Novel Insights into Diagnosis and Treatment of Adrenocortical Tumors

Adrenocortical tumors can cause two distinct clinical problems, with in some cases a combination of both: 1) hormonal overproduction, and 2) malignant tumor growth. The first clinical problem includes Cushing’s syndrome, due to chronic exposure to high levels of cortisol. Despite the fact that surgery is the first treatment approach, medical treatment is indicated in several settings, but is associated with limited efficacy and toxicity. In the first part of this dissertation, we aim to investigate the in vitro effects of two novel steroidogenesis inhibitors currently investigated in clinical trials, i.e. levoketoconazole and osilodrostat, on adrenocortical steroidogenesis and pituitary adenoma cells. We conclude that both steroidogenesis inhibitors are potential novel compounds for the treatment of Cushing’s syndrome. The second part of this dissertation focuses on adrenocortical carcinoma, of which diagnosis and monitoring is currently challenging. Therefore, we propose a novel diagnosti

The Efficacy of Mitotane in Human Primary Adrenocortical Carcinoma Cultures

CONTEXT: Patients with adrenocortical carcinoma (ACC) often fail mitotane treatment and deal with severe toxicity, marking the relevance of predictive parameters for treatment outcome. OBJECTIVE: Determine the effects of mitotane in primary ACC cultures, and correlate sensitivity with patient and tumor characteristics. METHODS: In 32 primary ACC cultures, the effects of mitotane on cell growth and cortisol production were determined. RRM1, SOAT1, and CYP2W1 expression were assessed using reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: The median percentage cell amount inhibition in primary ACC cultures at 50 µM mitotane was 57%. Seven patients were classified as nonresponders, 14 as partial responders, and 11 as responders. The mean median effective concentration (EC50) value of mitotane for inhibition of cell amount in responders was 14.2 µM (95% CI, 11.3-17.9), in partial responders 41.6 µM (95% CI, 33.5-51.8), and could not be calculated in nonresponders. The percentage cortisol-producing ACC was 14%, 43%, and 73% for nonresponders, partial responders, and responders (P = 0.068). Mitotane inhibited cortisol production with a mean EC50 of 1.4 µM (95% CI, 0.9-2.1), which was considerably lower than the EC5

Supplementary material belonging to: The Efficacy of Mitotane in Human Primary Adrenocortical Carcinoma Cultures

Manuscript nr: jc.2018-02453R

Diagnosis and management of neonatal leukaemia

Leukaemia in neonates (infants <1 month) is rare, whereby neonatal acute myeloid leukaemia (AML) is more frequent than neonatal acute lymphoblastic leukaemia (ALL). High mortality rates are observed, though AML has a better prognosis than ALL. Neonatal leukaemia is typically presented with hepatosplenomegaly, leukaemia cutis and/or hyperleucocytosis. Congenital infections should be ruled out before diagnosis. Rearrangement of the . MLL gene is the most frequently occurring genetic aberration. Treatment includes intensive multi-agent chemotherapy, usually with age-related dose adjustments next to supportive care. Treatment intensification for ALL could be indicated in the future as the dismal prognosis is subject to high relapse rates in ALL

How to differentiate benign from malignant adrenocortical tumors?

Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Adrenal incidentalomas are, however, commonly identified in clinical practice. Discrimination between benign and malignant adrenal tumors is of great importance considering the large differences in clinical behavior requiring different strategies. Diagnosis of ACC starts with a thorough physical examination, biochemical evaluation, and imaging. Computed tomography is the first-level imaging modality in adrenal tumors, with tumor size and Hounsfield units being important features for determining malignancy. New developments

Inhibition of human adrenocortical cancer cell growth by temozolomide in vitro and the role of the MGMT gene

Context: Treatment of patients with adrenocortical carcinomas (ACC) with mitotane and/or chemotherapy is often associated with toxicity and poor tumor response.Newtherapeutic options are urgently needed. Objective: The objectives of the study were to evaluate the therapeutic possibilities of temozolomide (TMZ) in ACC cells and to assess the potential predictive role of the DNA repair gene O6-Methylguanine-DNA methyltransferase (MGMT) in adrenocortical tumors. Methods: Three human ACC cell lines and eight primary ACC cultures were used to assess effects of TMZ in vitro. In the cell lines, 11 normal adrenals, 16 adrenocortical adenomas, and 29 ACC, MGMT promoter methylation and expression were determined. Results: IC50 values of TMZ on cell growth were 39 μM, 38 μM, and 44 μMfor H295R, HAC15, and SW13, respectively. TMZ induced apoptosis and provoked cytotoxic and cytostatic effects by reducing the surviving fraction of ACC colonies and the colony size. TMZ thereby induced cell cycle arrests in ACC cell lines. TMZ and mitotane both inhibited growth of ACC cells cultured as threedimensional spheroids.TMZinhibited cellamountin five of eight primaryACCculturesandinduced apoptosis in seven of eight primary ACC cultures. In ACC cell lines and adrenal tissues, MGMT promoter methylation was low. In ACCs, methylation was inversely correlated with MGMT mRNA expression. MGMT protein expression was not correlated with MGMT methylation. Conclusions: For the first time, we show the therapeutic potential of temozolomide for ACC, offering an urgently needed potential alternative for patients not responding to mitotane alone or with etoposide, doxorubicin, and cisplatin. (Pre-)clinical studies are warranted to assess efficacy in vivo