RESUMO
BACKGROUND: International oncology societies recommend early palliative care. Specific models to integrate early palliative care efficiently into clinical practice are debated. The authors designed a study to look at the quantitative and qualitative outcomes of an early palliative care intervention in oncological care to decrease stress and improve quality of life. AIMS: To compare a single structured early palliative care intervention added to a usual oncology care in terms of distress and health-related quality of life at baseline compared to 6 months after enrollment. DESIGN: This multicenter randomized controlled trial (NCT01983956) enrolled adult patients with advanced cancer. Participants were either randomly assigned to usual oncology care alone or usual care plus a structured early palliative care intervention. SETTING/PARTICIPANTS: One hundred fifty adult patients with a variety of advanced cancer diagnoses were randomized. Seventy-four participants were in the intervention and 76 participants in the control group. The primary outcome was the change in patient distress assessed by the National Comprehensive Cancer Network distress thermometer at 6 months. Health-related quality of life, the secondary outcome, was assessed by the Functional Assessment of Cancer Therapy-General Questionnaire. RESULTS: The results showed no significant effect of the early palliative care intervention neither on patient distress nor on health-related quality of life. CONCLUSION: The addition of an early intervention to usual care for patients with advanced cancer did not improve distress or quality of life. Thus, patients may need more intensive early palliative care with continuous professional support to identify and address their palliative needs early.
Assuntos
Enfermagem de Cuidados Paliativos na Terminalidade da Vida , Neoplasias , Adulto , Humanos , Neoplasias/terapia , Cuidados Paliativos , Qualidade de VidaRESUMO
The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells.
Assuntos
Diferenciação Celular/genética , Hexoquinase/fisiologia , Leucemia Promielocítica Aguda/patologia , Neutrófilos/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/fisiologia , Glicólise/genética , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/genética , Transativadores/metabolismo , Tretinoína/farmacologia , Tretinoína/uso terapêuticoRESUMO
AIMS: ID1 is an important component of the MET-SRC signaling pathway, which is a regulator of cell migration and invasion. We hypothesized that the ALK/MET inhibitor crizotinib inhibits migration via MET-SRC-ID1, rather than ALK. MATERIALS & METHODS: We used ALK fusion-positive and -negative lung cancer cell lines; crizotinib, PHA-665752, and saracatinib, and stable transfection with shMET. We performed western blotting for p-ALK, ALK, p-MET, MET, p-SRC, SRC and ID1, and quantitative real-time PCR for ID1. RESULTS: Crizotinib decreased p-MET, p-SRC and ID1 levels in ALK- and or MET-positive cell lines and inhibited cell migration. Knockdown of MET was comparable with the effect of crizotinib. CONCLUSION: The effects of crizotinib on ID1 expression and cancer cell migration were associated with the presence of activated MET, rather than ALK fusion.
Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Proteína 1 Inibidora de Diferenciação/metabolismo , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Linhagem Celular Tumoral , Crizotinibe , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
Modern oncology has much to offer, and the prognosis of cancer patients has undoubtedly improved over the last few decades. Nevertheless, medical and economic toxicities of modern cancer medicine demand that our many tools are viewed with a critical eye. Screening mammography and PSA screening for the detection of early breast, or prostate cancer, resp., are widely used. However, reduction of mortality from these disorders through early detection and treatment is quantitatively modest, whereas overdiagnosis of low-risk cancers and non-malignant conditions with these two methods is frequent. Cancer drug therapy increasingly uses predictive bio-markers to select patients (and their tumors) particularly likely to benefit from new drugs. Nevertheless palliative systemic treatment in oncology suffers from over-use of drugs with at times considerable toxicity and cost but little patient gain. It is still common practice to validate new cancer drugs in clinical trials using progression-free survival as a primary endpoint. PFS is easily measurable but often inadequate to discover true clinical benefit (i. e. prolonged overall survival and/or improved lasting quality of life). Licensing agencies such as the FDA or Swissmedic as well as clinical trialists are therefore challenged to review their criteria for the validation of new cancer drugs. Follow-up of cancer patients after treatment is widely practiced, often with "subscription series" for CT- or PET-scans and repetitive lab tests including tumor markers. Early detection of asymptomatic cancer relapse with these methods, however, is only warranted, if early re-treatment is proven to prolong survival, as cancer treatment in asymptomatic patients produces toxicity and costs that can only be justified if chances for long-term benefits are bettered.
Assuntos
Antineoplásicos/uso terapêutico , Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Seleção de Pacientes , Procedimentos Desnecessários , Antineoplásicos/efeitos adversos , Medicina Baseada em Evidências , Humanos , Neoplasias/prevenção & controle , Prevenção Primária/métodos , Prognóstico , Medição de Risco/métodos , Resultado do TratamentoRESUMO
Autophagy is an intracellular bulk degradation process involved in cell survival upon stress induction, but also with a newly identified function in myeloid differentiation. The autophagy-related (ATG)8 protein family, including the GABARAP and LC3 subfamilies, is crucial for autophagosome biogenesis. In order to evaluate the significance of the GABARAPs in the pathogenesis of acute myeloid leukemia (AML), we compared their expression in primary AML patient samples, CD34(+) progenitor cells and in granulocytes from healthy donors. GABARAPL1 and GABARAPL2/GATE-16, but not GABARAP, were significantly downregulated in particular AML subtypes compared to normal granulocytes. Moreover, the expression of GABARAPL1 and GATE-16 was significantly induced during ATRA-induced neutrophil differentiation of acute promyelocytic leukemia cells (APL). Lastly, knocking down GABARAPL2/GATE-16 in APL cells attenuated neutrophil differentiation and decreased autophagic flux. In conclusion, low GABARAPL2/GATE-16 expression is associated with an immature myeloid leukemic phenotype and these proteins are necessary for neutrophil differentiation of APL cells.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Autofagia , Regulação Leucêmica da Expressão Gênica , Leucemia Promielocítica Aguda/metabolismo , Proteínas dos Microfilamentos/antagonistas & inibidores , Neutrófilos/citologia , Tretinoína/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD34/metabolismo , Proteínas Reguladoras de Apoptose , Família da Proteína 8 Relacionada à Autofagia , Diferenciação Celular , Linhagem Celular , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Masculino , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Adulto JovemRESUMO
MET, also known as hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with an important role, both in normal cellular function as well as in oncogenesis. In many cancer types, abnormal activation of MET is related to poor prognosis and various strategies to inhibit its function, including small molecule inhibitors, are currently in preclinical and clinical evaluation. Autophagy, a self-digesting recycling mechanism with cytoprotective functions, is induced by cellular stress. This process is also induced upon cytotoxic drug treatment of cancer cells and partially allows these cells to escape cell death. Thus, since autophagy protects different tumor cells from chemotherapy-induced cell death, current clinical trials aim at combining autophagy inhibitors with different cancer treatments. We found that in a gastric adenocarcinoma cell line GTL-16, where MET activity is deregulated due to receptor overexpression, two different MET inhibitors PHA665752 and EMD1214063 lead to cell death paralleled by the induction of autophagy. A combined treatment of MET inhibitors together with the autophagy inhibitor 3-MA or genetically impairing autophagy by knocking down the key autophagy gene ATG7 further decreased cell viability of gastric cancer cells. In general, we observed the induction of cytoprotective autophagy in MET expressing cells upon MET inhibition and a combination of MET and autophagy inhibition resulted in significantly decreased cell viability in gastric cancer cells.
Assuntos
Adenocarcinoma/enzimologia , Autofagia/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Gástricas/enzimologia , Adenina/análogos & derivados , Adenina/farmacologia , Autofagia/genética , Proteína 7 Relacionada à Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Humanos , Indóis/farmacologia , Piridazinas/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P = .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. This trial is registered at www.trialregister.nl as #NTR230 and #NTR291.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Bussulfano/uso terapêutico , Terapia Combinada/métodos , Ciclofosfamida/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Prognóstico , Estudos Prospectivos , Indução de Remissão , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: We assessed adherence to the European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) at our institution. PATIENTS AND METHODS: The charts of 299 patients starting a new chemotherapy between November 2008 and April 2009 were reviewed. Baseline characteristics and prophylaxis of CINV during the first cycle were recorded, and adherence to ESMO recommendations was determined. Chi-square tests and logistic regression were used to test for predictors of adherence. RESULTS: Prophylaxis of acute CINV was not adherent in 39% of the patients: 39 of 54 patients with low emetogenic chemotherapy had a serotonin antagonist, and 24 of 100 with moderately emetogenic therapy had a neurokinin antagonist. Nevertheless, 71% of the patients treated with highly emetogenic therapy received the guideline-specified prescription. Prophylaxis of delayed CINV was not adherent in 89% of the patients: 101 of 125 patients with highly or moderately emetogenic single-day chemotherapy received a serotonin antagonist. Male gender (odds ratio (OR) 0.484, 95% confidence interval (CI) 0.291-0.806; P = 0.005) and hematologic neoplasia (OR 2.151, 95% CI 1.19-3.887; P = 0.011) were independent predictors of non-adherence. Age (OR 0.981, 95% CI 0.964-0.998; P = 0.029) and inpatient treatment (OR 0.457, 95% CI 0.25-0.836; P = 0.011) indicated a lower risk of non-adherence. CONCLUSION: Contrary to older studies reporting frequent omissions of corticosteroids, the current study demonstrated significant overuse of serotonin antagonists for prophylaxis of delayed CINV.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Náusea/prevenção & controle , Vômito/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antieméticos/farmacologia , Antineoplásicos/uso terapêutico , Distribuição de Qui-Quadrado , Feminino , Fidelidade a Diretrizes , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1 , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Antagonistas da Serotonina/uso terapêutico , Vômito/induzido quimicamente , Adulto JovemRESUMO
The in vitro production of recombinant protein molecules has fostered a tremendous interest in their clinical application for treatment and support of cancer patients. Therapeutic proteins include monoclonal antibodies, interferons, and haematopoietic growth factors. Clinically established monoclonal antibodies include rituximab (targeting CD20-positive B-cell lymphomas), trastuzumab (active in HER-2 breast and gastric cancer), and bevacizumab (blocking tumor-induced angiogenesis through blockade of vascular-endothelial growth factor and its receptor). Interferons have lost much of their initial appeal, since equally or more effective treatments with more pleasant side effects have become available, for example in chronic myelogenous leukaemia or hairy cell leukaemia. The value of recombinant growth factors, notably granulocyte colony stimulating factor (G-CSF) and erythropoietin is rather in the field of supportive care than in targeted anti-cancer therapy. Adequately powered clinical phase III trials are essential to estimate the true therapeutic impact of these expensive compounds, with appropriate selection of clinically relevant endpoints and sufficient follow-up. Monoclonal antibodies, interferons, and growth factors must also, and increasingly so, be subjected to close scrutiny by appropriate cost-effectiveness analyses to ensure that their use results in good value for money. With these caveats and under the condition of their judicious clinical use, recombinant proteins have greatly enriched the therapeutic armamentarium in clinical oncology, and their importance is likely to grow even further.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Eritropoetina/efeitos adversos , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/efeitos adversos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Interferons/efeitos adversos , Interferons/uso terapêutico , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Proteínas Recombinantes/efeitos adversosRESUMO
Survivin has received great attention due to its expression in many human tumors and its potential as a therapeutic target in cancer. Survivin expression has been described to be cell cycle-dependent and restricted to the G2-M checkpoint, where it inhibits apoptosis in proliferating cells. In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation. In contrast with immature cells, mature neutrophils contained only little or no survivin protein. Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo. Moreover, survivin-deficient mature neutrophils were unable to increase their lifespan after survival factor exposure. Together, our findings demonstrate the following: (a) overexpression of survivin occurs in primary, even terminally differentiated cells and is not restricted to proliferating cells; and (b) survivin acts as an inhibitor of apoptosis protein in a cell cycle-independent manner. Therefore, survivin plays distinct and independent roles in the maintenance of the G2-M checkpoint and in apoptosis control, and its overexpression is not restricted to proliferating cells. These data provide new insights into the regulation and function of survivin and have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases and cancer.
Assuntos
Apoptose/fisiologia , Proteínas Associadas aos Microtúbulos/farmacologia , Neutrófilos/citologia , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Inflamação/patologia , Inflamação/fisiopatologia , Proteínas Inibidoras de Apoptose , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias , Estadiamento de Neoplasias , Neoplasias/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/fisiologia , Proteínas Recombinantes , SurvivinaRESUMO
Acute promyelocytic leukaemia (APL) patients are successfully treated with all-trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes.
Assuntos
Antineoplásicos/farmacologia , Catequina/análogos & derivados , Leucemia Mieloide Aguda/patologia , Neutrófilos/efeitos dos fármacos , Tretinoína/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Reguladoras de Apoptose/fisiologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/fisiologia , Catequina/farmacologia , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proteínas Quinases Associadas com Morte Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Técnicas de Silenciamento de Genes , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS: Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS: Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING: German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).
Assuntos
Anemia/tratamento farmacológico , Transfusão de Eritrócitos , Hematínicos/efeitos adversos , Neoplasias/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Adulto , Idoso , Anemia/etiologia , Antineoplásicos/uso terapêutico , Modificador do Efeito Epidemiológico , Eritropoetina/efeitos adversos , Feminino , Hematínicos/uso terapêutico , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Modelos de Riscos Proporcionais , Proteínas Recombinantes , Projetos de Pesquisa , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
The literature on malignant lymphomas has grown to an extent which is hardly palatable for general practitioners and non-lymphoma aficionados. Nevertheless some lymphomas exhibit typical clinical and radiological features which permit to suspect the correct histopathological diagnosis even before a pathology report becomes available. The present article points out such "case vignettes" of particular types of malignant lymphoma.
Assuntos
Linfoma/patologia , Adulto , Idoso , Biópsia , Linfoma de Burkitt/classificação , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patologia , Diagnóstico Diferencial , Linfoma de Células T Associado a Enteropatia/classificação , Linfoma de Células T Associado a Enteropatia/diagnóstico , Linfoma de Células T Associado a Enteropatia/patologia , Feminino , Doença de Hodgkin/classificação , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma/classificação , Linfoma/diagnóstico , Linfoma de Células B/classificação , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma Folicular/classificação , Linfoma Folicular/diagnóstico , Linfoma Folicular/patologia , Linfoma de Célula do Manto/classificação , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Tomografia Computadorizada por Raios X , Macroglobulinemia de Waldenstrom/classificação , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/patologia , Adulto JovemRESUMO
The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments. We investigated the patterns of recurrence with respect to ER status for patients treated in two randomized trials with 25 years' median follow-up. In the ER-negative subpopulations most breast cancer events occurred within the first 5-7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding 1 year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment. Despite small numbers of patients, "old-fashioned" treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Receptores de Estrogênio/biossíntese , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sistema Endócrino/efeitos dos fármacos , Linfonodos/patologia , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Agências Internacionais , Linfonodos/efeitos dos fármacos , Metástase Linfática , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/patologia , Pós-Menopausa , Prognóstico , Taxa de Sobrevida , Tamoxifeno/administração & dosagem , Resultado do TratamentoRESUMO
Tumor suppressor genes, such as p53, RB, the INK4-ARF family and PML, suppress malignant transformation by regulating cell cycle progression, ensuring the fidelity of DNA replication and chromosomal segregation, or by inducing apoptosis in response to potentially deleterious events. In myeloid leukemia, hematopoietic differentiation resulting from highly coordinated, stage-wise expression of myeloid transcription and soluble signaling factors is disrupted leading to a block in terminal differentiation and uncontrolled proliferation. This virtually always involves functional inactivation or genetic disruption of one or several tumor suppressor genes in order to circumvent their checkpoint control and apoptosis-inducing functions. Hence, reactivation of tumor suppressor gene function has therapeutic potential and can possibly enhance conventional cytotoxic chemotherapy. In this review, we focus on the role of different tumor suppressor genes in myeloid differentiation and leukemogenesis, and discuss implications for therapy.
Assuntos
Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Genes Supressores de Tumor/fisiologia , Células-Tronco Hematopoéticas/citologia , Leucemia Mieloide/genética , Células-Tronco Hematopoéticas/fisiologia , HumanosRESUMO
BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality. OBJECTIVES: Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients. SEARCH STRATEGY: We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials. SELECTION CRITERIA: We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy. DATA COLLECTION AND ANALYSIS: We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint. MAIN RESULTS: A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42). AUTHORS' CONCLUSIONS: ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.