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1.
Int J Mol Sci ; 24(24)2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38139060

RESUMO

Natural killer (NK) cells are a vital component of cancer immune surveillance. They provide a rapid and potent immune response, including direct cytotoxicity and mobilization of the immune system, without the need for antigen processing and presentation. NK cells may also be better tolerated than T cell therapy approaches and are susceptible to various gene manipulations. Therefore, NK cells have become the focus of extensive translational research. Gamida Cell's nicotinamide (NAM) platform for cultured NK cells provides an opportunity to enhance the therapeutic potential of NK cells. CD38 is an ectoenzyme ubiquitously expressed on the surface of various hematologic cells, including multiple myeloma (MM). It has been selected as a lead target for numerous monoclonal therapeutic antibodies against MM. Monoclonal antibodies target CD38, resulting in the lysis of MM plasma cells through various antibody-mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, significantly improving the outcomes of patients with relapsed or refractory MM. However, this therapeutic strategy has inherent limitations, such as the anti-CD38-induced depletion of CD38-expressing NK cells, thus hindering ADCC. We have developed genetically engineered NK cells tailored to treat MM, in which CD38 was knocked-out using CRISPR-Cas9 technology and an enhanced chimeric antigen receptor (CAR) targeting CD38 was introduced using mRNA electroporation. This combined genetic approach allows for an improved cytotoxic activity directed against CD38-expressing MM cells without self-inflicted NK-cell-mediated fratricide. Preliminary results show near-complete abolition of fratricide with a 24-fold reduction in self-lysis from 19% in mock-transfected and untreated NK cells to 0.8% of self-lysis in CD38 knock-out CAR NK cells. Furthermore, we have observed significant enhancements in CD38-mediated activity in vitro, resulting in increased lysis of MM target cell lines. CD38 knock-out CAR NK cells also demonstrated significantly higher levels of NK activation markers in co-cultures with both untreated and αCD38-treated MM cell lines. These NAM-cultured NK cells with the combined genetic approach of CD38 knockout and addition of CD38 CAR represent a promising immunotherapeutic tool to target MM.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , Células Matadoras Naturais , Citotoxicidade Celular Dependente de Anticorpos
2.
Lancet Oncol ; 18(1): 143-154, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27979599

RESUMO

BACKGROUND: We applied mathematical models to clinical trial data available at Project Data Sphere LLC (Cary, NC, USA), a non-profit universal access data-sharing warehouse. Our aim was to assess the rates of cancer growth and regression using the comparator groups of eight randomised clinical trials that enrolled patients with metastatic castration-resistant prostate cancer. METHODS: In this retrospective analysis, we used data from eight randomised clinical trials with metastatic castration-resistant prostate cancer to estimate the growth (g) and regression (d) rates of disease burden over time. Rates were obtained by applying mathematical models to prostate-specific antigen levels as the representation of tumour quantity. Rates were compared between study interventions (prednisone, mitoxantrone, and docetaxel) and off-treatment data when on-study treatment had been discontinued to understand disease behaviour during treatment and after discontinuation. Growth (g) was examined for association with a traditional endpoint (overall survival) and for its potential use as an endpoint to reduce sample size in clinical trials. FINDINGS: Estimates for g, d, or both were obtained in 2353 (88%) of 2678 patients with data available for analysis; g differentiated docetaxel (a US Food and Drug Administration-approved therapy) from prednisone and mitoxantrone and was predictive of overall survival in a landmark analysis at 8 months. A simulated sample size analysis, in which g was used as the endpoint, compared docetaxel data with mitoxantrone data and showed that small sample sizes were sufficient to achieve 80% power (16, 47, and 25 patients, respectively, in the three docetaxel comparator groups). Similar results were found when the mitoxantrone data were compared with the prednisone data (41, 39, and 41 patients in the three mitoxantrone comparator groups). Finally, after discontinuation of docetaxel therapy, median tumour growth (g) increased by nearly five times. INTERPRETATION: The application of mathematical models to existing clinical data allowed estimation of rates of growth and regression that provided new insights in metastatic castration-resistant prostate cancer. The availability of clinical data through initiatives such as Project Data Sphere, when combined with innovative modelling techniques, could greatly enhance our understanding of how cancer responds to treatment, and accelerate the productivity of clinical development programmes. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Ensaios Clínicos Fase III como Assunto , Docetaxel , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Mitoxantrona/administração & dosagem , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem
3.
Cancer Invest ; 35(5): 333-344, 2017 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-28368708

RESUMO

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.


Assuntos
Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Serviços de Saúde Comunitária/tendências , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Padrões de Prática Médica/tendências , Sistema de Registros , Serviços de Saúde Comunitária/estatística & dados numéricos , Progressão da Doença , Recursos em Saúde/estatística & dados numéricos , Recursos em Saúde/tendências , Humanos , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Qualidade de Vida , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
4.
Blood Adv ; 8(5): 1200-1208, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38055922

RESUMO

ABSTRACT: Patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant (allo-HCT) require extensive care. Using the Merative MarketScan Commercial Claims and Encounters database (2016 Q1-2020 Q2), we quantified the costs of care and assessed real-world complication rates among commercially insured US patients diagnosed with a hematologic malignancy and aged between 12 and 64 years undergoing inpatient allo-HCT. Health care resource use and costs were assessed from 100 days before HCT to 100 days after HCT. Primary hospitalization was defined as the time from HCT until first discharge date. Incidence of complications was assessed using medical billing codes from HCT date to 100 days after HCT. Among the 1082 patients analyzed, allo-HCT grafts included peripheral blood (79%), bone marrow (11%), and umbilical cord blood (3%). In the 100 days after HCT, 52% of the patients experienced acute graft-versus-host disease; 21% had cytomegalovirus infection. The median primary hospitalization length of stay (LOS) was 28 days; 31% required readmission in first 100 days after HCT. Across the transplant period (14 days pretransplant to 100 days posttransplant), 44% of patients were admitted to the intensive care unit with a median LOS of 29 days. Among those with noncapitated health plans (n = 937), median cost of all-cause health care per patient during the transplant period was $331 827, which was driven by primary hospitalization and readmission. Additionally, the predicted median incremental costs per additional day in an inpatient setting increased with longer LOS (eg, $3381-$4071, 10th-20th day.) Thus, decreasing length of primary hospitalization and avoiding readmissions should significantly reduce the allo-HCT cost of care.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Custos de Cuidados de Saúde , Hospitalização , Neoplasias Hematológicas/terapia , Aloenxertos
5.
Adv Ther ; 41(4): 1637-1651, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38427220

RESUMO

INTRODUCTION: In a phase III clinical trial (NCT02730299), omidubicel-onlv, a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy, showed rapid hematopoietic and immune recovery compared with standard umbilical cord blood (UCB) transplant across all racial/ethnic groups. METHODS: A decision-tree model was used to project the effect of omidubicel-onlv availability on addressing health disparities in allogeneic hematopoietic cell transplantation (allo-HCT) access and outcomes for patients with hematologic malignancies. The model used a hypothetical population of 10,000 allo-HCT-eligible US adults, for whom matched related donors were not available. Patients received matched or mismatched unrelated donor, haploidentical, UCB transplant, or no transplant. Scenarios with omidubicel-onlv use of 0% (status quo), 10%, 15%, 20%, and 30% were modeled on the basis of proportional reductions in other allo-HCT sources or no transplant by racial/ethnic group. RESULTS: Increased omidubicel-onlv use was associated with a higher proportion of patients undergoing allo-HCT, decreased time to allo-HCT, decreased 1-year non-relapse mortality, and increased 1-year overall survival, particularly among racial minorities. In the scenario modeling 20% omidubicel-onlv use, the proportion of Black patients receiving allo-HCT increased by 129%; increases were also observed in Asian (64%), Hispanic (45%), and other (42%) patient groups. Modeled time to allo-HCT improved among transplanted patients (23%) from 11.4 weeks to 8.8 weeks. One-year OS in the overall population increased by 3%, with improvements ranging from 3% for White patients to 5% for Black patients. CONCLUSION: This study demonstrates that broad access to omidubicel-onlv could increase access to allo-HCT and improve outcomes for patients, with the greatest benefits seen among racial/ethnic minority groups.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Etnicidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/etnologia , Grupos Minoritários , Estudos Retrospectivos , Ensaios Clínicos Fase III como Assunto , Asiático , Hispânico ou Latino , Negro ou Afro-Americano , Brancos
6.
Sci Transl Med ; 15(705): eade3341, 2023 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-37467318

RESUMO

Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of l-selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 in this study support further development as a cancer therapy.


Assuntos
Interleucina-15 , Linfoma não Hodgkin , Humanos , Interleucina-15/metabolismo , Niacinamida/metabolismo , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/metabolismo , Rituximab/metabolismo , Células Matadoras Naturais
7.
Transplant Cell Ther ; 29(5): 338.e1-338.e6, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36775201

RESUMO

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Humanos , Seguimentos , Estudos Prospectivos , Intervalo Livre de Doença , Estudos Multicêntricos como Assunto
8.
N Engl J Med ; 356(2): 125-34, 2007 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-17215530

RESUMO

BACKGROUND: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma. METHODS: From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005. RESULTS: At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo. CONCLUSIONS: As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects. (ClinicalTrials.gov number, NCT00073307 [ClinicalTrials.gov].).


Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Carcinoma de Células Renais/mortalidade , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Sorafenibe
9.
Clin Genitourin Cancer ; 18(5): e598-e609, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32280027

RESUMO

BACKGROUND: A growing body of evidence suggests that age and gender play a role in cancer outcomes. The objective of this study was to investigate the effect of age and gender on survival of patients with metastatic renal cell carcinoma (RCC). METHODS: We conducted a pooled analysis of patients with metastatic RCC treated on phase II and III clinical trials. Patients were stratified by age (young [<50 years], intermediate [50-70 years], versus elderly [>70 years]) and gender. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: We identified 4736 patients with metastatic RCC. Overall, there was no difference in overall survival (OS) when stratified by age (21.0 vs. 17.3 months for elderly vs. intermediate age groups, P = .382; 20.0 vs. 17.3 months for young vs. intermediate age groups, P = .155) or gender (19.8 vs. 19.0 for male vs. female, P = .510). Progression-free survival (PFS) was shorter in younger individuals compared with the intermediate age patients (6.0 vs. 7.1 months, P < .001), but similar across gender groups. Although all grade adverse events were more common in elderly patients (fatigue, diarrhea, decreased appetite, and weight), serious adverse events were similar between groups. CONCLUSIONS: Although OS was similar between age groups, younger individuals had a shorter PFS. Gender was not an independent determinant of survival. Elderly patients experienced more adverse events than their younger counterparts. These findings are important to guide clinicians when counseling patients about expectations and toxicity associated with therapy.


Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Idoso , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
10.
Eur Urol Oncol ; 3(3): 372-381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31562048

RESUMO

BACKGROUND: Antibiotic use alters commensal gut microbiota, which is a key regulator of immune homeostasis. OBJECTIVE: To investigate the impact of antibiotic use on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with systemic agents. DESIGN, SETTING, AND PARTICIPANTS: We analyzed two cohorts: an institutional cohort (n=146) receiving programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) and a trial-database cohort (n=4144) receiving interferon-α (n=510), mammalian target of rapamycin (mTOR) inhibitors (n=660), and vascular endothelial growth factor targeted therapies (VEGF-TT; n=2974) on phase II/III clinical trials. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated using Cox regression, adjusted for known prognostic factors including International Metastatic RCC Database Consortium risk factors. RESULTS AND LIMITATIONS: Most patients were male, had clear cell histology, and were at an intermediate risk. Overall, in the institutional cohort, objective response rate (ORR) was 30%, PFS was 7.2 mo, and 1-yr OS was 77%. Antibiotic users (n=31, 21%) had a lower ORR (12.9% vs 34.8%, p=0.026) and shorter PFS (adjusted hazard ratio [HR]=1.96, 95% confidence interval [CI] 1.20-3.20, p=0.007) than antibiotic nonusers. In the trial-database cohort, antibiotic use (n=709, 17%) adversely impacted OS in patients treated with interferon (HR=1.62, 95% CI 1.13-2.31, p=0.008) or with VEGF-TT and prior cytokines (HR=1.65, 95% CI 1.04-2.62, p=0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines. Limitations include retrospective design, and limited details regarding concomitant medications and antibiotic indication/duration. CONCLUSIONS: Antibiotic use appears to reduce the efficacy of immunotherapy-based regimens in mRCC. The modulation of gut microbiota may play an important role in optimizing outcomes of patients treated with ICIs. PATIENT SUMMARY: We evaluated metastatic renal cell carcinoma patients and found that those who were treated with immunotherapy had worse outcomes if they also received antibiotics at the start of treatment. This study highlights the importance of judicious antibiotic use.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Carcinoma de Células Renais/secundário , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
11.
JCO Glob Oncol ; 6: 293-306, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32109159

RESUMO

PURPOSE: To investigate whether black race is an independent predictor of overall survival (OS) in metastatic renal cell carcinoma (mRCC). METHODS: We performed a retrospective 2-cohort (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] and trial-database) study of patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). Unmatched (UM) and matched (M) analyses accounting for imbalances in region, year of treatment, age, and sex between races were performed. Cox models adjusting for histology, number of metastatic sites, nephrectomy, and IMDC risk compared time to treatment failure (TTF; IMDC cohort), progression-free survival (PFS; trial-database cohort), and OS. RESULTS: The IMDC cohort included 73 black versus 3,381 (UM) and 1,236 (M) white patients. The trial-database cohort included 21 black versus 1,040 (UM) and 431 (M) white patients. Median OS for black versus white patients was 18.5 versus 25.8 months in the IMDC group and 21.0 versus 25.6 months in the trial-database group. Differences in OS were not significant in multivariable analysis in the IMDC group (hazard ratio [HR]M, 1.0; 95% CI, 0.7 to 1.5; HRUM, 1.1; 95% CI, 0.8 to 1.4) and trial-database (HRM, 1.5; 95% CI, 0.8 to 2.7; HRUM, 1.4; 95% CI, 0.8 to 2.6) cohorts. TTF for black patients was shorter in the UM IMDC cohort (HRUM, 1.4; 95% CI, 1.1 to 1.8; P = .003), but not in the M analysis. PFS was shorter for black patients in both analyses in the trial-database cohort (HRM, 2.3; 95% CI, 1.4 to 3.9; P = .002; HRUM, 2.3; 95% CI, 1.4 to 3.9; P = .002). CONCLUSION: Black patients had more IMDC risk factors and worse outcomes with TKIs versus white patients. Race was not an independent predictor of OS. Strategies to understand biologic determinants of outcomes for minority patients are needed to optimize care.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Negro ou Afro-Americano , Carcinoma de Células Renais/tratamento farmacológico , Intervalo Livre de Doença , Humanos , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos
12.
Nat Rev Drug Discov ; 5(10): 835-44, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17016424

RESUMO

Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 - was completed in just 11 years, with approval being received approximately 5 years after the initiation of the first Phase I trial.


Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Animais , Benzenossulfonatos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Ensaios Clínicos como Assunto , Técnicas de Química Combinatória , Humanos , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sorafenibe , Quinases raf/antagonistas & inibidores
13.
Clin Genitourin Cancer ; 17(6): 443-450.e1, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31601515

RESUMO

BACKGROUND: The relationship between weight change during treatment and survival remains poorly characterized in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In this retrospective analysis we included 3311 patients with mRCC treated in phase II/III first-line or second-line targeted therapy clinical trials and assessed the effect of weight change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) at 6 and 12 weeks from treatment initiation. Weight change was defined as weight loss (≥5% reduction), weight gain (≥2% increase), or stable weight from baseline. Survival analyses were performed using the Kaplan-Meier method and adjusted for known prognostic factors using Cox regression multivariable analysis. RESULTS: Overall, 1916 (58%) had stable weight, 936 (28%) had weight loss, and 459 (14%) had weight gain at 12 weeks. Patients with weight loss at 12 weeks had inferior OS compared with those with stable weight (hazard ratio [HR], 1.494; 95% confidence interval [CI], 1.322-1.688; P < .0001; median OS 18.7 vs. 26.9 months), and shorter PFS (HR, 1.315; 95% CI, 1.189-1.455; P < .0001; median PFS, 7.2 vs. 10.1 months). The ORRs for patients with weight loss, stable weight, and weight gain at 12 weeks were 23.4% (n = 219/936), 32.1% (n = 615/1916), and 35.9% (n = 165/459), respectively (adjusted odds ratio, 0.715; P = .03). Findings were consistent at 6 weeks. Adverse events were similar between groups. CONCLUSION: We showed that mRCC patients who experience weight loss during treatment have worse outcomes compared with patients with stable weight at 6 and 12 weeks of treatment. Weight loss at 6 weeks from treatment initiation might be an early clinical biomarker of worse survival and might provide prognostic utility.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Redução de Peso , Adulto , Carcinoma de Células Renais/mortalidade , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Terapêutica , Tempo para o Tratamento
14.
Eur Urol ; 76(6): 852-860, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31594707

RESUMO

BACKGROUND: Upfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials. OBJECTIVE: We investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox's models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses. RESULTS AND LIMITATIONS: In total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naïve, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16-23) in patients treated with first-line therapy (any type), 28% (22-33) in those treated with first-line VEGF-targeted therapy, and 23% (19-28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5-13) and 20% (15-27) in IMDC poor- and intermediate-risk patients, respectively. CONCLUSIONS: Systemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics. PATIENT SUMMARY: Antiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
16.
Clin Cancer Res ; 13(9): 2684-91, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17473200

RESUMO

PURPOSE: To evaluate the combination of sorafenib and gefitinib in patients with advanced non-small cell lung cancer. EXPERIMENTAL DESIGN: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. RESULTS: Thirty-one patients were treated (n=12, part A; n=19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C(max) (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n=8, part A; n=12, part B) had stable disease >or=4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. CONCLUSIONS: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non-small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piridinas/uso terapêutico , Quinazolinas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzenossulfonatos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Gefitinibe , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Quinazolinas/efeitos adversos , Sorafenibe
17.
J Glob Oncol ; 4: 1-14, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30241151

RESUMO

PURPOSE: Health determinants vary according to geographic region and may affect the outcomes of patients with metastatic renal cell carcinoma (mRCC) treated during clinical trials of targeted therapy. Here, we investigate the overall survival (OS) of patients with mRCC treated in the era of targeted therapy by geographic region. METHODS: We conducted a pooled analysis of patients with mRCC who were treated during phase II or III clinical trials. Clinical characteristics and survival data were collected. Statistical analyses were performed with the Kaplan-Meier method and log-rank test in univariable analysis. RESULTS: Overall, 4,736 patients were included in the analysis. Patient characteristics differed according to geographic region. No statistically significant differences in OS were observed when the United States/Canada (USC) was compared with the following other regions: Latin America, Asia/Oceania/Africa, and Eastern Europe. In a univariable analysis, OS differed among patients enrolled in trials in USC compared with Western Europe (20.3 v 17.4 months; hazard ratio, 1.15; 95% CI, 1.03 to 1.3; P = .015), but it did not differ in a multivariable analysis. All-grade treatment-related adverse events (AEs) were observed more frequently in USC. There were no significant differences in grade 3 to 5 AEs among groups. CONCLUSION: Despite different baseline characteristics, OS was similar among patients enrolled in clinical trials across different geographic regions. Access to clinical trials as well as disease biology, AE reporting, and quality of care may contribute to potential differences in outcomes.


Assuntos
Carcinoma de Células Renais/epidemiologia , Neoplasias Renais/epidemiologia , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
18.
Clin Genitourin Cancer ; 16(2): e327-e333, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29361425

RESUMO

BACKGROUND: Cardiac metastases from renal cell carcinoma (RCC) are uncommon and there are limited data regarding the presentation and outcomes of this population. The objective of this study was to evaluate the characteristics and outcomes of patients with RCC with cardiac metastasis without inferior vena cava (IVC) involvement. MATERIALS AND METHODS: We conducted a pooled retrospective analysis of metastatic RCC patients treated in 4 clinical trials. Additionally, we conducted a systematic review of cases reported in the literature from 1973 to 2015. Patients with cardiac metastases from RCC without IVC involvement were included. Patient and disease characteristics were described. Additionally, treatments, response to therapy, and survival outcomes were summarized. RESULTS: Of 1765 metastatic RCC patients in the clinical trials database, 10 had cardiac metastases without IVC involvement. All patients received treatment with targeted therapy. There was 1 observed partial response (10%) and 6 patients showed stable disease (60%). The median progression-free survival was 6.9 months. The systematic review of reported clinical cases included 39 patients. In these patients, the most common cardiac site of involvement was the right ventricle (51%; n = 20). Patients were treated with medical (28%; n = 11) and/or surgical treatment (49%; n = 19) depending on whether disease was isolated (n = 13) or multifocal (n = 26). CONCLUSION: To our knowledge, this is the first series to report on the presentation and outcomes of patients with cardiac metastasis without IVC involvement in RCC. We highlight that although the frequency of patients with cardiac metastases without IVC involvement is low, these patients have a unique clinical presentation and warrant special multidisciplinary management.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Cardíacas/tratamento farmacológico , Neoplasias Cardíacas/secundário , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Idoso , Carcinoma de Células Renais/cirurgia , Ensaios Clínicos como Assunto , Feminino , Neoplasias Cardíacas/cirurgia , Humanos , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Veia Cava Inferior/patologia
19.
J Clin Invest ; 113(1): 38-48, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14702107

RESUMO

A central tenet of fibrinolysis is that tissue plasminogen activator-dependent (t-PA- dependent) conversion of plasminogen to active plasmin requires the presence of the cofactor/substrate fibrin. However, previous in vitro studies have suggested that the endothelial cell surface protein annexin II can stimulate t-PA-mediated plasminogen activation in the complete absence of fibrin. Here, homozygous annexin II-null mice displayed deposition of fibrin in the microvasculature and incomplete clearance of injury-induced arterial thrombi. While these animals demonstrated normal lysis of a fibrin-containing plasma clot, t-PA-dependent plasmin generation at the endothelial cell surface was markedly deficient. Directed migration of annexin II-null endothelial cells through fibrin and collagen lattices in vitro was also reduced, and an annexin II peptide mimicking sequences necessary for t-PA binding blocked endothelial cell invasion of Matrigel implants in wild-type mice. In addition, annexin II-deficient mice displayed markedly diminished neovascularization of fibroblast growth factor-stimulated cornea and of oxygen-primed neonatal retina. Capillary sprouting from annexin II-deficient aortic ring explants was markedly reduced in association with severe impairment of activation of metalloproteinase-9 and -13. These data establish annexin II as a regulator of cell surface plasmin generation and reveal that impaired endothelial cell fibrinolytic activity constitutes a barrier to effective neoangiogenesis.


Assuntos
Anexina A2/deficiência , Anexina A2/fisiologia , Endotélio Vascular/fisiologia , Fibrina/metabolismo , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Anexina A2/genética , Aorta , Movimento Celular/fisiologia , Células Cultivadas , Colágeno/fisiologia , Homeostase , Cinética , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Knockout , Músculo Liso Vascular/fisiologia , Especificidade de Órgãos
20.
N Engl J Med ; 349(25): 2399-406, 2003 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-14681505

RESUMO

BACKGROUND: Although systemic lupus erythematosus is associated with premature myocardial infarction, the prevalence of underlying atherosclerosis and its relation to traditional risk factors for cardiovascular disease and lupus-related factors have not been examined in a case-control study. METHODS: In 197 patients with lupus and 197 matched controls, we performed carotid ultrasonography, echocardiography, and an assessment for risk factors for cardiovascular disease. The patients were also evaluated with respect to their clinical and serologic features, inflammatory mediators, and disease treatment. RESULTS: The risk factors for cardiovascular disease were similar among patients and controls. Atherosclerosis (carotid plaque) was more prevalent among patients than the controls (37.1 percent vs. 15.2 percent, P<0.001). In multivariate analysis, only older age, the presence of systemic lupus erythematosus (odds ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum cholesterol level were independently related to the presence of plaque. As compared with patients without plaque, patients with plaque were older, had a longer duration of disease and more disease-related damage, and were less likely to have multiple autoantibodies or to have been treated with prednisone, cyclophosphamide, or hydroxychloroquine. In multivariate analyses including patients with lupus, independent predictors of plaque were a longer duration of disease, a higher damage-index score, a lower incidence of the use of cyclophosphamide, and the absence of anti-Smith antibodies. CONCLUSIONS: Atherosclerosis occurs prematurely in patients with systemic lupus erythematosus and is independent of traditional risk factors for cardiovascular disease. The clinical profile of patients with lupus and atherosclerosis suggests a role for disease-related factors in atherogenesis and underscores the need for trials of more focused and effective antiinflammatory therapy.


Assuntos
Arteriosclerose/etiologia , Doenças das Artérias Carótidas/etiologia , Lúpus Eritematoso Sistêmico/complicações , Corticosteroides/uso terapêutico , Adulto , Fatores Etários , Arteriosclerose/diagnóstico por imagem , Arteriosclerose/epidemiologia , Autoanticorpos/sangue , Proteína C-Reativa/análise , Ligante de CD40/sangue , Doenças Cardiovasculares , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Fatores de Risco , Ultrassonografia
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