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International Journal of Pharmaceutics Dec 2022We employ differential scanning calorimetry, broadband dielectric spectroscopy and optical microscopy to investigate the glass transition, molecular relaxation dynamics,...
We employ differential scanning calorimetry, broadband dielectric spectroscopy and optical microscopy to investigate the glass transition, molecular relaxation dynamics, and isothermal recrystallization kinetics of amorphous mitotane, the only drug approved for the pharmacological treatment of adrenocortical carcinoma. Amorphous mitotane displays a glass transition at T = 243 ± 1 K, characterized by relatively low fragility index of 68 ± 2. Besides the structural and Johari-Goldstein relaxations, amorphous mitotane displays an intramolecular relaxation with activation energy of 25 ± 1 kJ mol. The same relaxation process, with virtually the same activation energy and relaxation times, is observed in the closely-related o,p'-dichlorobenzophenone compound, which allows identifying it as the rotation of the chlorobenzene ring with the chlorine closest to the central carbon. Such conformational relaxation is active at human body temperature, and may thus be potentially relevant for the mechanism of action of the drug. Our study shows that the comparative study of the relaxation map of related molecular species is a powerful tool to identify and classify secondary relaxation processes. The amorphous drug is found to be unstable against recrystallization at as well as slightly below room temperature, and to display-two-dimensional growth with only sporadic nucleation, characterized by an Avrami kinetic exponent of 2.05 ± 0.05. The kinetic stability of the amorphous form of mitotane, observed at room temperature in micellar formulations, is therefore limited to the nanoconfined sample and is not observed in the bulk compound.
Topics: Humans; Crystallization; Mitotane; Vitrification; Calorimetry, Differential Scanning; Kinetics; Glass
PubMed: 36379398
DOI: 10.1016/j.ijpharm.2022.122390 -
Cancers Oct 2022Adrenocortical cancer (ACC) typically presents in advanced stages of disease and has a dismal prognosis. One of the foremost reasons for this is the lack of available... (Review)
Review
Adrenocortical cancer (ACC) typically presents in advanced stages of disease and has a dismal prognosis. One of the foremost reasons for this is the lack of available systemic therapies, with mitotane remaining the backbone of treatment since its discovery in the 1960s, despite underwhelming efficacy. Surgery remains the only potentially curative option, but about half of patients will recur post-operatively, often with metastatic disease. Other local treatment options have been attempted but are only used practically on a case-by-case basis. Over the past few decades there have been significant advances in understanding the molecular background of ACC, but this has not yet translated to better treatment options. Attempts at novel treatment strategies have not provided significant clinical benefit. This paper reviews our current treatment options and molecular understanding of ACC and the reasons why a successful treatment has remained elusive. Additionally, we discuss the knowledge gaps that need to be overcome to bring us closer to successful treatment and ways to bridge them.
PubMed: 36358665
DOI: 10.3390/cancers14215245 -
Gland Surgery Oct 2022Adrenocortical carcinoma, a rare malignancy, has a poor prognosis, and the treatment modalities have not been well established. This study aimed to analyze the trend of...
BACKGROUND
Adrenocortical carcinoma, a rare malignancy, has a poor prognosis, and the treatment modalities have not been well established. This study aimed to analyze the trend of treatment modalities and outcomes of patients with adrenocortical carcinoma.
METHODS
We retrospectively analyzed 94 patients with adrenocortical carcinoma between January 1995 and June 2020 for distributions according to the American Joint Committee on Cancer (AJCC) 8th edition tumor-node-metastasis (TNM) staging, the yearly trend of demographic features, differences in multidisciplinary treatment, and prognostic outcomes. Multidisciplinary treatment included any combination of treatment including surgery, mitotane, chemotherapy or radiation.
RESULTS
The mean age and tumor size were 48.9 years and 11.7 cm, respectively. Fifteen patients (16.0%) underwent surgery only, and 56 (59.6%) underwent surgery with additional multidisciplinary treatments. Initial curative treatment was performed in all patients with stage 1 (n=5), 33 patients with stage 2 (n=34, 97.1%), 12 patients with stage 3 (n=19, 63.2%), and 11 patients with stage 4 (n=36, 30.6%) (P<0.0001). Two patients (40.0%) with stage 1 presented recurrence. In stages 2, 3, and 4, 57.6%, 58.3%, and 90.9% of patients who received curative treatment had recurrences, respectively. The annual trend presented statistical differences in mitotane use that have been increasing recently (P<0.0001).
CONCLUSIONS
Overall distribution of adrenocortical carcinoma stage was similar throughout the years. Although the rate of mitotane use in the treatment of patients with Adrenocortical carcinoma has increased over time, recurrences were common even after multidisciplinary curative treatment in all stages. The treatment effect and prognostic outcomes presented no promising progression even with adjuvant chemotherapy and mitotane use in addition to surgical treatment. Adrenocortical carcinoma still presented an extremely poor prognosis, and further prospective studies are needed.
PubMed: 36353581
DOI: 10.21037/gs-22-274 -
Journal of Community Hospital Internal... 2022Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.7-2 cases per million. Most patients present with steroid hormone excess or...
Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.7-2 cases per million. Most patients present with steroid hormone excess or abdominal mass effects, but 15% of patients with ACC are diagnosed incidentally. A careful history, physical exam, and pertinent lab investigations are necessary to reach the diagnosis. Surgical resection is the cornerstone of treatment in localized ACC; however, systemic chemotherapy with mitotane is preferred in patients with widespread disease or those who are not ideal candidates for surgery.
PubMed: 36262492
DOI: 10.55729/2000-9666.1108 -
Frontiers in Endocrinology 2022This study aimed to characterise the clinicopathological features and prognostic factors of a large cohort of Hungarian patients with adrenocortical cancer diagnosed...
OBJECTIVES
This study aimed to characterise the clinicopathological features and prognostic factors of a large cohort of Hungarian patients with adrenocortical cancer diagnosed between 2000-2021.
PATIENTS AND METHODS
This retrospective study included seventy-four patients (27 men and 47 women) with histologically confirmed adrenocortical cancer in a single tertiary referral endocrine centre. Descriptive statistics were performed, providing summaries of selected clinical and pathological parameters. Clinicopathological factors contributing to overall survival were analysed.
RESULTS
The median age of patients was 48,5 years (17-84 years) at diagnosis. The majority of cases were diagnosed at ENSAT stage II (39,2%) and stage IV (33,8%). At diagnosis, the median tumour size was 9,0 cm (4,5-20 cm). In 47 patients (71,6%), the tumour was hormonally active. The median overall survival and the 5-year survival rate were 23,5 months (95% CI, 17-30,5 months) and 18,3%, respectively. Primary tumour resection was performed in 68 patients (91,8%); R0 surgical resection was achieved in 30 patients. In univariate Cox regression model, tumours with stages III and IV, high proliferative activity (Ki67-index > 10%), R1-R2 surgical resection state and hormonal activity were associated with poorer survival. Cortisol excess, both isolated and combined with androgen production, was associated with poorer survival. Fifty-five patients were treated with mitotane. The overall survival of patients achieving therapeutic mitotane plasma concentration was significantly better compared to those who never reached it [27.0 (2-175) months vs 18.0 (2-83) months; p<0.05)]. The median age, the distribution of gender, ENSAT stage, resection state and Ki67-index did not differ between these two groups. The time needed to reach the therapeutic range of serum mitotane was 96.5 days (95% CI, 75-133 days).
CONCLUSION
Our results confirm previous data that disease stage, mitotic activity, the resection state and the mitotane treatment achieving therapeutic concentration are the most critical parameters influencing the prognosis of adrenocortical cancer. Our data suggest that hormonal activity may be more frequent than described previously, and it is a strong and independent prognostic factor of overall survival. To our knowledge, this is the first single-centre study confirming the prognostic importance of achieving therapeutic mitotane concentration.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Androgens; Antineoplastic Agents, Hormonal; Female; Humans; Hydrocortisone; Ki-67 Antigen; Male; Mitotane; Prognosis; Retrospective Studies
PubMed: 36246926
DOI: 10.3389/fendo.2022.952418 -
Journal of Translational Medicine Oct 2022Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized...
BACKGROUND
Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate.
METHODS
By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism.
RESULTS
Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way.
CONCLUSIONS
CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Animals; Apoptosis; Aurora Kinase A; CDC2 Protein Kinase; Cell Division; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Humans; Mice; Mice, Nude; Mitotane; Necroptosis; Pyroptosis; RNA-Binding Proteins
PubMed: 36184616
DOI: 10.1186/s12967-022-03641-y -
Case Reports in Endocrinology 2022Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. An accurate diagnosis of ACC is of paramount importance as it greatly impacts the management and prognosis...
Was It an Adrenocortical Adenoma or an Adrenocortical Carcinoma? Limitation of the Weiss Scoring System in Determining the Malignant Potential of Adrenocortical Tumor: Report on Two Cases.
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. An accurate diagnosis of ACC is of paramount importance as it greatly impacts the management and prognosis of a patient. However, the differentiation between early stage, low-grade ACC and adrenocortical adenoma (ACA) may not always be straightforward. The recommended classification system, namely, the Weiss scoring system, is not without flaws. We herein report two cases of ACC which were initially diagnosed as ACA according to the Weiss scoring system but developed distant metastases in subsequent years. . Case 1: A 60-year-old Chinese woman presented with a recent onset of worsening of blood pressure control and clinical features of Cushing's syndrome. Investigations confirmed ACTH-independent endogenous hypercortisolism, and a CT abdomen showed a 6 cm right adrenal mass. Twenty-four-hour urine steroid profiling revealed co-secretion of adrenal androgens and atypical steroid metabolites. Laparoscopic right adrenalectomy was performed, and pathology of the tumor was classified as an ACA by the Weiss scoring system. Four years later, the patient presented with an abrupt onset of severe hypercortisolism and was found to have a metastatic recurrence in the liver and peritoneum. The patient received a combination of mitotane, systemic chemotherapy, and palliative debulking surgery and succumbed 8.5 years after the initial presentation due to respiratory failure with extensive pulmonary metastases. : A 68-year-old Chinese woman presented with acute bilateral pulmonary embolism and was found to have a 3 cm left adrenal mass. Hormonal workup confirmed ACTH-independent endogenous hypercortisolism, and laparoscopic left adrenalectomy revealed an ACA according to the Weiss scoring system. Five years later, she presented with recurrent hypercortisolism due to hepatic and peritoneal metastases. The patient had progressive disease despite mitotane therapy and succumbed 7 years after initial presentation.
CONCLUSIONS
Although the Weiss scoring system is recommended as the reference pathological classification system to diagnose adrenocortical carcinoma, there remain tumors of borderline malignant potential which may escape accurate classification. Various alternative classification systems and algorithms exist but none are proven to be perfect. Clinicians should recognize the potential limitation of these histological criteria and scoring systems and incorporate other clinical parameters, such as the pattern of hormonal secretion, urinary steroid profiling, and radiographic features, to improve the prognostication and surveillance strategy of these tumors.
PubMed: 36160179
DOI: 10.1155/2022/7395050 -
Pharmaceutics Sep 2022Adrenocortical carcinoma (ACC) is a heterogeneous malignancy related to poor prognosis and limited treatment options. The orphan drug mitotane (MT) is still a...
Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids.
Adrenocortical carcinoma (ACC) is a heterogeneous malignancy related to poor prognosis and limited treatment options. The orphan drug mitotane (MT) is still a cornerstone in ACC therapy, however, its application is characterized by low aqueous solubility, poor bioavailability, and unfavorable pharmacokinetics, often resulting in below-target plasma concentrations or toxic side effects. Throughout the last decades, nanoparticulate formulations have become attractive carriers to improve anticancer therapy. In this study, injectable MT liposomes (DOPC-MT) and albumin-stabilized MT nanoparticles (BSA-MT) were investigated in depth with respect to their physicochemical properties, and their colloidal and therapeutical stability upon storage. Furthermore, in vitro cytotoxicity was evaluated using the ACC model cell line NCI-H295R for preparing multicellular tumor spheroids, and was compared to non-malignant human dermal fibroblasts. Our results clearly demonstrate that BSA-MT, unlike DOPC-MT, represents a stable and storable MT formulation with a high drug concentration in an aqueous medium. Dual centrifugation was established as a reproducible method for nanoparticle preparation. Although an efficient cytotoxic effect on ACC tumor spheroids was demonstrated, concomitant low toxicity to fibroblasts suggests that higher drug concentrations may be tolerated in vivo. Consequently, BSA-MT is a novel and promising therapeutical approach to address key challenges in MT treatment.
PubMed: 36145639
DOI: 10.3390/pharmaceutics14091891 -
Pediatric Endocrinology, Diabetes, and... 2022The purpose of this work was to present the current state of knowledge on the effects of frequently used therapeutic forms, selected pharmacotherapy (including... (Review)
Review
The purpose of this work was to present the current state of knowledge on the effects of frequently used therapeutic forms, selected pharmacotherapy (including glucocorticosteroids, immune checkpoint inhibitors, mitotane, metyrapone, aminoglutetimide, etomidate, ketoconazole, fluconazole), but also radiation therapy on the functioning of the hypothalamic-pituitary-adrenal axis in children and adolescent during and after oncological treatment. The most common pediatric cancers, where complications of adrenal insufficiency occur, are presented. Moreover, current recommendations how to diagnose the function of the adrenal axis in oncological pediatric patients, as well during oncological treatment as after it, including patients treated with steroids and also patients in severe stages, are reported. The rules of the treatment of adrenal dysfunction in those patients are presented. This understanding is of key importance for oncologists and endocrinologists in the process of diagnosing, treating and developing patient health care, as well as during therapy as after it, offering safety and improving the quality of life.
Topics: Adolescent; Adrenal Glands; Child; Etomidate; Fluconazole; Humans; Hypothalamo-Hypophyseal System; Immune Checkpoint Inhibitors; Ketoconazole; Metyrapone; Mitotane; Pituitary-Adrenal System; Quality of Life
PubMed: 36134674
DOI: 10.5114/pedm.2022.118319 -
Hormone and Metabolic Research =... Nov 2022Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs... (Review)
Review
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.
Topics: Child; Young Adult; Humans; Cushing Syndrome; Adrenalectomy; Adrenocorticotropic Hormone; Mitotane; Treatment Outcome; Adrenal Cortex Diseases
PubMed: 36130700
DOI: 10.1055/a-1948-6990