocytoma cells did not. These results indicate that a disease similar to primary bilateral macronodular adrenocortical hyperplasia in humans also occurs in dogs, with intra-adrenocortical expression of ACTH, glucocorticoids excess, and clinical signs of CS. Therefore, the term ACTH-independent could be inappropriate in some cases of bilateral adrenocortical hyperplasia and suppressed plasma ACTH concentration in dogs.

Ectopic localization of CYP11B1 and CYP11B2-expressing cells in the normal human adrenal gland.

The sharp line of demarcation between zona glomerulosa (ZG) and zona fasciculata (ZF) has been recently challenged suggesting that this interface is no longer a compartment boundary. We have used immunohistochemical analyses to study the steroid 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) pattern of expression and investigate the remodeling of the adrenal cortex in relation to aging. We analyzed human adrenal glands prepared from 47 kidney donors. No aldosterone-producing micronodules (APMs) were detectable in the younger donors aged between 22-39 but the functional ZG depicted by positive CYP11B2 staining demonstrated a lack of continuity. In contrast, the development of APMs was found in samples from individuals aged 40-70. Importantly, the progressive replacement of CYP11B2-expressing cells in the histological ZG by CYP11B1-expressing cells highlights the remodeling capacity of the adrenal cortex. In 70% of our samples, immunofluorescence studies revealed the presence of isolated or clusters of CYP11B2 positive cells in the ZF and zona reticularis. Our data emphasize that mineralocorticoid- and glucocorticoid-producing cells are distributed throughout the cortex and the medulla making the determination of the functional status of a cell or group of cells a unique tool in deciphering the changes occurring in adrenal gland particularly during aging. They also suggest that, in humans, steroidogenic cell phenotype defined by function is a stable feature and thus, the functional zonation might be not solely maintained by cell lineage conversion/migration.

Using 18F-FDG-PET/CT Metrics to Predict Survival in Ra-Dio-Iodine Refractory Thyroid Cancers.

Radio-iodine refractory (RAI-R) differentiated thyroid cancer (DTC) is a rare disease with a poor prognosis and limited therapeutic resources. Therefore, identifying prognostic factors is essential in order to select patients who could benefit from an early start of treatment. The aim of this study is to identify positron emission tomography with 18F-fluorodeoxyglucose with integrated computed tomography (18F-FDG-PET/CT) parameters to predict overall survival (OS) in patients with RAI-R DTC. In this single-center retrospective study, we analyze the 18F-FDG-PET/CT parameters of 34 patients with RAI-R DTC between April 2007 and December 2019. The parameters collected are MTV, SUVmax and progression for each site of metastasis (neck, mediastinum, lungs, liver, bone) and total sites. ROC curves, Kaplan-Meier survival analysis curves, univariate and multivariate Cox analyses determine prognostic factors for 1-year and 5-year OS. The parameters for mediastinum, liver and total sites are significantly associated with worse 1-year and 5-year OS by both ROC curve analysis and Kaplan-Meier survival analysis. Univariate Cox analysis confirms significance of mediastinum SUVmax (HR 1.08; 95% CI [1.02-1.15]; p = 0.014) and total SUVmax (HR 1.06; 95% CI [1-1.12]; p = 0.042) for worse 1-year OS; of mediastinum SUVmax (HR 1.06; 95% CI [1.02-1.10]; p = 0.003), liver SUVmax (HR 1.04; 95% CI [1.01-1.08]; p = 0.02), liver MTV (HR 2.56; 95% CI [1.13-5.82]; p = 0.025), overall SUVmax (HR 1.05; 95% CI [1.02-1.08]; p = 0.001) and total MTV (HR 1.41; 95% CI [1.07-1.86]; p = 0.016) for worse 5-year OS. Multivariate Cox analysis confirms a significant association between liver MTV (HR 1.02; 95% CI [1-1.04]; p = 0.042) and decrease 1-year OS. In this study, we demonstrate that in RAI-R DTC, 18F-FDG-PET/CT parameters of the mediastinum, liver and overall tumor burden were prognostic factors of poor 1-year and 5-year OS. Identifying these criteria could allow early therapeutic intervention in order to improve patients' survival.

Novel threshold value of midnight serum cortisol for diagnosis of hypercortisolism using the Roche Cortisol II assay.

BACKGROUND: The diagnosis of hypercortisolism requires multiple biochemical investigations, due to variations in cortisol production during the 24-hour circadian cycle. Midnight serum cortisol is difficult to interpret since the threshold value is dependent on the analytical method used and is often not provided by the manufacturer. Second-generation assays are more specific than first-generation assays and may have lower threshold values. OBJECTIVES: The aim of this study was to determine a novel threshold value of midnight serum cortisol for the biochemical diagnosis of hypercortisolism, using the Roche Cobas Cortisol® second-generation assay. METHODS: This study was performed in adult patients hospitalized in the endocrinology unit of a university hospital. Patients had a complete assessment of their 24-hour cortisol cycle, i.e., a serum cortisol test every four hours and at least two first-line tests: late night salivary cortisol, dexamethasone suppression test and/or 24-hour urinary free cortisol. First-line tests were used to identify patients with hypercortisolism. Serum samples were analyzed by second-generation electrochemiluminescence immunoassays (ECLIA) from Roche Cobas Cortisol®. RESULTS: Midnight serum cortisol samples were obtained from 175 hospitalized patients. The novel threshold value obtained was 157 nmol/L with a sensitivity of 82.9% (68.6 to 94.3%) and a specificity of 90.0% (85.0 to 95.0%). CONCLUSION: Our study confirms that the threshold value of midnight serum cortisol is not comparable between first- and second-generation Roche Cobas Cortisol® assays and that the threshold value is lower with the second-generation assay.