Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI.

OBJECTIVE: To determine if functional imaging using 11C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment. DESIGN/METHODS: Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied. RESULTS: Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS. CONCLUSIONS: In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. OK, ASP, NB, JDP and MG are supported by the NIHR Cambridge Biomedical Research Centre. JDP has received support by an NIHR Senior Investigator award and NIHR brain injury HTC.This is the author accepted manuscript. The final version is available from BioScientifica via https://doi.org/10.1530/EJE-16-063

The impact of mitotane therapy on serum free proteins in patients with adrenocortical carcinoma

Adrenocortical Carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or in the absence of surgery to attenuate progression.Aims: To evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort.Methods: Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels noted to be sub-/supra-/therapeutic. Data were tested for normality, reported as Means ± SD, and compared to other two cohorts using paired-sample t-test with 5% p-value for significance and 95% confidence interval (CI).Results: Patients on mitotane therapy had higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI:33.6, 125.4nmol/L), therapeutic: 85.3 (95% CI:37.1-133.6nmol/L), supra-therapeutic: 75.7 (95% CI: -19.3,170.6nmol/L): adrenal neoplasm 25.5 (95% CI:17.5,33.5nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-/therapeutic plasma mitotane and adrenal neoplasm groups.Conclusion: Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. While there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect

Mitotane Inhibits Proliferation and Affects Mitochondrial Metabolism in Human Breast, Lung and Colon Cancer Cell Lines

<p>Mitotane acts specifically on adrenocortical tissue and is used as a standard treatment in adrenocortical cancer. The exact mechanism of its action remains unknown, despite its clinical use for more than 60 years. Recently it has been suggested that in human adrenocortical cancer cells, mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect. The aim of the study was to assess the effect of Mitotane on proliferation, apoptosis and mitochondrial metabolism in human breast (MCF7), lung (H1975) and colon (HKe-3) cancer cell lines and compare it with our previous results in human adrenocortical cancer (H295R). The proliferation rate of cells was assessed by the resazurin assay. The apoptosis induction was determined by the caspase-3-like activity assay. Changes in expression of the 84 genes involved in mitochondrial metabolism (Complex I: NADH-Coenzyme Q Reductase; Complex II: Succinate-Coenzyme Q Reductase; Complex III: Coenzyme Q-Cytochrome c Reductase; Complex IV: Cytochrome c Oxidase; Complex V: ATP Synthase) were assessed using Mitochondrial Energy Metabolism Plus PCR Arrays, Qiagen. Optimum cytotoxic effects of Mitotane were observed after 24 and 48 hours incubation for H295R cells and HKe-3, MCF7, H1975; respectively. In the H295R cell line a 10uM concentration of Mitotane resulted in 27.0±0.9% cytotoxicity, whereas in HKe-3, MCF7 and H1975 cell lines concentration of 40uM caused cytotoxicity of 48.5±5.2%; 40.2±2.5% and 28.6±2.1%, respectively. 100% cytotoxicity was achieved at a concentration of 20uM for H295R and 100uM for HKe-3, MCF7 and H1975. Cytotoxic effects were negatively influenced by the number of cells/well in H295R, HKe-3, and H1975 but not in MCF7. Although Mitotane had a strong cytotoxic effect on all tested cell lines, caspase-3 activity was induced only in H295R cell line. Expression levels of several genes involved in mitochondrial metabolism was changed by Mitotane; however different genes were affected in different cell lines. Of 84 genes investigated, mRNA levels were decreased/increased by >2 folds in 18/4; 10/29; 6/7 and 28/2 in H295R, HKe-3, MCF7 and H1975, respectively. Mitotane exhibits anti-proliferative activity in breast, colon and lung cancer cell lines. It affects mitochondrial metabolism regardless of the type of cancer and hence his cytotoxic effect is not specific to the adrenal cortex only. <br><em>Mitotane Inhibits Proliferation and Affects Mitochondrial Metabolism in Human Breast, Lung and Colon Cancer Cell Lines</em>. Available from: <a href="https://www.researchgate.net/publication/274961069_Mitotane_Inhibits_Proliferation_and_Affects_Mitochondrial_Metabolism_in_Human_Breast_Lung_and_Colon_Cancer_Cell_Lines">https://www.researchgate.net/publication/274961069_Mitotane_Inhibits_Proliferation_and_Affects_Mitochondrial_Metabolism_in_Human_Breast_Lung_and_Colon_Cancer_Cell_Lines</a> [accessed Apr 14, 2015].</p> <p> </p