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Cancers Jun 2023Clinical evidence has shown frequent hypogonadism following mitotane (MTT) treatment in male patients with adrenocortical carcinoma. This study aimed to evaluate the...
BACKGROUND
Clinical evidence has shown frequent hypogonadism following mitotane (MTT) treatment in male patients with adrenocortical carcinoma. This study aimed to evaluate the impact of MTT on male gonadal function.
METHODS
Morphological analysis of testes and testosterone assays were performed on adult CD1 MTT-treated and untreated mice. The expression of key genes involved in interstitial and tubular compartments was studied by real-time PCR. Moreover, quantitative and qualitative analysis of spermatozoa was performed.
RESULTS
Several degrees of damage to the testes and a significant testosterone reduction in MTT-treated mice were observed. A significant decline in and mRNA expression in the interstitial compartment confirmed an impairment of androgen production. mRNA expression was unaffected by MTT, proving that Sertoli cells are not the drug's primary target. Sperm concentrations were significantly lower in MTT-treated animals. Moreover, the drug caused a significant increase in the percentage of spermatozoa with abnormal chromatin structures.
CONCLUSION
MTT negatively affects the male reproductive system, including changes in the morphology of testicular tissue and reductions in sperm concentration and quality.
PubMed: 37370841
DOI: 10.3390/cancers15123234 -
Asia Oceania Journal of Nuclear... 2023Adrenocortical carcinoma (ACC) is a rare type of cancer that is associated with a high rate of recurrence and poor prognosis. The main diagnostic approaches to...
Adrenocortical carcinoma (ACC) is a rare type of cancer that is associated with a high rate of recurrence and poor prognosis. The main diagnostic approaches to adrenocortical cancer include CT scan, MRI and the promising role of F-FDG PET/CT. The main therapeutic approaches include radical surgery of local disease and recurrences, as well as adjuvant mitotane therapy. The evaluation of adrenocortical carcinoma (ACC) could be difficult by using F-FDG PET/CT in view of the significant association between the F-FDG uptake and ACC. At the same time, not all adrenal glands with F-FDG uptake are considered to be malignant, so awareness of these various findings is substantial for ACC management, especially with limited data regarding the role of F-FDG PET/CT in ACC post-operative settings. This report discusses the case of a 47-year-old man with a history of left adrenocortical carcinoma who underwent adrenalectomy and received adjuvant mitotane therapy. 9 months after the surgery, a follow-up F-FDG PET/CT scan showed that the F-FDG uptake was prominent in the right adrenal gland without corresponding abnormal CT scan findings.
PubMed: 37324222
DOI: 10.22038/AOJNMB.2022.67950.1472 -
Frontiers in Oncology 2023Adrenocortical carcinoma (ACC) is a rare, heterogeneous, and aggressive malignancy with a generally poor prognosis. Surgical resection is the optimal treatment plan....
Long-term partial response in a patient with liver metastasis of primary adrenocortical carcinoma with adjuvant mitotane plus transcatheter arterial chemoembolization and microwave ablation: a case report.
Adrenocortical carcinoma (ACC) is a rare, heterogeneous, and aggressive malignancy with a generally poor prognosis. Surgical resection is the optimal treatment plan. After surgery, both mitotane treatment or the etoposide-doxorubicin-cisplatin (EDP) protocol plus mitotane chemotherapy have a certain effect, but there is still an extremely high possibility of recurrence and metastasis. The liver is one of the most common metastatic targets. Therefore, techniques such as transcatheter arterial chemoembolization (TACE) and microwave ablation (MWA) for liver tumors can be attempted in a specific group of patients. We present the case of a 44-year-old female patient with primary ACC, who was diagnosed with liver metastasis 6 years after resection. During mitotane treatment, we performed four courses of TACE and two MWA procedures in accordance with her clinical condition. The patient has maintained the partial response status and has currently returned to normal life to date. This case illustrates the value of the practical application of mitotane plus TACE and MWA treatment.
PubMed: 37313469
DOI: 10.3389/fonc.2023.1157740 -
Hinyokika Kiyo. Acta Urologica Japonica May 2023A 59-year-old man presented with high blood pressure, hypokalemia and muscle weakness. His aldosterone/renin ratio was high and plasma renin activity was low. Computed...
A 59-year-old man presented with high blood pressure, hypokalemia and muscle weakness. His aldosterone/renin ratio was high and plasma renin activity was low. Computed tomography (CT) showed a heterogeneous left adrenal mass. Primary aldosteronism was diagnosed and laparoscopic left adrenalectomy was performed. The pathological diagnosis was adrenocortical carcinoma with positive surgical margins. He underwent radiotherapy and mitotane as adjuvant therapies. Subsequently, CT revealed multiple metastases, in the liver and retroperitoneum. After six courses of EDP (a combination of etoposide, doxorubicin and cisplatin), CT showed widespread metastases in the retroperitoneum and he chose to receive the best supportive care. Aldosterone-producing adrenocortical carcinoma is exceedingly rare. To the best of our knowledge, only67 cases have been reported. Complete resection is needed to improve prognosis and this was not achieved in our case. We therefore recommend careful selection of the operative procedure.
Topics: Male; Humans; Middle Aged; Adrenocortical Carcinoma; Aldosterone; Renin; Mitotane; Adrenal Cortex Neoplasms
PubMed: 37312493
DOI: 10.14989/ActaUrolJap_69_5_131 -
European Journal of Cancer (Oxford,... Aug 2023At metastatic stage, treatment of adrenocortical carcinoma (ACC) relies in first line on mitotane therapy, combination of mitotane with locoregional therapies or... (Clinical Trial)
Clinical Trial
BACKGROUND
At metastatic stage, treatment of adrenocortical carcinoma (ACC) relies in first line on mitotane therapy, combination of mitotane with locoregional therapies or cisplatin-based chemotherapy according to initial presentation. In second line, ESMO-EURACAN recommendations favour enrolment of patients in clinical trials investigating experimental therapies. However, the benefit of this approach remains unknown.
METHODS
The aim of our retrospective study was to analyse the inclusion and outcomes of all patients of the French cohort ENDOCAN-COMETE included in early clinical trials between 2009 and 2019.
RESULTS
Of the 141 patients for whom a local or national multidisciplinary tumour board recommended, as first choice, to look for clinical trial, 27 patients (19%) were enroled in 30 early clinical trials. Median progression-free survival (PFS) was 3.02 months (95% confidence interval [95% CI]; 2.3-4.6) and median overall survival (OS) was 10.2 months (95% CI; 7.13-16.3) while the best response, evaluable in 28 of 30 trial participants according to RECIST 1.1 criteria, was partial response for 3 patients (11%) stable disease for 14 patients (50%) and progressive disease for 11 patients (39%), resulting in a disease control rate of 61%. Median growth modulation index (GMI) in our cohort was 1.32, with a significantly prolonged PFS in 52% of the patients compared to the previous line. The Royal Marsden Hospital (RMH) prognostic score was not associated with OS in this cohort.
CONCLUSION
Our study suggests that patients with metastatic ACC benefit from inclusion in early clinical trials in second line. As recommended, if a clinical trial is available, it should be the first choice for suitable patients.
Topics: Humans; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Combined Chemotherapy Protocols; Mitotane; Retrospective Studies; Treatment Outcome
PubMed: 37277263
DOI: 10.1016/j.ejca.2023.05.006 -
European Journal of Endocrinology Jun 2023Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and...
OBJECTIVE
Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting.
DESIGN
Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at 6 German reference centres between 2016 and 2022.
METHODS
Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAE) were assessed.
RESULTS
In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR was 24% (16-41). PFS was 3.0 months (95% CI, 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs 2.5 (2.0-3.0) months (HR 0.29, 95% CI, 0.13-0.66, P = 0.001) and OS of 28.2 (9.5-46.8) vs 7.0 (4.1-10.2) months (HR 0.34, 95% CI, 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs 2.3 (1.6-3.0, P < 0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab.
CONCLUSIONS
In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Nivolumab; Retrospective Studies; Adrenocortical Carcinoma; B7-H1 Antigen; Antineoplastic Agents, Immunological; Immunotherapy; Adrenal Cortex Neoplasms
PubMed: 37260092
DOI: 10.1093/ejendo/lvad054 -
AACE Clinical Case Reports 2023To describe a case highlighting a rare malignancy that can be camouflaged by the hormonal milieu of pregnancy.
BACKGROUND/OBJECTIVE
To describe a case highlighting a rare malignancy that can be camouflaged by the hormonal milieu of pregnancy.
CASE REPORT
We present the case of a 28-year-old pregnant female who was diagnosed with stage IV metastatic adrenocortical carcinoma at 15-weeks gestation. The patient declined palliative chemotherapy at first with the hope of continuing her pregnancy. She had elevated dehydroepiandrosterone sulfate, testosterone, and cortisol levels consistent with Cushing's syndrome and hyperandrogenism. The patient eventually had a spontaneous abortion and elected to start chemotherapy and mitotane treatment. She passed away 3 months after initial presentation.
DISCUSSION
Adrenocortical carcinoma is difficult to detect and diagnose in pregnant patients because of the physiologic hormonal changes that take place during gestation. The patient described in this case report is an example of this diagnostic challenge.
CONCLUSION
Adrenocortical carcinoma is a rare, fatal disease that often presents at an advanced stage with limited treatment options making earlier diagnosis imperative; however, diagnosis and treatment are complicated by pregnancy. More data is necessary to determine how best to approach these challenges in future patients.
PubMed: 37251968
DOI: 10.1016/j.aace.2023.03.002 -
Proceedings of the National Academy of... May 2023Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin...
Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented by LCDV-1, while human insulin had no effect. Fas-induced apoptosis, necroptosis, mitotane-induced cell death and growth hormone-releasing hormone antagonist-induced necrosis were unaffected, suggesting the specificity to ferroptosis inhibition by the LCDV-1 VILP. Mechanistically, we identified the viral C-peptide to be required for inhibition of lipid peroxidation and ferroptosis inhibition, while the human C-peptide exhibited no antiferroptotic properties. In addition, the deletion of the viral C-peptide abolishes radical trapping activity in cell-free systems. We conclude that iridoviridae, through the expression of insulin-like viral peptides, are capable of preventing ferroptosis. In analogy to the viral mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevents necroptosis, we rename the LCDV-1 VILP a viral peptide inhibitor of ferroptosis-1. Finally, our findings indicate that ferroptosis may function as a viral defense mechanism in lower organisms.
Topics: Humans; Insulin; C-Peptide; Apoptosis; Necrosis; Cell Death
PubMed: 37186845
DOI: 10.1073/pnas.2300320120 -
Medicina 2023Adrenocortical carcinomas are rare tumors, usually hyperfunctioning, with poor overall survival. Frequent age of presentation is described in adults between 40 and 60...
Adrenocortical carcinomas are rare tumors, usually hyperfunctioning, with poor overall survival. Frequent age of presentation is described in adults between 40 and 60 years of age, predominantly female. Two unusual cases of adrenal carcinoma diagnosed in young women are presented. The first one was discovered in the second trimester of gestation, with signs and symptoms of hypercortisolism and localized adrenal lesion, which was resolved with complete resection by week 20 of pregnancy. In the second case, the patient begined with clinical manifestations of rapidly progressive virilization, the biochemical pattern being pure hyperandrogenism. In both cases, despite complete resection, the high Ki67 as the main prognostic factor leaded to categorization as "high risk of recurrence". In addition, pregnancy and glucocorticoid secretory pattern have been associated as additional risk factors of recurrence. This is particularly high within the first two years after diagnosis. There is controversy about the use of adjuvant mitotane in these patients, and the general recommendation is to be started no longer than 3 months after surgery. However, the available evidence does not suggest that its use is ineffective beyond that period. Limitations, such as the course of pregnancy and the immediate puerperium, as well as the difficulty of accessing this medication in our environment, prevented the early initiation of adjuvant treatment with mitotane in both cases, although there is still concern whether its administration would still be appropriate.
Topics: Adult; Humans; Female; Middle Aged; Male; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Antineoplastic Agents, Hormonal
PubMed: 37094202
DOI: No ID Found -
Frontiers in Endocrinology 2023Hypogonadism is common in male patients with adrenocortical carcinoma (ACC) who are under treatment with mitotane, but the phenomenon is underestimated, and its...
OBJECTIVE
Hypogonadism is common in male patients with adrenocortical carcinoma (ACC) who are under treatment with mitotane, but the phenomenon is underestimated, and its prevalence has been poorly studied. This single-center retrospective longitudinal study was undertaken to assess the frequency of testosterone deficiency before and after mitotane therapy, the possible mechanism involved, and the relationship between hypogonadism with serum mitotane levels and prognosis.
RESEARCH DESIGN AND METHODS
Consecutive male ACC patients followed at the Medical Oncology of Spedali Civili Hospital in Brescia underwent hormonal assessment to detect testosterone deficiency at baseline and during mitotane therapy.
RESULTS
A total of 24 patients entered the study. Of these patients, 10 (41.7%) already had testosterone deficiency at baseline. During follow-up, total testosterone (TT) showed a biphasic evolution over time with an increase in the first 6 months followed by a subsequent progressive decrease until 36 months. Sex hormone binding globulin (SHBG) progressively increased, and calculated free testosterone (cFT) progressively decreased. Based on cFT evaluation, the proportion of hypogonadic patients progressively increased with a cumulative prevalence of 87.5% over the study course. A negative correlation was observed between serum mitotane levels >14 mg/L and TT and cFT.
CONCLUSION
Testosterone deficiency is common in men with ACC prior to mitotane treatment. In addition, this therapy exposes these patients to further elevated risk of hypogonadism that should be promptly detected and counteracted, since it might have a negative impact on quality of life.
Topics: Humans; Male; Adrenocortical Carcinoma; Mitotane; Androgens; Retrospective Studies; Longitudinal Studies; Quality of Life; Testosterone; Hypogonadism; Adrenal Cortex Neoplasms
PubMed: 37077359
DOI: 10.3389/fendo.2023.1128061