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1.
Kardiologiia ; 60(7): 98-102, 2020 Aug 11.
Artigo em Russo | MEDLINE | ID: mdl-33155947

RESUMO

Aim      An attempt to prevent the development of diastolic dysfunction (DD) with the mitochondrial antioxidant plastomitin on a model of doxorubicin-induced cardiomyopathy. DD is a type of chronic heart failure. Due to the increasing number of patients with this condition and the absence of effective therapy, development of means for DD correction is a relevant objective.Material and methods  Cardiomyopathy was modeled in 17 rats by two subcutaneous injections of doxorubicin 2 mg/kg/week. The other group (n=17), also administered with doxorubicin, received plastomicin 0.32 mg/kg daily subcutaneously. Left ventricular function was evaluated with echocardiography (EchoCG) and cardiac catheterization with simultaneous pressure and volume monitoring.Results According to EchoCG data the ejection fraction remained unchanged in the experimental groups. Cardiac catheterization showed disorders of both myocardial contractility and relaxability only in the doxorubicin group.Conclusion      A course of plastomitin in combination with the doxorubicin treatment can maintain normal heart contractility and thereby, prevent the known doxorubicin cardiotoxicity.


Assuntos
Cardiomiopatias , Insuficiência Cardíaca , Animais , Antioxidantes/farmacologia , Cardiomiopatias/induzido quimicamente , Doxorrubicina/efeitos adversos , Humanos , Ratos , Função Ventricular Esquerda
2.
Medicine (Baltimore) ; 99(45): e23084, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157976

RESUMO

BACKGROUND: Tumor is a common and frequently-occurring disease that seriously threatens human health, and is one of the main causes of death. Adriamycin (ADM) is the most commonly used and effective anti-tumor chemotherapeutics in clinical practice, but they can cause severe cardiotoxicity, which obviously limits their clinical application. Shengmai injection is a modern injection form of traditional Chinese medicine widely used for heart failure, myocardial infarction, cardiogenic shock, and cardiotoxicity patients in China. Therefore, we design this systematic review and meta-analysis to assess the effectiveness and safety of Shengmai injection for treating ADM-related cardiotoxicity. METHODS: We will methodically search PubMed, EMBASE, Cochrane Library, Science Network, China National Knowledge Infrastructure, Wanfang Database, Chinese Journal Database, and China Biomedical Literature Database, in order to include randomized controlled trials which used Shengmai injection in treating ADM-related cardiotoxicity up to September 2020. The search strategies will use the following phrase: "Shengmai injection," "Adriamycin," "doxorubicin," "cardiotoxicity," "cardiomyopathy," "randomized controlled trial." The outcomes included cardiotoxicity rate, echocardiography, electrocardiogram, myocardial enzymes. Two researchers will independently select the study, extract the data and assess the quality by using Stata 14.0 and RevMan 5.3 software. The plan follows the preferred reporting items declared by the systematic review and meta-analysis plan, and the complete systematic review will follow the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. CONCLUSION: The effectiveness and safety of Shengmai injection will be assessed in treating ADM-related cardiotoxicity which can give some evidence for clinical decision making. TRIAL REGISTRATION NUMBER: INPLASY202090040.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Combinação de Medicamentos , Quimioterapia Combinada , Humanos , Injeções
3.
J Vasc Interv Radiol ; 31(11): 1784-1791, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33023805

RESUMO

PURPOSE: The purpose of this study was to assess the safety and efficacy of drug-eluting embolic (DEE) transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients who are ineligible for curative treatment, using doxorubicin-loaded Tandem (Varian Medical) microspheres. MATERIALS AND METHODS: Between October 2015 and December 2017, 98 patients with unresectable HCC (69 males, 29 females; mean age, 60.5 ± 10.0 years of age; and American Joint Committee on Cancer [AJCC] stage ≦T3a) treated with DEE transarterial chemoembolization using 100-µm doxorubicin-loaded microspheres were enrolled prospectively. All studies were reviewed and approved by the Institutional Review Board of Chang Gung Memorial Hospital. Dynamic contrast-enhanced computed tomography or magnetic resonance imaging 1 month after treatment was used for tumor response assessment according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Outcomes included overall survival (OS), progression-free survival (PFS), and downstaging profile. RESULTS: Median follow-up was 21.2 months. At follow-up examinations at 0.5-, 1-, 1.5- and 2.5-year follow-up, OS rates were 93.8%, 89.5%, 79.4%, and 77.0%, respectively. Complete response (CR), partial response, stable disease, and progressive disease were noted in 50 (51.0%), 23 (23.5%), 18 (18.4%), and 7 (7.1%) patients, respectively, with 93.9% disease control rate and 74.5% objective response rate. Mean OS was 28.7 months, and mean PFS was 19.6 months. Number of nodules >3, bilobar disease, larger tumor, and higher AJCC stage correlated with worse CR. No serious adverse events occurred after DEE transarterial chemoembolization. Successful downstage rate was 73.3% (22 of 30) and number of nodules predicting successful downstaging was 7 nodules (cutoff). CONCLUSIONS: Tandem DEE transarterial chemoembolization provides safe and effective treatment for HCC and a bridge or downstage therapy for liver transplantation.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Doxorrubicina/administração & dosagem , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/mortalidade , Doxorrubicina/efeitos adversos , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Microesferas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tamanho da Partícula , Intervalo Livre de Progressão , Estudos Prospectivos , Taiwan , Fatores de Tempo
4.
Lancet Oncol ; 21(11): 1423-1432, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035459

RESUMO

BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). FUNDING: Epizyme.


Assuntos
Benzamidas/administração & dosagem , Piridonas/administração & dosagem , Proteína SMARCB1/genética , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Piridonas/farmacocinética , Sarcoma/genética , Sarcoma/patologia , Resultado do Tratamento , Adulto Jovem
5.
Lancet ; 396(10257): 1090-1100, 2020 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-32966830

RESUMO

BACKGROUND: Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC. METHODS: This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II-III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ≥1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing. FINDINGS: Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20·6 months (IQR 8·7-24·9) in the atezolizumab plus chemotherapy group and 19·8 months (8·1-24·5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50-65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34-49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6-27; one-sided p=0·0044 [significance boundary 0·0184]). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57-79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38-61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4-35; one-sided p=0·021 [significance boundary 0·0184]). In the neoadjuvant phase, grade 3-4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group). INTERPRETATION: In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile. FUNDING: F Hoffmann-La Roche/Genentech.


Assuntos
Albuminas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Método Duplo-Cego , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante
6.
Zhonghua Zhong Liu Za Zhi ; 42(8): 617-623, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867451

RESUMO

As a new type of anthracyclines, pegylated liposomal doxorubicin (PLD) is widely used in the treatment of a variety of malignant tumors, including soft tissue sarcoma, ovarian cancer, breast cancer, multiple myeloma, and so on. Compared with traditional anthracyclines, PLD can significantly decrease the incidences of adverse events such as cardiac toxicity and alopecia. However, the use of PLD will be accompanied with toxic side effects such as hand-foot syndrome, oral mucositis, and infusion reaction. This consensus will mainly focus on the mechanism, prevention and treatment of adverse events of PLD, in order to improve the therapeutic efficacy of PLD and life quality of patients.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/análogos & derivados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Síndrome Mão-Pé/complicações , Neoplasias/tratamento farmacológico , Estomatite/complicações , Antibióticos Antineoplásicos/uso terapêutico , Consenso , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Guias de Prática Clínica como Assunto
7.
Anticancer Res ; 40(9): 5237-5243, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878812

RESUMO

BACKGROUND/AIM: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory CD4-positive peripheral T-cell lymphoma. VCAP-AMP-VECP (mLSG15) is one of the standard chemotherapeutic regimens for patients with aggressive ATLL. Mogamulizumab (moga), a monoclonal antibody for C-C chemokine receptor 4 antigen expressed on the cell surface, has recently been poised for use as monotherapy and in combination with chemotherapy. However, to date, a significant survival benefit has not been obtained with the combination of moga + mLSG15 therapy. PATIENTS AND METHODS: We retrospectively analyzed 77 patients diagnosed with aggressive ATLL. Of them, 22 were treated with moga + a chemotherapy regimen comprised of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (EPOCH), 16 with moga + mLSG15, and 39 with chemotherapy alone. RESULTS: A risk reduction of approximately 30% was obtained with moga + EPOCH compared with moga + mLSG15. CONCLUSION: The addition of moga to chemotherapy did not result in a survival benefit compared with chemotherapy alone. However, a statistically significant overall survival benefit was observed in patients with moga-induced skin disorders.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Esquema de Medicação , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Retratamento , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
8.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892275

RESUMO

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Indução de Remissão , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
9.
Int J Hematol ; 112(6): 807-816, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32880824

RESUMO

CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) -/+ rituximab (R) is the standard chemotherapeutic regimen for aggressive lymphoma, but is insufficient for aggressive lymphoma with adverse prognostic factors. Dose-adjusted (DA)-EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisolone) -/+ R demonstrates excellent efficacy against some aggressive lymphoma. Thus, we conducted a retrospective study to evaluate the feasibility and efficacy of this therapy in clinical practice. We enrolled 149 patients from 17 institutions diagnosed between 2007 and 2015. The median follow-up period for survivors was 27 months (range 0.2-123). The complete response (CR) rate of newly diagnosed patients was 79% (95% CI 68-87%). All patients were hospitalized to receive this therapy and 94% of patients also received granulocyte-colony-stimulating factor support. There were no treatment-related deaths. Febrile neutropenia (FN) and grade 3 or 4 infection occurred in 55% and 28% of patients, respectively. There were no significant differences in FN or infection between young (≤ 65 years) and elderly patients (> 65 years). In newly diagnosed diffuse large B-cell lymphoma-not otherwise specified patients (n = 46), the CR rate was 80% (95% CI 64-91%) and the 2-year OS rate was 81% (95% CI 66-90%). In the present study, DA-EPOCH -/+ R exhibited excellent efficacy and feasibility for aggressive lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/etiologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Neutropenia Febril/epidemiologia , Neutropenia Febril/etiologia , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto Jovem
10.
J Vasc Interv Radiol ; 31(10): 1645-1653, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32951974

RESUMO

PURPOSE: To determine the efficacy and safety of the combination of bronchial arterial infusion (BAI) chemotherapy and transarterial chemoembolization with the use of drug-eluting embolic (DEE) particles in the treatment of unresectable advanced lung cancer. MATERIALS AND METHODS: A retrospective review was performed of 23 patients with unresectable lung cancer (stage III/IV) who received BAI chemotherapy and DEE chemoembolization. Treatment response was assessed by enhanced CT and evaluated on the basis of Response Evaluation Criteria In Solid Tumors at 30 d after the last combination treatment. Patients were followed up until death or March 15, 2020, whichever was first. Overall survival (OS) was estimated by Kaplan-Meier analysis, and factors associated with OS were evaluated by Cox proportional-hazards test. RESULTS: Complete response, partial response, stable disease, and progressive disease were seen in 2, 16, 5, and 0 patients at 30 d after the last combination treatment, respectively; therefore, the overall response rate was 78.3% and the disease control rate was 100%. Preprocedure symptoms (hemoptysis in 7 patients and dyspnea in 10) resolved in all cases after combination therapy. Nineteen patients died during follow-up, and 4 survived. Median OS was 15.6 mo (95% confidence interval, 10.1-21.1 mo). On univariate analysis and multivariate analysis, tumor/node/metastasis staging was an independent risk factor for prognosis. There were no serious adverse events during the procedures. CONCLUSIONS: The combination of BAI chemotherapy plus DEE chemoembolization appears to be a promising method for treatment of advanced lung cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Artérias Brônquicas , Quimioembolização Terapêutica , Doxorrubicina/análogos & derivados , Irinotecano/administração & dosagem , Neoplasias Pulmonares/terapia , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase II/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/mortalidade , Progressão da Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Infusões Intra-Arteriais , Irinotecano/efeitos adversos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase II/efeitos adversos , Resultado do Tratamento
11.
Chem Biol Interact ; 330: 109219, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846153

RESUMO

The lack of tissue selectivity of anticancer drugs generates intense collateral and adverse effects of cancer patients, making the incorporation of vitamins or micronutrients into the diet of individuals to reduce side or adverse effects of antineoplastics. The study aimed to evaluate the effects of retinol palmitate (RP) on the toxicogenic damages induced by cyclophosphamide (CPA), doxorubicin (DOX) and its association with the AC protocol (CPA + DOX), in Sarcoma 180 (S-180) tumor cell line, using the micronuclei test with a block of cytokinesis (CBMN); and in non-tumor cells derived from Mus musculus using the comet assay. The results suggest that CPA, DOX and AC protocol induced significant toxicogenic damages (P < 0.05) on the S-180 cells by induction of micronuclei, cytoplasmic bridges, nuclear buds, apoptosis, and cell necrosis, proving their antitumor effects, and significant damage (P < 0.001) to the genetic material of peripheral blood cells of healthy mice, proving the genotoxic potential of these drugs. However, RP modulated the toxicogenic effects of antineoplastic tested both in the CBMN test (P < 0.05), at the concentrations of 1, 10 and 100 IU/mL; as in the comet assay (P < 0.001) at the concentration of 100 IU/kg for the index and frequency of genotoxic damage. The accumulated results suggest that RP reduced the action of antineoplastics in non-tumor cells as well as the cytotoxic, mutagenic, and cell death in neoplastic cells.


Assuntos
Antineoplásicos/toxicidade , Diterpenos/farmacologia , Vitamina A/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ensaio Cometa , Ciclofosfamida/efeitos adversos , Ciclofosfamida/toxicidade , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Interações Medicamentosas , Humanos , Camundongos , Testes para Micronúcleos , Mutagênese/efeitos dos fármacos , Vitamina A/farmacologia
12.
Ann Hematol ; 99(8): 1771-1778, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32601796

RESUMO

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoterapia , Linfoma de Célula do Manto/terapia , Sirolimo/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Trombocitopenia/mortalidade , Vincristina/administração & dosagem , Vincristina/efeitos adversos
13.
Chem Biol Interact ; 328: 109190, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32652078

RESUMO

BACKGROUND: Doxorubicin (DOX) administration decreases cardiac soluble guanylate cyclase (sGC) activity. We hypothesized that bypassing impaired NO-sGC-cGMP pathway resulting from the activation of oxidized and heme-free soluble guanylate cyclase (sGC) could be a therapeutic target for DOX-mediated cardiomyopathy (DOX-CM). The present study investigated the therapeutic roles and mechanism of BAY60-2770, an activator of oxidized sGC, in alleviating DOX-CM. METHODS: H9c2 cardiomyocytes were pretreated with BAY60-2770 followed by DOX. Cell viability and intracellular reactive oxygen species (ROS) were subsequently measured. To determine the role BAY60-2770 in mitochondrial ROS generation and mitochondrial membrane potential, we examined mitoSOX RED and TMRE fluorescence under DOX exposure. As animal experiments, rats were orally administered with 5 mg/kg of BAY60-2770 at 1 h prior to every DOX treatment and then assessed by echocardiography and apoptotic marker and autophagy. RESULTS: BAY60-2770 ameliorated cell viability and DOX-induced oxidative stress in H9c2 cells, which was mediated by PKG activation. Mitochondrial ROS and TMRE fluorescence were attenuated by BAY60-2770 in DOX-treated H9c2 cells. DOX-induced caspase-3 activation decreased after pretreatment with BAY60-2770 in vivo and in vitro. Echocardiography showed that BAY60-2770 significantly improved DOX-induced myocardial dysfunction. Autophagosome was increased by BAY60-2770 in vivo. CONCLUSIONS: BAY60-2770 appears to mitigate DOX-induced mitochondrial ROS, membrane potential loss, autophagy, and subsequent apoptosis, leading to protection of myocardial injury and dysfunction. These novel results highlighted the therapeutic potential of BAY60-2770 in preventing DOX-CM.


Assuntos
Autofagia/efeitos dos fármacos , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Cardiotoxicidade/patologia , Doxorrubicina/efeitos adversos , Hidrocarbonetos Fluorados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
14.
Proc Natl Acad Sci U S A ; 117(26): 15182-15192, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554494

RESUMO

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.


Assuntos
Antineoplásicos/efeitos adversos , Cromatina/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Animais , Linhagem Celular , Doxorrubicina/análogos & derivados , Doxorrubicina/síntese química , Doxorrubicina/metabolismo , Doxorrubicina/uso terapêutico , Cardiopatias/induzido quimicamente , Histonas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos
15.
Orv Hetil ; 161(26): 1094-1102, 2020 06.
Artigo em Húngaro | MEDLINE | ID: mdl-32541088

RESUMO

INTRODUCTION: The incidence of dilated cardiomyopathy after anthracycline chemotherapy is mainly influenced by anthracycline cumulative dose. Previous researches showed doxorubicin treatment under cumulative dose of 450 mg/m2 associated with a low incidence of heart failure. Nowadays, doxorubicin is administered with a lower dose, the development of heart failure is largely determined by other factors. AIM: Our purpose was to identify the risk factors for heart failure due to doxorubicin therapy. METHOD: With the use of the Hungarian financial healthcare databases merged with the National Cancer Registry, we performed a retrospective study. All the patients having confirmation for breast carcinoma between 2004 and 2015 were enrolled. The subjects with a preceding period characterized by any chemotherapy or diagnoses suggesting heart failure were excluded. Heart failure outcome event was defined by the assignment of I50 diagnosis code at hospital discharge or in autopsy reports. STATISTICAL ANALYSIS: We used multivariate binary logistic regression to calculate odds ratios for heart failure. Besides the baseline characteristics, oncological state and cumulative doses of the chemotherapies were also taken into account. RESULTS: Among the analysed 3288, doxorubicin-treated patients, heart failure cumulative incidence was 6.2%. Doxorubicin cumulative dose over 400 mg/m2 increased the risk. The heart failure incidence was essentially influenced by age, even over 50 years the risk rose. Diabetes mellitus and the treatments with pyrimidine-analogues, carboplatin or bevacizumab were also associated with higher risk. CONCLUSION: By the integration of national financial and clinical databases, we could identify the risk factors for doxorubicin-associated heart failure. Orv Hetil. 2020; 161(26): 1094-1102.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Hungria , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
17.
Int J Hematol ; 112(3): 369-376, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32529585

RESUMO

Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is one of the standard regimens for indolent B-cell non-Hodgkin's lymphoma (NHL). It is unclear whether the prednisolone (PSL) dosage affects the therapeutic effect or the adverse event profile. We retrospectively examined 48 patients with indolent B-cell NHL who were treated with R-CHOP (PSL 50 mg/m2/day for 5 days) at our institute between 2006 and 2016. We compared them with 149 patients with indolent B-cell lymphoma who were treated with R-CHOP (PSL 100 mg for 5 days) in the JCOG 0203 trial. The proportions of patients with bulky disease, extranodal involvement, and increased nodal sites were higher at our institute. Nevertheless, there was no difference in the CR rate, PFS, OS or the frequency of adverse events, except for peripheral neuropathy, between the two treatment groups. In our institute, there was no difference in the CR rate, PFS, OS or adverse event profile between patients who received PSL at 60-80 mg/day and at 81-100 mg/day. Patients who received PSL at 60-80 mg/day included many female and light-weight patients. In conclusion, the PSL dose adjusted based on body surface area appeared to be appropriate in terms of efficacy and safety.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Prednisolona/administração & dosagem , Rituximab/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Superfície Corporal , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Linfoma Folicular/mortalidade , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisolona/efeitos adversos , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Indução de Remissão , Estudos Retrospectivos , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
18.
J Vis Exp ; (159)2020 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-32478722

RESUMO

Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed cardiac performance in the absence of hypertension, valvular, congenital, or ischemic heart diseases, and which may be related to infection, autoimmune or metabolic abnormalities, or family inheritance. It can progress into congestive heart failure with a poor prognosis. Doxorubicin (Dox) is widely employed as a chemotherapeutic drug, but its use is limited because it causes DCM-like changes of the myocardium. Its myocardial toxicity is attributed to oxidative stress, chronic inflammation, and cardiomyocyte apoptosis. A model of DCM exploiting these Dox-induced DCM symptoms has not been established.


Assuntos
Cardiomiopatia Dilatada/induzido quimicamente , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
19.
BMC Bioinformatics ; 21(1): 187, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32408861

RESUMO

BACKGROUND: Cardiotoxicity, characterized by severe cardiac dysfunction, is a major problem in patients treated with different classes of anticancer drugs. Development of predictable human-based models and assays for drug screening are crucial for preventing potential drug-induced adverse effects. Current animal in vivo models and cell lines are not always adequate to represent human biology. Alternatively, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show great potential for disease modelling and drug-induced toxicity screenings. Fully automated high-throughput screening of drug toxicity on hiPSC-CMs by fluorescence image analysis is, however, very challenging, due to clustered cell growth patterns and strong intracellular and intercellular variation in the expression of fluorescent markers. RESULTS: In this paper, we report on the development of a fully automated image analysis system for quantification of cardiotoxic phenotypes from hiPSC-CMs that are treated with various concentrations of anticancer drugs doxorubicin or crizotinib. This high-throughput system relies on single-cell segmentation by nuclear signal extraction, fuzzy C-mean clustering of cardiac α-actinin signal, and finally nuclear signal propagation. When compared to manual segmentation, it generates precision and recall scores of 0.81 and 0.93, respectively. CONCLUSIONS: Our results show that our fully automated image analysis system can reliably segment cardiomyocytes even with heterogeneous α-actinin signals.


Assuntos
Cardiotoxicidade/patologia , Processamento de Imagem Assistida por Computador , Células-Tronco Pluripotentes Induzidas/patologia , Miócitos Cardíacos/patologia , Automação , Comunicação Celular , Contagem de Células , Linhagem Celular , Doxorrubicina/efeitos adversos , Humanos , Fenótipo
20.
Toxicol Appl Pharmacol ; 398: 115018, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32333917

RESUMO

The incorporation of mesenchymal-epithelial transition factor (c-Met) inhibitors with conventional chemotherapeutics may increase the anticancer efficacy of chemotherapeutic agents, but bears the risk of enhancing the adverse effects. To test the hypothesis, co-administration of the novel c-Met inhibitor capmatinib with cisplatin (CIS) or doxorubicin (DOX) was investigated on nephrotoxicity and cardiotoxicity induced by these agents in mice, as well as their in vitro cytotoxicities. The results demonstrated that capmatinib in vivo offered protection against nephrotoxicity and cardiotoxicity by both CIS and DOX, respectively. The underlying mechanisms behind capmatinib protective effect were found to be i) limiting excessive generation of reactive oxygen species by decreasing the level of lipid peroxidation and nitrosative stress products; and ii) suppressing overproduction of pro-inflammatory mediators like TNF-α and IL-6 that coincided with less inflammatory cell infiltration as denoted by lower levels of serum MCP-1 and Ly6G immunostaining. Besides, capmatinib effectively improved the in vivo anticancer efficacy of both CIS and DOX against solid tumors. In vitro, capmatinib increased the apoptotic activity of DOX against cancerous cells, but did not affect that of CIS. This effect might be linked to capmatinib and DOX abilities to lower IL-12(p40) that has an inhibitory effect on IL-12(p70)/IFN-γ-mediated apoptotic activity. In conclusion, the favorable effects of capmatinib can be applied clinically to decrease the toxicity of DOX and CIS chemotherapeutic agents.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Imidazóis/farmacologia , Rim/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/farmacologia , Animais , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Feminino , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
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