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Dermatitis : Contact, Atopic,... Apr 2024
PubMed: 38593446
DOI: 10.1089/derm.2023.0325 -
Cureus Mar 2024Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Its diagnosis requires clinical suspicion and confirmation through laboratory and imaging...
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Its diagnosis requires clinical suspicion and confirmation through laboratory and imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI), and abdominal ultrasound, as well as histological confirmation. Positron emission tomography (PET) is useful for distinguishing between benign and malignant lesions and for evaluating tumor recurrences or metastases. A case is described in which the uptake of fluorodeoxyglucose (18F-FDG) in a remnant adrenal gland could be misinterpreted as tumoral pathology. The article presents the case of a patient with ACC who, after treatment, showed increased FDG uptake in the remnant adrenal gland, which disappeared after discontinuation of treatment with mitotane. Possible explanations for this increase in FDG uptake are discussed, including the action of mitotane. In summary, it is highlighted that FDG uptake in remnant adrenal glands in patients treated with mitotane does not always indicate tumor recurrence or adrenal hypertrophy.
PubMed: 38571874
DOI: 10.7759/cureus.55486 -
European Journal of Endocrinology Mar 2024Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still...
OBJECTIVE
Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects.
METHODS
A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements.
RESULTS
We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required.
CONCLUSIONS
The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.
Topics: Humans; Child; Mitotane; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Adrenal Cortex Neoplasms; Drug-Related Side Effects and Adverse Reactions
PubMed: 38552173
DOI: 10.1093/ejendo/lvae038 -
Frontiers in Pharmacology 2024Cancer continues to be a significant source of both illness and death on a global scale, traditional medicinal plants continue to serve as a fundamental resource of...
Cancer continues to be a significant source of both illness and death on a global scale, traditional medicinal plants continue to serve as a fundamental resource of natural bioactive compounds as an alternative source of remedies. Although there have been numerous studies on the therapeutic role of , the study of the role of peptides has not been thoroughly investigated. This study aimed to investigate the anticancer activity of lectin peptides from using and analysis. Different computational tools were used to extract and predict anticancer peptides from the true lectins of . Nine peptides that are bioactive substances have been investigated for their anticancer activity against MCF-7 and T47D (two forms of breast cancer). To counteract the unfavorable effects of mitotane, the most potent peptides (U3 and U7) were combined with it and assessed for anticancer activity against MCF-7 and HepG2. analysis revealed that nine peptides were predicted with anticancer activity. In cell lines, the lowest IC values were measured in U3 and U7 against MCF-7 and T47D cells. U3 or U7 in combination with mitotane demonstrated the lowest IC against MCF-7 and HepG2. The maximum level of cell proliferation inhibition was 22% when U3 (500 µg/mL) and 25 µg/mL mitotane were combined, compared to 41% when 25 µg/mL mitotane was used alone. When mitotane and U3 or U7 were combined, it was shown that these bioactive substances worked synergistically with mitotane to lessen its negative effects. The combination of peptides and mitotane could be regarded as an efficient chemotherapeutic medication having these bioactive properties for treating a variety of tumors while enhancing the reduction of side effects.
PubMed: 38464729
DOI: 10.3389/fphar.2024.1322865 -
Cancer Research Communications Mar 2024Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed...
UNLABELLED
Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors.
SIGNIFICANCE
ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.
Topics: Humans; Animals; Mice; Adrenocortical Carcinoma; Mitotane; Heterografts; Ubiquitin-Activating Enzymes; Adrenal Cortex Neoplasms; Cell Line, Tumor; Antineoplastic Agents; Organoids; Proto-Oncogene Proteins c-bcl-2; Nuclear Proteins; Bridged Bicyclo Compounds, Heterocyclic; Sulfides; Sulfonamides; Pyrimidines; Pyrazoles
PubMed: 38451783
DOI: 10.1158/2767-9764.CRC-24-0085 -
Frontiers in Endocrinology 2024While suggested, surgery is not always possible as a first-line treatment of Cushing's Disease (CD). In such cases, patients require medical therapy in order to prevent... (Review)
Review
While suggested, surgery is not always possible as a first-line treatment of Cushing's Disease (CD). In such cases, patients require medical therapy in order to prevent complications resulting from hypercortisolism. Although there has been a wide expansion in pharmacological options in recent years, mitotane was the agent of choice for treating hypercortisolism decades ago. Due to the introduction of other therapies, long-term experience with mitotane remains limited. Here, we report the case of a woman with CD who was treated with mitotane for 37 years. During the treatment period, biochemical and clinical disease control was achieved and the patient had two uncomplicated pregnancies. Drug-related side effects remained moderate and could be controlled by several dose adjustments. Our case highlights the ability of mitotane to allow an effective control of hypercortisolism and to represent a safe treatment option in special situations where CD requires an alternative therapeutic approach. Furthermore, we provide a literature review of the long-term use of mitotane and reported cases of pregnancy in the context of mitotane therapy.
Topics: Female; Pregnancy; Humans; Cushing Syndrome; Mitotane; Pituitary ACTH Hypersecretion; Drug-Related Side Effects and Adverse Reactions
PubMed: 38440784
DOI: 10.3389/fendo.2024.1294415 -
Environmental Science and Pollution... Mar 2024Are the residues of organochlorine pesticides (OCPs) in freshwater in China still of concern after prohibition and restriction for decades? The scarcity of monitoring...
Are the residues of organochlorine pesticides (OCPs) in freshwater in China still of concern after prohibition and restriction for decades? The scarcity of monitoring data on OCPs in freshwater in China over the past few years has hampered understanding of this issue. In this study, water and suspended particulate matter (SPM) samples were collected from the middle reach of the Huai River for OCP analyses. Residues of ∑OCPs in water and SPM ranged from ND to 8.6 ng L and 0.50 to 179 ng L, with mean concentrations of 1.7 ± 1.3 ng L and 6.1 ± 31 ng L, respectively. ∑HCHs (α-, β-, γ-, and δ-HCH) and ∑HEPTs (heptachlor and heptachlor epoxide) were the most predominant pesticides in the dissolved phase and SPM, respectively, accounting for 43 ± 35% and 27 ± 29% of ∑OCPs. HCHs and heptachlor epoxide mainly existed in the dissolved phase, while heptachlor mainly existed in SPM. The isomeric composition pattern of HCHs in water differed from that in SPM. Briefly, β-HCH dominated in water, while δ-HCH dominated in SPM. However, the composition pattern of DDT and its metabolites in water was similar to that in SPM. o,p'-DDD and p,p'-DDE dominated in both water and SPM. The ratios of α-/γ-HCH and (DDD + DDE)/DDTs indicated that HCHs and DDTs were mainly derived from historical residues. Risk assessments indicated that OCPs may not pose carcinogenic and non-carcinogenic risks to residents.
Topics: Humans; Rivers; Heptachlor Epoxide; Pesticides; Hydrocarbons, Chlorinated; Heptachlor; Mitotane; Water; China; Hexachlorocyclohexane; Dwarfism; Lordosis; Bone and Bones; Limb Deformities, Congenital
PubMed: 38400976
DOI: 10.1007/s11356-024-32534-4 -
Cancers Feb 2024International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation...
International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation (TA(C)E), and transarterial radioembolisation (TARE) as therapeutic options for advanced adrenocortical carcinoma (ACC). However, the evidence for these recommendations is scarce. We retrospectively analysed patients receiving LTs for advanced ACC. Time to progression of the treated lesion (tTTP) was the primary endpoint. The secondary endpoints were best objective response, overall progression-free survival, overall survival, adverse events, and the establishment of predictive factors by multivariate Cox analyses. A total of 132 tumoural lesions in 66 patients were treated with LTA (n = 84), TA(C)E (n = 40), and TARE (n = 8). Complete response was achieved in 27 lesions (20.5%; all of them achieved by LTA), partial response in 27 (20.5%), and stable disease in 38 (28.8%). For the LTA group, the median tTTP was not reached, whereas it was reached 8.3 months after TA(C)E and 8.2 months after TARE ( < 0.001). The median time interval from primary diagnosis to LT was >47 months. Fewer than four prior therapies and mitotane plasma levels of >14 mg/L positively influenced the tTTP. In summary, this is one of the largest studies on LTs in advanced ACC, and it demonstrates a very high local disease control rate. Thus, it clearly supports the guideline recommendations for LTs in these patients.
PubMed: 38398097
DOI: 10.3390/cancers16040706 -
The Oncologist Feb 2024Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy in the advanced setting with poor prognosis. This narrative review provides an overview of the...
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy in the advanced setting with poor prognosis. This narrative review provides an overview of the epidemiology of ACC and its molecular pathogenesis with a summary of the main involved signaling pathways. We then provide an update on the clinical presentation, diagnosis, and current management strategies of both localized and metastatic disease from a multidisciplinary perspective. We highlight the debate around the use of mitotane in the adjuvant setting and review the use of combination chemotherapy with etoposide, doxorubicin, and cisplatin. The review also focuses on emerging data providing hope for the use of immune checkpoint inhibitors and targeted therapies in ACC with a summary of ongoing trials.
PubMed: 38381694
DOI: 10.1093/oncolo/oyae029 -
Journal of the Endocrine Society Jan 2024Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal cortex. The aim of the study was to report the incidence of ACC and survival of ACC in...
OBJECTIVES
Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal cortex. The aim of the study was to report the incidence of ACC and survival of ACC in Denmark. The secondary objective was to describe the impact of treatment with mitotane on survival.
DESIGN
Retrospective population study of patients diagnosed with ACC between 2003 and 2019 in Denmark.
METHODS
Individuals at risk for ACC were identified in the national Danish Health registries, and diagnosis of ACC was confirmed by review of the health records. Data on demographics, presentation, treatment, recurrence, and death was evaluated.
RESULTS
138 patients were included in the study with more females (59.4%) than males (40.6%). Incidence rate was 1.4 per million per year. The incidence rate ratio significantly increased only in females by 1.06 [95% confidence interval (CI): 1.02-1.12] per year. Overall median survival was 1.93 (95% CI: 1.24-3.00) years with no differences between males and females. The proportion of patients treated with mitotane (either as adjuvant treatment or as part of a chemotherapeutic regime) was 72.3%. Survival was significantly decreased in women not treated with mitotane compared to women treated with mitotane (either as adjuvant or as part of a chemotherapeutic regime) hazards ratio .30 (95% CI: .10-.89), adjusted for European Network for the Study of Adrenal Tumours score, age at diagnosis, and year of diagnosis, but survival was unaffected by mitotane treatment in men.
CONCLUSION
Incidence of ACC in Denmark was 1.4 per million per year and increased in women but not in males during the study period 2003-2019.
PubMed: 38370442
DOI: 10.1210/jendso/bvae012