RESUMO
BACKGROUND: Previous studies have investigated the protective effect of vitamin D serum levels, at diagnosis and during the follow-up period after treatment, on melanoma outcome. In the present study we assess whether vitamin D supplementation, in the follow-up period after diagnosis and surgical resection of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and Vitamin D Receptor immunoreactivity in the primary tumor. METHODS/DESIGN: This study is a multicenter randomized double blind placebo- controlled phase III trial. Patients between the age of 18 and 80 years diagnosed and treated surgically for a melanoma stage IB-III are eligible for randomization in a 1:1 ratio to active treatment or placebo. The study drug is taken each month and consists of either 100,000 International Unit cholecalciferol or arachidis oleum raffinatum used as a placebo. The primary endpoint is relapse free survival. The secondary endpoints are 25 hydroxyvitamin D3 serum levels at diagnosis and at 6 month intervals, melanoma subtype, melanoma site and stage of melanoma at diagnosis according to the 2009 American Joint Committee on Cancer melanoma staging and classification. At randomization a bloodsample is taken for DNA analysis. The study is approved by the local Ethics Committees. DISCUSSION: If we can confirm our hypothesis that vitamin D supplementation after removal of the tumor has a protective effect on relapse of cutaneous malignant melanoma we may reduce the burden of CMM at several levels. Patients, diagnosed with melanoma may have a better clinical outcome and improved quality of life. There will be a decrease in health care costs related to treatment of metastatic disease and there will be a decrease in loss of professional years, which will markedly reduce the economic burden of the disease. TRIAL REGISTRATION: Clinical Trial.gov, NCT01748448 , 05/12/2012.
Assuntos
Protocolos Clínicos , Suplementos Nutricionais , Melanoma/epidemiologia , Neoplasias Cutâneas/epidemiologia , Vitamina D , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bélgica/epidemiologia , Calcifediol/sangue , Progressão da Doença , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Melanoma/etiologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Resultados da Assistência ao Paciente , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Fatores de Risco , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Vitamina D/administração & dosagem , Vitamina D/efeitos adversos , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.
Assuntos
Neoplasias Ósseas/patologia , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Osteoprotegerina/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Neoplasias Ósseas/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Genes src/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proto-Oncogene Mas , Ligante RANK/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.
Assuntos
Carcinoma de Células Renais/terapia , Determinação de Ponto Final/normas , Fidelidade a Diretrizes/normas , Neoplasias Renais/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Carcinoma de Células Renais/mortalidade , Técnica Delphi , Intervalo Livre de Doença , Determinação de Ponto Final/métodos , Humanos , Neoplasias Renais/mortalidade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
BACKGROUND: BRAF inhibitors frequently cause significant cutaneous adverse reactions. OBJECTIVE: To study the timing, prevalence and response to treatment of skin lesions in patients receiving V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors. METHODS: We prospectively studied the cutaneous side-effects of patients with a BRAF mutant (V600E, V600K, V600R) metastatic malignant melanoma treated with a BRAF inhibitor. We systematically registered prevalence, timing of onset and response to treatment. RESULTS: Twenty patients were treated for 2-52 weeks with a BRAF inhibitor. Eleven patients on vemurafenib (58%) developed cutaneous side-effects and 10 patients (42%) had more than one cutaneous adverse event. Verrucous papillomas were observed in eight patients (42%), after 1-12 weeks. We diagnosed four keratoacanthomas in two patients (11%) after 6-10 weeks and two squamous cell carcinomas in two patients (11%) after 10-16 weeks. Seven patients (37%) developed a hyperkeratotic, folliculocentric eruption after 2-8 weeks, resolving quickly under topical steroids. Four patients (21%) presented a facial erythema, two patients (11%) a seborrhoeic dermatitis-like eczema on the scalp. Three patients (16%) developed cystic lesions after 2-11 weeks. Three patients (16%) presented a hand-foot skin reaction after 4-6 weeks, which was successfully treated with topical steroids and keratolytics. Hyperkeratosis of the nipples was seen in one patient (5%). We observed phototoxic reactions after UV exposure in five patients (26%) and alopecia in two patients (11%) after 8-10 weeks. One patient on dabrafenib developed curly hairs (24 weeks), keratotic papules (1 and 36 weeks), a keratoacanthoma (4 weeks) and a hand-foot skin reaction (31 weeks). CONCLUSION: Multiple cutaneous toxicities were observed in patients under BRAF inhibitors, mostly well controlled with adequate treatment. We recommend a multidisciplinary approach with regular assessments of the skin by a dermatologist. This allows early identification and adequate treatment to avoid premature discontinuation of a life-prolonging therapy.
Assuntos
Antineoplásicos/efeitos adversos , Indóis/efeitos adversos , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/induzido quimicamente , Carcinoma de Células Escamosas/induzido quimicamente , Dermatite Fototóxica/etiologia , Eczema/induzido quimicamente , Eritema/induzido quimicamente , Dermatoses Faciais/induzido quimicamente , Feminino , Síndrome Mão-Pé/etiologia , Humanos , Imidazóis/efeitos adversos , Ceratoacantoma/induzido quimicamente , Masculino , Melanoma/genética , Melanoma/secundário , Pessoa de Meia-Idade , Oximas/efeitos adversos , Papiloma/induzido quimicamente , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , VemurafenibRESUMO
BACKGROUND: In a randomized phase III study, trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma. PATIENTS AND METHODS: Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire. RESULTS: In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent. CONCLUSIONS: This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.
Assuntos
Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Nível de Saúde , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/mortalidade , Pessoa de Meia-Idade , Mutação , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Qualidade de Vida , Inquéritos e QuestionáriosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/uso terapêutico , Melanoma/tratamento farmacológico , Oximas/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Humanos , Imidazóis/farmacologia , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , Mutação , Oximas/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacologia , Pirimidinonas/farmacologia , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Accurate prediction of outcome for metastatic renal cell carcinoma (mRCC) patients receiving targeted therapy is essential. Most of the available models have been developed in patients treated with cytokines, while most of them are fairly complex, including at least five factors. We developed and externally validated a simple model for overall survival (OS) in mRCC. We also studied the recently validated International Database Consortium (IDC) model in our data sets. METHODS: The development cohort included 170 mRCC patients treated with sunitinib. The final prognostic model was selected by uni- and multivariate Cox regression analyses. Risk groups were defined by the number of risk factors and by the 25th and 75th percentiles of the model's prognostic index distribution. The model was validated using an independent data set of 266 mRCC patients (validation cohort) treated with the same agent. RESULTS: Eastern Co-operative Oncology Group (ECOG) performance status (PS), time from diagnosis of RCC and number of metastatic sites were included in the final model. Median OS of patients with 1, 2 and 3 risk factors were: 24.7, 12.8 and 5.9 months, respectively, whereas median OS was not reached for patients with 0 risk factors. Concordance (C) index for internal validation was 0.712, whereas C-index for external validation was 0.634, due to differences in survival especially in poor-risk populations between the two cohorts. Predictive performance of the model was improved after recalibration. Application of the mRCC International Database Consortium (IDC) model resulted in a C-index of 0.574 in the development and 0.576 in the validation cohorts (lower than those recently reported for this model). Predictive ability was also improved after recalibration in this analysis. Risk stratification according to IDC model showed more similar outcomes across the development and validation cohorts compared with our model. CONCLUSION: Our model provides a simple prognostic tool in mRCC patients treated with a targeted agent. It had similar performance with the IDC model, which, however, produced more consistent survival results across the development and validation cohorts. The predictive ability of both models was lower than that suggested by internal validation (our model) or recent published data (IDC model), due to differences between observed and predicted survival among intermediate and poor-risk patients. Our results highlight the importance of external validation and the need for further refinement of existing prognostic models.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Modelos Estatísticos , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/secundário , Estudos de Coortes , União Europeia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Valor Preditivo dos Testes , Prognóstico , Sunitinibe , Análise de SobrevidaRESUMO
BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Pirróis/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Metástase Neoplásica , Estudos Retrospectivos , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. METHODS: Patients with advanced solid malignancies received docetaxel 75 mg/m(2) intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. RESULTS: Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m(2) docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m(2). The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤ 2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. CONCLUSION: Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Afatinib , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel , Esquema de Medicação , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Dermatopatias/induzido quimicamente , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Taxoides/farmacocinéticaRESUMO
It is often logistically impractical to measure forest defoliation events in the field due to seasonal variability in larval feeding phenology (e.g., start, peak, and end) in any given year. As such, field data collections are either incomplete or at coarse temporal resolutions, both of which result in inaccurate estimation of annual defoliation (frass or foliage loss). Using Choristoneura pinus F. and Lymantria dispar dispar L., we present a novel approach that leverages a weather-driven insect simulation model (BioSIM) and defoliation field data. Our approach includes optimization of a weighting parameter (w) for each instar and imputation of defoliation. Results show a negative skew in this weighting parameter, where the second to last instar in a season exhibits the maximum consumption and provides better estimates of annual frass and foliage biomass loss where sampling data gaps exist. Respective cross-validation RMSE (and normalized RMSE) results for C. pinus and L. dispar dispar are 77.53 kg·ha-1 (0.16) and 38.24 kg·ha-1 (0.02) for frass and 74.85 kg·ha-1 (0.10) and 47.77 kg·ha-1 (0.02) for foliage biomass loss imputation. Our method provides better estimates for ecosystem studies that leverage remote sensing data to scale defoliation rates from the field to broader landscapes and regions.â¢Utilize fine temporal resolution insect life cycle data derived from weather-driven insect simulation model (BioSIM) to bridge critical gaps in coarse temporal resolution defoliation field data.â¢Fitting distributions to optimize the instar weighting parameter (w) and impute frass and foliage biomass loss based on a cumulative density function (CDF).â¢Enables accurate estimation of annual defoliation impacts on ecosystems across multiple insect taxa that exhibit distinct but seasonally variable feeding phenology.
RESUMO
BACKGROUND: The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ). METHODS: Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk. RESULTS: Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates. CONCLUSION: Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Neoplasias Renais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/patologia , Carcinoma de Células Renais/patologia , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Indóis/administração & dosagem , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Osteonecrose/induzido quimicamente , Compostos de Fenilureia/administração & dosagem , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Pirróis/administração & dosagem , Estudos Retrospectivos , Sorafenibe , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: The aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib. PATIENTS AND METHODS: We reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST). RESULTS: Two hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P<0.0001) and 19.5 versus 38.5 months (P<0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P<0.0001) and OS (P=0.001). CONCLUSION: The presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirróis/uso terapêutico , Neoplasias Ósseas/secundário , Carcinoma de Células Renais/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Estudos Retrospectivos , Sunitinibe , Tomografia Computadorizada por Raios X , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Terapia de Salvação , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Cladribina/efeitos adversos , Cladribina/uso terapêutico , Terapia Combinada , Ensaios de Uso Compassivo , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia de Células Pilosas/sangue , Leucemia de Células Pilosas/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Neutropenia/induzido quimicamente , Neutropenia/complicações , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/genética , Aspergilose Pulmonar/etiologia , Indução de Remissão , Rituximab , EsplenectomiaRESUMO
Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant or -intolerant gastrointestinal stromal tumours (GIST). Several studies have identified unexpected rates of thyroid dysfunction with sunitinib treatment. We performed a prospective observational study with the aim of more accurately defining the incidence and severity of hypothyroidism in RCC or GIST patients receiving sunitinib. Thyroid function was assessed at baseline and on days 1 and 28 of each treatment cycle. Thyroid antibodies were assessed at baseline and during follow-up if abnormal thyroid function tests were recorded. Sixteen patients (27%) developed sub- or clinical hypothyroidism and required hormone replacement and 20 patients (34%) showed at least one elevated thyroid-stimulating hormone not requiring therapeutic intervention. Twenty patients (34%) did not develop any biochemical thyroid abnormality. Thus, sunitinib can induce (sub-) clinical hypothyroidism, warranting close monitoring of thyroid function. We propose a new algorithm for managing this side effect in clinical practise.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Hipotireoidismo/induzido quimicamente , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Pirróis/efeitos adversos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/fisiopatologia , Feminino , Tumores do Estroma Gastrointestinal/fisiopatologia , Humanos , Hipotireoidismo/fisiopatologia , Indóis/uso terapêutico , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirróis/uso terapêutico , Sunitinibe , Testes de Função TireóideaRESUMO
The conserved Myb-MuvB (MMB) multiprotein complex has an important role in transcriptional activation of mitotic genes. MMB target genes are overexpressed in several different cancer types and their elevated expression is associated with an advanced tumor state and a poor prognosis. This suggests that MMB could contribute to tumorigenesis by mediating overexpression of mitotic genes. However, although MMB has been extensively characterized biochemically, the requirement for MMB in tumorigenesis in vivo has not been investigated. Here we demonstrate that MMB is required for tumor formation in a mouse model of lung cancer driven by oncogenic K-RAS. We also identify a requirement for the mitotic kinesin KIF23, a key target gene of MMB, in tumorigenesis. RNA interference-mediated depletion of KIF23 inhibited lung tumor formation in vivo and induced apoptosis in lung cancer cell lines. Our results suggest that inhibition of KIF23 could be a strategy for treatment of lung cancer.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Cinesinas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Cinesinas/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Knockout , Mitose/genética , Complexos Multiproteicos/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-myb/genética , Carga TumoralAssuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Humanos , Indóis/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirróis/efeitos adversos , Projetos de Pesquisa , Sunitinibe , Resultado do TratamentoRESUMO
OBJECTIVES: This study was performed in order to evaluate the frequency of DI, the predictive factors of DI and to list the related complications. STUDY DESIGN: Prospective non randomized, open study. PATIENTS AND METHODS: All patients intubated in the critical care unit during the five months of the study were included. The previous history and clinical setting of the patients, the conditions and the complications of intubation were collected. DI was defined when the procedure required more than two laryngoscopies. RESULTS: The study included 80 patients. The rate of DI was 22.5%. The Mallampati score (p < 0.001) was the only predictive factor. The frequency of complications was 25%. This rate was 55% for DI versus 16% for easy intubations (p < 0.001). CONCLUSION: This study confirms the high incidence of DI and associated complications in critical care. We suggest the development of airway management protocols in critical care unit in order to reduce the rate of DI.
Assuntos
Cuidados Críticos , Intubação Intratraqueal/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Intubação Intratraqueal/estatística & dados numéricos , Laringoscopia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de RiscoRESUMO
Both volume preset and pressure preset ventilators are available for domiciliary nasal ventilation. Owing to their technical characteristics, it has been suggested that impaired ventilatory mechanics might cause a drop in the tidal volume (Vt) delivered by pressure preset devices, thereby placing mechanical ventilation at risk of inefficacy. We have assessed two ventilator systems (one pressure preset and one volume preset) with regard to the tidal volume and end-tidal carbon dioxide tension (PetCO(2)) changes that may be achieved in a group of awake patients with stable chronic respiratory failure (CRF). Eleven patients with stable CRF were ventilated in the assist/control mode for two consecutive one-hour periods. One ventilator was tested each hour, in random order. The VIGIL'AIR(R) system was used to record Vt, Respiratory Rate (RR), and Inspiratory/Expiratory ratio (I/E). The deviation E (E=preset value - measured value) was calculated for each measurement. Changes in PetCO(2) and arterial oxygen saturation were determined respectively by a capnometer and a pulse oximeter. Comparison of the mean deviation of Vt calculated for the two ventilators revealed a difference in patients with chronic obstructive pulmonary disease (COPD). The deviation was greatest with the pressure preset ventilator (PPV), which gave mean measured values higher than the mean preset values. The same comparison failed to reveal any difference in restrictive CRF. Comparison of the volume preset and pressure preset ventilators for RR, I/E and PetCO(2) did not reveal any difference. Compared to the volume preset ventilator, the efficacy of PPV to ventilate is not affected by the restrictive or obstructive nature of CRF. Our results show that pressure-preset ventilator is an adequate alternative to the volume-preset device for daytime non invasive ventilation in chronic respiratory insufficiency.
Assuntos
Pressão do Ar , Pressão Positiva Contínua nas Vias Aéreas/instrumentação , Serviços Hospitalares de Assistência Domiciliar , Medidas de Volume Pulmonar , Doença Pulmonar Obstrutiva Crônica/terapia , Insuficiência Respiratória/terapia , Idoso , Resistência das Vias Respiratórias/fisiologia , Calibragem , Dióxido de Carbono/sangue , Desenho de Equipamento , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Mecânica Respiratória/fisiologia , Volume de Ventilação Pulmonar/fisiologia , Resultado do TratamentoRESUMO
The steady increase in the use of oral anticancer drugs in modern oncology has created a paradigm shift, challenging traditional attitudes towards cancer care and requiring new concepts of organization of oncology services. Important issues are the prolonged treatment period, management of toxicity, treatment adherence, reimbursement conditions and patient and family education. Although most patients generally prefer oral therapy over intravenous treatment for reasons of convenience, the daily use of oral anticancer drugs can be a challenging commitment for many patients. Reports on adherence and persistence among patients with cancer show that adherence ranges from 16% to 100%, depending on the type of therapy and the measurement/definition of adherence. Apart from demographic, disease and therapy related factors, the determinants that mostly influence (non-)adherence are the satisfaction with care activities performed at the initiation of the drug treatment, and the perceived necessity of treatment. Therefore, patient education addressing these issues is considered the cornerstone of successful oral anticancer treatment. Studies examining the role of different health care providers in the pharmacotherapeutic care of patients with cancer, treated with oral anti-cancer drugs, support the need for a multidisciplinary approach to achieve a maximum benefit for the individual patient and consequently for the whole health system. Limiting adverse events and developing appropriate supportive care are only some aspects that need to be considered in this.