Many epidemiological studies have shown that the incidence of immune thrombocytopenia (ITP) increases after age 60 years and peaks in patients over age 80 years. Therefore, ITP is a concern for physicians taking care of older patients, especially regarding its diagnosis and management. The diagnostic work-up should exclude other causes of thrombocytopenia and secondary ITP, including myelodysplastic syndrome and drug-induced ITP. The treatment decision is influenced by an increased risk of bleeding, infectious diseases and thrombosis in this population and should take into account comorbidities and concomitant medications such as anticoagulant drugs. First-line treatment is based on short corticosteroids courses and intravenous immunoglobulin, which should be reserved for patients with more severe bleeding complications, with their higher risk of toxic effects as compared with younger patients. Second-line treatment should be tailored to the patient's history, comorbidities and preferences. Preferred second-line treatments are thrombopoietin receptor agonists for most groups and guidelines given their good efficacy/tolerance ratio, but the thrombotic risk is increased in older people. Other second-line options that can be good alternatives depending on the clinical context include rituximab, dapsone, fostamatinib or immunosuppressive drugs. Splenectomy is less often performed but remains an option for fit patients with chronic refractory disease. Emerging treatments such as Syk or Bruton tyrosine kinase inhibitors and FcRn antagonists are becoming available for ITP and may modify the treatment algorithm in the near future. The aim of this review is to describe the particularities of the diagnosis and treatment of ITP in older people, including the response and tolerance to the currently available drugs. We also discuss some situations related to co-morbidities that can frequently lead to adapt the management strategy in older patients.

Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. Immune checkpoint inhibitor(ICI)-mediated hypophysitis is an important life-threatening complication of therapy. Patients presenting with clinical features and findings consistent with ICI-mediated hypophysitis were considered in the current study. In the absence of severe features (sodium <125 mmol/L, hypotension, reduced consciousness, hypoglycaemia and/or visual field defect), patients were administered a single intravenous dose of hydrocortisone (100 mg), observed for at least 4 h and then discharged on oral hydrocortisone (20 mg, 10 mg and 10 mg). Patients were then seen urgently in the endocrinology outpatient setting for further management. Fourteen patients (median age 64, 10 male) were managed using the pathway. All patients had biochemically confirmed adrenocorticotropic hormone (ACTH) deficiency. Seven of the 14 were treated with combination ICI therapy, with four having pan-anterior hypopituitarism. There were no 30-day readmissions or any associated hypophysitis-related mortality. All patients continued ICI therapy without interruption.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA4) and anti-programmed death cell protein 1 (anti-PD-1), are increasingly prescribed in metastatic carcinoma therapy. ICI-related kidney injury is gradually recognized by clinicians. However, immune-related ureteritis and cystitis easily go undiagnosed. We report three cases of PD-1 monoclonal antibody (mAb)-related ureteritis and cystitis. We further carried out a review of the literature about ICI-related ureteritis and cystitis. The cases in our reports manifest urinary irritation, sterile pyuria, gross hematuria, hydronephrosis, dilation of the ureters, and acute kidney injury. Urinary irritation improved effectively; urinalysis and renal function returned to normal after glucocorticoid therapy. During ICI therapy, urinalysis and renal function and urinary imaging examination are recommended to be monitored regularly. It contributes to identify immune-related ureteritis/cystitis earlier to efficiently alleviate urinary symptoms and immunologic urinary tract injury through glucocorticoid therapy while avoiding the abuse of antibiotics.

Vitamin A has a key role in lung development and its deficiency is associated with an increased risk of bronchopulmonary dysplasia. This secondary cohort analysis of the ImNuT trial (Immature, Nutrition Therapy NCT03555019) aimed to (1) explore vitamin A status in preterm infants <29 weeks gestation and (2) assess the influence of inflammation and postnatal dexamethasone exposure on vitamin A concentrations in blood. We report detailed information on vitamin A biochemistry, vitamin A intake, markers of inflammation and dexamethasone exposure. After four weeks of age, infants exposed to dexamethasone (n = 39) showed higher vitamin A concentrations compared to unexposed infants (n = 41); median (IQR) retinol was 1.0 (0.74, 1.5) vs. 0.56 (0.41, 0.74) µmol/L, p < 0.001. Pretreatment retinol concentrations were lower in the dexamethasone group compared to non-exposed infants (p < 0.001); 88% vs. 60% of the infants were considered deficient in vitamin A (retinol < 0.7 µmol/L) at one week of age. Small size for gestational age, mechanical ventilation and elevated levels of interleukin-6 were factors negatively associated with first-week retinol concentrations. In conclusion, preterm infants <29 weeks gestation are at risk of vitamin A deficiency despite intakes that accommodate current recommendations. The presence of inflammation and dexamethasone exposure should be considered when interpreting vitamin A status.

Since depression produces a long-term negative impact on quality of life, understanding the pathophysiological changes implicated in this disorder is urgent. There is growing evidence that demonstrates a key role for dysfunctional energy metabolism in driving the onset of depression; thus, bioenergetic alterations should be extensively studied. Brain metabolism is known to be a glucocorticoid-sensitive process, but the long-lasting consequences in adulthood following high levels of glucocorticoids at the early stages of life are unclear. We examined a possible association between brain energetic changes induced by synthetic glucocorticoid-dexamethasone treatment in the prenatal period and depressive-like behavior. The results show a reduction in the oxidative phosphorylation process, Krebs cycle impairment, and a weakening of the connection between the Krebs cycle and glycolysis in the frontal cortex of animals receiving dexamethasone, which leads to ATP reduction. These changes appear to be mainly due to decreased expression of pyruvate dehydrogenase, impairment of lactate transport to neurons, and pyruvate to the mitochondria. Acute stress in adulthood only slightly modified the observed alterations in the frontal cortex, while in the case of the hippocampus, prenatal exposure to dexamethasone made this structure more sensitive to future adverse factors.

Glucocorticoids (GCs) are anti-inflammatory and immunosuppressive steroid molecules secreted by the adrenal gland and regulated by the hypothalamic-pituitary-adrenal (HPA) axis. GCs present a circadian release pattern under normal conditions; they increase their release under stress conditions. Their mechanism of action can be via the receptor-independent or receptor-dependent pathway. The receptor-dependent pathway translocates to the nucleus, where the ligand-receptor complex binds to specific sequences in the DNA to modulate the transcription of specific genes. The glucocorticoid receptor (GR) and its endogenous ligand cortisol (CORT) in humans, and corticosterone in rodents or its exogenous ligand, dexamethasone (DEX), have been extensively studied in breast cancer. Its clinical utility in oncology has mainly focused on using DEX as an antiemetic to prevent chemotherapy-induced nausea and vomiting. In this review, we compile the results reported in the literature in recent years, highlighting current trends and unresolved controversies in this field. Specifically, in breast cancer, GR is considered a marker of poor prognosis, and a therapeutic target for the triple-negative breast cancer (TNBC) subtype, and efforts are being made to develop better GR antagonists with fewer side effects. It is necessary to know the type of breast cancer to differentiate the treatment for estrogen receptor (ER)-positive, ER-negative, and TNBC, to implement therapies that include the use of GCs.

The pro-inflammatory cytokine, chemokine (C-C motif) ligand 20 (CCL20), is emerging as a therapeutic target for immune-based therapies. Cooperative regulation of CCL20 by glucocorticoids and progestins used in endocrine therapy and pro-inflammatory mediators could modulate immune function and affect disease outcomes. We show that glucocorticoids as well as medroxyprogesterone acetate (MPA), the progestin widely used in injectable contraception in sub-Saharan Africa, cooperate with pro-inflammatory mediators to upregulate CCL20 protein and/or mRNA in human peripheral blood mononuclear cells (PBMCs) and human cervical cell lines. Changes in CCL20 mRNA levels were shown to be synergistic, as assessed by Chou analysis, cell- and gene-specific and to involve transcriptional regulation, with a requirement for a nuclear factor kappa B (NF-κB) site and glucocorticoid receptor (GR) involvement. The novel results suggest a mechanism whereby MPA, like glucocorticoids, may impact inflammation both systemically and in the genital tract in patients using MPA and/or glucocorticoid therapy.

Per- and polyfluoroalkyl substances (PFAS) are a chemical class of highly stable, fluorinated compounds popular for use in a variety of consumer products. PFAS environmental persistence in drinking water contributes to acute exposure in humans and subsequent bioaccumulation of the compounds in the liver and lung tissue. Prenatal PFAS exposure has been associated with lowered birth weight, premature birth, and developmental defects including cranio-facial abnormalities. The cytochrome P450 enzyme CYP3A7 is responsible for facilitating a variety of reactions essential for proper fetal development in humans. In addition to drug metabolism, CYP3A7 is responsible for metabolizing endogenous ligands in the developing human liver, including the steroid precursor dehydroepiandrosterone 3-sulfate (DHEA-S), essential for estriol synthesis during pregnancy, along with the morphogen all-trans-retinoic acid (atRA). Interference with estriol synthesis during pregnancy, as well as atRA clearance, is known to result in similar effects associated with prenatal PFAS exposure including lowered birth weight, premature birth, and developmental defects. We hypothesized that PFAS compounds bind to the CYP3A7 enzyme resulting in its inhibition. We implemented a series of binding studies using spectral characterization of six PFAS compounds (PFOA, PFOS, GenX, PFNA, PFNS, and PFHxS), and evaluated their interactions with recombinant CYP3A7. In addition, we screened PFAS for their ability to inhibit CYP3A7 oxidative activity using dibenzylfluorescein, a fluorescent probe, and DHEA-S, an endogenous substrate of CYP3A7. Our data demonstrate that of the six PFAS tested, PFOA, PFOS, PFNA, and PFHxS bind to and inhibit CYP3A7.

Checkpoint inhibitor-related pneumonitis (CIP) is one of the most important immune checkpoint inhibitors side effects, and it is rare but fatal. Identifying patients at risk of refractory CIP before the start of CIP therapy is important for controlling CIP. We retrospectively analyzed the clinical data of 60 patients with lung cancer who developed CIP. Refractory CIP was defined as CIP with poor response to corticosteroid treatment, including CIP not relieved with corticosteroid administration or CIP recurrence during the corticosteroid tapering period. We analyzed clinical characteristics, peripheral blood biomarkers, treatment, and outcomes in nonrefractory and refractory CIP. Risk factors associated with refractory CIP were assessed. Among 60 patients with CIP, 16 (26.7%) had refractory CIP. The median onset time for patients with nonrefractory and those with refractory CIP was 16.57 (interquartile range [IQR], 6.82-28.14) weeks and 7.43 (IQR, 2.71-19.1) weeks, respectively. The level of lactate dehydrogenase (LDH) was significantly higher in the refractory CIP group at baseline (255 [222, 418] vs. 216 [183, 252], P =0.031) and at CIP onset (321.5 [216.75, 487.5] vs. 219 [198. 241], P =0.019). An LDH level >320 U/L at CIP onset was an independent risk factor of refractory CIP (odds ratio [OR], 8.889; 95% confidence interval [CI]: 1.294-61.058; P =0.026). The incidence of refractory CIP is high among patients with CIP. An increased LDH level at CIP onset is independently associated with refractory CIP. Monitoring LDH levels during immune checkpoint inhibitors treatment is recommended.

Glucocorticoids are used in the treatment of rheumatoid arthritis since many decades. Glucocorticoids are proven effective in decreasing inflammatory activity of this disease and in retarding the progression of erosive joint damage. However, they also have multiple possible adverse effects, which are depending on dose and duration of treatment. Due to increasing treatment options (i.e. biologic and targeted synthetic disease modifying antirheumatic drugs) the use of glucocorticoids is subject of debate. The GLORIA study recently showed that addition of 5 mg prednisolone during 2 years is an effective treatment strategy in elderly patients with rheumatoid arthritis, without a substantial risk of adverse events. So, low dose prednisolone remains an attractive treatment option due to its effacacy, ease of use, safety and low cost.

The simultaneous measurement of dexamethasone and cortisol has proven the ability to increase the diagnostic performance of the overnight dexamethasone-suppression test. Furthermore, the therapeutic drug monitoring of administered corticosteroid drugs could represent a crucial tool for investigating unexpected variations of steroid hormones' circulating levels. In this work, an LC-MS/MS method for the quantification of cortisol, cortisone, dexamethasone and six additional exogenous corticosteroids in the serum/plasma matrix was developed and validated in compliance with the ISO/IEC requirements. To assess the efficiency of the validated method, serum samples of 75 patients undergoing the dexamethasone-suppression test and 21 plasma samples of patients under immunosuppressive treatment after kidney transplant were analyzed. In all dexamethasone-suppression test samples, it was possible to measure the circulating levels of cortisol, cortisone and dexamethasone. Concentrations of the latter were for all tested patients above the proposed cutoff for the dexamethasone-suppression test's results, and the cortisol concentrations showed good correlation with the ones measured by routine immunometric analysis, therefore confirming the screening outcome for all enrolled patients. Prednisone was detected and quantified in all enrolled patients, confirming the use of such a corticosteroid for immunosuppressive therapy. Thanks to these two applications, we proved the overall performance of the developed LC-MS/MS method for four target analytes. The future implementation of such an analytical tool in the clinical biochemistry laboratory's routine will guarantee a single and versatile tool for simultaneously monitoring dexamethasone-suppression-test results and corticosteroid drugs' administration.

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D3 (VitD3) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD3, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11β-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD3, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.

We report a case of a man in his early 60s presenting with bilateral adrenal and pulmonary haemorrhages as an initial presentation of polycythaemia vera (PV). Symptomatology included severe compressive chest pain radiating to epigastrium, with unremarkable physical findings, parameters and ECG. Blood investigations showed an elevated haemoglobin (174 g/L, reference range (RR): 141-172g/L) and haematocrit (55.7%, RR: 40.4%-50.4%) levels.Cross-sectional imaging excluded aortic dissection, but imaging repeated 48 hours after his admission for acute dyspnoea and worsening abdominal pain showed bilateral alveolar and adrenal haemorrhages. Cortisol level was 27 nmol/L (RR: 145-619 nmol/L). Investigations confirming PV included the presence of a Janus kinase 2 (JAK2V617F) gene mutation, hypercellularity with erythroid hyperplasia on bone marrow microscopy and a low serum erythropoietin (2.6 mIU/mL, RR: 4.3-29.0 mIU/mL). Aspirin, hydroxyurea, venesection and cortisol replacement were initiated to get good treatment outcome.

The last decade has witnessed important advances in retinal drug discovery, administered intravitreally, allowing high intraocular concentration and low systemic passage. However, local and systemic adverse events have been described and should be discussed before proposing treatment. In diabetes mellitus specifically, the choice of molecule and treatment regimen should limit the therapeutic burden, avoiding the need for frequent ophthalmological appointments, in patients receiving multi-disciplinary care.

BACKGROUND Carney complex (CNC) is a rare multiple neoplasia syndrome with autosomal dominant inheritance. CNC is frequently misdiagnosed owing to its diverse clinical characteristics. We reported the case of a 14-year-old Saudi boy with a history of gynecomastia, Cushing syndrome, large-cell calcifying Sertoli cell tumor of the testis, and CNC. CASE REPORT The patient was referred to the pediatric endocrine clinic for evaluation of bilateral slow progressing gynecomastia for 1-year duration. His clinical examination revealed lentigenes, bilateral diffuse breast enlargement (consistent with Tanner stage III), and asymmetrical testicular enlargement, more on the left side. Other systemic examinations were unremarkable. The initial blood workup showed elevated estradiol level with unsuppressed cortisol after an overnight 1-mg dexamethasone suppression test. Breast ultrasound (US) confirmed true gynecomastia. Testicular US revealed microcalcification and the testicular biopsy confirmed diagnoses of large-cell calcifying Sertoli cell tumor (LCCSCT). A 2-step dexamethasone suppression test showed a paradoxical rise in serum and urine cortisol levels, which are characteristic for PPNAD. LCCSCT and PPNAD are 2 major criteria fulfilling a diagnosis of CNC. The gene test showed heterozygous mutation in the PRKAR1A gene, which is diagnostic for CNC. The patient underwent bilateral mastoplasty and was planned for radical left orchiectomy. CONCLUSIONS Gynecomastia and LCCSCT can be presenting features of CNC, which mandates careful, thorough clinical examination and tailored investigation to reach a diagnosis.