Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

BACKGROUND: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). OBJECTIVE: To evaluate current management of new cases of CS with a focus on VTE and thromboprophylaxis. DESIGN AND METHODS: A survey was conducted within those that report in electronic reporting tool (e-REC) of The European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 until July 2022. RESULTS: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%) and 12 patients ectopic CS (5.4%). The mean follow-up period post CS diagnosis was 15 months (range 3-30). Cortisol lowering medications were initiated in 38% of patients. One hundred and fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular weight-heparins were used in 96% of cases. VTE was reported in 6 patients (2.7%), of which 1 was fatal: 2 long before CS diagnosis, 2 between diagnosis and surgery and 2 post-operatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. CONCLUSIONS: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage and half of the VTE cases even occurred during this stage despite thromboprophylaxis Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed.

Iron overload disorders: Growth and gonadal dysfunction in childhood and adolescence.

Hemochromatosis (HC) is characterized by the progressive accumulation of iron in the body, resulting in organ damage. Endocrine complications are particularly common, especially when the condition manifests in childhood or adolescence, when HC can adversely affect linear growth or pubertal development, with significant repercussions on quality of life even into adulthood. Therefore, a timely and accurate diagnosis of these disorders is mandatory, but sometimes complex for hematologists without endocrinological support. This is a narrative review focused on puberty and growth disorders during infancy and adolescence aiming to offer guidance for diagnosis, treatment, and proper follow-up. Additionally, it aims to highlight gaps in the existing literature and emphasizes the importance of collaboration among specialists, which is essential in the era of precision medicine.

Exploring sexual function in adrenal insufficiency: findings from the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent therapy in hypocortisolism (DREAM) trial.

BACKGROUND: Data on sexual function in patients with adrenal insufficiency are scarce and largely controversial. OBJECTIVES: To investigate sexual dysfunction in patients with primary and secondary adrenal insufficiency and the effects of switching to once-daily dual-release hydrocortisone on sexual function in outcome assessors blinded, randomized, multicenter, active comparator clinical trial. MATERIALS AND METHODS: Eighty-nine adrenal insufficiency patients on conventional, multiple daily doses of glucocorticoid replacement, enrolled in the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent in hypocortisolism (DREAM) trial, were randomly assigned to continue their therapy or to switch to an equivalent dose of dual-release hydrocortisone. Sixty-three patients (34 women) consented to sex steroid measurements and questionnaires completion for quality of life (Addison's disease-specific quality-of-life questionnaire) and sexual function evaluation (female sexual function index for women, International Index of Erectile Function-Erectile Function for men) at baseline and 24 weeks after randomization. RESULTS: At baseline, sexual dysfunction was observed in 41% of women and 59% of men with adrenal insufficiency. In both sexes, no associations were found between sexual function and hormone levels, whereas Addison's disease-specific quality-of-life questionnaire total and fatigue domain scores positively correlated with total female sexual function index and International Index of Erectile Function-Erectile Function scores. At 24 weeks, there was no significant difference either in sexual function or sex steroid levels between study groups. In the dual-release hydrocortisone group, the variation in the female sexual function index desire domain score was positively associated with the change in Addison's disease-specific quality-of-life questionnaire's symptom domain score (ρ = 0.478, p = 0.045). DISCUSSION: Sexual dysfunction is common in adrenal insufficiency patients and is likely explained by multiple factors. dual-release hydrocortisone treatment is not directly associated with sexual function improvement, but an indirect effect mediated by quality-of-life amelioration cannot be excluded.

From Klinefelter Syndrome to High Grade Aneuploidies: Expanding the Gene-dosage Effect of Supernumerary X Chromosomes.

OBJECTIVE: High-grade aneuploidies of X and Y sex chromosomes (HGAs) are exceedingly rare and complex conditions. We aimed to investigate the effect of supernumerary X chromosomes (extra-Xs) on the clinical, hormonal, metabolic, and echocardiographic features of patients with HGAs. DESIGN AND METHODS: In a cross-sectional study, we compared 23 subjects with HGAs and 46 age-matched subjects with 47,XXY Klinefelter syndrome (KS), according to the number of extra-Xs: two (47,XXY and 48,XXYY), three (48,XXXY and 49,XXXYY), or four supernumerary Xs (49,XXXXY). A second cohort consisting of 46 pubertal stage-matched KS subjects was employed for validation. Clinical, hormonal, metabolic and ultrasonographic parameters were collected and analyzed. RESULTS: The increase in the number of extra-Xs was associated with a progressive adverse effect on height, pubertal development, testicular volume and function, adrenal steroidogenesis, and thyroid function. A progressive linear increase in ACTH and a decrease in cortisol/ACTH ratios were found. Weight and body mass index, Sertoli cell function, lipid profile, and glucose tolerance post-oral glucose tolerance test were all worse in the HGA cohort compared to KS. Cardiac evaluation revealed a linear association with reduced left and right end-diastolic diameters and reduced ejection fraction. CONCLUSION: The increase in the number of extra-Xs is associated with a "dose-dependent" progressive impairment in steroid producing glands, thyroid function, cardiac structure, and performance.

Does an increase in adipose tissue 'weight' affect male fertility? A systematic review and meta-analysis based on semen analysis performed using the WHO 2010 criteria.

INTRODUCTION: Obesity negatively impact on the metabolism of sex hormones, leading to reduced testosterone serum levels. However, how the obesity could negatively impact on the overall gonadal function, particularly on male fertility, remained unclear so far. OBJECTIVE: To systematically review evidences regarding the influence of body weight excess on the sperm production. METHODS: A meta-analysis was conducted, searching all prospective and retrospective observational studies reporting male subjects older than 18 years old, with body weight excess from overweight to severe obesity were considered. Only studies using the V edition of the World Health Organization (WHO) manual for semen analysis interpretation were considered. No specific interventions were considered. Search was focused on studies comparing overweight/obese to normal weight subjects. RESULTS: Twenty-eight studies were considered. Total sperm count and sperm progressive motility were significantly lower in overweight compared to normal weight subjects. Meta-regression analyses demonstrated that patients' age impacted on sperm parameters. Similarly, obese men showed lower sperm concentration, total sperm number, progressive and total motilities, and normal morphology lower than normal weight subjects. Reduced sperm concentration in obese men was influenced by age, smoking habit, varicocele, and total testosterone serum levels at meta-regression analyses. CONCLUSIONS: The male potential fertility is reduced in subjects with increased body weight, compared to normal weight men. The higher was the increased body weight, the worst was the sperm quantity/quality. This result comprehensively included obesity among non-communicable risk factor for male infertility, shedding new lights on the negative impact of increased body weight on overall gonadal function.

Effect of antioxidants on semen parameters in men with oligo-astheno-teratozoospermia: a network meta-analysis.

BACKGROUND: Although antioxidants are largely used in subfertile men with oligo-astheno-teratozoospermia (OAT), the choice among different molecules is challenged by the lack of comparative head-to-head studies. The network meta-analysis (NMA) can overcome limitations of pairwise meta-analyses, since it incorporates direct and indirect evidence into a single model generating an effectiveness hierarchy. OBJECTIVE: To assess with a NMA the effects of antioxidants in improving seminal parameters in idiopathic OAT. MATERIALS AND METHODS: PubMed, Scopus, Cinahl, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing any antioxidant treatment to each other or placebo in men with at least one idiopathic seminal abnormality. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). RESULTS: 29 RCTs provided information on 2045 men (mean age: 33.5 years) with idiopathic OAT and 19 antioxidant preparations. Compared to placebo, l-carnitine, especially in combination with l-acetyl-carnitine (LAC), had the highest SUCRA for sperm concentration, progressive motility, and morphology. Folate was the only other compound effective on sperm concentration. Vitamin E+selenium or zinc had the highest SUCRA for total motility. A contribution on progressive motility was revealed for pentoxifylline and vitamin E+CoQ10.

Nutritional and metabolic aspects related to vulvodynia: What do we really know?

OBJECTIVES: Vulvodynia is an emerging health problem, still insufficiently studied, that causes a significant reduction in quality of life in many women and individuals assigned female sex at birth. Little is known about the effects of diet and metabolic disorders on this condition. The objective of this study was to review currently available evidence on the diet and the nutritional and metabolic status of patients affected by vulvodynia. METHODS: Published articles were systematically searched in the PubMed, Scopus, and Web of Science databases. RESULTS: The few available studies that reported data on patients' body mass index (BMI) described a BMI within the normal range in most patients affected by vulvodynia, showing no difference or a slightly lower BMI with respect to control individuals. Data on the relationship between metabolic diseases and vulvodynia are lacking. Regarding nutrition, the few available data do not support the prescription of a low-oxalate diet in women with vulvodynia. To date, studies on other dietary behaviors are also lacking. CONCLUSIONS: This review emphasizes-for the first time, to our knowledge-the lack of data and the importance of conducting prospective studies investigating the nutritional and metabolic aspects related to the onset, maintenance, and therapy of vulvodynia.

Efficacy and tolerability of somatostatin analogues according to gender in patients with neuroendocrine tumors.

As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life.

Effects of Dual-Release Hydrocortisone on Bone Metabolism in Primary and Secondary Adrenal Insufficiency: A 6-Year Study.

Context: Patients with primary (PAI) and secondary adrenal insufficiency (SAI) experience bone metabolism alterations, possibly due to excessive replacement. Dual-release hydrocortisone (DR-HC) has shown promising effects on several parameters, but bone metabolism has seldom been investigated. Objective: We evaluated the long-term effects of once-daily DR-HC on bone in PAI and SAI. Methods: Patients on immediate-release glucocorticoid therapy were evaluated before and up to 6 years (range, 4-6) after switching to equivalent doses of DR-HC, yielding data on bone turnover markers, femoral and lumbar spine bone mineral density (BMD), and trabecular bone score (TBS). Results: Thirty-two patients (19 PAI, 18 female), median age 52 years (39.4-60.7), were included. At baseline, osteopenia was observed in 38% of patients and osteoporosis in 9%, while TBS was at least partially degraded in 41.4%. Higher body surface area-adjusted glucocorticoid doses predicted worse neck (P < .001) and total hip BMD (P < .001). Longitudinal analysis showed no significant change in BMD. TBS showed a trend toward decrease (P = .090). Bone markers were stable, albeit osteocalcin levels significantly varied. PAI and SAI subgroups behaved similarly, as did patients switching from hydrocortisone or cortisone acetate. Compared with men, women exhibited worse decline in TBS (P = .017) and a similar trend for neck BMD (P = .053). Conclusion: After 6 years of chronic DR-HC replacement, BMD and bone markers remained stable. TBS decline is more likely due to an age-related derangement of bone microarchitecture rather than a glucocorticoid effect. Our data confirm the safety of DR-HC replacement on bone health in both PAI and SAI patients.

Multiparametric Ultrasound for Diagnosing Testicular Lesions: Everything You Need to Know in Daily Clinical Practice.

BACKGROUND: Ultrasonography (US) represents the gold standard imaging method for the assessment of testicular lesions (TL). The gray-scale (GSUS) and color-Doppler (CDUS) ultrasound examination allow sonographers to investigate the size, margins, echotexture, and vascular features of TLs with the aim to differentiate benign from malignant lesions. Recently, the use of contrast-enhanced US (CEUS) and sonoelastography (SE) has led to further improvements in the differential diagnosis of TL. Although GSUS and CDUS are often sufficient to suggest the benign or malignant nature of the TL, CEUS can be decisive in the differential diagnosis of unclear findings, while SE can help to strengthen the diagnosis. The contemporary combination of GSUS, CDUS, CEUS, and SE has led to a new diagnostic paradigm named multiparametric US (mp-US), which is able to provide a more detailed characterization of TLs than single techniques alone. This narrative and pictorial review aimed to describe the mp-US appearance of several TLs. METHODS: An extensive Medline search was performed to identify studies in the English language focusing on the mp-US evaluation of TLs. RESULTS: A practical mp-US "identity card" and iconographic characterization of several benign and malignant TLs is provided herein. CONCLUSIONS: The mp-US characterization of TL reported herein can be useful in daily clinical practice.

The adult growth hormone multicentric retrospective observational study: a 24-month Italian experience of adherence monitoring via Easypod™ of recombinant growth hormone treatment in adult GH deficiency.

Introduction: Non-compliance to recombinant human growth hormone (rhGH) treatment is universally recognized as a key detrimental factor to achieve the expected clinical outcomes in adult GH deficiency (aGHD). The Easypod™ electronic device allows objective measurement of adherence. Adherence to treatment has been reported to be related with IGF-1 levels and consequently with clinical satisfactory results. The aim of this multicentric, observational, retrospective, 24- month study, is to objectively assess aGHD patients' compliance to rhGH, using the Easypod™ device. Additionally, the study aims to compare the biochemical responses of adherent vs non-adherent patients. Methods: Forty-three patients (28 females and 15 males) affected by aGHD and equipped with Easypod™ from 3 Italian centers were included in the study. Adherence to treatment was defined as the proportion of injections correctly administered during the observational period, out of the expected total number of injections. All patients were evaluated for IGF-1, glucose, insulin, HOMA and QUICKI index, total/LDL/HDL cholesterol and triglycerides. Results: Mean adherence rate was consistently under 85% across the 2-year observation period (73% at year 2). A trend toward significant difference in adherence was shown when comparing female and male patients (respectively 76% and 61%) after a 2-year period. Among the anamnestic features, the prescribed frequency of administration of rhGH and the number of administered therapies appeared to be the most relevant adherence-influencing factors. A strong direct correlation between IGF-1 z-score and adherence to rhGH therapy was detected in the whole population. Discussion: Compliance to rhGH therapy is still a major issue in aGHD treatment. Adherence relates to therapy efficacy in aGHD. The use of Easypod™ could be beneficial for physicians to better manage aGHD patients and to achieve improved better biochemical and clinical responses.

EMAS position statement: Testosterone replacement therapy in older men.

INTRODUCTION: Late-onset hypogonadism is the clinical entity characterised by low testosterone concentrations associated with clinical symptoms in the absence of organic disease in ageing men. It has been associated with metabolic syndrome, reduced bone mineral density, and increased cardiovascular morbidity and mortality risk. Although testosterone replacement therapy (TRT) reverses most of these conditions in young hypogonadal men, the risk/benefit ratio of TRT in older men is debatable. AIM: To update the 2015 EMAS statement on TRT in older men with new research on late-onset hypogonadism and TRT. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: TRT should be offered only to symptomatic older men with confirmed low testosterone concentrations after explaining the uncertainties regarding the long-term safety of this treatment. TRT may be offered to men with severe hypogonadism and erectile dysfunction to improve sexual desire, erectile, and orgasmic function. It should also be considered in hypogonadal men with severe insulin resistance or pre-diabetes mellitus. TRT may also be considered, in combination with proven treatment strategies, for osteoporosis, or for selected patients with persistent mild depressive symptoms and/or low self-perceived quality of life, combined with standard medical care for each condition. TRT is contraindicated in hypogonadal men actively seeking fertility treatment. Due to a lack of data, TRT should not be routinely used in older men to improve exercise capacity/physical function, improve cognitive function, or prevent cognitive decline. TRT must be avoided in older, frail men with known breast cancer or untreated prostate cancer and all men who have had myocardial infarction or stroke within the last four months, and those with severe or decompensated heart failure. The quality of evidence regarding patients with previous prostate cancer or cardiovascular disease is too low to draw definitive conclusions. Any limits on duration of use are arbitrary, and treatment should continue for as long as the man feels the benefits outweigh the risks for him, and decisions must be made on an individual basis. Withdrawal should be considered when hypogonadism is reversed after the resolution of underlying disorder. Short-acting transdermal preparations should be preferred for TRT initiation in older men, but injectable forms may be considered subsequently. Older men on TRT should be monitored at 3, 6, and 12 months after initiation and at least yearly thereafter, or earlier and more frequently if indicated. Evaluation should include assessment of the clinical response, and measurement of total testosterone, haematocrit, and prostate-specific antigen (PSA) concentrations. Bone density and/or quality should also be assessed. Obese and overweight patients should be encouraged to undergo lifestyle modifications, including exercise and weight loss, to increase endogenous testosterone.

Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known men syndrome.

PURPOSE: Multiple endocrine neoplasia type 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome, associated with a wide tumor spectrum but hallmarked by primary hyperparathyroidism, which represents the most common clinical feature, followed by pituitary (functional and non-functional) adenomas, and neuroendocrine tumors. MEN4 clinically overlaps MEN type 1 (MEN1) but differs from it for milder clinical features and an older patient's age at onset. The underlying mutated gene, CDKN1B, encodes the cell cycle regulator p27, implicated in cellular proliferation, motility and apoptosis. Given the paucity of MEN4 cases described in the literature, possible genotype-phenotype correlations have not been thoroughly assessed, and specific clinical recommendations are lacking. The present review provides an extensive overview of molecular genetics and clinical features of MEN4, with the aim of contributing to delineate peculiar strategies for clinical management, screening and follow-up of the last and least known MEN syndrome. METHODS: A literature search was performed through online databases like MEDLINE and Scopus. CONCLUSIONS: MEN4 is much less common that MEN1, tend to present later in life with a more indolent course, although involving the same primary organs as MEN1. As a consequence, MEN4 patients might need specific diagnostic and therapeutic approaches and a different strategy for screening and follow-up. Further studies are needed to assess the real oncological risk of MEN4 carriers, and to establish a standardized screening protocol. Furthermore, a deeper understanding of molecular genetics of MEN4 is needed in order to explore p27 as a novel therapeutic target.

Platelet-derived circRNAs signature in patients with gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors (NETs) early diagnosis is a clinical challenge that require a deep understanding of molecular and genetic features of this heterogeneous group of neoplasms. However, few biomarkers exist to aid diagnosis and to predict prognosis and treatment response. In the oncological field, tumor-educated platelets (TEPs) have been implicated as central players in the systemic and local responses to tumor growth, thereby altering tumor specific RNA profile. Although TEPs have been found to be enriched in RNAs, few studies have investigated the potential of a type of RNA, circular RNAs (circRNA), as platelet-derived biomarkers for cancer. In this proof-of-concept study, we aim to demonstrate whether the circRNAs signature of tumor educated platelets can be used as a liquid biopsy biomarker for the detection of gastroenteropancreatic (GEP)-NETs and the prediction of the early response to treatment. METHODS: We performed a 24-months, prospective proof-of-concept study in men and women with histologically proven well-differentiated G1-G2 GEP-NET, aged 18-80 years, naïve to treatment. We performed a RNAseq analysis of circRNAs obtained from TEPs samples of 10 GEP-NETs patients at baseline and after 3 months from therapy (somatostatin analogs or surgery) and from 5 patients affected by non-malignant endocrinological diseases enrolled as a control group. RESULTS: Statistical analysis based on p < 0.05 resulted in the identification of 252 circRNAs differentially expressed between GEP-NET and controls of which 109 were up-regulated and 143 were down-regulated in NET patients. Further analysis based on an FDR value ≤ 0.05 resulted in the selection of 5 circRNAs all highly significant downregulated. The same analysis on GEP-NETs at baseline and after therapy in 5 patients revealed an average of 4983 remarkably differentially expressed circRNAs between follow-up and baseline samples of which 2648 up-regulated and 2334 down-regulated, respectively. Applying p ≤ 0.05 and FDR ≤ 0.05 filters, only 3/5 comparisons gave statistically significant results. CONCLUSIONS: Our findings identified for the first time a circRNAs signature from TEPs as potential diagnostic and predictive biomarkers for GEP-NETs.

Assessing treatment adherence is crucial to determine adequacy of mineralocorticoid therapy.

Background: There is no consensus strategy for mineralocorticoid (MC) therapy titration in patients with primary adrenal insufficiency (PAI). We aim to measure serum fludrocortisone (sFC) and urine fludrocortisone (uFC) levels and to determine their utility, alongside clinical/biochemical variables and treatment adherence to guide MC replacement dose titration. Methods: Multi-centre, observational, cross-sectional study on 41 patients with PAI on MC replacement therapy. sFC and uFC levels (measured by liquid chromatography-tandem mass spectrometry), plasma renin concentration (PRC), electrolytes (Na+, K+), mean arterial blood pressure (MAP), total daily glucocorticoid (dGC) and MC (dMC) dose, and assessment of treatment adherence were incorporated into statistical models. Results: We observed a close relationship between sFC and uFC (r = 0.434, P = 0.005) and between sFC and the time from the last fludrocortisone dose (r = -0.355, P = 0.023). Total dMC dose was related to dGC dose (r = 0.556, P < 0.001), K+ (r = -0.388, P = 0.013) as well as sFC (r = 0.356, P = 0.022) and uFC (r = 0.531, P < 0.001). PRC was related to Na+ (r = 0.517, P < 0.001) and MAP (r = -0.427, P = 0.006), but not to MC dose, sFC or uFC. Regression analyses did not support a role for sFC, uFC or PRC measurements and confirmed K+ (B = -44.593, P = 0.005) as the most important variable to guide dMC titration. Of the patients, 32% were non-adherent with replacement therapy. When adherence was inserted into the regression model, it was the only factor affecting dMC. Conclusions: sFC and uFC levels are not helpful in guiding dMC titration. Treatment adherence impacts on clinical variables used to assess MC replacement and should be included as part of routine care in patients with PAI.

Circulating Natural Killer Cells as Prognostic Value for Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Correlation with Sarcopenia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of tumors. Natural killer (NK) cells can play an important role in cancer immune surveillance. The aim of this prospective observational study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICIs in order to identify predictive factors for better survival outcomes. METHODS: Forty-seven stage IV NSCLC patients were enrolled. Patients underwent baseline (T0) and longitudinal (T1) evaluations after ICIs. Peripheral immune blood cell counts were analyzed using flow cytometry. RESULTS: Basal levels of CD3-CD56+ NK cells were higher in patients with controlled disease (DC) compared to progression disease (PD) patients (127 cells/µL vs. 27.8 cells/µL, p < 0.001). Lower NK cell values were independent prognostic factors for shorter overall survival (OS) (HR 0.992; 95% CI 0.987-0.997, p < 0.001) and progression-free survival (PFS) (HR 0.988; 95% CI 0.981-0.994, p < 0.001). During the longitudinal evaluation, CD3-CD56+ NK cells (138.1 cells/µL vs. 127 cells/µL, p = 0.025) and CD56bright NK cells (27.4 cells/µL vs. 18.1 cells/µL, p = 0.034) significantly increased in the DC group. Finally, lower values of CD3-CD56+ NK cells (28.3 cells/µL vs. 114.6 cells/µL, p = 0.004) and CD56dim NK cells (13.2 cells/µL vs. 89.4 cells/µL, p < 0.001) were found in sarcopenic patients compared to patients without sarcopenia. CONCLUSIONS: Peripheral NK cells could represent a non-invasive and useful tool to predict ICI therapy response in NSCLC patients, and the association of low NK cell levels with sarcopenia deserves even more attention in clinical evaluation.

Pituitary T1 signal intensity at magnetic resonance imaging is reduced in patients with obesity: results from the CHIASM study.

BACKGROUND: Despite obesity being well known to be associated with several pituitary hormone imbalances, pituitary appearance in magnetic resonance imaging (MRI) in patients with obesity is understudied. OBJECTIVE: To evaluate the pituitary volume and signal intensity at MRI in patients with obesity. METHODS: This is a prospective study performed in an endocrine Italian referral center (ClinicalTrial.gov Identifier: NCT03458533). Sixty-nine patients with obesity (BMI > 30 kg/m2) and twenty-five subjects without obesity were enrolled. Thirty-three patients with obesity were re-evaluated after 3 years of diet and lifestyle changes, of whom 17 (51.5%) achieved a > 5% loss of their initial body weight, whereas the remaining 16 (48.5%) had maintained or gained weight. Evaluations included metabolic and hormone assessments, DEXA scan, and pituitary MRI. Pituitary signal intensity was quantified by measuring the pixel density using ImageJ software. RESULTS: At baseline, no difference in pituitary volume was observed between the obese and non-obese cohorts. At the 3-year follow-up, pituitary volume was significantly reduced (p = 0.011) only in participants with stable-increased body weight. Furthermore, a significant difference was noted in the mean pituitary intensity of T1-weighted plain and contrast-enhanced sequences between the obese and non-obese cohorts at baseline (p = 0.006; p = 0.002), and a significant decrease in signal intensity was observed in the subgroup of participants who had not lost weight (p = 0.012; p = 0.017). Insulin-like growth factor-1 levels, following correction for BMI, were correlated with pituitary volume (p = 0.001) and intensity (p = 0.049), whereas morning cortisol levels were correlated with pituitary intensity (p = 0.007). The T1-weighted pituitary intensity was negatively correlated with truncal fat (p = 0.006) and fibrinogen (p = 0.018). CONCLUSIONS: The CHIASM study describes a quantitative reduction in pituitary intensity in T1-weighted sequences in patients with obesity. These alterations could be explained by changes in the pituitary stromal tissue, correlated with low-grade inflammation.

The role of the pediatrician in the management of the child and adolescent with gender dysphoria.

Gender dysphoria is a clinical condition characterized by significant distress due to the discordance between biological sex and gender identity. Currently, gender dysphoria is also found more frequently in children and adolescents, thanks to greater social sensibleness and new therapeutic possibilities. In fact, it is estimated that the prevalence of gender dysphoria in pediatric age is between 0.5% and 2% based on the statistics of the various countries. Therefore, the pediatrician cannot fail to update himself on these issues and above all should be the reference figure in the management of these patients. Even if the patient must be directed to a referral center and be followed up by a multidisciplinary team, the treating pediatrician will care to coordinate the clinical and therapeutic framework. The aim of the present report is therefore to integrate literature data with our clinical experience to propose a new clinical approach in which the pediatrician should be the reference in the care of these patients, directing them towards the best therapeutic approach and staying in contact with the specialists of the referral center.

COVID-19 pandemic and adrenals: deep insights and implications in patients with glucocorticoid disorders.

PURPOSE: Coronavirus disease-19 (COVID-19) has spread throughout the world. It was initially defined as a potentially severe syndrome affecting the respiratory tract, but it has since been shown to be a systemic disease with relevant extrapulmonary manifestations that increase mortality. The endocrine system has been found to be vulnerable to COVID-19 infection. The current review aims to evaluate the available data on the impact of COVID-19 infection and treatment, as well as COVID-19 vaccines, on adrenal gland function, particularly in patients with GC disorders. METHODS: A thorough search of published peer-reviewed studies in PubMed was performed using proper keywords. RESULTS: Adrenal viral tropism and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the adrenal glands have been demonstrated, and adrenal insufficiency (AI) is a rare, but potentially severe complication in COVID-19 disease, whose recognition can be difficult if only for the empirical treatments administered in the early stages. Glucocorticoid (GC) treatment have had a pivotal role in preventing clinical deterioration in patients with COVID-19, but long-term GC use may increase COVID-19-related mortality and the development of iatrogenic AI. Patients with GC disorders, especially AI and Cushing's syndrome, have been identified as being at high risk of COVID-19 infection and complications. Published evidence suggests that AI patient awareness and proper education may help adjust GC replacement therapy appropriately when necessary, thereby reducing COVID-19 severity. The COVID-19 pandemic has had an impact on AI management, particularly in terms of adherence to patients' care plans and self-perceived challenges. On the other hand, published evidence suggests that the clinical course of COVID-19 may be affected by the severity of hypercortisolism in patients with CS. Therefore, to ameliorate the risk profile in these patients, cortisol levels should be adequately controlled, along with careful monitoring of metabolic and cardiovascular comorbidities. To date, the COVID-19 vaccine remains the only available tool to face SARS-CoV-2, and it should not be treated differently in patients with AI and CS. CONCLUSION: SARS-CoV-2 infection has been linked to adrenal damage and AI is a rare complication in COVID-19 disease, requiring prompt recognition. Educational efforts and patient awareness may reduce COVID-19 severity in patients with AI. Control of cortisol levels and monitoring of complications may improve the clinical course of COVID-19 in patients with CS.