Sex Differences on Mitotane Concentration and Treatment Outcome in Patients with Adrenocortical Carcinoma

(1) Background: In clinical settings, data regarding sex are rarely investigated. In women, factors such as body size and composition, hormonal variations, metabolism, and access to care systems and therapy could strongly influence the pharmacological management and the outcome of the therapy. To underline this sex-related difference, we retrospectively collected data from adrenocortical carcinoma patients treated with mitotane, and then evaluated sex-related pharmacokinetics parameters. (2) Methods: A fully validated chromatographic method was used to quantify mitotane concentration in plasma collected from adult patients, also considering the active metabolite ortho,para,dichlorodiphenylethene (o,p′-DDE). Statistical analyses were used to evaluate the sex influence on drugs pharmacokinetics. (3) Results: We found that sex resulted as predictive factor of plasma mitotane and o,p′-DDE concentrations and significantly influenced the attainment of the therapeutic target of mitotane, implying that female sex could be a risk factor of treatment failure. (4) Conclusions: These results suggest that mitotane therapy should be modulated according to patient sex. Furthermore, the proposed approach could contribute to facilitating and disseminating sex-specific pharmacology

Expression of orexin A and its receptor 1 in the rat epididymis.

The hypothalamic peptide orexin A (oxA) derives from the proteolytic cleavage of the precursor molecule prepro-orexin. It binds with the high affinity G-protein-coupled orexin receptor 1 (OX1R). Here, we report the detection of oxA and OX1R in the principal cells of the rat caudal epididymis by immunohistochemistry. Both oxA and OX1R immunolabelling showed cytoplasmic supranuclear localization, filling the apical portion of the cells. The expression of prepro-orexin and OX1R mRNA transcripts in the rat epididymis was assessed by reverse-transcriptase polymerase chain reaction, while the presence of both these proteins in the tissue was confirmed by Western blotting analysis. Our findings provide the evidence for the presence of oxA and OX1R in the rat epididymis, and demonstrate that both proteins are locally synthesised, thus suggesting a role for oxA in governing the fertilizing capability of the immature male gamete

Cost-effectiveness for high dose quadrivalent versus the adjuvanted quadrivalent influenza vaccine in the Italian older adult population

ObjectivesTo assess the cost-effectiveness of switching from adjuvanted quadrivalent vaccine (aQIV) to high-dose quadrivalent influenza vaccine (HD-QIV) in those aged ≥65 years from the Italian National Health Service perspective.MethodsWe developed a decision tree model over a 1-year time-horizon to assess influenza-related costs and health outcomes. Two hospitalization approaches were considered: “hospitalization conditional on developing influenza” and “hospitalization possibly related to Influenza.” The first approach considered only hospitalizations with influenza ICD-9-CM diagnosis codes. The second included hospitalizations for cardiorespiratory events possibly related to influenza to better capture the “hidden burden”. Since comparative efficacy of high-dose quadrivalent influenza vaccine versus adjuvanted quadrivalent vaccine was lacking, we assumed relative efficacy versus a common comparator, standard-dose influenza quadrivalent vaccines (SD-QIV). We assumed the relative efficacy of HD-QIV vs. SD-QIV was 24.2 and 18.2% for the first and second hospitalization approaches, respectively, based on published information. Due to lack of comparative efficacy data for aQIV vs. SD-QIV, we assumed three different scenarios: 0, 6, and 12% relative efficacy in scenarios 1, 2, and 3, respectively.ResultsFor the first hospitalization approach, HD-QIV was a cost-effective alternative to aQIV in all scenarios at a willingness-to-pay threshold of €30,000 per Quality Adjusted Life Years. The incremental cost-effectiveness ratios across the scenarios were €7,301, €9,805, and €14,733, respectively, much lower than the willingness-to-pay per Quality Adjusted Life Years threshold. For the second hospitalization approach, HD-QIV was a dominant alternative to aQIV across all scenarios. The robustness of the results was confirmed in one-way and probabilistic sensitivity analyses.ConclusionSwitching to HD-QIV from aQIV for the older adult in Italy would improve health-related outcomes, and would be cost-effective or cost saving

Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma

Objective: Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane. Design and methods: We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. Results: We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). Conclusions: The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency

Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma

Background: Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC. Methods: This was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories. Results: We identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival. Conclusions: GVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families

What Is the Optimal Duration of Adjuvant Mitotane Therapy in Adrenocortical Carcinoma? An Unanswered Question

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence

Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study

BACKGROUND Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health