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1.
J Exp Clin Cancer Res ; 37(1): 55, 2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29530101

RESUMO

BACKGROUND: Precision medicine calls for an early indicator of treatment efficiency. Circulating tumor DNA (ctDNA) is a promising marker in this setting. Our prospective study explored the association between disease development and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). METHODS: The study included 138 patients with mCRC receiving standard first line treatment. In patients with RAS/RAF mutated tumor DNA the same mutation was quantified in the plasma using droplet digital PCR. The fractional abundance of ctDNA was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease. RESULTS: RAS/RAF mutations were detected in the plasma from 77 patients. Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of mutated DNA in plasma was correlated with poor overall survival. A low level of ctDNA after the first cycle of chemotherapy was associated with a low risk of progression. On the other hand, a significant increase of ctDNA at any time during the treatment course was associated with a high risk of progression on continuous treatment. The first increase in ctDNA level occurred at a median of 51 days before radiologically confirmed progression. CONCLUSIONS: The results indicate that the ctDNA level holds potential as a clinically valuable marker in first line treatment of mCRC. A rapid decrease was associated with a prolonged progression free interval, whereas a significant increase gave notice of early progression with a relevant lead time.


Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA de Neoplasias , Genes ras , Mutação , Quinases raf/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
3.
Br J Cancer ; 109(12): 3067-72, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24263065

RESUMO

BACKGROUND: We investigated the clinical implications of KRAS and BRAF mutations detected in both archival tumor tissue and plasma cell-free DNA in metastatic colorectal cancer patients treated with irinotecan monotherapy. METHODS: Two hundred and eleven patients receiving second-line irinotecan (350 mg m(-2) q3w) were included in two independent cohorts. Plasma was obtained from pretreatment EDTA blood-samples. Mutations were detected in archival tumour and plasma with qPCR methods. RESULTS: Mutation status in tumor did not correlate to efficacy in either cohort, whereas none of the patients with mutations detectable in plasma responded to therapy. Response rate and disease control rate in plasma KRAS wt patients were 19 and 66% compared with 0 and 37%, in patients with pKRAS mutations, (P=0.04 and 0.01). Tumor KRAS status was not associated with PFS but with OS in the validation cohort. Plasma BRAF and KRAS demonstrated a strong influence on both PFS and OS. The median OS was 13.0 mo in pKRAS wt patients and 7.8 in pKRAS-mutated, (HR=2.26, P<0.0001). PFS was 4.6 and 2.7 mo, respectively (HR=1,69, P=0.01). Multivariate analysis confirmed the independent prognostic value of pKRAS status but not KRAS tumor status. CONCLUSION: Tumor KRAS has minor clinical impact, whereas plasma KRAS status seems to hold important predictive and prognostic information.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , DNA de Neoplasias/sangue , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/genética , Proteínas ras/sangue , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/uso terapêutico , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA de Neoplasias/genética , Intervalo Livre de Doença , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/sangue , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Resultado do Tratamento
4.
Br J Cancer ; 109(5): 1243-51, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-23922111

RESUMO

BACKGROUND: This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC). METHODS: A total of 230 patients from a randomised phase III study were included. The primary microRNA-126 (pri-miRNA-126) A24G single-nucleotide polymorphism and the mature miRNA-126 were analysed by PCR using genomic DNA (full blood) and formalin-fixed paraffin-embedded tissue sections, respectively. The epidermal growth factor-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry. RESULTS: High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio=0.49, 95% confidence interval=0.29-0.84, P=0.009). Although not significant, a relationship between EGFL7 expression and response rates is suggested, with EGFL7 expression at the invasive front being lower in responding patients than in the non-responders (P=0.063). CONCLUSION: The results validate the previous findings on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Fatores de Crescimento Endotelial/metabolismo , MicroRNAs/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Capecitabina , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Dinamarca , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Família de Proteínas EGF , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Oxaloacetatos , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Suécia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
5.
Acta Physiol (Oxf) ; 207(3): 536-45, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23216619

RESUMO

In diseases with proteinuria, for example nephrotic syndrome and pre-eclampsia, there often are suppression of plasma renin-angiotensin-aldosterone system components, expansion of extracellular volume and avid renal sodium retention. Mechanisms of sodium retention in proteinuria are reviewed. In animal models of nephrotic syndrome, the amiloride-sensitive epithelial sodium channel ENaC is activated while more proximal renal Na(+) transporters are down-regulated. With suppressed plasma aldosterone concentration and little change in ENaC abundance in nephrotic syndrome, the alternative modality of proteolytic activation of ENaC has been explored. Proteolysis leads to putative release of an inhibitory peptide from the extracellular domain of the γ ENaC subunit. This leads to full activation of the channel. Plasminogen has been demonstrated in urine from patients with nephrotic syndrome and pre-eclampsia. Urine plasminogen correlates with urine albumin and is activated to plasmin within the urinary space by urokinase-type plasminogen activator. This agrees with aberrant filtration across an injured glomerular barrier independent of the primary disease. Pure plasmin and urine samples containing plasmin activate inward current in single murine collecting duct cells. In this study, it is shown that human lymphocytes may be used to uncover the effect of urine plasmin on amiloride- and aprotinin-sensitive inward currents. Data from hypertensive rat models show that protease inhibitors may attenuate blood pressure. Aberrant filtration of plasminogen and conversion within the urinary space to plasmin may activate γ ENaC proteolytically and contribute to inappropriate NaCl retention and oedema in acute proteinuric conditions and to hypertension in diseases with chronic microalbuminuria/proteinuria.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Proteinúria/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Diuréticos/uso terapêutico , Canais Epiteliais de Sódio/efeitos dos fármacos , Fibrinolisina/metabolismo , Taxa de Filtração Glomerular , Humanos , Ativação do Canal Iônico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/fisiopatologia , Nefropatias/urina , Proteinúria/tratamento farmacológico , Proteinúria/fisiopatologia , Proteinúria/urina , Sistema Renina-Angiotensina , Cloreto de Sódio na Dieta/urina , Equilíbrio Hidroeletrolítico
6.
Pharmacogenomics J ; 11(1): 53-60, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20125120

RESUMO

Single-nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGF-A) gene may have clinical implications. The aim of this study was to investigate the possible predictive value of the VEGF-A SNPs, in patients with metastatic colorectal cancer (mCRC) treated with first-line capecitabine and oxaliplatin (XELOX). The study included 72 patients with mCRC. Genomic DNA was isolated from whole blood, and SNPs were analyzed by PCR. SNPs were correlated with response and progression-free survival (PFS). Haplotypes were estimated using the PHASE program. Response was observed in 21% of the patients with the -2578 CA genotype compared with 59% of the patients with CC+AA, P=0.002, in 26% of the patients with the -460 CT genotype compared with 57% with CC+TT, P=0.01, and in 27% of the patients with the +405 GC genotype compared with 54% with GG+CC, P=0.02. Two SNPs were significantly related to PFS. A haplotype with a significant relationship to response was identified. The results demonstrated obvious relationships between genetic variations in the VEGF-A gene and response to first-line XELOX in patients with mCRC, which translated to a significant difference in PFS. The results call for validation in a larger cohort of patients.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Oxaloacetatos , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/sangue
7.
Ann Oncol ; 21(3): 535-539, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19850635

RESUMO

BACKGROUND: The purpose of the present study was to investigate polymorphisms related to the metabolism of fluoropyrimidine and oxaliplatin, thymidylate synthase (TS) and excision repair cross-complementing gene 1 (ERCC1) 118, in metastatic colorectal cancer patients treated with capecitabine and oxaliplatin (XELOX). We also investigated the importance of the EGF61A>G polymorphism, which holds a functional influence on the tyrosine kinase receptor regulation. MATERIALS AND METHODS: We included 68 patients treated with first-line XELOX. Polymorphism analyses were carried out on pretreatment blood samples. Response was evaluated according to the RECIST. Survival analysis was described by the Kaplan-Meier method and log-rank testing. RESULTS: The overall response rate was 38% and the median overall survival 19.4 months. A favorable outcome was seen in patients with the EGF61A/G genotype compared with the combined group of A/A and G/G, with response rates of 57% and 18%, respectively (P = 0.001). There was a significantly different progression-free survival (P = 0.018) in favor of the A/G group. The TS and ERCC1 genotypes failed to provide any significant impact on the outcome. CONCLUSION: Polymorphism analysis of a simple blood sample is a feasible approach to biomarker analysis and the EGF61A>G polymorphism may influence the effect of first-line XELOX. Consequently, this marker deserves further investigation.


Assuntos
Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/genética , Fator de Crescimento Epidérmico/genética , Polimorfismo Genético/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Capecitabina , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Endonucleases/genética , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Taxa de Sobrevida , Timidilato Sintase/genética , Resultado do Tratamento
8.
Scand J Urol Nephrol ; 43(5): 409-15, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19921987

RESUMO

OBJECTIVE: Renal involvement in Henoch-Schönlein purpura (HSP) constitutes a risk of end-stage renal disease (ESRD), especially in patients presenting with nephrotic syndrome. PATIENTS AND METHODS: The clinical courses of six patients (mean age 13.2 years; four boys and two girls) admitted from 2000 to 2007 with HSP and nephrotic syndrome were reviewed. Average follow-up was 44 months (28-59). Treatment protocols included oral prednisolone and in non-responders cyclosporin A, cyclophosphamide, mycophenolate mofetil or tacrolimus. Five patients were treated immediately after presentation of nephrotic syndrome/nephrotic range proteinuria (median 277 mg/m(2)/h). The last patient was treated locally with low-dose prednisolone (0.2-0.9 mg/kg/day) and 3 months of low-dose cyclophosphamide (1 mg/kg/day). RESULTS: All five patients treated promptly with high-dose immunosuppressant had normal estimated glomerular filtration rate (eGFR) (median 159 ml/min/1.73 m(2)) at follow-up. One obtained complete remission, two had positive dipstick proteinuria and two needed angiotensin-converting enzyme inhibitors to stay normotensive. The patient receiving low-dose immunosuppression at onset progressed to ESRD 44 months later. At initial presentation eGFR, blood pressure, renal biopsy grading, proteinuric range and plasma albumin were similar in all patients. CONCLUSION: Follow-up data from the patients suggest that an early aggressive immunosuppressive approach improves long-term renal outcome in HSP patients with nephrotic syndrome.


Assuntos
Glucocorticoides/administração & dosagem , Vasculite por IgA/tratamento farmacológico , Terapia de Imunossupressão/métodos , Imunossupressores/administração & dosagem , Síndrome Nefrótica/tratamento farmacológico , Adolescente , Biópsia , Criança , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Vasculite por IgA/complicações , Vasculite por IgA/diagnóstico , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
9.
Ann Oncol ; 20(5): 879-84, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19179548

RESUMO

BACKGROUND: The effect of anti-epidermal growth factor receptor (EGFR) antibodies (mAb) in metastatic colorectal cancer seems limited to KRAS wild-type (wt) tumours, but still a major fraction of KRASwt patients are nonresponders and supplementary selection criteria are needed. We investigated methodological aspects of KRAS testing and the predictive and prognostic value of KRAS status combined with three EGFR-related gene polymorphisms [single-nucleotide polymorphisms (SNPs)] in patients treated with cetuximab and irinotecan. PATIENTS AND METHODS: The study included 71 patients referred to third-line cetuximab-irinotecan. Blood samples were analysed for SNPs. KRAS analysis was carried out by sequencing analysis and quantitative PCR (DxS kit) in primary tumour and distant metastases. RESULTS: There was a clear correlation between KRAS status in primary tumours and metastasis. The DxS kit presented the highest sensitivity. Response was confined to KRASwt patients (40% response rate versus 0%, P < 0.1(-3)), which translated into a significant difference in PFS. The EGF61A>G polymorphism showed relation to clinical outcome. A combined biomarker analysis showed a 19% progression rate in KRASwt-EGF61 homozygote patients and 60% in the EGF61A/G patients (P = 0.006) and a significant increase in overall survival (17.1 versus 5.9 months, log-rank, P = 0.002). CONCLUSION: The combined biomarker analysis maybe an attractive approach to selection of patients for third-line treatment including anti-EGFR mAbs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fator de Crescimento Epidérmico/genética , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Seleção de Pacientes , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Medição de Risco , Fatores de Tempo , Resultado do Tratamento
10.
Infect Immun ; 74(10): 5933-42, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16988273

RESUMO

The safety, immunogenicity, and efficacy of DNA and modified vaccinia virus Ankara (MVA) prime-boost regimes were assessed by using either thrombospondin-related adhesion protein (TRAP) with a multiple-epitope string ME (ME-TRAP) or the circumsporozoite protein (CS) of Plasmodium falciparum. Sixteen healthy subjects who never had malaria (malaria-naive subjects) received two priming vaccinations with DNA, followed by one boosting immunization with MVA, with either ME-TRAP or CS as the antigen. Immunogenicity was assessed by ex vivo gamma interferon (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) and antibody assay. Two weeks after the final vaccination, the subjects underwent P. falciparum sporozoite challenge, with six unvaccinated controls. The vaccines were well tolerated and immunogenic, with the DDM-ME TRAP regimen producing stronger ex vivo IFN-gamma ELISPOT responses than DDM-CS. One of eight subjects receiving the DDM-ME TRAP regimen was completely protected against malaria challenge, with this group as a whole showing significant delay to parasitemia compared to controls (P = 0.045). The peak ex vivo IFN-gamma ELISPOT response in this group correlated strongly with the number of days to parasitemia (P = 0.033). No protection was observed in the DDM-CS group. Prime-boost vaccination with DNA and MVA encoding ME-TRAP but not CS resulted in partial protection against P. falciparum sporozoite challenge in the present study.


Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária Falciparum/prevenção & controle , Plasmodium falciparum , Proteínas de Protozoários/imunologia , Vaccinia virus/genética , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Feminino , Humanos , Imunização Secundária , Interferon gama/sangue , Vacinas Antimaláricas/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Protozoários/genética , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Proteínas Virais/genética
11.
Contraception ; 26(3): 229-43, 1982 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-6217028

RESUMO

A triphasic, combined oral contraceptive containing 30 - 40 - 30 micrograms ethinyloestradiol (EE), and 50 - 75 - 125 micrograms levonorgestrel was compared with a fixed dose combination containing 30 micrograms EE and 150 micrograms desogestrel in a randomized multicentre trial in 193/199 women and 1 063/1 073 cycles, respectively. The duration of the trial was six months. Eleven centres in Denmark, Sweden, and Norway participated. Contraceptive reliability, bleeding control and side effects were evaluated. Influence on serum sex hormone binding globulin (SHBG) and transcortin was assayed as well as lipid metabolism. Three pregnancies occurred in the group using the triphasic regimen but none in the fixed dose regimen. Two of the three pregnancies were considered drug failures and the third a possible interaction. Possible reasons for the triphasic contraceptive failure are discussed with special reference to a British report on eight pregnancies. Bleeding control appeared to be equally good for the two preparations. However, the number of cycles with spotting, breakthrough bleeding and missed withdrawal bleeding were above the levels reported earlier on the triphasic regimen. About 80 per cent of the women completed the planned six months on either combination. Side effects were generally mild and in accordance with earlier reports on low dose oral contraceptives. Metabolically the triphasic levonorgestrel combination increased SHBG 100 per cent versus 200 per cent for the fixed desogestrel combination. Transcortin rose about 98 and 110 per cent, respectively. Both preparations induced similar changes in the levels of lipids and lipoproteins with the exception of a significant increase in the arachidonic content of cholesterol during treatment with the desogestrel-containing preparation.


Assuntos
Proteínas Sanguíneas/metabolismo , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais/administração & dosagem , Lipídeos/sangue , Adolescente , Adulto , Ensaios Clínicos como Assunto , Dinamarca , Desogestrel , Relação Dose-Resposta a Droga , Etinilestradiol/administração & dosagem , Ácidos Graxos/sangue , Feminino , Humanos , Levanogestrel , Lipoproteínas/sangue , Norgestrel/administração & dosagem , Norpregnenos/administração & dosagem , Noruega , Gravidez , Globulina de Ligação a Hormônio Sexual/metabolismo , Suécia , Transcortina/metabolismo
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