Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 173
Filtrar
1.
BMC Complement Altern Med ; 19(1): 188, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351461

RESUMO

BACKGROUND: Apiole was isolated from the leaves of various plants and vegetables and has been demonstrated to inhibit human colon cancer cell (COLO 205 cells) growth through induction of G0/G1 cell cycle arrest and apoptotic cell death. This study further explored the antitumor effects of apiole derivatives AP-02, 04, and 05 in COLO 205 cancer cells. METHODS: Human breast (MDA-MB-231, ZR75), lung (A549, PE089), colon (COLO 205, HT 29), and hepatocellular (Hep G2, Hep 3B) cancer cells were treated with apiole and its derivatives in a dose-dependent manner. Flow cytometry analysis was subsequently performed to determine the mechanism of AP-02-induced G0/G1 cell cycle arrest. The in vivo antitumor effect of AP-02 (1 and 5 mg/kg, administered twice per week) was examined by treating athymic nude mice bearing COLO 205 tumor xenografts. The molecular mechanisms of AP-02-induced antitumor effects were determined using western blot analysis. RESULTS: AP-02 was the most effective compound, especially for inhibition of COLO 205 colon cancer cell growth. The cytotoxicity of AP-02 in normal colon epithelial (FHC) cells was significantly lower than that in other normal cells derived from the breast, lung or liver. Flow cytometry analysis indicated that AP-02-induced G0/G1 cell cycle arrest in COLO 205 cells but not in HT 29 cells (< 5 µM for 24 h, **p < 0.01). Tumor growth volume was also significantly inhibited in AP-02 (> 1 mg/kg)-treated athymic nude mice bearing COLO 205 tumor xenografts compared to control mice (*p < 0.05). Furthermore, G0/G1 phase regulatory proteins (p53 and p21/Cip1) and an invasion suppressor protein (E-cadherin) were significantly upregulated, while cyclin D1 was significantly downregulated, in AP-02-treated tumor tissues compared to the control group (> 1 mg/kg, *p < 0.05). CONCLUSIONS: Our results provide in vitro and in vivo molecular evidence of AP-02-induced anti-proliferative effects on colon cancer, indicating that this compound might have potential clinical applications.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Dioxóis/administração & dosagem , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Petroselinum/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias do Colo/fisiopatologia , Ciclina D1/genética , Ciclina D1/metabolismo , Dioxóis/efeitos adversos , Dioxóis/química , Feminino , Humanos , Camundongos , Camundongos Nus , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Food Chem Toxicol ; 123: 561-565, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30458269

RESUMO

Fludioxonil is a phenylpyrrole pesticide that is applied to fruit and vegetable crops post-harvest to minimize losses to mold, both during transport and at point of sale. Its effectiveness is reflected in the dramatic increase in its production/usage since its introduction in 1994, an increase that has peaked in recent years as it became licenced for use abroad. Recently, doubts as to the nature of its mechanism of action have been raised. Given that the pesticide has long been known to induce stress intermediates in target and non-target organisms alike, the lack of a firmly established mechanism might be cause for concern. Troubling reports further delineate a capacity to disrupt hepatic, endocrine and neurological systems, indicating that fludioxonil may represent a health threat to consumers. In the absence of a clear, safe mechanism of action, fludioxonil should be re-evaluated for its potential to impact human health.


Assuntos
Produtos Agrícolas/química , Dioxóis/efeitos adversos , Fungicidas Industriais/efeitos adversos , Pirróis/efeitos adversos , Qualidade de Produtos para o Consumidor , Dioxóis/análise , Contaminação de Alimentos/análise , Fungicidas Industriais/análise , Humanos , Pirróis/análise
3.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 2972-2982, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29902549

RESUMO

Transformation of white adipose tissue (WAT) to a brown adipose tissue-like (BAT-like) phenotype has emerged as an attractive approach against obesity e.g. using g ß3 adrenergic receptor agonists. These could however, produce side-effects following systemic exposure. The present study explored the possibility of local use of CL-316,243 - a selective ß3 agonist - to circumvent this problem. Rats treated s.c. for 2 weeks (0.3 and 1 mg/kg) showed decreased inguinal fat pad (IFP) weight/volume, increased UCP-1 staining and expressed BAT-like features in H&E stained micrographs. Interscapular BAT increased in weight/volume. In contrast, local treatment into the IFP was not efficacious in terms of weight/volume, despite slight increases in UCP-1 staining and changes in histological features. After local treatment, the exposure of the IFP was lower than after systemic treatment. In turn higher local doses (0.5 and 5 mg/ml) were then tested which produced a strong trend for decreased volume of the IFP, a significant increase in UCP-1 staining, and also a decrease in adipocytes size but increased number. However, after this treatment the systemic exposure was in the same range as following systemic treatment. In conclusion, we saw no evidence for the possibility of converting inguinal WAT to a BAT-phenotype solely through local activation of ß3 receptors. This is in concert with our in vitro experiments which detected direct effects of PPARγ agonists at the gene/protein expression and functional level, but were unable to detect any effect of CL-316,243.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Obesidade/tratamento farmacológico , Receptores Adrenérgicos beta 3/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Adulto , Animais , Peso Corporal/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Feminino , Humanos , Injeções Subcutâneas , Masculino , Obesidade/patologia , Ratos , Ratos Sprague-Dawley , Adulto Jovem
4.
J Cancer Res Clin Oncol ; 144(6): 1185-1195, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29623421

RESUMO

PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany. METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination. RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months. CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Estudos Prospectivos , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
5.
Oncology ; 95(1): 1-7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29510410

RESUMO

OBJECTIVES: Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS. METHODS: Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on ≥1 anthracycline ± ifosfamide regimen were retrospectively reviewed. RESULTS: Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups. CONCLUSIONS: The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Índice de Massa Corporal , Dioxóis/efeitos adversos , Dioxóis/uso terapêutico , Neutropenia/induzido quimicamente , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/uso terapêutico , Magreza/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Ifosfamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Sarcopenia/fisiopatologia , Trabectedina
6.
Nutrients ; 10(3)2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29495607

RESUMO

Severe fatigue can negatively affect quality of life, and oxidative stress may play a role in its mechanism. The aim of this study was to evaluate the effect of dietary supplementation of astaxanthin and sesamin (AS), strong food-derived antioxidants, on fatigue. Twenty-four healthy volunteers were supplemented with AS and placebo, each for four weeks. After each supplementation period, participants underwent tasks inducing mental and physical fatigue (visual display terminal task and ergometer task, respectively). Subjective fatigue was evaluated using a visual analogue scale during and after the mental and physical tasks, and daily subjective fatigue was evaluated by the Chalder fatigue questionnaire. Secondary outcomes included other subjective feelings, work efficiency, autonomic nerve activity, levels of an oxidative stress marker (plasma phosphatidylcholine hydroperoxide (PCOOH)) and safety. AS supplementation was associated with significantly improved recovery from mental fatigue compared with placebo. Increased PCOOH levels during mental and physical tasks were attenuated by AS supplementation. No differences between AS and placebo were detected in secondary outcomes, and no adverse effects of AS supplementation were observed. In conclusion, AS supplementation may be a candidate to promote recovery from mental fatigue which is experienced by many healthy people.


Assuntos
Antioxidantes/administração & dosagem , Suplementos Nutricionais , Dioxóis/administração & dosagem , Lignanas/administração & dosagem , Fadiga Mental/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Adulto , Antioxidantes/efeitos adversos , Biomarcadores/sangue , Estudos Cross-Over , Suplementos Nutricionais/efeitos adversos , Dioxóis/efeitos adversos , Método Duplo-Cego , Feminino , Nível de Saúde , Humanos , Japão , Lignanas/efeitos adversos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fadiga Mental/diagnóstico , Fadiga Mental/fisiopatologia , Fadiga Mental/psicologia , Saúde Mental , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fosfatidilcolinas/sangue , Recuperação de Função Fisiológica , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Xantofilas/administração & dosagem , Xantofilas/efeitos adversos
7.
Anticancer Drugs ; 28(10): 1157-1165, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28926423

RESUMO

This prospective, noninterventional study is the first phase IV trial designed to evaluate trabectedin in patients with advanced soft tissue sarcoma in real-life clinical practice across Europe. To be included in the study, patients must have received more than or equal to one cycle of trabectedin and be currently on treatment. The primary endpoint was progression-free survival as defined by investigators. The secondary endpoints included objective response rate, disease control rate, time to progression and the growth modulation index (GMI), overall survival, and an assessment of the cancer-related symptoms and safety. A total of 218 patients from 41 European centers were evaluated. Patients received a median of six cycles per patient, mostly on an outpatient basis (n=132; 60.6%). The median progression-free survival was 5.9 months, with 70 and 49% of patients free from progression at 3 and 6 months after treatment, respectively. Three (1.4%) patients achieved a complete response and 55 (25.2%) patients achieved a partial response for an objective response rate of 26.6%. A total of 85 (39.0%) patients had disease stabilization for a disease control rate of 65.6%. The median GMI was 0.8, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and greater than or equal to 1.33, respectively. The median overall survival was 21.3 months. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 serious adverse drug reactions. Trabectedin confers clinically meaningful long-term benefits to patients with multiple soft tissue sarcoma histotypes, being either comparable or better than those observed previously in clinical trials, and with a manageable safety profile.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Dioxóis/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Adulto Jovem
8.
Clin Cancer Res ; 23(24): 7448-7453, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28774898

RESUMO

On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44-0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448-53. ©2017 AACR.


Assuntos
Cardiomiopatias/patologia , Dioxóis/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Lipossarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/induzido quimicamente , Citocromo P-450 CYP3A/genética , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Lipossarcoma/genética , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Adulto Jovem
9.
Gynecol Oncol ; 147(1): 47-53, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28751117

RESUMO

PURPOSE: In 2012, due to a shortage of pegylated liposomal doxorubicin, single agent trabectedin was proposed as an alternative of treatment to our patients with recurrent ovarian cancer (ROC) at our center. The aim of this retrospective study was to evaluate efficacy and tolerability of trabectedin in this context. PATIENTS AND METHODS: This retrospective study included all patients who received intravenous trabectedin 1.3mg/m2 over 3h every 3weeks for ROC between January 2012 and December 2015 at the Centre hospitalier de l'Université de Montreal. The primary outcome was the progression-free survival (PFS) based on CA-125 levels, clinical exam and/or Response Evaluation Criteria in Solid Tumors criteria. We also evaluated overall survival (OS), response rate and toxicities. RESULTS: A total of 42 patients with a median age of 59years received trabectedin in 2nd or 3rd line (12% of patients), 4th or 5th line (43%), and ≥6 lines (45%) and 45% were platinum-resistant. The median number of cycles received was 6 (range 1-19cycles). Complete response (CR), partial response (PR), stable disease (SD) and progression occurred in 19%, 29%, 33% and 19% of patients, respectively. The median PFS and OS was 4.3months (95% CI, 3.4-5.1) and 16.2months (95% CI, 9.0-23.5), respectively. In patients with a clinical benefit (CR, PR, SD), the median PFS was 4.6months. Trabectedin was well tolerated with few adverse events. CONCLUSION: Our results demonstrate that trabectedin has an interesting efficacy as a single agent in heavily treated ROC patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Carcinoma/tratamento farmacológico , Dioxóis/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
10.
Gynecol Oncol ; 146(3): 531-537, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28651804

RESUMO

OBJECTIVE: Trabectedin demonstrated significantly improved disease control in leiomyosarcoma and liposarcoma patients in a global phase 3 trial (NCT01343277). A post hoc analysis was conducted to assess the efficacy and safety of trabectedin or dacarbazine in women with uterine leiomyosarcoma (uLMS), the largest subgroup of enrolled patients (40%). METHODS: Of 577 patients randomized 2:1 to receive trabectedin 1.5mg/m2 by 24-hour IV infusion or dacarbazine 1g/m2 by 20-120-minute IV infusion once every three weeks, 232 had uLMS (trabectedin: 144; dacarbazine: 88). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR: complete responses+partial responses+stable disease [SD] for at least 18weeks), duration of response (DOR), and safety. RESULTS: PFS for trabectedin was 4.0months compared with 1.5months for dacarbazine (hazard ratio [HR]=0.57; 95% CI 0.41-0.81; P=0.0012). OS was similar (trabectedin 13.4months vs. dacarbazine 12.9months, HR=0.89; 95% CI 0.65-1.24; P=0.51) between groups. ORR was 11% with trabectedin vs. 9% with dacarbazine (P=0.82). CBR for trabectedin was 31% vs. 18% with dacarbazine (P=0.05); median DOR was 6.5months for trabectedin vs. 4.1months for dacarbazine (P=0.32). Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients in the trabectedin group included transient aminotransferase (aspartate/alanine) elevations, anemia, leukopenia, and thrombocytopenia. CONCLUSIONS: In this post hoc subset analysis of patients with uLMS who had received prior anthracycline therapy, trabectedin treatment resulted in significantly longer PFS versus dacarbazine, with an acceptable safety profile. There was no difference in OS.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/uso terapêutico , Dioxóis/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Anemia/induzido quimicamente , Antraciclinas/uso terapêutico , Aspartato Aminotransferases/sangue , Dacarbazina/efeitos adversos , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Leucopenia/induzido quimicamente , Pessoa de Meia-Idade , Retratamento , Taxa de Sobrevida , Tetra-Hidroisoquinolinas/efeitos adversos , Trombocitopenia/induzido quimicamente , Trabectedina , Falha de Tratamento
11.
Int J Gynecol Cancer ; 27(6): 1141-1148, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28574933

RESUMO

BACKGROUND: Trabectedin (T) plus pegylated liposomal doxorubicin (PLD) is approved for treatment of platinum-sensitive recurrent ovarian cancer (ROC). Despite the recommendations and guidelines, variations in managing T/PLD administration in routine clinical practice cannot be excluded. We aimed at setting up an Italian survey collecting data about management of T/PLD administration in ROC patients. METHODS: We carried out the development of a questionnaire-based survey on routine clinical practice in the management of ROC patients administered T/PLD. The survey registered the physicians' approach to modification/discontinuation of treatment, type of modifications, reasons why, and so on. The survey was transmitted to medical oncologists and gynecologic oncologists practicing in national centers/institutions. RESULTS: Fifty-eight Italian centers/institutions returned the compiled questionnaire; participants practiced at community cancer centers or hospitals (56.9%), academic institutions (36.2%), and other settings (private clinics, etc) (6.9%). There was no statistically significant difference in the distribution of practice setting according to geographic areas. Most responders were medical oncologists (84.5%) and were members (82.8%) of at least 1 scientific society or cooperative group. Almost 31.5% of responders reported interruption of the whole treatment, mostly because of toxicity (41.2%), followed by patients' choice (29.4%), or achievement of clinical benefit (23.5%). Dose reduction was referred by 47.4% of responders. Reduction of dose for both drugs was referred by 88.5% of responders, and the extent of dose reduction ranged between 10% and 30%. CONCLUSIONS: This survey highlights the gaps in transposing evidence-based or consensus guidelines in the real-world management of T/PLD administration; these findings could be useful in order to focus the attention on specific knowledge and/or experience gaps and plan pertinent educational programs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Oncologistas/estatística & dados numéricos , Neoplasias Ovarianas/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Humanos , Itália/epidemiologia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/epidemiologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Inquéritos e Questionários , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
12.
Clin Cancer Res ; 23(17): 5149-5161, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28600479

RESUMO

Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested.Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer.Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression.Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors. Clin Cancer Res; 23(17); 5149-61. ©2017 AACR.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Dioxóis/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/efeitos adversos , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/imunologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Dioxóis/administração & dosagem , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética
13.
Oncologist ; 22(8): 979-988, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28526720

RESUMO

BACKGROUND: Trabectedin is reported as effective, especially against translocation-related sarcomas (TRSs) after failure of or intolerance to standard chemotherapy. We conducted two phase II studies of TRS, confirming high efficacy of 1.2 mg/m2 trabectedin. The updated data of 66 patients in these studies was integrated to evaluate the efficacy of trabectedin against each histological subtype, and analyze final overall survival (OS). METHODS: Trabectedin was administered on day one of a 21-day cycle. Efficacy was assessed using progression-free survival (PFS), OS, and best overall response. An analysis of OS and PFS was performed for subgroups divided by baseline lymphocyte count (<1,000/µL, ≥1,000/µL) or number of previous chemotherapy regimens (0, 1, 2, ≥3 regimens), and a Weibull parametric model was used to estimate the numerical relationship between lymphocyte count and PFS and OS. RESULTS: Median PFS and OS in overall patients were 5.6 (95% confidence interval [CI]: 4.1-7.3) and 17.5 months (95% CI: 12.6-23.6), respectively. PFS in the myxoid and round-cell liposarcoma (MRCL) group (7.4 months [95% CI: 5.6-11.1]) was longer than in the other subtypes. The response rate was also highest in the MRCL group. Median OS was longer in patients with baseline lymphocyte counts ≥1,000/µL than in those with counts of <1,000/µL, but median PFS was not different between the two subgroups. CONCLUSION: Our updated and pooled data showed that trabectedin exerted prolonged disease control and antitumor effects in patients with advanced TRS, especially in MRCL. We consider that the subgroup analyses also provide important information for trabectedin treatment in patients with TRS. IMPLICATIONS FOR PRACTICE: The progression-free survival (PFS) for the integrated data of 66 patients with translocation-related sarcomas (TRSs) in two phase II studies of trabectedin 1.2 mg/m2 was 5.6 months (95% confidence interval: 4.1-7.3). PFS and response rate in myxoid/round-cell liposarcoma was longer than that of other subtypes. The overall survival (OS) in all TRS subtypes was similar to previous data of TRS patients. In subgroup analysis, the patients with baseline lymphocyte count ≥1,000/µL exhibited better OS, although PFS was not different by baseline lymphocyte count. Our data are considered important information for trabectedin treatment in TRS patients.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Dioxóis/administração & dosagem , Lipossarcoma Mixoide/tratamento farmacológico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/administração & dosagem , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Lipossarcoma Mixoide/epidemiologia , Lipossarcoma Mixoide/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sarcoma/epidemiologia , Sarcoma/patologia , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Resultado do Tratamento
14.
Curr Treat Options Oncol ; 18(6): 34, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28534249

RESUMO

OPINION STATEMENT: Trabectedin and eribulin are two agents that have been recently approved for the treatment of specific soft tissue sarcoma subtypes. They have proved to be a much-needed line of additional treatment for patients with these rare tumors, but their activity remains admittedly modest in most cases. Further exploitation of these novel agents is likely to require a more granular understanding of the salient mechanisms of action. For example, if as some studies suggest, eribulin derives its benefit from restructuring of tumor vasculature to improve efficacy of subsequent lines of therapy, then patients may benefit from its use earlier in the treatment pathway. The sequencing of trabectedin with other agents is also worth examining. In a disease like myxoid liposarcoma, consideration should be given to using trabectedin before other salvage regimens like gemcitabine and docetaxel, given its tolerability and excellent efficacy against this sarcoma subtype. Also, to be further investigated is the use of trabectedin in sarcoma subtypes which were excluded from the phase III study, but in which activity has been documented in earlier trials and subsequent reports. Combinations of trabectedin with other agents, particularly doxorubicin, have been explored, but the data to date do not support the routine use of these regimens.


Assuntos
Antineoplásicos/uso terapêutico , Dioxóis/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Furanos/administração & dosagem , Furanos/efeitos adversos , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Terapia de Alvo Molecular , Sarcoma/diagnóstico , Sarcoma/metabolismo , Sarcoma/mortalidade , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Resultado do Tratamento
15.
Breast ; 34: 18-23, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28467918

RESUMO

Specific alkylators may allow synthetic lethality among patients with germline BRCA1/2-mutations related cancers. The tetrahydroisoquinolone trabectedin administered at 1.3 mg/m2 as a 3-h intravenous infusion every 3 weeks showed activity in patients with pretreated metastatic breast cancer (MBC) and BRCA germline mutations, but mainly in BRCA2 carriers. Data from a phase II study were retrospectively analyzed to compare the efficacy and safety of this trabectedin dose and schedule in pretreated MBC patients bearing germline BRCA1/2 mutations. The primary efficacy endpoint was the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST) by independent expert review. Duration of response (DR) and progression-free survival (PFS) were secondary efficacy endpoints. Safety was evaluated using the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Data from 26 BRCA1-mutated and 13 BRCA2-mutated patients were analyzed. 69% of BRCA1-mutated cancers were triple-negative vs. 31% of BRCA2-mutated ones. 77% of BRCA1 and 31% of BRCA2 carriers were platinum-pretreated. The ORR in BRCA2-mutated patients was higher than in BRCA1-mutated patients (33.3% vs. 9.1%). DR ranged for 1.4-6.8 months in BRCA2-mutated patients and for 1.5-1.7 months in BRCA1-mutated patients. More BRCA2-mutated patients had disease stabilization for ≥4 months (25.0% vs. 9.1%) and their median PFS was longer (4.7 vs. 2.5 months). Trabectedin was well tolerated in both patient subtypes. In conclusion, trabectedin showed higher antitumor activity in relapsed MBC patients with germline BRCA2 mutations than in those with BRCA1 mutations.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Dioxóis/uso terapêutico , Genes BRCA1 , Genes BRCA2 , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Antineoplásicos Alquilantes/efeitos adversos , Dioxóis/efeitos adversos , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Pessoa de Meia-Idade , Critérios de Avaliação de Resposta em Tumores Sólidos , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
16.
J Hematol Oncol ; 10(1): 84, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28399901

RESUMO

BACKGROUND: Trabectedin has recently been approved in the USA and in Europe for advanced soft-tissue sarcoma patients who have been treated with anthracycline-based chemotherapy without success. The mechanism of action of trabectedin depends on the status of both the nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways. Trabectedin results in DNA double-strand breaks. We hypothesized that PARP-1 inhibition is able to perpetuate trabectedin-induced DNA damage. METHODS: We explored the effects of combining a PARP inhibitor (rucaparib) and trabectedin in a large panel of soft-tissue sarcoma (STS) cell lines and in a mouse model of dedifferentiated liposarcoma. RESULTS: The combination of rucaparib and trabectedin in vitro was synergistic, inhibited cell proliferation, induced apoptosis, and accumulated in the G2/M phase of the cell cycle with higher efficacy than either single agent alone. The combination also resulted in enhanced γH2AX intranuclear accumulation as a result of DNA damage induction. In vivo, the combination of trabectedin and rucaparib significantly enhanced progression-free survival with an increased percentage of tumor necrosis. CONCLUSION: The combination of PARP inhibitor and trabectedin is beneficial in pre-clinical models of soft-tissue sarcoma and deserves further exploration in the clinical setting.


Assuntos
Dioxóis/uso terapêutico , Indóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reparo do DNA , Dioxóis/efeitos adversos , Sinergismo Farmacológico , Xenoenxertos , Humanos , Indóis/efeitos adversos , Camundongos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
17.
Expert Opin Pharmacother ; 18(3): 313-323, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28140689

RESUMO

INTRODUCTION: The majority of women with epithelial ovarian cancer present with advanced stage disease and there is a critical need for novel drugs and treatment strategies to improve outcomes. Trabectedin is a unique cytotoxic agent with a complex mechanism of action. It binds to guanines in the N2 position in the minor groove of DNA and its cytotoxicity involves DNA repair pathways and transcription regulation. Trabectedin's activity is also related to the drug-induced changes of the tumor microenvironment. It has been shown to improve progression-free survival in combination with pegylated liposomal doxorubicin in patients with platinum-sensitive relapsed ovarian cancer. The most common adverse events experienced with trabectedin are nausea, vomiting, fatigue, neutropenia and transaminitis. Studies of biomarkers that are predictors of trabectedin benefit are underway. Areas covered: This review covers trabectedin's mechanism of action and pharmacology, the clinical development of the drug in ovarian cancer, ongoing trials, and the use of biomarkers to predict efficacy to trabectedin. Expert opinion: Ongoing phase III trials with biomarker studies will help to elucidate the patient population that will best benefit from trabectedin and pave the way for personalized treatment decisions and potential future approval of trabectedin in the United States.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Descoberta de Drogas , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/química , Carcinoma Epitelial do Ovário , Ensaios Clínicos Fase III como Assunto , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Dioxóis/química , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Epiteliais e Glandulares/patologia , Neutropenia/induzido quimicamente , Neoplasias Ovarianas/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/química , Trabectedina , Microambiente Tumoral/efeitos dos fármacos
18.
Support Care Cancer ; 25(6): 1743-1748, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28101677

RESUMO

The MITO 15 was a prospective, single-arm trial, evaluating trabectedin monotherapy in patients with recurrent ovarian cancer (OC) who were BRCA mutation-carriers or had a BRCAness phenotype. It is largely reported that trabectedin may induce nausea and vomiting but the real emetogenic potential of the drug, in the different schedules, has never been fully described; furthermore, OC patients are known to have an enhanced risk of developing nausea and vomiting due to female gender, abdominal spreading of the disease, and major surgery experienced by most of them. We thought to carry on a sub-study in the MITO 15 context focused on chemotherapy-induced nausea and vomiting (CINV) associated with trabectedin single agent. For all patients enrolled in the trial, we evaluated the antiemetic regimen at the first cycle, acute and delayed CINV, any rescue therapy, any change in the prophylactic antiemetic regimen, and the potential relationship between dexamethasone dosage and incidence of CINV. Overall, our findings were consistent with literature and confirmed that trabectedin can be classified as moderately emetogenic. We observed slightly higher rates of both nausea and vomiting compared to previous experiences with trabectedin monotherapy, probably due to intrinsic features of our population: all females and suffering from ovarian cancer. It seems that in preventing acute CINV, the combination of three drugs was more effective than the doublet; however, the difference did not reach statistical significance; further studies are required to verify such hypothesis. Given the extreme heterogeneity of the antiemetic regimens used, it appears that a standard antiemetic protocol does not exist and more specific guidelines for clinicians are needed.


Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Dioxóis/efeitos adversos , Náusea/induzido quimicamente , Neoplasias Ovarianas/tratamento farmacológico , Tetra-Hidroisoquinolinas/efeitos adversos , Vômito/induzido quimicamente , Adulto , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Trabectedina
19.
J Chemother ; 28(6): 494-499, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27535294

RESUMO

INTRODUCTION: The active clinical research programme of trabectedin continues to improve knowledge on the therapeutic activity and toxicity of the drug in the treatment of soft tissue sarcomas (STS). In contrast, limited number of data is available on its use outside of clinical trials. PATIENTS AND METHODS: We retrospectively analysed efficacy and safety of trabectedin when given in daily practice to patients with advanced/recurrent STS. Outcomes were compared with previously published works including clinical and retrospective studies. RESULTS: Forty-five patients received trabectedin between January 2005 and May 2014. Sarcomas were histologically heterogeneous in our cohort (37.9% of other types of sarcomas than L-sarcomas). Our patients had poor baseline health status (ECOG ≥ 2 [17.8%]) and had received multiple previous lines of chemotherapy. Patients received a median of five cycles of treatment (1-22). The objective response rate was statistically superior in our study (37.8%) compared to the other works. However, median PFS was similar. Trabectedin-related serious adverse events (AEs) induced hospitalizations and treatment discontinuation in 22 and 15% of patients. CONCLUSION: This analysis confirms the efficacy of trabectedin in clinical practice (with a third of patients experiencing prolonged disease control) and highlighted the importance of its administration as early line therapy to allow the best management of serious AEs.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Intervalo Livre de Doença , França , Humanos , Estudos Retrospectivos , Sarcoma/diagnóstico , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
20.
Clin Breast Cancer ; 16(5): 364-371, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27266804

RESUMO

BACKGROUND: Preclinical and clinical data suggest that xeroderma pigmentosum G gene (XPG) status might predict trabectedin efficacy. This phase 2 study evaluated the efficacy of trabectedin at a dose of 1.3 mg/m2 as a 3-hour intravenous infusion every 3 weeks in hormone receptor-positive, HER-2 (human epidermal growth factor receptor 2)-negative, advanced breast cancer patients according to the tumor level of XPG mRNA expression. PATIENTS AND METHODS: Patients were stratified into high-XPG (>3) or low-XPG (≤ 3) groups. The primary efficacy end point was progression-free survival (PFS) rate at 16 weeks (PFS4); secondary efficacy end points were overall response rate (ORR), duration of response, PFS, overall survival, and safety of trabectedin in this patient population. RESULTS: Forty-four patients were treated, 21 with high XPG and 23 with low XPG. Four high-XPG and 6 low-XPG patients experienced PFS4; the criterion for further recruitment (> 6 patients experienced PFS4) was thus not met, and recruitment was stopped. One high-XPG patient had a partial response (ORR, 5%). One low-XPG patient had a complete response, and 2 low-XPG patients had partial responses (ORR, 13%). Comparison of efficacy parameters between high-XPG and low-XPG patients showed no statistically significant differences. ORR in the efficacy population was 9.3%, median PFS was 1.9 months, and overall survival was 11.8 months. The safety of trabectedin in breast carcinoma was similar to that shown in other indications. CONCLUSION: Trabectedin as single agent had limited activity in hormone-positive, HER-2-negative advanced breast cancer. XPG mRNA expression was not predictive of trabectedin efficacy.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dioxóis/uso terapêutico , Endonucleases/metabolismo , Proteínas Nucleares/metabolismo , Tetra-Hidroisoquinolinas/uso terapêutico , Fatores de Transcrição/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Biomarcadores Farmacológicos/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Análise de Sobrevida , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA