Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/imunologia , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Humanos , Neoplasias/imunologiaRESUMO
BACKGROUND: The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies. METHODS: Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m(-2) loading dose then 250 mg m(-2) weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses. RESULTS: Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months. CONCLUSIONS: The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.
Assuntos
Alanina/análogos & derivados , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Terapia de Salvação , Triazinas/farmacocinética , Triazinas/uso terapêutico , Adulto , Idoso , Alanina/farmacocinética , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Cetuximab , Quimioterapia Combinada , Feminino , Neoplasias Gastrointestinais/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Taxa de Sobrevida , Distribuição Tecidual , Resultado do Tratamento , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.
Assuntos
Alanina/análogos & derivados , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Triazinas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina/farmacologia , Alanina/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/mortalidade , Neovascularização Patológica , Triazinas/uso terapêuticoRESUMO
Scientific advances have significantly improved the practice of medicine by providing objective and quantitative means for exploring the human body and disease states. These innovative technologies have already profoundly improved disease detection, imaging, treatment and patient follow-up. Today's analytical limits are at the nanoscale level (one-billionth of a meter) enabling a detailed exploration at the level of DNA, RNA, proteins and metabolites which are in fact nano-objects. This translational review aims at integrating some recent advances from micro- and nano-technologies with high potential for improving daily oncology practice.
Assuntos
Antineoplásicos , Técnicas Biossensoriais , Sistemas de Liberação de Medicamentos/métodos , Nanomedicina , Nanotecnologia , Neoplasias , Biomarcadores Tumorais , Humanos , Microfluídica , Nanopartículas , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Fisiológica , Transdução de SinaisRESUMO
BACKGROUND: It is well known that there is considerable inter-observer variability in assessment of the pathological parameters that are used to select node-negative breast cancer patients for adjuvant systemic treatment. There are only limited data available as to in how many patients this leads to differences in treatment decisions. METHODS: Clinical and pathological data of 694 patients <61 years with primary unilateral T1-4N0M0 breast cancer were analysed. Grade, estrogen receptor (ER) status and human epidermal growth factor receptor 2 (HER2) status were first assessed locally; subsequent central re-evaluation of these parameters was carried out. Clinicopathological low or high risk was assessed using national Dutch guidelines and the Adjuvant! Online (www.adjuvantonline.com). RESULTS: The local pathological examination was discordant with central review for grade, ER and HER2 in 28% (kappa 0.56; grade 2 tumours 35% discordant), 5% (kappa 0.85) and 4% (kappa 0.81) of patients, respectively. If clinical risk were assessed based on Dutch guidelines or Adjuvant! Online, respectively, 15% (one of seven patients; kappa 0.70) or 8% (kappa 0.83) of patients would have been assigned to a different clinical risk group. CONCLUSION: Inter-observer variation in pathological examination of breast carcinomas results in significant differences in grade, ER status, HER2 status, clinicopathological risk and subsequently in adjuvant systemic treatment advice.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Oncologia/estatística & dados numéricos , Patologia/estatística & dados numéricos , Adulto , Neoplasias da Mama/genética , Feminino , Humanos , Oncologia/normas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Variações Dependentes do Observador , Patologia/normas , Guias de Prática Clínica como Assunto , Receptor ErbB-2/biossíntese , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Estudos Retrospectivos , Medição de RiscoRESUMO
PURPOSE: The 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530-536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. METHODS: We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer (N = 123; <55 years; pT1-2N0; diagnosed between 1996 and 1999; median follow-up 5.8 years) by classifying these patients as having a good or poor prognosis signature. In addition, we updated the follow-up of the node-negative patients of the previously published validation-series (Van de Vijver et al., N Engl J Med 347(25):1999-2009, 2002; N = 151; median follow-up 10.2 years). The prognostic value of the 70-gene prognosis signature was compared with that of four commonly used clinicopathological risk indexes. The endpoints were distant metastasis (as first event) free percentage (DMFP) and overall survival (OS). RESULTS: The 5-year OS was 82 +/- 5% in poor (48%) and 97 +/- 2% in good prognosis signature (52%) patients (HR 3.4; 95% CI 1.2-9.6; P = 0.021). The 5-years DMFP was 78 +/- 6% in poor and 98 +/- 2% in good prognosis signature patients (HR 5.7; 95% CI 1.6-20; P = 0.007). In the updated series (N = 151; 60% poor vs. 40% good), the 10-year OS was 51 +/- 5% and 94 +/- 3% (HR 10.7; 95% CI 3.9-30; P < 0.01), respectively. The DMFP was 50 +/- 6% in poor and 86 +/- 5% in good prognosis signature patients (HR 5.5; 95% CI 2.5-12; P < 0.01). In multivariate analysis, the prognosis signature was a strong independent prognostic factor in both series, outperforming the clinicopathological risk indexes. CONCLUSION: The 70-gene prognosis signature is also an independent prognostic factor in node-negative breast cancer patients for women diagnosed in recent years.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Perfilação da Expressão Gênica , Adulto , Área Sob a Curva , Neoplasias da Mama/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/genética , Metástase Linfática/patologia , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Curva ROC , Fatores de RiscoRESUMO
Tumour proliferation is one of the main biological phenotypes limiting cure in oncology. Extensive research is being performed to unravel the key players in this process. To exploit the potential of published gene expression data, creation of a signature for proliferation can provide valuable information on tumour status, prognosis and prediction. This will help individualizing treatment and should result in better tumour control, and more rapid and cost-effective research and development. From in vitro published microarray studies, two proliferation signatures were compiled. The prognostic value of these signatures was tested in five large clinical microarray data sets. More than 1000 patients with breast, renal or lung cancer were included. One of the signatures (110 genes) had significant prognostic value in all data sets. Stratifying patients in groups resulted in a clear difference in survival (P-values <0.05). Multivariate Cox-regression analyses showed that this signature added substantial value to the clinical factors used for prognosis. Further patient stratification was compared to patient stratification with several well-known published signatures. Contingency tables and Cramer's V statistics indicated that these primarily identify the same patients as the proliferation signature does. The proliferation signature is a strong prognostic factor, with the potential to be converted into a predictive test. Furthermore, evidence is provided that supports the idea that many published signatures track the same biological processes and that proliferation is one of them.
Assuntos
Proliferação de Células , Perfilação da Expressão Gênica , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Área Sob a Curva , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias/mortalidade , Valor Preditivo dos Testes , Prognóstico , Curva ROCRESUMO
The axillary lymph node status is the most powerful prognostic factor for breast cancer patients to date. The molecular mechanisms that control lymph node metastasis, however, remain poorly understood. To define patterns of genes or gene regulatory pathways that drive breast cancer lymph node metastasis, we compared the gene expression profiles of 15 primary breast carcinomas and their matching lymph node metastases using microarrays. In general, primary breast carcinomas and lymph node metastases do not differ at the transcriptional level by a common subset of genes. No classifier or single gene discriminating the group of primary tumours from those of the lymph node metastases could be identified. Also, in a series of 295 breast tumours, no classifier predicting lymph node metastasis could be developed. However, subtle differences in the expression of genes involved in extracellular-matrix organisation and growth factor signalling are detected in individual pairs of matching primary and metastatic tumours. Surprisingly, however, different sets of these genes are either up- or downregulated in lymph node metastases. Our data suggest that breast carcinomas do not use a shared gene set to accomplish lymph node metastasis.
Assuntos
Neoplasias da Mama/patologia , Carcinoma/genética , Carcinoma/fisiopatologia , Perfilação da Expressão Gênica , Metástase Linfática/genética , Metástase Linfática/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Regulação para Baixo , Feminino , Humanos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Regulação para CimaRESUMO
The aims of this study were to examine the late components of the auditory event-related potentials (AERPs), i.e. N(100), P(200) and P(300), in recently detoxified alcohol-dependent patients compared to normal controls and to investigate whether there is a relationship between alterations in these AERPs and signs of activation of the inflammatory response system (IRS). The study subjects consisted of 14 healthy volunteers and 14 recently detoxified alcohol-dependent patients. All subjects performed a two-tone auditory discrimination task, using a standard "oddball" paradigm. The alcohol-dependent patients had their blood sampled to examine IRS markers, such as erythrocyte sedimentation rate (ESR), serum copper concentrations and the number of leukocytes. The P(300) latency was significantly greater in recently detoxified alcohol-dependent patients than in normal controls. There were significant correlations between the P(300) latency and the ESR (r = 0.84, p = 0.009), serum copper concentrations (r = 0.73, p = 0.01) and number of monocytes (r = 0.71, p = 0.006). It is concluded that the P(300) latency is prolonged in detoxified, chronic alcohol-dependent patients and is positively related to indicators of IRS activation. It is hypothesized that activation of the IRS may play a role in the delayed P(300) latency in recently detoxified, alcohol-dependent patients.
Assuntos
Alcoolismo/sangue , Sedimentação Sanguínea , Cobre/sangue , Potenciais Evocados Auditivos , Leucócitos , Fígado/enzimologia , Alcoolismo/enzimologia , Alcoolismo/imunologia , Alcoolismo/terapia , Estudos de Casos e Controles , Potenciais Evocados P300 , Humanos , Contagem de Leucócitos , Monócitos , NeutrófilosRESUMO
BACKGROUND: Some studies have shown disturbances in auditory event related potentials (AERPs) in patients with major depression. METHODS: In this exploratory study, the late AERP components, N100 (latency), P200 (amplitude and latency) and P300 (amplitude and latency) were recorded in 68 subjects, i.e. 39 major depressed subjects, with (n=4) or without (n=35) cognitive deterioration, 18 patients with Alzheimer's dementia (SDAT) and 11 normal volunteers. Twenty-five major depressed patients had repeated measurements of AERPs both before and after treatment with antidepressants. RESULTS: Major depressed subjects without cognitive deterioration had significantly higher P300 latency and P200 amplitude than normal volunteers. SDAT patients and major depressed patients with cognitive impairment had a significantly higher P300 latency than depressed patients without cognitive impairment. In the latter, no significant alterations in any of the AERP components upon subchronic treatment with antidepressants were recorded. Nonresponders to antidepressant therapy had significantly higher pretreatment P300 latency and P200 amplitude than responders to treatment (P=0.006) and normal volunteers (P=0.0004). CONCLUSIONS: The findings may suggest that delayed P300 latency as well as increased P200 amplitude accompany major depression and may predict a nonresponse to subsequent antidepressive therapy.