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

Results and clinical interpretation of germline RET analysis in a series of patients with medullary thyroid carcinoma: The challenge of the variants of uncertain significance

Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively

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

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

Basal and stimulated calcitonin for the diagnosis of medullary thyroid cancer: updated thresholds and safety assessment

Purpose Reliable cut-offs for basal (bCT) and calcium stimulated calcitonin (casCT) are needed for an early and accurate diagnosis of medullary thyroid cancer (MTC). Patients and methods Fifty-four new patients with nodular goiter were enrolled and analysed together with those previously published by our group for a total of 135 cases. bCT and casCT were measured by a highly sensitive method and the results compared with histological findings. In a subgroup of patients, cardiac rhythm was recorded before and during the calcium test. Results In both females (F) and males (M), there was a significant correlation between tumor size and bCT levels (P < 0.001). The receiver operating characteristic plot analyses showed that, for bCT, the new cut-off points able to separate non-MTC from MTC patients were > 30 (F) and > 34 pg/mL (M), whereas the best casCT thresholds were > 79 (F) and > 466 pg/mL (M). bCT was shown to harbour a high accuracy, though some cases were diagnosed only upon stimulation test. Importantly, combining bCT, below or above the cut-offs, with casCT above the cut-offs, all the MTC cases were correctly identified. A reversible sinus bradycardia was observed in 9% of cases during the test. Conclusions Refined cut-offs for bCT and casCT in patients with nodular goiter are reported. Sensitive bCT was shown to have a high accuracy, but the combination with casCT data was needed to identify all MTC cases. The reliability and safety of calcium test strongly favour the routine use of CT determination in nodular thyroid disease

Basal and stimulated calcitonin for the diagnosis of medullary thyroid cancer: updated thresholds and safety assessment

Purpose: Reliable cut-offs for basal (bCT) and calcium stimulated calcitonin (casCT)are needed for an early and accurate diagnosis of medullary thyroid cancer (MTC). Patients and methods: Fifty-four new patients with nodular goiter were enrolled and analysed together with those previously published by our group for a total of 135 cases. bCT and casCT were measured by a highly sensitive method and the results compared with histological findings. In a subgroup of patients, cardiac rhythm was recorded before and during the calcium test. Results: In both females (F) and males (M), there was a significant correlation between tumor size and bCT levels (P 30 (F) and > 34 pg/mL (M), whereas the best casCT thresholds were > 79 (F) and > 466 pg/mL (M). bCT was shown to harbour a high accuracy, though some cases were diagnosed only upon stimulation test. Importantly, combining bCT, below or above the cut-offs, with casCT above the cut-offs, all the MTC cases were correctly identified. A reversible sinus bradycardia was observed in 9% of cases during the test. Conclusions: Refined cut-offs for bCT and casCT in patients with nodular goiter are reported. Sensitive bCT was shown to have a high accuracy, but the combination with casCT data was needed to identify all MTC cases. The reliability and safety of calcium test strongly favour the routine use of CT determination in nodular thyroid disease

The Current-Temperature Phase Diagram of Layered Superconductors

The behavior of clean layered superconductors in the presence of a finite electric current and in zero-magnetic field behavior is addressed. The structure of the current temperature phase diagram and the properties of each of the four regions will be explained. We will discuss the expected current voltage and resistance characteristics of each region as well as the effects of finite size and weak disorder on the phase diagram. In addition, the reason for which a weakly non-ohmic region exists above the transition temperature will be explained.Comment: 8 pages (RevTeX), 4 encapsulated postscript figure

Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders

Objective: The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma. Design: We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants. Methods: Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses. Results: A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitro transcriptional activity, including increased stimulation of the PTH promoter. Conclusions: We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease