Long-term surgical outcome and impact on daily life activities of strabismus surgery in thyroid-associated ophthalmopathy with and without previous orbital decompression.

BACKGROUNDS: To report the long-term surgical outcomes and the impact on daily life activities of strabismus surgery in patients with Thyroid Associated Orbitopathy (TAO) with and without previous orbital decompression. METHODS: Patients who underwent strabismus surgery for TAO were retrospectively reviewed. The primary outcome was to evaluate the influence of orbital decompression on the outcomes of TAO related strabismus surgery. Surgical success was defined by the resolution of diplopia and a post-operative deviation < 10 prism diopters (PD). The secondary outcomes were the clinical features, surgical approaches, and impact on daily life activities. RESULTS: A total of 45 patients were included in the study. The decompression surgery group (DS) included 21 patients (46.7%), whereas the non-decompression surgery group (NDS) patients were 24 (53.3%). The mean follow-up time from the last strabismus surgery was 2,8 years (range 8-200 months). Successful surgical outcome was achieved in 57,1% of patients in the DS, and 75% of patients in the NDS (p = 0,226). DS patients required almost twice the number of surgical interventions for strabismus compared to the NDS (1,95 vs. 1,16 respectively, p = 0,006), a higher number of extraocular muscles recessed in the first surgery (2,67 vs. 1,08 respectively, p < 0.001), and a lower rate of unidirectional surgery compared to NDS (23% vs. 95%, p < 0,001). At the pre-operative assessment, 71.4% of DS patients had eso-hypotropia, while no patients had this type of strabismus in the NDS group (p < 0.001). On the other hand, the hypotropia rate was 79.2% in NDS patients and only 4.8% in DS patients (p < 0.001). Moreover, 21,8% of NDS patients used prism lenses in daily life activities, compared to 42.9% of patients that used prism lenses to reduce the impairment in their daily life activities (p = 0.016). CONCLUSIONS: The results of our study showed that DS patients required almost twice the number of strabismus surgical procedures, a higher number of extraocular muscles recessed in the first surgery, and an increased need for prism lenses to correct the residual deviation compared to the NDS, but with similar long-term surgical outcomes.

Radioiodine whole body scan pitfalls in differentiated thyroid cancer.

PURPOSE: whole body scan (WBS) performed following diagnostic or therapeutic administration of I-131 is useful in patients with differentiated thyroid carcinoma. However, it can be falsely positive in various circumstances. We aimed to report a series of pitfalls in a clinical perspective. METHODS: A search in the database PubMed utilizing the following terms: "false radioiodine uptake" and "false positive iodine 131 scan" has been made in January 2023. Among the 346 studies screened, 230 were included in this review, with a total of 370 cases collected. Physiological uptakes were excluded. For each patient, sex, age, dose of I-131 administered, region and specific organ of uptake and cause of false uptake were evaluated. RESULTS: 370 cases of false radioiodine uptake were reported, 19.1% in the head-neck region, 34.2% in the chest, 14.8% in the abdomen, 20.8% in the pelvis, and 11.1% in the soft tissues and skeletal system. The origin of false radioiodine uptake was referred to non-tumoral diseases in 205/370 cases (55.1%), benign tumors in 108/370 cases (29.5%), malignant tumors in 25/370 cases (6.7%), and other causes in 32/370 cases (8.7%). CONCLUSIONS: WBS is useful in the follow-up of patients with differentiated thyroid carcinoma, however it can be falsely positive in various circumstances. For this reason, it is critically important to correlate the scintigraphic result with patient's medical history, serum thyroglobulin levels, additional imaging studies and cytologic and/or histologic result.

Semaglutide for Treating Obesity Induced by Craniopharyngioma Resection: A Successful Case Study.

Surgical treatment of craniopharyngioma often leads to a rapid and dramatic weight gain, leading to hypothalamic obesity. Treatment focused on the diet, physical activity, and different types of drugs have very often provided unsatisfactory results. To date, no data have been reported on hypothalamic obesity (HO) regarding the use of semaglutide, a novel type 1 receptor glucagon-like peptide-1 agonist, to limit body weight gain after surgical removal of a neoplasm, despite its already documented efficacy in obesity treatment. In this case report, we tested semaglutide in an 18-year-old patient with HO induced by a surgical intervention for craniopharyngioma. A very favorable treatment response was found in terms of body weight reduction and improvement in metabolic parameters. Our patient lost more than than 30 kg after only 6 months of therapy, which has never been reported before in the literature on HO.

Is it possible to achieve an acceptable disease control by dietary therapy alone in Berardinelli Seip type 1? Experience from a case report.

Background and objective: Severe metabolic complications generally manifest at an early age in Berardinelli - Seip congenital lipodystrophy (BSCL) and their management is especially challenging. Nutritional intervention with low lipid diets is considered by experts to be fundamental in treating the disease when associated with medical therapy, however little is known about the beneficial effects of dietary interventions alone. Aim: To underline the importance of a well-structured low-fat diet in BSCL patients. Methods and results: A BSCL male patient strictly followed a hypocaloric hypolipemic diet (60% carbohydrates, 22% fats and 18% proteins) since clinical diagnosis at the age of one year. Interestingly, pharmacological interventions were not required at any point during the follow-up. Aged 16 years the patient was referred to our center. Biochemistry, hormonal evaluation, 75 mg oral glucose tolerance test, cardiac evaluation and abdominal ultrasound were performed, revealing no abnormalities. Genetic analysis and leptin dosage were carried out, confirming the diagnosis of BSCL type 1 (homozygosity for c.493-1G>C pathogenic variant in AGPAT2 gene) and showing undetectable circulating levels of leptin (< 0.2 mcg/L). Diet therapy alone was therefore maintained, scheduling follow-up visits every six months, with acceptable disease control ever since. Conclusions: This report proves how a low-fat diet is of great help in the management of BSCL and its complications. In addition, a specific hypolipemic diet could be used alone as an effective treatment in selected cases with high compliance and, probably, a milder phenotype.

Mild autonomous cortisol secretion in adrenal incidentalomas and risk of fragility fractures: a large cross-sectional study.

OBJECTIVE: Mild autonomous cortisol secretion (MACS) has been associated with a higher prevalence of osteoporosis, although most data rely on single-center studies with limited sample size. We aimed to assess the prevalence of fragility fractures and contributing factors in a large cohort of patients with adrenal incidentalomas. DESIGN AND METHODS: Medical records of 1023 patients with adrenal incidentalomas from 1990 to 2019 were reviewed, and 735 patients were selected. Clinically obtained electronic radiological images closest to first endocrine evaluation, such as lateral views of spine X-rays or CT thoraco-abdominal scans, were reviewed to screen for asymptomatic morphometric vertebral fractures. Clinical fragility fractures, hormonal, and dual-energy x-ray absorptiometry (DXA) indices were also recorded. RESULTS: Four hundred seventy-four patients had nonfunctioning (NF) adrenal incidentalomas, 238 had MACS and 23 adrenal Cushing's syndrome (AC). Prevalence of fragility fractures was different (P = .018) between groups, respectively, 24.1% (NF), 34.0% (MACS), and 30.4% (AC), with significant difference between NF and MACS (P = .012). When analyzed separately by sex and menopausal status, this difference remained significant in postmenopausal women (P = .011), with a fracture prevalence of 22.2% (NF) and 34.6% (MACS). Fracture prevalence was similar in males. Women with MACS aged ≥65 years reported a 48.8% prevalence of fractures, as compared with 29.5% in NF (P < .01). In postmenopausal women, fragility fractures were associated with age (odds ratio [OR] 1.1, P < .001), smoking (OR 1.8, P = .048), and 1 mg-dexamethasone suppression test (DST) cortisol (OR 3.1, P = .029), while in men, only age was associated with fragility fractures. CONCLUSIONS: A considerable fracture burden was shown in postmenopausal women with adrenal incidentalomas and MACS, with clinical implications for the evaluation and management of bone metabolism.

Exploring the human chorionic gonadotropin induced steroid secretion profile of mouse Leydig tumor cell line 1 by a 20 steroid LC-MS/MS panel.

The canonical androgen synthesis in Leydig cells involves Δ5 and Δ4 steroids. Besides, the backdoor pathway, eompassing 5α and 5α,3α steroids, is gaining interest in fetal and adult pathophysiology. Moreover, the role of androgen epimers and progesterone metabolites is still unknown. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring 20 steroids and used it to investigate the steroid secretion induced by human chorionic gonadotropin (hCG) in the mouse Leydig tumor cell line 1 (mLTC1). Steroids were extracted from 500 µL supernatants from unstimulated or 100 pM hCG-exposed mLTC1 cells, separated on a Luna C8 100 × 3 mm, 3 µm column, with 100 µM NH4F and methanol as mobile phases, and analyzed by positive electrospray ionization and multiple reaction monitoring. Sensitivity ranged within 0.012-38.0 nmol/L. Intra-assay and inter-assay imprecision were < 9.1% and 10.0%, respectively. Trueness, recovery and matrix factor were within 93.4-122.0, 55.6-104.1 and 76.4-106.3%, respectively. Levels of 16OH-progesterone, 11-deoxycortisol, androstenedione, 11-deoxycorticosterone, testosterone, 17OH-progesterone, androstenedione, epitestosterone, dihydrotestosterone, progesterone, androsterone and 17OH-allopregnanolone were effectively measured. Traces of 17OH-dihydroprogesterone, androstanediol and dihydroprogesterone were found, whereas androstenediol, 17OH-pregnenolone, dehydroepiandrosterone, pregnenolone and allopregnanolone showed no peak. hCG induced an increase of 80.2-102.5 folds in 16OH-progesterone, androstenedione and testosterone, 16.6 in dihydrotestosterone, 12.2-27.5 in epitestosterone, progesterone and metabolites, 8.1 in 17OH-allopregnanolone and ≤ 3.3 in 5α and 5α,3α steroids. In conclusion, our LC-MS/MS method allows exploring the Leydig steroidogenesis flow according to multiple pathways. Beside the expected stimulation of the canonical pathway, hCG increased progesterone metabolism and, to a low extent, the backdoor route.

Determinants of sexual function in men living with HIV younger than 50 years old: Focus on organic, relational, and psychological issues.

BACKGROUND: Sexual dysfunctions, particularly erectile dysfunction, are common in men living with HIV, whose organic and psychological components remain to be clarified. The aim of the study is to investigate the impact of risk factors of sexual dysfunctions, including organic, relational, and psychological determinants of erectile function, in men living with HIV younger than 50 years old. METHODS: A cross-sectional, observational study was conducted in men living with HIV < 50 years. The questionnaire International Index of Erectile Function-15 was used to assess the prevalence and degree of erectile dysfunction. The structured interview of erectile dysfunction was used to explore the organic (Scale 1), relational (Scale 2), and psychological (Scale 3) components of erectile dysfunction. Total testosterone, estradiol, and dihydrotestosterone were measured by liquid chromatography-tandem-mass spectrometry; free testosterone was calculated by the Vermeulen equation. RESULTS: A total of 313 consecutive men living with HIV were prospectively enrolled (median age 47.0 years; median HIV-infection duration 16.2 years). 187 patients (59.7%) had erectile dysfunction, with a higher prevalence of non-heterosexual (138 out of 187, 73.8%) than heterosexual patients (p = 0.003). Patients with erectile dysfunction showed a worse score of structured interview of erectile dysfunction scale 3 compared to patients without erectile dysfunction (p = 0.025); the International Index of Erectile Function-15 was inversely related to structured interview of erectile dysfunction scale 3 (p = 0.042). No difference was found for sex steroids (total testosterone, estradiol, free testosterone, and dihydrotestosterone) between men living with HIV with and without erectile dysfunction. In the multivariate analysis sexual orientation, and lack of stable relationships were major determinants for erectile dysfunction. Only 35 of 187 patients with erectile dysfunction (18.7%) reported the use of erectile dysfunction medications. CONCLUSIONS: Within the multidimensional network of erectile dysfunction in men living with HIV, the psychological component is predominant, highlighting the contribution of peculiar factors related to HIV distress (e.g., fear of virus transmission, stigma) rather than gonadal status and other classical risk factors. In contrast to the high prevalence, only a few patients reported the use of erectile dysfunction medications suggesting a general under-management of such issues.

The Diagnostic Value of Contrast Enhanced Ultrasound for Localization of Parathyroid Lesions in Primary Hyperparathyroidism: Comparison With Color Doppler Ultrasound: Comparison With Color Doppler Ultrasound.

OBJECTIVES: Preoperative localization of pathological parathyroid glands with imaging is essential for focused unilateral neck exploration and minimally invasive techniques. Recently published studies suggested that contrast-enhanced ultrasonography (CEUS) had high accuracy in the localization of hyperfunctioning parathyroid glands, with a general increase in the sensitivity as compared to conventional sonography. The purpose of this study was to determine the usefulness of CEUS in the localization of parathyroid lesions relating to surgical and histopathological data, in comparison to color Doppler ultrasound (CDUS), in the same series of patients. METHODS: Records of 142 patients who underwent parathyroidectomy were retrospectively examined comparing imaging and intraoperative/histopathologic findings. RESULTS: The overall sensitivity of CEUS was 77.6% compared with 74.6% for CDUS, although no significative differences were found (P = .516). Conversely, CDUS has shown higher sensitivity than CEUS in the group of patients with associated thyroid pathology but there was no statistical difference (P = .529). The sensitivity for detection of multiple adenomas was the same for both procedures. CONCLUSIONS: We found no significative superior sensitivity of CEUS also in case of concomitant thyroid pathology and multiple glands disease.

Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System.

Background: We described clinical features of adrenal insufficiency (AI) reported with tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports of AI recorded in FAERS (January 2004-March 2022) were identified through the high-level term "adrenal cortical hypofunctions". Demographic and clinical features were inspected, and disproportionality signals were detected through the Reporting Odds Ratio (ROR) and Information Component (IC) with relevant 95% confidence/credibility interval (CI), using different comparators and adjusting the ROR for co-reported corticosteroids and immune checkpoint inhibitors (ICIs). Results: Out of 147,153 reports with VEGFR-TKIs, 314 cases of AI were retained, mostly of which were serious (97.1%; hospitalization recorded in 44.9%). In a combination regimen with ICIs (43% of cases), VEGFR-TKIs were discontinued in 52.2% of the cases (26% as monotherapy). The median time to onset was 72 days (IQR = 14-201; calculated for 189 cases). A robust disproportionality signal emerged, also in comparison with other anticancer drugs (ROR = 2.71, 95%CI = 2.42-3.04; IC = 0.25, 95%CI = 0.07-0.39). Cabozantinib, sunitinib and axitinib generated robust disproportionality even after ROR adjustment. Conclusions: We call pharmacologists, internists, oncologists and endocrinologists to raise awareness of serious AI with VEGFR-TKIs, and to develop dedicated guidelines, especially for combination regimens with immunotherapy.

The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System.

CONTEXT: Adrenal insufficiency (AI) is a life-threatening condition complicating heterogeneous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. OBJECTIVE: This work aimed to describe the spectrum of drug-induced AI through adverse drug event reports received by the US Food and Drug Administration (FDA). METHODS: A retrospective disproportionality analysis reporting trends of drug-induced AI was conducted on the FDA Adverse Event Reporting System (FAERS) (> 15 000 000 reports since 2004). AE reports were extracted from FAERS over the past 2 decades. Interventions included cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI, and signals of disproportionate reporting for drugs recorded in 10 or more cases as primary suspect. RESULTS: We identified 8496 cases of AI: 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5282 (62.2%) cases in 2015 to 2020. We identified 56 compounds associated with substantial disproportionality: glucocorticoids (N = 1971), monoclonal antibodies (N = 1644, of which N = 1330 were associated with immune checkpoint inhibitors-ICIs), hormone therapy (N = 291), anti-infectives (N = 252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N = 169), and protein kinase inhibitors (N = 138). Cases of AI by glucocorticoids were stable in each 5-year period (22%-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010 to 2015 to 33% in 2015 to 2020. CONCLUSION: We provide a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for the urgent identification of predictive factors for drug-induced AI, and the establishment of screening and educational protocols for patients and caregivers.

Report from the HarmoSter study: impact of calibration on comparability of LC-MS/MS measurement of circulating cortisol, 17OH-progesterone and aldosterone.

OBJECTIVES: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is recommended for measuring circulating steroids. However, assays display technical heterogeneity. So far, reproducibility of corticosteroid LC-MS/MS measurements has received scant attention. The aim of the study was to compare LC-MS/MS measurements of cortisol, 17OH-progesterone and aldosterone from nine European centers and assess performance according to external quality assessment (EQA) materials and calibration. METHODS: Seventy-eight patient samples, EQA materials and two commercial calibration sets were measured twice by laboratory-specific procedures. Results were obtained by in-house (CAL1) and external calibrations (CAL2 and CAL3). We evaluated intra and inter-laboratory imprecision, correlation and agreement in patient samples, and trueness, bias and commutability in EQA materials. RESULTS: Using CAL1, intra-laboratory CVs ranged between 2.8-7.4%, 4.4-18.0% and 5.2-22.2%, for cortisol, 17OH-progesterone and aldosterone, respectively. Trueness and bias in EQA materials were mostly acceptable, however, inappropriate commutability and target value assignment were highlighted in some cases. CAL2 showed suboptimal accuracy. Median inter-laboratory CVs for cortisol, 17OH-progesterone and aldosterone were 4.9, 11.8 and 13.8% with CAL1 and 3.6, 10.3 and 8.6% with CAL3 (all p<0.001), respectively. Using CAL1, median bias vs. all laboratory-medians ranged from -6.6 to 6.9%, -17.2 to 7.8% and -12.0 to 16.8% for cortisol, 17OH-progesterone and aldosterone, respectively. Regression lines significantly deviated from the best fit for most laboratories. Using CAL3 improved cortisol and 17OH-progesterone between-method bias and correlation. CONCLUSIONS: Intra-laboratory imprecision and performance with EQA materials were variable. Inter-laboratory performance was mostly within specifications. Although residual variability persists, adopting common traceable calibrators and RMP-determined EQA materials is beneficial for standardization of LC-MS/MS steroid measurements.

Immune-related adverse events in the treatment of non-Hodgkin lymphoma with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) show efficacy in the treatment of non-Hodgkin lymphomas (NHL). However, these agents are associated with a unique group of side effects called immune-related adverse events (irAEs). We conducted an observational retrospective/prospective study on patients with relapsed/refractory NHL treated with ICI to determine the incidence of irAEs assessing the type, severity, and timing of onset, outcome and relationship with study drugs of these events. Thirty-two patients underwent ICI as single agent (N = 20) or in combination (N = 12). Ten patients (31.3%) developed at least one irAE for a total of 17 irAEs. Median time to presentation of irAEs was 69 days (range 0-407) with a median resolution time of 16 days (range 0-98). Progression free survival at 24 months for patients who developed an irAE was 40% and 31.8% for who did not. Overall survival for the two groups did not differ (at 24 months 40.0% and 62.5% for patients without and with irAE, respectively), but the median for who developed an irAE was not reached. The incidence of irAEs was associated with better long-term survival in NHL treated with ICIs but patients' disease conditions need to be carefully evaluated to decide the optimal management.

Minimally invasive adrenalectomy: a comprehensive systematic review and network meta-analysis of phase II/III randomized clinical controlled trials.

PURPOSE: The best approach for minimally invasive adrenalectomy is still under debate. METHODS: A systematic search of randomized clinical trials was carried out. A frequentist random-effects network meta-analysis was made reporting the surface under the cumulative ranking (SUCRA). The primary endpoint regarded both in-hospital mortality and morbidity. The secondary endpoints were operative time (OP), blood loss (BL), length of stay (LOS), conversion, incisional hernia, and disease recurrence rate. RESULTS: Eight studies were included, involving 359 patients clustered as follows: 175 (48.7%) in the TPLA arm; 55 (15.3%) in the RPLA arm; 10 (2.8%) in the Ro-TPLA arm; 25 (7%) in the TPAA arm; 20 (5.6%) in the SILS-LA arm; and 74 (20.6%) in the RPA arm. The RPLA had the highest probability of being the safest approach (SUCRA 69.6%), followed by RPA (SUCRA 63.0%). TPAA, Ro-TPLA, SILS-LA, and TPLA have similar probability of being safe (SUCRA values 45.2%, 43.4%, 43.0%, and 38.5%, respectively). Analysis of the secondary endpoints confirmed the superiority of RPA regarding OP, BL, LOS, and incisional hernia rate. CONCLUSIONS: The best choice for patients with adrenal masses candidate for minimally invasive surgery seems to be RPA. An alternative could be RPLA. The remaining approaches could have some specific advantages but do not represent the first minimally invasive choice.

Unexpected Widespread Bone Metastases from a BRAF K601N Mutated Follicular Thyroid Carcinoma within a Previously Resected Multinodular Goiter.

Follicular thyroid carcinoma (FTC) represents the second most common malignant thyroid neoplasm after papillary carcinoma (PTC). FTC is characterized by the tendency to metastasize to distant sites such as bone and lung. In the last 20 years, the understanding of the molecular pathology of thyroid tumors has greatly improved. Uncommon BRAF non-V600E mutations have been identified and are generally believed to associate with follicular patterned tumors of low malignant potential, particularly non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (i.e., non-invasive encapsulated follicular variant PTC). We here report for the first time widespread bone metastases from a BRAF K601N mutated follicular tumor.

Association Between Aldosterone and Parathyroid Hormone Levels in Patients With Adrenocortical Tumors.

OBJECTIVE: Patients with primary aldosteronism (PA) can present with high PTH levels and negative calcium balance, with some studies speculating that aldosterone could directly stimulate PTH secretion. Either adrenalectomy or mineralocorticoid receptor blockers could reduce PTH levels in patients with PA. The aim of this study was to assess the relationship between aldosterone levels and parathyroid hormone (PTH)-vitamin D-calcium axis in a cohort of patients with PA, compared with patients with nonsecreting adrenocortical tumors in conditions of vitamin D sufficiency. METHODS: We enrolled a series of 243 patients retrospectively, of whom 66 had PA and 177 had nonsecreting adrenal tumors, and selected those with full mineral metabolism evaluation and 25(OH) vitamin D levels >20 ng/mL at the time of initial endocrine screening. The final cohort was composed of 26 patients with PA and 39 patients, used as controls, with nonsecreting adrenal tumors. The relationships between aldosterone, PTH levels, and biochemistries of mineral metabolism were assessed. RESULTS: Aldosterone was positively associated with PTH levels (r = 0.260, P < .05) in the whole cohort and in the PA cohort alone (r = 0.450; P = .02). In the multivariate analysis, both aldosterone concentrations and urinary calcium excretion were significantly related to PTH levels, with no effect of 25(OH) vitamin D or other parameters of bone metabolism. CONCLUSION: PTH level is associated with aldosterone, probably independent of 25(OH) vitamin D levels and urinary calcium. Whether aldosterone interacts directly with the parathyroid glands remains to be established.

Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors.

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.

Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome.

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.

Basal and Calcium-Stimulated Procalcitonin for the Diagnosis of Medullary Thyroid Cancers: Lights and Shadows.

Background: Procalcitonin (proCt) was recently proposed as an alternative or in addition to calcitonin (Ct) in medullary thyroid cancer (MTC) diagnostics. Methods: Serum basal Ct (bCt) and proCt (bproCt) levels were measured before surgery from a consecutive series of patients with (n=43) and without (n=75) MTC, retrospectively collected in Padua. Serum bproCt, bCt and stimulated proCt and Ct (sproCt and sCt) were measured in another consecutive series of 33 patients seen at three tertiary-level institutions undergoing a calcium stimulation test prior to surgery, 20 of them with a final diagnosis of MTC, and 13 with non-MTC nodular disease. Results: Median bproCt levels were higher in MTC than in non-MTC. A positive correlation was found for bproCt with bCt (P<0.01, R2 = 0.75), and with tumor size (P<0.01, R2 = 0.39). The cut-off for bproCt differentiating between MTC and non-MTC patients was >0.07 ng/ml (sensitivity: 85.7%, specificity: 98.9%, positive predictive value [PPV]: 98.2%, negative predictive value [NPV]: 90.6%, P<0.01). While bproCt was >0.07 ng/ml in 38/39 (97.4%) patients with MTC >10 mm, it was above said cut-off only in 15/23 (65.2%) patients with tumors ≤10 mm. A sproCt >0.19 ng/ml was able to identify MTC [sensitivity: 90.0%, specificity:100.0%, PPV: 100.0%, NPV: 86.7% (P<0.01)]. Conclusions: Our data suggest that bproCt can be a good adjunct to Ct for MTC diagnostic purposes. In consideration of its high specificity, it can be used in combination with Ct in MTC diagnostics, particularly in the case of mildly elevated basal Ct levels.

Biomediators in Polycystic Ovary Syndrome and Cardiovascular Risk.

Polycystic ovary syndrome (PCOS) is extremely heterogeneous in terms of clinical manifestations. The variability of the syndrome's phenotype is derived from the genetic and molecular heterogeneity, with a great deal of environmental factors that may have long-term health consequences, such as metabolic and cardiovascular (CV) diseases. There is no doubt that women with PCOS suffer from metabolic complications more than their age-matched counterparts in the general population and at an earlier age. Obesity, low steroid hormone-binding globulin (SHBG), hyperandrogenemia, insulin resistance, and compensatory hyperinsulinemia are biomediators and early predictors of metabolic complications in PCOS. Doubts remain about the real risk of CV diseases in PCOS and the molecular mechanisms at the basis of CV complications. Based on that assumption, this review will present the available evidence on the potential implications of some biomediators, in particular, hyperandrogenism, estrogen-progesterone imbalance, insulin resistance, and low SHBG, in the processes leading to CV disease in PCOS, with the final aim to propose a more accurate CV risk assessment.

Impact of 18F-FDG PET/CT on Clinical Management of Suspected Radio-Iodine Refractory Differentiated Thyroid Cancer (RAI-R-DTC).

BACKGROUND: As reported in the literature, [18F]-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) provides useful qualitative and semi-quantitative data for the prognosis of advanced differentiated thyroid cancer. Instead, there is a lack of data about the real clinical impact of 18F-FDG PET/CT on the choice of the more effective therapeutic approach for advanced differentiated thyroid cancer (DTC) that starts to lose iodine avidity. The primary aim of this retrospective study was to assess how 18F-FDG PET/CT can guide the choice of the best therapeutic approach to RAI-refractory DTC (RAI-R-DTC) in patients with a doubtful iodine uptake/negative 18F-FDG PET/CT I whole-body scan after several radioactive iodine therapies (RAIT). The secondary aim was to assess the prognostic role of clinical and semi-quantitative metabolic 18F-FDG PET/CT parameters in comparison to published data. MATERIALS AND METHODS: A monocentric retrospective observational study was performed, reviewing the medical records of 53 patients recruited from a database of 208 patients treated at our Institution between 2011 and 2019, with advanced DTC that underwent FDG PET/CT scan for a suspected RAI-R-DTC. Selected patients had to perform a 18F-FDG PET/CT scan after the second RAIT based on a doubtful iodine uptake/negative 131 I whole-body scan and/or persistent elevated thyroglobulin levels. Metabolic response was defined according to positron emission tomography response criteria in solid tumors (PERCIST) guidelines. Standardized uptake value (SUV)max, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. The association between metabolic features, clinical parameters and progression free survival (PFS) was assessed applying Kruskal-Wallis, chi-square-Pearson correlation tests, and Cox regression analyses when appropriate. RESULTS: Among our sample of 53 patients (mean age 52.0 ± 19.9 years; 31 women and 22 men), 27 (51.0%) presented a positive 18F-FDG PET/CT scan: 16 (59.0%) underwent watchful waiting, 4 (15.0%) received external-beam radiation therapy (EBRT), 4 (15.0%) underwent surgery, 2 (7.4%) received another course of RAI therapy, and 1 underwent surgery + EBRT. PERCIST response was evaluated in 14/27 patients. Median follow-up was 5.8 ± 3.9 years and median PFS was 38.0 ± 21.8 months. At the last follow-up assessment, 14/53 (26.4%) demonstrated disease progression, 13/53 (24.5) persistence of structural disease, 25/53 (47%) persistence of biochemical disease, and 15/53 (28%) had an excellent response. A significant association was found between therapeutic approach, metabolic response, and final disease response evaluation, as well as a linear correlation between MTV and TLG with thyroglobulin level. CONCLUSIONS: Our Institutional experience confirmed the role of 18F-FDG PET/CT as a useful guide in the clinical management of RAI-R-DTC and obviated further unnecessary RAIT.