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1.
Invest New Drugs ; 37(4): 755-762, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31172443

RESUMO

Background Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Fitogênicos/uso terapêutico , Gossipol/análogos & derivados , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Feminino , Gossipol/efeitos adversos , Gossipol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2 , Critérios de Avaliação de Resposta em Tumores Sólidos
2.
J Drugs Dermatol ; 18(5): 468-469, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141856

RESUMO

Sorafenib is an oral multikinase inhibitor approved by the United States Food and Drug Administration for the treatment of advanced hepatocellular and renal cell carcinoma. Cases of sorafenib-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been reported in the literature. DRESS syndrome is a potentially fatal, drug-induced hypersensitivity reaction that occurs 2-8 weeks after drug exposure. DRESS syndrome presents with generalized morbilliform eruption, facial edema, eosinophilia, and end-organ damage. We present the first reported case of sorafenib toxicity mimicking DRESS syndrome in a patient with metastatic adrenocortical carcinoma presenting with fever, morbilliform rash, and transaminitis in the absence of eosinophilia three days following initiation of sorafenib therapy. It is critical that clinicians are equipped to accurately diagnose DRESS syndrome due to its high mortality rate and the morbidity associated with prolonged steroid therapy. J Drugs Dermatol. 2019;18(5):468-469.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Sorafenibe/toxicidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/secundário , Diagnóstico Diferencial , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica
3.
Eur J Endocrinol ; 180(6): 387-396, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991359

RESUMO

Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I-II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58-4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mitotano/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
4.
Int J Oncol ; 54(6): 2149-2156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942448

RESUMO

Mitotane (also termed o,p'­DDD) is the most effective therapy for advanced adrenocortical carcinoma (ACC). Mitotane­induced dyslipidemia is treated with statins. Mitotane and statins are known to exert anti­proliferative effects in vitro; however, the effects of statins have never been directly evaluated in patients with ACC and ACC cells, at least to the best of our knowledge. Thus, in this study, we aimed to examine the effects of the rosuvastatin on ACC cells. It has been shown that the combined use of mitotane and statins significantly increases the tumor control rate in patients with ACC; however, it would be of interest to elucidate the molecular mechanisms involved in this potentiation. In this study, we examined the effects of mitotane, rosuvastatin and their combination in NCI­H295R human ACC cells using proliferation assays, gene expression analyses and free intracellular cholesterol measurements. The results revealed that mitotane dose­dependently reduced cell viability, induced apoptosis and increased intracellular free cholesterol levels, considered as one of the key features of mitotane action, while rosuvastatin alone reduced cell viability and increased apoptosis at high concentrations. We also demonstrated that rosuvastatin potentiated the effects of mitotane by reducing cell viability, inducing apoptosis, increasing intracellular free cholesterol levels, and by decreasing the expression of 3­hydroxy­3­methylglutaryl­CoA reductase (HMGCR) and ATP binding cassette subfamily a member 1 (ABCA1), genes involved in cholesterol metabolism, and inhibiting steroidogenesis. Collectively, potentiating the effects of mitotane with the use of rosuvastatin may provide novel therapeutic strategies for ACC, given that the combination of these drugs, pending clinical validation, may lead to the better management of ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Mitotano/farmacologia , Rosuvastatina Cálcica/farmacologia , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Mitotano/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico
5.
J Chemother ; 31(2): 105-108, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831058

RESUMO

A 43-years old woman was diagnosed an adrenocortical carcinoma (AC) that was excised, whereas two lung metastases were un-operable. Mitotane 6 g/day was started as standard therapy but it was responsible for severe central nervous system (CNS) and gastrointestinal toxicities associated with a 10 kg body weight loss. A therapeutic drug monitoring (TDM) protocol demonstrated that mitotane plasma concentrations (>30 mg/L) exceeded the therapeutic range (14-20 mg/L) and increased even when drug daily dose was reduced by 50%. The increase in drug plasma concentrations was probably due to body slimming. Under continuous TDM control, a reduced mitotane dose (1.5 g/day) was definitively administered and it proved to be tolerable and effective. Indeed, lung metastases were excised and two years later there was no evidence of other neoplastic lesions. In conclusion, the adoption of therapeutic mitotane monitoring allowed the treatment of an AC patient with a reduced, tolerable and effective dose.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Monitoramento de Medicamentos/normas , Mitotano/administração & dosagem , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Prognóstico
7.
Minerva Endocrinol ; 44(1): 70-81, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29808641

RESUMO

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. It has undergone in-depth clinical and laboratory investigations, with the help of the most important research groups all over the world. Nonetheless the cure for this kind of neoplasia is not right around the corner, given its complexity and multi-faceted feature, that lead researchers to think at "one person one ACC." Currently total resection is the most concrete option for ACC patients, whenever possible. Mitotane remains the main drug for primary or adjuvant therapy, but gives partial and unsatisfactory therapeutic results, especially in metastatic ACC. This prompted the researchers to find other ways to fight against this malignancy: targeted therapy seems the most promising answer, as it is based on biomolecular and genetic cancer signature. Numerous specific targets were explored for the treatment of ACC, such as those involving angiogenesis, steroidogenesis, Wnt/ß-catenin pathway and many others key factors. Even if large efforts have been made, no effective target therapy entered in the clinical use. This data should not be considered only as detrimental, rather it should propel scientific research to invest more resources into the therapeutic exploration of ACC and in particular on the most promising strategy, the targeted therapy.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma/terapia , Terapia de Alvo Molecular/métodos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Humanos
8.
Nat Prod Res ; 33(11): 1646-1649, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29334260

RESUMO

Oregano (Origanum vulgare L.) is a common aromatic plant used in Mediterranean and Asian Regions for treating respiratory diseases, painful menstruation, rheumatoid arthritis, etc. Recently its role as an anticancer plant has been suggested, although oregano has been never evaluated into adrenocortical tumour cell models. This study analysed for the first time the anticancer effects of a crude extract of wild mountain oregano (Origanum vulgare L.) in SW13 and H295R cell lines. The crude extract was characterised by GC/MS and the toxic effects of oregano were first analysed by brine shrimp lethality assay. Our findings demonstrated that oregano decreased cell viability, survival, modified cell cycle and induced cell death (through necrotic process) and that the effects can be attributed to a blockade of MAPK and PI3 K/Akt pathways. These results suggest that oregano extract exerts anticancer activities in adrenocortical tumour cell lines, providing evidence for further research in higher models.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Origanum/química , Extratos Vegetais/farmacologia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Animais , Artemia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/análise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
J Cell Biochem ; 120(1): 894-906, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30256438

RESUMO

Unraveling molecular mechanisms that regulate tumor development and proliferation is of the utmost importance in the quest to decrease the high mortality rate of adrenocortical carcinomas (ACC). Our aim was to evaluate the role of two of the mitogen-activated protein kinase (MAPK) signaling pathways (extracellular signal-regulated protein kinases [ERKs 1/2] and p38) in the adrenocortical tumorigenesis, as well as the therapeutic potential of MAPK/ERK inhibition. ERKs 1/2 and p38 activation were evaluated in incidentalomas (INC; n = 10), benign Cushing's syndrome (BCS; n = 12), malignant Cushing's syndrome (MCS; n = 6) and normal adrenal glands (NAG; 8). ACC cell line (H295R) was used to evaluate the ability of PD184352 (0.1, 1, and 10 µM), a specific MEK-MAPK-ERK pathway inhibitor, to modulate cell proliferation, viability, metabolism, and steroidogenesis. ERKs 1/2 activation was significantly higher in MCS (2.83 ± 0.17) compared with NAG (1.00 ± 0.19 "arbitrary units"), INC (1.20 ± 0.13) and BCS (2.09 ± 0.09). Phospho-p38 expression was absent in all the MCS analyzed. MAPK/ERK kinase (MEK) inhibition with PD184352 significantly decreased proliferation as well as steroidogenesis and also increased the redox state of the H295R cells. This data suggests that MEK-MAPK-ERK signaling has a role in adrenocortical tumorigenesis that could be potentially used as a diagnostic marker for malignancy and targeted treatment in ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/metabolismo , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Adulto , Idoso , Benzamidas/farmacologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Proteína Quinase 3 Ativada por Mitógeno , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Exp Clin Endocrinol Diabetes ; 127(2-03): 109-116, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30469158

RESUMO

Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression-free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Antibióticos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Humanos
11.
Exp Clin Endocrinol Diabetes ; 127(9): 578-584, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30428495

RESUMO

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. In advanced stages, tumour control by mitotane and cytotoxic chemotherapy is often temporary and salvage treatments are warranted. METHODS: Retrospective cohort study of participants in the prospective European Networks for the Study of Adrenal Tumours (ENSAT) registry. Main outcome measures were best response during treatment, progression-free survival (PFS), both measured according to RECIST 1.1 by two blinded radiologists, and overall survival (OS). RESULTS: Twenty-seven patients (13 males; median age 44.1 years) progressing after mitotane and a median of 4 further systemic treatments were included. Thalidomide was administered as tolerated with a starting dose of 50 mg and target dose of 200 mg /d. The median interval between treatment initiation and first imaging was 10.5 (4.4-17.5) weeks. The best response to treatment was stable disease (SD, n=2) and progressive disease (n=25), with a median PFS of 11.2 weeks and a median OS of 36.4 weeks. The first patient with SD discontinued treatment due to mild epistaxis and diarrhea after 22.3 weeks. The second patient had SD at the second treatment evaluation after 25.2 weeks and continued thalidomide but then had clinical progression and deceased after 54.3 weeks. In general, thalidomide induced only mild or moderate adverse effects (mainly fatigue and gastrointestinal complaints). CONCLUSION: Thalidomide was overall well tolerated but resulted in disease control in only 2/27 (7.4%) patients. In the absence of predictive response markers, thalidomide should only be considered in exceptional cases as a salvage therapy in ACC.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Sistema de Registros , Talidomida/administração & dosagem , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
12.
Medicine (Baltimore) ; 97(52): e13517, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593126

RESUMO

RATIONALE: In the setting of metastatic or locally advanced adrenocortical carcinoma, a limited number of therapies are available and their efficacy is generally below modest. The backbone of treatment remains surgery, even for metastatic disease, whenever it is possible, and mitotane. Chemotherapy can be used with limited results. A small subset of patients with adrenocortical carcinoma may have high mutational burden and harbor mutations in mismatch-repair genes. PATIENT CONCERNS: We report a 40-year old and a 28-year-old female patients with metastatic adrenocortical carcinoma refractory to multiple treatments. DIAGNOSIS: Next-generation sequencing detected high mutational burden (>10 mutations/megabase) in both patients, one of them with MSH2 mutation. INTERVENTIONS: They were treated with pembrolizumab (100 to 200 mg every 3 weeks). OUTCOMES: The patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response. LESSONS: To the best of our knowledge, this is the first report in the literature of a durable complete response after pembrolizumab in a patient with metastatic adrenocortical carcinoma. Differences in therapy sequencing, possibly abscopal effect related to multiple previous radiotherapy exposition, predictive values of high mutational burden and mutations in mismatch-repair genes are discussed.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Adrenocortical/secundário , Adulto , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Proteína 2 Homóloga a MutS/genética , Mutação , Resultado do Tratamento
13.
BMJ Case Rep ; 20182018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30173131

RESUMO

Mitotane is a cytostatic antineoplastic agent that is used in the treatment of adrenocortical carcinoma and Cushing's syndrome. The commonly reported side effects associated with mitotane are anorexia, nausea, vomiting, diarrhoea, decreased memory, rash, gynaecomastia, arthralgias and leucopenia. We present a case of a 68-year-old female who developed gradual dyspnoea concurrent with the use of mitotane for the treatment of adrenocortical carcinoma. To the best of our knowledge and literate review, this is the first reported case of dyspnoea associated with the use of this medication. The purpose of this case report is to raise awareness about this uncommon adverse effect of mitotane that may have gone unrecognised on postmarketing surveillance because of under-reporting, lack of case follow-up or other comorbidities masking shortness of breath.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/efeitos adversos , Dispneia/induzido quimicamente , Mitotano/efeitos adversos , Idoso , Diagnóstico Diferencial , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos
14.
Semin Oncol ; 45(3): 151-155, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-30262398

RESUMO

CONTEXT: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. CASE REPORT: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure. CONCLUSION: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/metabolismo , Neoplasias Colorretais/metabolismo , Hidrocortisona/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo
15.
J Clin Endocrinol Metab ; 103(12): 4511-4523, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113656

RESUMO

Context: Adrenocortical carcinoma (ACC) has a heterogeneous prognosis, and current medical therapies have limited efficacy in its advanced stages. Genome-wide multiomics studies identified molecular patterns associated with clinical outcome. Objective: Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine. Design: In total, 117 tumor samples from 107 patients with ACC were analyzed. Targeted next-generation sequencing of 160 genes and pyrosequencing of 4 genes were applied to formalin-fixed, paraffin-embedded (FFPE) specimens to detect point mutations, copy number alterations, and promoter region methylation. Molecular results were combined with clinical/histopathological parameters (tumor stage, age, symptoms, resection status, and Ki-67) to predict progression-free survival (PFS). Results: In addition to known driver mutations, we detected recurrent alterations in genes not previously associated with ACC (e.g., NOTCH1, CIC, KDM6A, BRCA1, BRCA2). Best prediction of PFS was obtained integrating molecular results (more than one somatic mutation, alterations in Wnt/ß-catenin and p53 pathways, high methylation pattern) and clinical/histopathological parameters into a combined score (P < 0.0001, χ2 = 68.6). Accuracy of prediction for early disease progress was 83.3% (area under the receiver operating characteristic curve: 0.872, 95% confidence interval 0.80 to 0.94). Furthermore, 17 potentially targetable alterations were found in 64 patients (e.g., in CDK4, NOTCH1, NF1, MDM2, and EGFR and in DNA repair system). Conclusions: This study demonstrates that molecular profiling of FFPE tumor samples improves prognostication of ACC beyond clinical/histopathological parameters and identifies new potential drug targets. These findings pave the way to precision medicine in this rare disease.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Medicina de Precisão/métodos , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Variações do Número de Cópias de DNA , Metilação de DNA , Análise Mutacional de DNA , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação Puntual , Prognóstico , Intervalo Livre de Progressão , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
16.
Eur J Endocrinol ; 179(5): 287-297, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30087117

RESUMO

OBJECTIVE: Mitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1- 6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life, and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring. METHODS: Appropriate dosing information, plasma concentrations (1137 data points) and covariates were available from therapeutic drug monitoring (TDM) of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules. RESULTS: A one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. Body mass index was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity. CONCLUSION: The proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/farmacocinética , Mitotano/farmacocinética , Modelos Biológicos , Adolescente , Neoplasias do Córtex Suprarrenal/enzimologia , Carcinoma Adrenocortical/enzimologia , Adulto , Idoso , Antineoplásicos Hormonais/uso terapêutico , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/uso terapêutico , Adulto Jovem
17.
Biomed Res Int ; 2018: 9362108, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29967789

RESUMO

Background: The adjuvant use of mitotane on adrenocortical carcinoma (ACC) has always been in controversy. We aimed to assess the prognostic benefits of adjuvant mitotane after resection of ACC in patients without distant metastasis. Methods: The PubMed, WoS, Embase, and Cochrane Library databases were systematically searched. Recurrence-free survival (RFS) and overall survival (OS) were adopted as measurements. A meta-analysis was conducted based on hazard ratio (HR) with 95% confidence interval (CI). A study was included only if the enrolled patients underwent resection of ACC without adjuvant chemotherapy except mitotane. Results: A total of 5 retrospective studies reporting on 1249 patients were included for this meta-analysis. The meta-analysis showed that adjuvant mitotane was significantly associated with prolonged RFS (HR = 0.62; 95%CI, 0.42-0.94; P < 0.05) and prolonged OS (HR = 0.69; 95%CI, 0.55-0.88, P < 0.05). Conclusion: After comprehensive review, current evidence suggests that adjuvant mitotane significantly decreases the recurrence rate and mortality after resection of ACC in patients without distant metastasis, but these findings need further demonstration from prospective controlled trials.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Quimioterapia Adjuvante , Mitotano/uso terapêutico , Adolescente , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
18.
Proteomics ; 18(17): e1800203, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30035358

RESUMO

Fibroblast growth factor 2 (FGF2) is a well-known cell proliferation promoter; however, it can also induce cell cycle arrest. To gain insight into the molecular mechanisms of this antiproliferative effect, for the first time, the early systemic proteomic differences induced by this growth factor in a K-Ras-driven mouse tumor cell line using a quantitative proteomics approach are investigated. More than 2900 proteins are quantified, indicating that terms associated with metabolism, RNA processing, replication, and transcription are enriched among proteins differentially expressed upon FGF2 stimulation. Proteomic trend dynamics indicate that, for proteins mainly associated with DNA replication and carbohydrate metabolism, an FGF2 stimulus delays their abundance changes, whereas FGF2 stimulation accelerates other metabolic programs. Transcription regulatory network analysis indicates master regulators of FGF2 stimulation, including two critical transcription factors, FOSB and JUNB. Their expression dynamics, both in the Y1 cell line (a murine model of adenocarcinoma cells) and in two other human cell lines (SK-N-MC and UM-UC-3) also susceptible to FGF2 antiproliferative effects, are investigated. Both protein expression levels depend on fibroblast growth factor receptor (FGFR) and src signaling. JUNB and FOSB knockdown do not rescue cells from the growth arrest induced by FGF2; however, FOSB knockdown rescue cells from DNA replication delay, indicating that FOSB expression underlies one of the FGF2 antiproliferative effects, namely, S-phase progression delay.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Proliferação de Células , Fator 2 de Crescimento de Fibroblastos/farmacologia , Proteoma/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Animais , Humanos , Camundongos , Mapas de Interação de Proteínas , Proteoma/análise , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
19.
J Clin Endocrinol Metab ; 103(9): 3477-3485, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020487

RESUMO

Context: Aldosterone biosynthesis is regulated principally by ACTH and gene mutations as well as by angiotensin II and serum potassium. In addition, previous studies have reported the potential effects of KCNJ5 mutations in aldosterone-producing adenoma (APA) on cardiovascular diseases. However, responsiveness to ACTH in APAs according to potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) mutations remains unknown. Objective: To investigate KCNJ5 genotype-specific differences in aldosterone biosynthesis in response to ACTH stimulation. Design and Setting: A cross-sectional study through retrieval of clinical records. Participants: One hundred forty-one patients aged ≥20 years with APA were examined. Main Outcome Measures: Associations between KCNJ5 mutations and clinical parameters reflecting the renin-angiotensin system [saline infusion test (SIT)] and ACTH pathways [dexamethasone suppression test (DST)]. Results: KCNJ5 mutations were detected in 107 cases. In the crude comparison, patients with mutations in KCNJ5 had higher plasma aldosterone concentrations (PACs) both at baseline and after the SIT. PAC after the DST showed a significant inverse association with KCNJ5 genotypes after controlling for age, sex, tumor size, and PAC after the SIT. Immunohistochemical analysis of 101 cases revealed more abundant immunoreactivity of CYP11B1 and CYP17 in the KCNJ5-mutated group than in the KCNJ5 wild-type group. Conclusion: This report of marked suppression of PAC by dexamethasone in patients with KCNJ5-mutated APAs indicates that such APAs respond to endogenous ACTH more readily than APAs in nonmutated cases. Further molecular and epidemiologic studies are required to validate our results and clarify the clinical effectiveness of the DST for predicting KCNJ5 mutations before adrenalectomy.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Adenoma Adrenocortical/tratamento farmacológico , Aldosterona/biossíntese , Antineoplásicos Hormonais/administração & dosagem , Dexametasona/administração & dosagem , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Hormônio Adrenocorticotrópico/sangue , Adulto , Aldosterona/sangue , Estudos Transversais , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
20.
Eur J Endocrinol ; 179(2): R95-R110, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29773584

RESUMO

Adrenocortical carcinomas (ACCs) are rather rare endocrine tumors that often have a poor prognosis. The reduced survival rate associated with these tumors is due to their aggressive biological behavior, combined with the scarcity of effective treatment options that are currently available. The recent identification of the genomic alterations present in ACC have provided further molecular mechanisms to develop consistent strategies for the diagnosis, prevention of progression and treatment of advanced ACCs. Taken together, molecular and genomic advances could be leading the way to develop personalized medicine in ACCs similarly to similar developments in lung or breast cancers. In this review, we focused our attention to systematically compile and summarize the alterations in the cell cycle regulation that were described so far in ACC as they are known to play a crucial role in cell differentiation and growth. We have divided the analysis according to the major transition phases of the cell cycle, G1 to S and G2 to M. We have analyzed the most extensively studied checkpoints: the p53/Rb1 pathway, CDC2/cyclin B and topoisomerases (TOPs). We reached the conclusion that the most important alterations having a potential application in clinical practice are the ones related to p53/Rb1 and TOP 2. We also present a brief description of on-going clinical trials based on molecular alterations in ACC. The drugs have targeted the insulin-like growth factor receptor 1, TOP 2, polo-like kinase1, cyclin-dependent kinase inhibitors, p53 reactivation and CDC25.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Córtex Suprarrenal/efeitos dos fármacos , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos/uso terapêutico , Modelos Biológicos , Terapia de Alvo Molecular , Medicina de Precisão , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/tendências , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Guias de Prática Clínica como Assunto , Medicina de Precisão/tendências , Prognóstico
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