Parathyroid Apoplexy Following Cinacalcet Treatment in Primary Hyperparathyroidism

Cinacalcet, a calcimimetic drug, is considered a safe and valid option for the treatment of hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. Hypocalcemia and gastrointestinal adverse reactions are the main side effects reported in patients treated with cinacalcet. We present here the case of an 80-years-old patient with primary hyperparathyroidism treated with cinacalcet for 17 months who developed a severe and symptomatic episode of hypocalcemia requiring hospitalization 1 month after reaching a daily dose of 180 mg. Follow-up laboratory and imaging exams showed remission of primary hyperparathyroidism and disappearance of the parathyroid adenoma, suggesting a possible association between cinacalcet therapy and parathyroid infarction resulting in normalization of the elevated serum parathyroid hormone levels and severe hypocalcemia. No known cases of iatrogenic parathyroid apoplexy have thus far been described. We report here the first case of parathyroid apoplexy associated with the administration of cinacalcet in a patient with primary hyperparathyroidism. Parathyroid apoplexy features heterogeneous clinical manifestations ranging from relatively asymptomatic to potentially life-threatening cases. The occurrence of this complication should be carefully considered in patients with primary hyperparathyroidism in therapy with cinacalcet

Yang-Lee Zeros of the Ising model on Random Graphs of Non Planar Topology

We obtain in a closed form the 1/N^2 contribution to the free energy of the two Hermitian N\times N random matrix model with non symmetric quartic potential. From this result, we calculate numerically the Yang-Lee zeros of the 2D Ising model on dynamical random graphs with the topology of a torus up to n=16 vertices. They are found to be located on the unit circle on the complex fugacity plane. In order to include contributions of even higher topologies we calculated analytically the nonperturbative (sum over all genus) partition function of the model Z_n = \sum_{h=0}^{\infty} \frac{Z_n^{(h)}}{N^{2h}} for the special cases of N=1,2 and graphs with n\le 20 vertices. Once again the Yang-Lee zeros are shown numerically to lie on the unit circle on the complex fugacity plane. Our results thus generalize previous numerical results on random graphs by going beyond the planar approximation and strongly indicate that there might be a generalization of the Lee-Yang circle theorem for dynamical random graphs.Comment: 19 pages, 7 figures ,1 reference and a note added ,To Appear in Nucl.Phys

On the amplitudes for non-critical n=2 supuerstrings

We compute correlation functions in $N=2$ non critical superstrings on the sphere. Our calculations are restrained to the ($s=0$) bulk amplitudes. We show that the four point function factorizes as a consequence of the non-critical kinematics, but differently from the $N=0,1$ cases no extra discrete state appears in the $\hat c\to 1^-$ limit.Comment: 10 page

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

Identifying new potential biomarkers in adrenocortical tumors based on mrna expression data using machine learning

Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC

Long-term outcome of primary bilateral macronodular adrenocortical hyperplasia after unilateral adrenalectomy

CONTEXT Unilateral adrenalectomy has been proposed in selected patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but its long-term outcome is unclear. OBJECTIVE The aim of this study was to analyze long-term clinical and biochemical outcome of unilateral adrenalectomy versus bilateral adrenalectomy in patients with PBMAH in comparison to outcome of cortisol-producing adenoma (CPA) treated by unilateral adrenalectomy. DESIGN Retrospective observational study in three German and one Italian academic tertiary care center. PATIENTS AND METHODS 25 PBMAH patients after unilateral adrenalectomy (unilat-ADX-PBMAH), 9 patients with PBMAH and bilateral adrenalectomy (bilat-ADX-PBMAH) and 39 patients with CPA and unilateral adrenalectomy (unilat-ADX-CPA) were included. RESULTS Baseline clinical and biochemical parameters were comparable in unilat-ADX-PBMAH, bilat-ADX-PBMAH and unilat-ADX-CPA. Directly after surgery, 84% of the unilat-ADX-PBMAH patients experienced initial remission of Cushing's syndrome. In contrast, at last follow-up (median 50 months) 32% of the unilat-ADX-PBMAH patients were biochemically controlled compared to nearly all patients in the other two groups (p=0.000). Adrenalectomy of the contralateral side had to be performed in 12% of the initially unilat-ADX-PBMAH patients. 3 of 20 unilat-ADX-PBMAH patients (15%) died during follow-up presumably of Cushing's syndrome related causes whereas no deaths occurred in the other two groups (p=0.008). Deaths occurred exclusively in patients who were not biochemically controlled after unilateral ADX. CONCLUSIONS Our data suggest that unilateral adrenalectomy of PBMAH patients leads to clinical remission and a lower incidence of adrenal crisis, but less sufficient biochemical control of hypercortisolism potentially provoking a higher mortality

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