Digoxin treatment does not reinduce radioiodine uptake in radioiodine refractory non-medullary thyroid carcinoma.

OBJECTIVES: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so called redifferentiation, are promising but not suitable for all patients. Preclinical studies have shown that the cardiac glycoside digoxin restored RAI uptake, both in human cell lines as in a murine model. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI refractory NMTC. METHODS: Eight patients with metastasized RAI refractory NMTC were included between November 2022 and June 2023. Before treatment a baseline [123I]NaI-scintigraphy was performed. Thereafter, patients were treated with digoxin for three weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After one week, the digoxin plasma concentration as measured and digoxin dose was adjusted if necessary. After three weeks of digoxin treatment, a second [123I]NaI-scintigraphy was performed. RAI uptake was compared between the two scintigraphies. RESULTS: Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial. CONCLUSION: Contrary to results from preclinical trials, in this trial, three weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach towards optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.

11-deoxycortisol positively correlates with T cell immune traits in physiological conditions.

BACKGROUND: Endogenous steroid hormones have significant effects on inflammatory and immune processes, but the immunological activities of steroidogenesis precursors remain largely unexplored. METHODS: We conducted a systematic approach to examine the association between steroid hormones profile and immune traits in a cohort of 534 healthy volunteers. Serum concentrations of steroid hormones and their precursors (cortisol, progesterone, testosterone, androstenedione, 11-deoxycortisol and 17-OH progesterone) were determined by liquid chromatography-tandem mass spectrometry. Immune traits were evaluated by quantifying cellular composition of the circulating immune system and ex vivo cytokine responses elicited by major human pathogens and microbial ligands. An independent cohort of 321 individuals was used for validation, followed by in vitro validation experiments. FINDINGS: We observed a positive association between 11-deoxycortisol and lymphoid cellular subsets numbers and function (especially IL-17 response). The association with lymphoid cellularity was validated in an independent validation cohort. In vitro experiments showed that, as compared to androstenedione and 17-OH progesterone, 11-deoxycortisol promoted T cell proliferation and Candida-induced Th17 polarization at physiologically relevant concentrations. Functionally, 11-deoxycortisol-treated T cells displayed a more activated phenotype (PD-L1high CD25high CD62Llow CD127low) in response to CD3/CD28 co-stimulation, and downregulated expression of T-bet nuclear transcription factor. INTERPRETATION: Our findings suggest a positive association between 11-deoxycortisol and T-cell function under physiological conditions. Further investigation is needed to explore the potential mechanisms and clinical implications. FUNDING: Found in acknowledgements.

Persistent improvement of bone mineral density up to 20 years after treatment of Cushing's syndrome.

OBJECTIVE: Cushing's syndrome (CS) is associated with osteoporosis and high fracture risk. Besides male sex, it is unknown which variables influence bone mineral density (BMD) at diagnosis and it is unclear to what extent BMD normalizes during long-term follow-up after treatment of CS. The aim of this study was to determine factors associated with BMD at diagnosis of CS and to determine the long-term course of BMD and fracture rate after successful treatment of CS. DESIGN: Retrospective cross-sectional and longitudinal cohort study. METHODS: Data were collected from 231 patients with CS who were treated at the Radboud University Medical Centre between 1968 and 2020. RESULTS: At diagnosis, male sex was associated with lower Z-scores at the lumbar spine (LS) compared with female sex: -0.97s.d. (-1.45 to -0.49) after correction for possible confounders. Shorter duration of symptoms and younger age were also associated with lower Z-scores at diagnosis, while etiology of CS, urinary cortisol excretion and gonadal status were not associated with Z-scores at diagnosis. Z-scores improved up to 20 years after treatment. Fifteen years after treatment, men showed larger improvements of Z-scores than women; +2.56 (1.82-3.30) increase in LS Z-score vs +1.48 (0.96-2.00) respectively. Fracture incidence was highest during the 2 years before diagnosis and decreased after treatment. CONCLUSION: Male sex, younger age and shorter duration of symptoms are associated with lower BMD at diagnosis of CS. BMD continues to improve up to 20 years after treatment of CS. Fracture rate decreases after treatment of CS.

Spontaneous bone infarction of the distal femur in a patient with Cushing's disease: a case report.

Avascular necrosis of the femoral head is a well-known complication of treatment with high dosage glucocorticoids and has been described in a few patients with Cushing's syndrome. In this case report, we describe the, to our knowledge, first case of a patient with endogenous Cushing's syndrome with a bone infarction located in the distal femur. In patients with Cushing's syndrome and bone pain, the diagnosis of bone infarction should be considered as it can occur as a rare complication of hypercortisolism.

Venous thromboembolism in patients with adrenocortical carcinoma after surgery.

BACKGROUND: Adrenocortical carcinoma is a rare malignancy with a poor prognosis. We hypothesized that patients with adrenocortical carcinoma are at high risk for venous thromboembolism, given the numerous risk factors such as malignancy, abdominal surgery, immobility and hormonal excess. The aim of this study was to determine retrospectively the incidence of venous thromboembolisms after surgical treatment in patients with adrenocortical carcinoma. MATERIALS AND METHODS: A retrospective study was performed, collecting data from all patients diagnosed with adrenocortical carcinoma from 2003 to 2018 at the Radboud University Medical Centre, The Netherlands. RESULTS: In 34 patients, eight postoperative venous thromboembolisms, all pulmonary embolisms, were diagnosed in the first 6 months after adrenalectomy (23.5%). In addition, one patient developed pulmonary embolism just prior to surgery and one patient 7 years after surgery. Five of the eight patients with postoperative venous thromboembolisms presented with symptomatic pulmonary embolism whereas the other three pulmonary embolisms were incidentally found on regular follow up CT scans. Seven of the eight venous thromboembolisms occurred within 10 weeks after surgery. Seven of the eight patients had advanced stage adrenocortical carcinoma and four patients already received low-molecular weight heparin during the development of the venous thromboembolism. There was one case of fatal pulmonary embolism in a patient with a cortisol producing tumor with pulmonary metastases, despite the use of a therapeutic dose thromboprophylaxis. CONCLUSION: Patients with adrenocortical carcinoma are at high risk of developing postoperative venous thromboembolisms. Prolonged postoperative thromboprophylaxis could be considered in these patients.