RESUMO
BACKGROUND: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018). PATIENTS AND METHODS: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. RESULTS: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. CONCLUSIONS: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.
Assuntos
Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Camptotecina/análogos & derivados , Carcinoma de Células de Transição , Imunoconjugados , Neoplasias da Bexiga Urinária , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Neoplasias da Bexiga Urinária/tratamento farmacológico , Imunoconjugados/efeitos adversosRESUMO
BACKGROUND: No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus. METHODS: Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0). RESULTS: PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus). CONCLUSIONS: The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT01136733.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Everolimo/administração & dosagem , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Intervalo Livre de Progressão , Quinolinas/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines. METHODS: In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ⩾median), and tumour burden (baseline sum of the longest diameter < vs ⩾median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated. RESULTS: Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy. CONCLUSIONS: AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Axitinibe , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Citocinas/uso terapêutico , Intervalo Livre de Doença , Humanos , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Indóis/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirróis/uso terapêutico , Sorafenibe , Sunitinibe , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND: This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours. METHODS: Two schedules with sunitinib (25-50 mg per day) and IV gemcitabine (750-1250 mg m(-2)) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib on a 2-weeks-on-1-week-off schedule (Schedule 2/1) plus gemcitabine on days 1 and 8. The primary endpoint was determination of MTD and tolerability. RESULTS: Forty-four patients received the combination (Schedule 4/2, n=8; Schedule 2/1, n=36). With no dose-limiting toxicities (DLTs) at maximum dose levels on Schedule 2/1, MTD was not reached. Grade 4 treatment-related AEs and laboratory abnormalities included cerebrovascular accident, hypertension, and pulmonary embolism (n=1 each), and neutropenia (n=3), thrombocytopenia and increased uric acid (both n=2), and lymphopenia (n=1). There were no clinically significant drug-drug interactions. Antitumor activity occurred across dose levels and tumour types. In poor-risk and/or high-grade renal cell carcinoma patients (n=12), 5 had partial responses and 7 stable disease ≥ 6 weeks. CONCLUSION: Sunitinib plus gemcitabine on Schedule 2/1 with growth factor support was well tolerated and safely administered at maximum doses of each drug, without significant drug-drug interactions.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacocinética , Sunitinibe , GencitabinaRESUMO
BACKGROUND: In a randomized phase III trial of sunitinib vs interferon-alfa (IFN-α) in metastatic renal cell carcinoma (mRCC), better baseline quality of life (QoL) was predictive of longer survival. Using this dataset, we have developed a novel prognostic tool that establishes a relationship between baseline QoL scores and median survival time. METHODS: Baseline QoL was assessed using the FACT-Kidney Symptom Index-15 item (FKSI-15), its disease-related symptoms (FKSI-DRS) subscale, and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. Weibull models estimated median progression-free survival (mPFS) and overall survival (mOS) as a function of baseline QoL. RESULTS: Longer PFS and OS were associated with higher baseline FKSI-15, FKSI-DRS, and FACT-G scores (P<0.05), and baseline FKSI-15 score was the best predictor of survival. For example, for a baseline FKSI-15 score of 60, the predicted mPFS was 67.9 weeks, and predicted mOS was 240.6 weeks. The magnitude of benefit was greater with sunitinib vs IFN-α for a given baseline QoL score. CONCLUSION: This novel tool indicates that baseline FKSI-15 scores were linked to mPFS and mOS in a clear and interpretable way. The results support evaluation of patient-reported QoL symptoms at baseline as a prognostic indicator of survival in clinical research and practice.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/psicologia , Indóis/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/psicologia , Pirróis/uso terapêutico , Qualidade de Vida , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Interferon-alfa/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , SunitinibeRESUMO
BACKGROUND: In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis. METHODS: In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes. RESULTS: Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α. CONCLUSION: Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirróis/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Humanos , Indóis/efeitos adversos , Interferon-alfa/efeitos adversos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Metástase Neoplásica/tratamento farmacológico , Pirróis/efeitos adversos , SunitinibeRESUMO
BACKGROUND: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP). RESULTS: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase. CONCLUSIONS: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.
Assuntos
Dioxóis/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Estudos de Coortes , Dioxóis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Orquiectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Sarcoma/patologia , Sarcoma/cirurgia , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina , Falha de Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: Analysis of prognostic factors for progression-free survival (PFS) and overall survival (OS) was performed using final data from a randomized phase III trial of sunitinib versus interferon-α (IFN-α) as first-line metastatic renal cell carcinoma (RCC) therapy. DESIGN: A multivariate Cox regression model analyzed baseline variables for prognostic significance. Each variable was investigated univariately and then multivariately using a stepwise algorithm. RESULTS: Each treatment arm comprised 375 patients. For sunitinib, multivariate analysis of PFS identified five independent predictors, including serum lactate dehydrogenase (LDH) level, presence of ≥2 metastatic sites, no prior nephrectomy, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline platelet count, while multivariate analysis of OS identified serum LDH level, corrected serum calcium level, time from diagnosis to treatment, hemoglobin level, ECOG performance status, and presence of bone metastasis as predictors. For IFN-α, LDH level and presence of ≥2 metastatic sites were common predictors of PFS to those for sunitinib, as were all predictors of OS except ECOG status. CONCLUSIONS: This analysis identified prognostic factors for PFS and OS with sunitinib as first-line metastatic RCC therapy and confirmed that the Memorial Sloan-Kettering Cancer Center model is applicable in the era of targeted therapy.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirróis/uso terapêutico , Idoso , Carcinoma de Células Renais/patologia , Progressão da Doença , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Metástase Neoplásica , Sunitinibe , Análise de SobrevidaRESUMO
BACKGROUND: In a randomised phase III trial, sunitinib significantly improved efficacy over interferon-alpha (IFN-alpha) as first-line therapy for metastatic renal cell carcinoma (mRCC). We report the final health-related quality of life (HRQoL) results. METHODS: Patients (n=750) received oral sunitinib 50 mg per day in 6-week cycles (4 weeks on, 2 weeks off treatment) or subcutaneous IFN-alpha 9 million units three times weekly. Health-related quality of life was assessed with nine end points: the Functional Assessment of Cancer Therapy-General and its four subscales, FACT-Kidney Symptom Index (FKSI-15) and its Disease-Related Symptoms subscale (FKSI-DRS), and EQ-5D questionnaire's EQ-5D Index and visual analogue scale. Data were analysed using mixed-effects model (MM), supplemented with pattern-mixture models (PMM), for the total sample and the US and European Union (EU) subgroups. RESULTS: Patients receiving sunitinib reported better scores in the primary end point, FKSI-DRS, across all patient populations (P<0.05), and in nine, five, and six end points in the total sample, in the US and EU groups respectively (P<0.05). There were no significant differences between the US and EU groups for all end points with the exception of the FKSI item 'I am bothered by side effects of treatment' (P=0.02). In general, MM and PMM results were similar. CONCLUSION: Patients treated with sunitinib in this study had improved HRQoL, compared with patients treated with IFN-alpha. Treatment differences within the US cohort did not differ from those within the EU cohort.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirróis/uso terapêutico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/psicologia , Feminino , Geografia , Nível de Saúde , Humanos , Neoplasias Renais/psicologia , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Sunitinibe , Inquéritos e QuestionáriosRESUMO
Programmed cell death (PCD) of sympathetic neurons is inhibited by nerve growth factor. However, factors that induce PCD of these cells are unknown. Leukemia inhibitory factor (LIF) and ciliary neurotrophic factor, neuropoietic cytokines known to regulate sympathetic neuron gene expression, were examined for effects on survival of cultured sympathetic neurons. Treatment with LIF or ciliary neurotrophic factor caused neuronal death in a dose-dependent fashion. Inhibition of RNA or protein synthesis, or treatment with potassium, all of which prevent PCD after nerve growth factor deprivation, prevented LIF-induced death. The morphologic and ultrastructural characteristics of the neuronal death induced by LIF and by nerve growth factor deprivation were similar. Furthermore, LIF treatment resulted in DNA fragmentation with a characteristic "ladder" on Southern blot analysis. These observations suggest that neuron numbers may be regulated by factors which initiate PCD, as well as by factors which prevent it.
Assuntos
Apoptose/efeitos dos fármacos , Citocinas/farmacologia , Inibidores do Crescimento/farmacologia , Interleucina-6 , Linfocinas/farmacologia , Fatores de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Neurônios/citologia , Gânglio Cervical Superior/citologia , Análise de Variância , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fator Neurotrófico Ciliar , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cinética , Fator Inibidor de Leucemia , Microscopia Eletrônica , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos , Receptores de Fator de Crescimento Neural/metabolismo , Fatores de TempoRESUMO
Ischemic heart disease (IHD) and systemic hypertension commonly coexist in a large number of patients, and the presence of hypertension is a risk factor for worsening IHD. A monotherapy that would effectively treat both is thus an attractive idea, and calcium antagonists have been evaluated in this role. Calcium antagonists exert therapeutic effects through a combination of actions, including systemic and peripheral vasodilation, negative inotropy, and reduced nodal conduction. In randomized, double-blind clinical trials, verapamil compares favorably with propranolol in the alleviation of angina and hypertension. Both diltiazem and nifedipine, as well as long-acting diltiazem, are also effective in treating the combined condition. In addition, each of these drugs enhances exercise tolerance and favors compliance with calcium antagonist therapy. Recent questions regarding the safety of this class of drug have tempered the enthusiasm for their use as first-line therapy in cardiovascular disease. In particular, short-acting dihydropyridine derivatives, including nifedipine and isradipine, may increase cardiovascular morbidity and mortality because of reflex sympathetic stimulation. The results of appropriately controlled, prospective clinical trials will provide more definitive conclusions. For now, we must be cautious in the use of calcium antagonist monotherapy for combined IHD and hypertension.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/efeitos adversos , Ensaios Clínicos Controlados como Assunto , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão/complicações , Isquemia Miocárdica/complicaçõesRESUMO
Obesity is a major risk factor for morbidity and mortality, and a series of pharmacologic approaches are available for helping to manage the problem. Obesity is caused by an imbalance between caloric intake and energy expenditure, which is influenced by both environmental and genetic factors. Pharmacologic treatments include anorexigenic agents, which fall into two broad categories: those that act via brain catecholamine pathways and those that act via serotonin pathways. The most recent oral agents approved are dexfenfluramine, which is currently being marketed, and sibutramine. Both agents inhibit the control reuptake of serotonin but in addition may have effects on thermogenesis. Under investigation are agents that increase energy expenditure: the beta 3-adrenergic receptor agonists and drugs that prevent the intestinal absorption of free fatty acids and cholesterol. In development are innovative approaches to influence leptin and its receptors, various obesity genes, and biologic substances thought to influence satiety (neuropeptide Y, enterostatin, cholecystokinin, bombesin, and amylin). Obesity has now become a major target for drug development not only for affecting obesity per se but also for managing and preventing comorbid conditions such as diabetes and cardiovascular disease.
Assuntos
Obesidade/tratamento farmacológico , Agonistas Adrenérgicos beta/uso terapêutico , Depressores do Apetite/uso terapêutico , Doenças Cardiovasculares/etiologia , Ciclobutanos/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Fenfluramina/uso terapêutico , Fluoxetina/uso terapêutico , Humanos , Obesidade/complicaçõesRESUMO
Transient retinal ischemia results in a delayed cell death of the inner retinal layers. This study demonstrates that this ischemic cell death occurs, at least in part, through apoptosis. The general endonuclease inhibitor, aurintricarboxylic acid, protected rat retinal cells from ischemic cell damage when administered before the onset of ischemia and, more importantly, when administered 6 hr after the insult. Thus, the demonstration that transient retinal ischemia results in cell damage as a result of apoptosis opens new therapeutic strategies aimed at lessening retinal damage as a result of this process.
Assuntos
Apoptose/efeitos dos fármacos , Ácido Aurintricarboxílico/uso terapêutico , Isquemia/fisiopatologia , Retina/fisiologia , Animais , Fragmentação do DNA , Marcadores Genéticos , Isquemia/tratamento farmacológico , Isquemia/patologia , Masculino , Microscopia Eletrônica , Ratos , Ratos Sprague-Dawley , Retina/ultraestruturaRESUMO
BACKGROUND: To determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study. METHODS: The relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan-Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test. RESULTS: In the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P<0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan-Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P<0.0001). CONCLUSIONS: A positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirróis/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Determinação de Ponto Final , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sunitinibe , Fatores de Tempo , Resultado do TratamentoRESUMO
Interleukin-7 (IL7) is a hematopoietic cytokine with critical functions in both B- and T-lymphocyte development. In this study, we find that IL7 exhibits trophic properties in the developing brain as well. Treatment of cultures of embryonic brain with exogenous IL7 increases neuronal survival and results in greater numbers of cells manifesting neurite outgrowth. As demonstrated with single-cell cultures, IL7 acts directly to promote neuronal survival. Expression of the mRNA encoding the high-affinity IL7 receptor (IL7R) is observed in vitro in neurons as well as in subventricular zone progenitor cells. Phosphorylation of p59fyn, which is activated by IL7 in pre-B cells and is thought to be important in neural development, occurs rapidly following IL7 treatment of cultured embryonic neurons. Additionally, the expression of c-myc mRNA, which is modulated by IL7 in lymphoid cells, is upregulated by IL7 in the same CNS cultures. Finally, the messenger RNAs encoding IL7 and IL7R are expressed in vivo in developing brain. The direct neurotrophic properties of IL7 combined with the expression of ligand and receptor in developing brain suggest that IL7 may be a neuronal growth factor of physiological significance during central nervous system (CNS) ontogeny.
Assuntos
Encéfalo/embriologia , Interleucina-7/fisiologia , Neurônios/fisiologia , Receptores de Fator de Crescimento Neural/fisiologia , Animais , Antígenos CD/biossíntese , Encéfalo/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Genes myc/efeitos dos fármacos , Interleucina-7/farmacologia , Neuritos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Gravidez , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-fyn , RNA Mensageiro/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina/biossíntese , Receptores de Interleucina-7 , Regulação para Cima/efeitos dos fármacosRESUMO
Invasive transitional cell carcinoma (TCC) of the urinary bladder is traditionally treated with radical cystectomy. This approach results in great morbidity and lifestyle changes, and approximately half of the patients treated in this way will experience recurrent TCC despite surgery. An alternative approach using selective bladder-preservation techniques incorporates transurethral resection of bladder tumours, radiation therapy, and chemotherapy. Over the past 20 years, international experience has demonstrated that this approach is feasible, safe, and well tolerated. Furthermore, the long-term outcomes of overall survival and disease-free survival compare favourably with the outcomes from radical cystectomy. The most important predictor of response is stage, with significantly higher long-term survival in patients with T2 disease. Another important positive predictor of complete response to therapy is the ability of the urologic oncologist to remove all visible tumour through a transurethral approach prior to initiation of radiation therapy. A negative predictive factor is the presence of hydronephrosis, and age and gender do not affect disease-free survival. The majority of patients who enjoy long-term survival do so with an intact native bladder. Quality of life studies have demonstrated that the retained bladder functions well in nearly all of these patients. Selective bladder preservation will not entirely take the place of radical cystectomy, but should be offered as an important alternative to patients newly diagnosed with muscle-invasive TCC.
Assuntos
Carcinoma de Células de Transição/cirurgia , Cistectomia , Estadiamento de Neoplasias , Neoplasias da Bexiga Urinária/cirurgia , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/radioterapia , Ensaios Clínicos como Assunto , Terapia Combinada , Intervalo Livre de Doença , Humanos , Hidronefrose/complicações , Morbidade , Seleção de Pacientes , Prognóstico , Qualidade de Vida , Terapia de Salvação , Resultado do Tratamento , Uretra/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/radioterapiaRESUMO
Colony stimulating factor-1 (CSF-1) was initially identified as a growth factor for mononuclear phagocytes. This study examines the role of CSF-1 in the development of the central nervous system (CNS). CSF-1 treatment of neurons cultured from embryonic brain promoted survival and process outgrowth in a dose-dependent manner. By contrast, CSF-1 treatment of neurons cultured from the osteopetrotic (op/op) mouse, a null mutant for CSF-1, promoted significantly less process outgrowth, suggesting that there are neural abnormalities in op/op animals. Nuclease protection assays were used to determine whether CSF-1 and its receptor are expressed at times appropriate to regulate neural development. Both CSF-1 and its receptor are expressed in developing mouse brain, with a unique pattern of CSF-1 mRNA splice variant expression encoding secreted, and not membrane-bound, growth factor. To determine whether brain function is altered by null mutation of CSF-1, op/op mice were examined using electrophysiologic assays. Brainstem auditory and visual evoked potentials were both abnormal in op/op mice. Further, intracortical recordings revealed aberrant neuronal function within visual cortex and alterations in the cortical circuitry that balances excitation and inhibition. Daily CSF-1 injection of postnatal op/op mice largely rescued the abnormal neural phenotype, confirming that the absence of CSF-1 during development is responsible for the abnormalities. The effects of CSF-1 on cultured embryonic neural cells, the developmentally appropriate expression of CSF-1 and its receptor, and the neurological abnormalities in op/op mice suggest a role for CSF-1 in brain development.