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1.
BMC Cancer ; 22(1): 264, 2022 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-35279104

RESUMO

BACKGROUND: With the improved knowledge of disease biology and the introduction of immune checkpoints, there has been significant progress in treating renal cell carcinoma (RCC) patients. Individual treatment will differ according to risk stratification. As the clinical course varies in RCC, it has developed different predictive models for assessing patient's individual risk. However, among other prognostic scores, no transparent preference model was given. MicroRNA as a putative marker shown to have prognostic relevance in RCC, molecular analysis may provide an innovative benefit in the prophetic prediction and individual risk assessment. Therefore, this study aimed to establish a prognostic-related microRNA risk score model of RCC and further explore the relationship between the model and the immune microenvironment, immune infiltration, and immune checkpoints. This practical model has the potential to guide individualized surveillance protocols, patient counseling, and individualized treatment decision for RCC patients and facilitate to find more immunotherapy targets. METHODS: Downloaded data of RCC from the TCGA database for difference analysis and divided it into a training set and validation set. Then the prognostic genes were screened out by Cox and Lasso regression analysis. Multivariate Cox regression analysis was used to establish a predictive model that divided patients into high-risk and low-risk groups. The ENCORI online website and the results of the RCC difference analysis were used to search for hub genes of miRNA. Estimate package and TIMER database were used to evaluate the relationship between risk score and tumor immune microenvironment (TME) and immune infiltration. Based on Kaplan-Meier survival analysis, search for immune checkpoints related to the prognosis of RCC. RESULTS: There were nine miRNAs in the established model, with a concordance index of 0.702 and an area under the ROC curve of 0.701. Nine miRNAs were strongly correlated with the prognosis (P < 0.01), and those with high expression levels had a poor prognosis. We found a common target gene PDGFRA of hsa-miR-6718, hsa-miR-1269b and hsa-miR-374c, and five genes related to ICGs (KIR2DL3, TNFRSF4, LAG3, CD70 and TNFRSF9). The immune/stromal score, immune infiltration, and immune checkpoint genes of RCC were closely related to its prognosis and were positively associated with a risk score. CONCLUSIONS: The established nine-miRNAs prognostic model has the potential to facilitate prognostic prediction. Moreover, this model was closely related to the immune microenvironment, immune infiltration, and immune checkpoint genes of RCC.


Assuntos
Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Adulto , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Microambiente Tumoral
2.
Dis Markers ; 2022: 1452861, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35265223

RESUMO

Objectives: Hexokinase 2 (HK2) is one of the key factors involved in the development of several human cancers. However, its role in immune cell infiltration (ICI) and tumor development in renal cell carcinoma is not yet known. Thus, we aimed to explore its relationship with ICI, overall survival, and prognosis of renal cell carcinoma. Methods: In this study, RNA-seq data from renal cancer and normal tissues were extracted from TCGA and the relationship between HK2 expression and pathological features of RCC patients was analyzed using the GEPIA and UALCAN databases. Subsequently, Western blot and qRT-PCR were performed to analyze the protein and mRNA expression of HK2 in renal cell carcinoma tissues and cell lines. Lastly, various bioinformatics tools were applied to determine the immune cell infiltration, survival, and developing prediction model. Results: The analysis of RNA-seq data revealed a high expression of HK2 in renal cell carcinoma; furthermore, Western blot and qRT-PCR also showed high expression of HK2 in renal cancer tissues and cell lines. The high expression of HK2 showed a significant positive correlation with the advanced stage of the tumor, lymph node metastasis, and worst survival in renal carcinoma patients. The high expression of HK2 was further identified as an independent risk factor of RCC patients; it also showed a significant positive immune cell infiltration RCC tumor microenvironment including macrophages, B cells, neutrophils, dendritic cells, and CD8+ T cells. Conclusion: the expression of HK2 is positively correlated with the immune cell infiltration and prognosis of renal cell carcinoma patients, thus playing an important role in renal cancer development.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Regulação Neoplásica da Expressão Gênica , Hexoquinase/genética , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Carcinoma de Células Renais/mortalidade , Correlação de Dados , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
3.
Int J Med Sci ; 19(2): 377-392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35165523

RESUMO

Background: Necroptosis, a cell death of caspase-independence, plays a pivotal role in cancer biological regulation. Although necroptosis is closely associated with oncogenesis, cancer metastasis, and immunity, there remains a lack of studies determining the role of necroptosis-related genes (NRGs) in the highly immunogenic cancer type, kidney renal clear cell carcinoma (KIRC). Methods: The information of clinicopathology and transcriptome was extracted from TCGA database. Following the division into the train and test cohorts, a three-NRGs (TLR3, FASLG, ZBP1) risk model was identified in train cohort by LASSO regression. The overall survival (OS) comparison was conducted between different risk groups through Kaplan-Meier analysis, which was further validated in test cohort. The Cox proportional hazards regression model was introduced to assess its impact of clinicopathological factors and risk score on survival. ESTIMATE and CIBERSORT algorithms were introduced to evaluate immune microenvironment, while enrichment analysis was conducted to explore the biological significance. Correlation analysis was applied for the correlation assessment between checkpoint gene expression and risk score, between gene expression and therapeutic response. Gene expressions from TCGA were verified by GEO datasets and immunohistochemistry (IHC) analysis. Results: This NRGs-related signature predicted poorer OS in high-risk group, which was also verified in test cohort. Risk score could also independently predict survival outcome of KIRC. Significant changes were also found in immune microenvironment and checkpoint gene expressions between different risk groups, with immune functional enrichment in high-risk group. Interestingly, therapeutic response was correlated with the expressions of NRGs. The expressions of NRGs from TCGA were consistent with those from GEO datasets and IHC analysis. Conclusion: The NRGs-related signature functions as a novel prognostic predictor of immune microenvironment and therapeutic response in KIRC.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Necroptose/genética , Transcriptoma/genética , Microambiente Tumoral/genética , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Fatores de Risco
4.
BMC Cancer ; 22(1): 140, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35120484

RESUMO

BACKGROUND: Tumor-associated macrophages (TAMs) are closely related to unfavorable prognosis of patients with clear cell renal cell carcinoma (ccRCC). However, the important molecules in the interaction between ccRCC and TAMs are unclear. METHODS: TCGA-KIRC gene expression data of tumor tissues and normal tissues adjacent to tumor were compared to identify differentially expressed genes in ccRCC. TAMs related genes were discovered by analyzing the correlation between these differentially expressed genes and common macrophage biomarkers. Gene set enrichment analysis was performed to predict functions of TAMs related gene. The findings were further validated using RNA sequencing data obtained from the CheckMate 025 study and immunohistochemical analysis of samples from 350 patients with ccRCC. Kaplan-Meier survival curve, Cox regression analysis and Harrell's concordance index analysis were used to determine the prognostic significance. RESULTS: In this study, we applied bioinformatic analysis to explore TAMs related differentially expressed genes in ccRCC and identified 5 genes strongly correlated with all selected macrophage biomarkers: STAC3, LGALS9, TREM2, FCER1G, and PILRA. Among them, FCER1G was abundantly expressed in tumor tissues and showed prognostic importance in patients with ccRCC who received treatment with Nivolumab; however, it did not exhibit prognostic value in those treated with Everolimus. We also discovered that high expression levels of FCER1G are related to T cell suppression. Moreover, combination of FCER1G and macrophage biomarker CD68 can improve the prognostic stratification of patients with ccRCC from TCGA-KIRC. Based on the immunohistochemical analysis of samples from patients with ccRCC, we further validated that FCER1G and CD68 are both highly expressed in tumor tissue and correlate with each other. Higher expression of CD68 or FCER1G in ccRCC tissue indicates shorter overall survival and progression-free survival; patients with high expression of both CD68 and FCER1G have the worst outcome. Combining CD68 and FCER1G facilitates the screening of patients with a worse prognosis from the same TNM stage group. CONCLUSIONS: High expression of FCER1G in ccRCC is closely related to TAMs infiltration and suppression of T cell activation and proliferation. Combining the expression levels of FCER1G and macrophage biomarker CD68 may be a promising postoperative prognostic index for patients with ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Receptores Fc/imunologia , Macrófagos Associados a Tumor/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Proliferação de Células/genética , Galectinas/imunologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Ativação Linfocitária/genética , Glicoproteínas de Membrana/imunologia , Prognóstico , Modelos de Riscos Proporcionais , Receptores Imunológicos/imunologia , Análise de Sequência de RNA
5.
Oxid Med Cell Longev ; 2022: 5831247, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35096270

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. Redox metabolism has been recognized as the hallmark of cancer. But the concrete role of redox-related genes in patient stratification of ccRCC remains unknown. Herein, we aimed to characterize the molecular features of ccRCC based on the redox gene expression profiles from The Cancer Genome Atlas. Differentially expressed redox genes (DERGs) and vital genes in metabolism regulation were identified and analyzed in the ccRCC. Consensus clustering was performed to divide patients into three clusters (C1, C2, and C3) based on 139 redox genes with median FPKM value > 1. We analyzed the correlation of clusters with clinicopathological characteristics, immune infiltration, gene mutation, and response to immunotherapy. Subclass C1 was metabolic active with moderate prognosis and associated with glucose, lipid, and protein metabolism. C2 had intermediate metabolic activity with worse prognosis and correlated with more tumor mutation burden, neoantigen, and aneuploidy, indicating possible drug sensitivities towards immune checkpoint inhibitors. Metabolic exhausted subtype C3 showed high cytolytic activity score, suggesting better prognosis than C1 and C2. Moreover, the qRT-PCR was performed to verify the expression of downregulated DERGs including ALDH6A1, ALDH1L1, GLRX5, ALDH1A3, and GSTM3, and upregulated SHMT1 in ccRCC. Overall, our study provides an insight into the characteristics of molecular classification of ccRCC patients based on redox genes, thereby deepening the understanding of heterogeneity of ccRCC and allowing prediction of prognosis of ccRCC patients.


Assuntos
Carcinoma de Células Renais/classificação , Neoplasias Renais/classificação , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Oxirredução , Prognóstico , Análise de Sobrevida
6.
BMC Cancer ; 22(1): 1, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34979993

RESUMO

BACKGROUND: It is of great urgency to explore useful prognostic markers for patients with clear cell renal cell carcinoma (ccRCC). Prognostic models based on ferroptosis-related gene (FRG) in ccRCC is poorly reported for now. METHODS: Comprehensive analysis of 22 FRGs were performed in 629 ccRCC samples from two independent patient cohorts. We carried out least absolute shrinkage and selection operator analysis to screen out prognosis-related FRGs and constructed prognosis model for patients with ccRCC. Weighted gene co-expression network analysis was also carried out for potential functional enrichment analysis. RESULTS: Based on the TCGA cohort, a total of 11 prognosis-associated FRGs were selected for the construction of the prognosis model. Significantly differential overall survival (hazard ratio = 3.61, 95% CI: 2.68-4.87, p < 0.0001) was observed between patients with high and low FRG score in the TCGA cohort, which was further verified in the CPTAC cohort with hazard ratio value of 5.13 (95% CI: 1.65-15.90, p = 0.019). Subgroup survival analysis revealed that our FRG score could significantly distinguish patients with high survival risk among different tumor stages and different tumor grades. Functional enrichment analysis illustrated that the process of cell cycle, including cell cycle-mitotic pathway, cytokinesis pathway and nuclear division pathway, might be involved in the regulation of ccRCC through ferroptosis. CONCLUSIONS: We developed and verified a FRG signature for the prognosis prediction of patients with ccRCC, which could act as a risk factor and help to update the tumor staging system when integrated with clinicopathological characteristics. Cell cycle-related pathways might be involved in the regulation of ccRCC through ferroptosis.


Assuntos
Carcinoma de Células Renais/genética , Ciclo Celular/genética , Ferroptose/genética , Testes Genéticos/estatística & dados numéricos , Neoplasias Renais/genética , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nomogramas , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida
7.
BMC Cancer ; 22(1): 76, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35038991

RESUMO

BACKGROUND: The impact of hepatic resection for liver metastases (LM) on the survival of pediatric patients with Wilms' tumor (WT) is unclear. So far, there is a lack of studies investigating the best suited treatment for patients with WTLM, and the role of liver resection has rarely been investigated. Thus, the development of evidence-based guidelines concerning indications of liver resection for WTLM remains difficult. AIM: To investigate the role of surgery in the therapy of WTLM. All available data on liver resections and subgroup outcomes of patients with WTLM are analyzed. Main research question is whether liver resection improves survival rates of patients with WTLM compared to non-surgical treatment. METHODS: A systematic literature search of MEDLINE, Web of Science, and Central provided the basis for this PRISMA-compliant systematic review. For the main analysis (I), all studies reporting on surgical treatment of pediatric WTLM were included. To provide a representative overview of the general outcome of WTLM patients, in analysis II all studies with cohorts of at least five WTLM patients, regardless of the kind of treatment, were reviewed and analyzed. A Multiple meta-regression model was applied to investigate the impact liver resection on overall survival. RESULTS: 14 studies with reports of liver resection for WTLM were found (Analysis I). They included a total of 212 patients with WTLM, of which 93 underwent a liver resection. Most studies had a high risk of bias, and the quality was heterogenous. For the analysis II, eight studies with subgroups of at least five WTLM patients were found. The weighted mean overall survival (OS) of WTLM patients across the studies was 55% (SD 29). A higher rate of liver resection was a significant predictor of better OS in a multiple meta-regression model with 4 covariates (I2 29.43, coefficient 0.819, p = 0.038). CONCLUSIONS: This is the first systematic review on WTLM. Given a lack of suited studies that specifically investigated WTLM, ecological bias was high in our analyses. Generating evidence is complicated in rare pediatric conditions and this study must be viewed in this context. Meta-regression analyses suggest that liver resection may improve survival of patients with WTLM compared to non-surgical treatment. Especially patients with persisting disease after neoadjuvant chemotherapy but also patients with metachronous LM seem to benefit from resection. Complete resection of LM is vital to achieve higher OS. Studies that prospectively investigate the impact of surgery on survival compared to non-surgical treatment for WTLM are highly needed to further close the current evidence gap. STUDY REGISTRATION: PROSPERO 2021 CRD42021249763  https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249763 .


Assuntos
Hepatectomia/mortalidade , Neoplasias Renais/cirurgia , Neoplasias Hepáticas/cirurgia , Tumor de Wilms/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Análise Multivariada , Análise de Regressão , Taxa de Sobrevida , Resultado do Tratamento , Tumor de Wilms/mortalidade , Tumor de Wilms/patologia
8.
Lancet Oncol ; 23(2): 292-303, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35032437

RESUMO

BACKGROUND: In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER. METHODS: In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment. FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0-26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20-3·56], nominal p<0·0001, effect size 0·33 [95% CI 0·17-0·50] for FKSI-19 total score; 1·33 [0·84-1·83], nominal p<0·0001, 0·45 [0·28-0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58-5·39], nominal p=0·0004, 0·30 [0·14-0·47] for EQ-5D-3L VAS; and 0·04 [0·01-0·07], nominal p=0·0036, 0·25 [0·08-0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56-0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50-0·80], nominal p=0·0001). INTERPRETATION: PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma. FUNDING: Bristol Myers Squibb.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Idoso , Anilidas/administração & dosagem , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/psicologia , Feminino , Nível de Saúde , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/psicologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Piridinas/administração & dosagem , Qualidade de Vida , Sunitinibe/administração & dosagem
9.
Am J Clin Oncol ; 45(2): 66-73, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34991104

RESUMO

OBJECTIVES: The US Food and Drug Administration (FDA) approved nivolumab-ipilimumab and pembrolizumab-axitinib as first-line treatments for metastatic, clear-cell, renal cell carcinoma (mRCC) based on results from CheckMate 214 and KEYNOTE-426. Our objective was to compare the adjusted, lifetime cost-effectiveness between nivolumab-ipilimumab, pembrolizumab-axitinib, and sunitinib for patients with mRCC. MATERIALS AND METHODS: A 3-state Markov model was developed comparing nivolumab-ipilimumab and pembrolizumab-axitinib to each other and sunitinib, over a 20-year lifetime horizon from a US medical center perspective. The clinical outcomes of nivolumab-ipilimumab and pembrolizumab-axitinib were compared using matching-adjusted indirect comparison. Costs of drug treatment, adverse events, and utilities associated with different health states and adverse events were determined using national sources and published literature. Our outcome was incremental cost-effectiveness ratio (ICER) using quality-adjusted life years (QALY). One-way and probabilistic sensitivity analyses were conducted. RESULTS: Nivolumab-ipilimumab was the most cost-effective option in the base case analysis with an ICER of $34,190/QALY compared with sunitinib, while the pembrolizumab-axitinib ICER was dominated by nivolumab-ipilimumab and was not cost-effective (ICER=$12,630,828/QALY) compared with sunitinib. The mean total costs per patient for the nivolumab-ipilimumab and pembrolizumab-axitinib arms were $284,683 and $457,769, respectively, compared with sunitinib at $241,656. QALY was longer for nivolumab-ipilimumab (3.23 QALY) than for adjusted pembrolizumab-axitinib (1.99 QALY), which was longer than sunitinib's (1.98 QALY). These results were most sensitive to treatment cost in both groups, but plausible changes did not alter the conclusions. CONCLUSIONS: The base case scenario indicated that nivolumab-ipilimumab was the most cost-effective treatment option for mRCC compared with pembrolizumab-axitinib and sunitinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/economia , Axitinibe/administração & dosagem , Axitinibe/economia , Carcinoma de Células Renais/economia , Carcinoma de Células Renais/mortalidade , Análise Custo-Benefício , Custos de Medicamentos , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/economia , Neoplasias Renais/economia , Neoplasias Renais/mortalidade , Nivolumabe/administração & dosagem , Nivolumabe/economia , Anos de Vida Ajustados por Qualidade de Vida , Sunitinibe/administração & dosagem , Sunitinibe/economia , Estados Unidos
10.
Anticancer Res ; 42(2): 973-979, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35093897

RESUMO

BACKGROUND/AIM: The survival benefit of immune checkpoint inhibitors for non-clear cell renal cell carcinoma (nccRCC) is unclear. Our purpose was to evaluate the real-world survival benefit of ipilimumab plus nivolumab retrospectively. PATIENTS AND METHODS: We retrospectively reviewed medical records of 33 patients with metastatic nccRCC who received combination therapy with ipilimumab plus nivolumab or monotherapy with a molecular targeted agent as initial systemic therapy. Progression-free survival (PFS), overall survival (OS) and objective response rate were compared between the two groups. RESULTS: Median PFS of each therapy was 3.5 and 4.7 months (p=0.61) and median OS was 19.6 and 10.6 months (p=0.23), respectively. Three patients treated with ipilimumab and nivolumab had a complete response, resulting in an objective response rate of 30.0%, while that for molecular targeted therapy was 4.5% (p=0.04). CONCLUSION: Ipilimumab plus nivolumab achieved statistically non-significant, but longer overall survival and significantly higher objective response rate.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Ipilimumab/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Nivolumabe/uso terapêutico , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
11.
Cancer Sci ; 113(1): 297-307, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34687579

RESUMO

Precise quantification of copy-number alterations (CNAs) in a tumor genome is difficult. We have applied a comprehensive copy-number analysis method, digital multiplex ligation-dependent probe amplification (digitalMLPA), for targeted gene copy-number analysis in clear cell renal cell carcinoma (ccRCC). Copy-number status of all chromosomal arms and 11 genes was determined in 60 ccRCC samples. Chromosome 3p loss and 5q gain, known as early changes in ccRCC development, as well as losses at 9p and 14q were detected in 56/60 (93.3%), 31/60 (51.7%), 11/60 (18.3%), and 33/60 (55%), respectively. Through gene expression analysis, a significant positive correlation was detected in terms of 14q loss determined using digitalMLPA and downregulation of mRNA expression ratios with HIF1A and L2HGDH (P = .0253 and .0117, respectively). Patients with early metastasis (<1 y) (n = 18) showed CNAs in 6 arms (in median), whereas metastasis-free patients (n = 34) showed those in significantly less arms (3 arms in median) (P = .0289). In particular, biallelic deletion of CDKN2A/2B was associated with multiple CNAs (≥7 arms) in 3 tumors. Together with sequence-level mutations in genes VHL, PBRM1, SETD2, and BAP1, we performed multiple correspondence analysis, which identified the association of 9p loss and 4q loss with early metastasis (both P < .05). This analysis indicated the association of 4p loss and 1p loss with poor survival (both, P < .05). These findings suggest that CNAs have essential roles in aggressiveness of ccRCC. We showed that our approach of measuring CNA through digitalMLPA will facilitate the selection of patients who may develop metastasis.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 9/genética , Variações do Número de Cópias de DNA , Neoplasias Renais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Estudos de Casos e Controles , Deleção Cromossômica , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Metástase Neoplásica , Análise de Sobrevida
12.
Urology ; 159: 152-159, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34536409

RESUMO

OBJECTIVE: To compare procedure burden, oncologic, surgical and renal-function outcomes between patients with low-grade upper urothelial cancer (UTUC) who were referred for either radical management (RM) or kidney-sparing endoscopic management (EM). PATIENTS AND METHODS: We retrospectively reviewed data of all patients treated for UTUC at our tertiary medical center between 2000 and 2018 and selected patients diagnosed with unilateral low-grade UTUC. RESULTS: Twenty-four patients were treated with EM and 37 with RM. Surgical and oncologic risk factors were similar between the arms except for tumor size. Mean follow-up was 4.9 ± 3.4 years. The 5-year overall-survival rate was 85% with EM and 84% with RM (P = .707). Metastasis-free and cancer-specific survival were also similar (P = .994, P = .960). End-of-follow-up average glomerular filtration rates were 58.7 ± 21.5 and 49.2 ± 22.1 mL/min/1.73 m2, respectively (P = .12). Ninety-two percent of patients managed endoscopically had local recurrences, with an average of 3.2 recurrences per patient. Four (17%) patients underwent salvage radical nephroureterectomy. Procedure burden was higher with EM, having 6.5 ± 4.4 operations and 344 ± 272 minutes under anesthesia compared with 1.9 ± 0.4 operations (P <.0001) and 213 ± 84 minutes under anesthesia (P = .031) with RM. Cost-of-care analysis revealed higher costs for EM in both private and publicly funded medical insurance plans. CONCLUSION: Patients undergoing endoscopic management had an 83% chance of preserving their kidney and an 81% chance of 5-year metastasis-free survival at a cost of 6.5 ± 4.4 operations during a mean follow-up of 4.9 ± 3.4 years. Our findings support EM for low-grade UTUC as a valid option from oncological aspects but highlight the associated costs.


Assuntos
Carcinoma de Células de Transição , Endoscopia , Neoplasias Renais , Efeitos Adversos de Longa Duração , Recidiva Local de Neoplasia , Nefroureterectomia , Complicações Pós-Operatórias , Neoplasias Ureterais , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Pesquisa Comparativa da Efetividade , Custos e Análise de Custo , Endoscopia/efeitos adversos , Endoscopia/economia , Endoscopia/métodos , Endoscopia/estatística & dados numéricos , Feminino , Humanos , Israel/epidemiologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Efeitos Adversos de Longa Duração/diagnóstico , Efeitos Adversos de Longa Duração/epidemiologia , Efeitos Adversos de Longa Duração/etiologia , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/etiologia , Nefroureterectomia/efeitos adversos , Nefroureterectomia/economia , Nefroureterectomia/métodos , Nefroureterectomia/estatística & dados numéricos , Avaliação de Processos e Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Análise de Sobrevida , Neoplasias Ureterais/mortalidade , Neoplasias Ureterais/patologia , Neoplasias Ureterais/cirurgia
13.
Br J Cancer ; 126(5): 771-777, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34824449

RESUMO

BACKGROUND: Traditional histopathology performed by pathologists through naked eyes is insufficient for accurate survival prediction of clear cell renal cell carcinoma (ccRCC). METHODS: A total of 483 whole slide images (WSIs) data from three patient cohorts were retrospectively analyzed. We performed machine learning algorithm to identify optimal digital pathological features and constructed machine learning-based pathomics signature (MLPS) for ccRCC patients. Prognostic performance of the prognostic model was also verified in two independent validation cohorts. RESULTS: MLPS could significantly distinguish ccRCC patients with high survival risk, with hazard ratio of 15.05, 4.49 and 1.65 in three independent cohorts, respectively. Cox regression analysis revealed that the MLPS could act as an independent prognostic factor for ccRCC patients. Integration nomogram based on MLPS, tumour stage system and tumour grade system improved the current survival prediction accuracy for ccRCC patients, with area under curve value of 89.5%, 90.0%, 88.5% and 85.9% for 1-, 3-, 5- and 10-year disease-free survival prediction. DISCUSSION: The machine learning-based pathomics signature could act as a novel prognostic marker for patients with ccRCC. Nevertheless, prospective studies with multicentric patient cohorts are still needed for further verifications.


Assuntos
Carcinoma de Células Renais/patologia , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Renais/patologia , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Neoplasias Renais/mortalidade , Aprendizado de Máquina , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Nomogramas , Prognóstico , Estudos Prospectivos , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida
14.
Clin Nutr ; 41(1): 131-143, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34872047

RESUMO

INTRODUCTION: Body composition has been associated with disease outcome in several cancer types. Results for localized and metastatic renal cell cancer (RCC) are limited and inconsistent. Our aim was to examine the association between body composition and survival in RCC. METHODS: We conducted a population-based historical cohort study including patients diagnosed with RCC from 2008 to 2012. Diagnostic Computed Tomography images at the third lumbar vertebra (L3) were assessed for skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue index (VATI) and subcutaneous adipose tissue index (SATI). Clinical data was retrieved from medical records. Multivariable Cox regressions with restricted cubic splines were used to determine hazard ratios (HRs) and 95% confidence intervals (95%CIs) for 10-unit increases in body composition features with overall survival (OS) and recurrence-free survival (RFS). RESULTS: We included 719 stage I-III (of whom 254 (35.3%) died and 148 (21.9%) experienced recurrence) and 320 stage IV RCC patients (of whom 298 (93.1%) died). Median follow-up was 6.35 years (interquartile range; 1.41-8.23). For stage I-III, higher SMD was associated with better OS (men: HR 0.86; 95% CI 0.68-1.08; women: HR 0.69; 95% CI 0.50-0.95). Lower compared to median VATI was associated with worse OS for both men (HR 1.38; 95%CI 1.05-1.83 for VATI = 25) and women (HR 1.67; 95%CI 1.01-2.78 for VATI = 20). For stage IV, higher SMD and higher VATI were associated with better OS among men (HR 0.74; 95% CI 0.59-0.94 and HR 0.93; 95% CI 0.88-0.99, respectively). Results for women were similar but non-significant. No statistically significant associations were found for SMI or SATI. CONCLUSION: Higher SMD and higher VATI were marginally associated with better survival in RCC patients and might be useful for better prognostication. However, the added value to current prognostic scores needs to be investigated.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Densitometria/estatística & dados numéricos , Indicadores Básicos de Saúde , Gordura Intra-Abdominal/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Idoso , Composição Corporal , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Estudos de Coortes , Feminino , Humanos , Gordura Intra-Abdominal/patologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/patologia , Tomografia Computadorizada por Raios X
15.
Can J Physiol Pharmacol ; 100(1): 5-11, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34779659

RESUMO

The optimal cutoff point for evaluating the prognosis of localized renal cell carcinoma (LRCC) remains unclear. This study aimed to verify the efficacy of tumor diameter in the 2010 American Joint Committee on Cancer (AJCC) TNM staging system and contribute to the modification of TNM staging on the prognosis of this disease. A total of 3748 patients with LRCC were enrolled and grouped according to the 2010 AJCC TNM staging system. COX analysis was used to stratify the prognosis. The optimal cutoff point of the tumor diameter in the T1 and T2 prognosis was explored. There were 3330 (88.9%) patients in stage T1 and 418 (11.1%) in stage T2. The cancer-specific mortality rate was 2.7% (100/3748). The mean follow-up was 49.8 months. A tumor diameter of 7 cm can determine the prognosis of patients at stages T1 and T2; however, 4.5 cm and 11 cm as the cutoff points for T1 and T2 sub-classification of patients with LRCC might show better recognition ability than 4 cm and 10 cm, respectively. The 2010 AJCC TNM stage can predict the prognosis of LRCC in stages T1 and T2. In addition, a tumor diameter of 4.5 cm and 11 cm might be the optimal cutoff points for the sub-classification of stages T1 and T2.


Assuntos
Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/patologia , Neoplasias Renais/classificação , Neoplasias Renais/patologia , Estadiamento de Neoplasias/classificação , Estadiamento de Neoplasias/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
16.
J Cancer Res Clin Oncol ; 148(2): 361-375, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34689221

RESUMO

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney tumor characterized by the highest mortality rate of the genitourinary cancers, and, therefore, new diagnostic and/or prognostic biomarkers are urgently needed. METHODS: Based on genome-wide DNA methylation profiling in 11 pairs of ccRCC and non-cancerous renal tissues (NRT), the methylation at regulatory regions of ZNF677, FBN2, PCDH8, TFAP2B, TAC1, and FLRT2 was analyzed in 168 renal tissues and 307 urine samples using qualitative and quantitative methylation-specific PCR (MSP). RESULTS: Significantly higher methylation frequencies for all genes were found in ccRCC tissues compared to NRT (33-60% vs. 0-11%). The best diagnostic performance demonstrated a panel of ZNF677, FBN2, PCDH8, TFAP2B & TAC1 with 82% sensitivity and 96% specificity. Hypermethylation of ZNF677 and PCDH8 in the tissue samples was significantly related to numerous adverse clinicopathologic parameters. For the urine-based ccRCC detection, the highest diagnostic power (AUC = 0.78) was observed for a panel of ZNF677 & PCDH8 (with or without FBN2 or FLRT2) with 69-78% sensitivity and 69-80% specificity, albeit with lower values in the validation cohort. Besides, methylation of PCDH8 was significantly related to higher tumor stage and fat invasion in the study and validation cohorts. Moreover, PCDH8 was strongly predictive for OS (HR, 5.7; 95% CI 1.16-28.12), and its prognostic power considerably increased in combination with ZNF677 (HR, 12.5; 95% CI 1.47-105.58). CONCLUSION: In summary, our study revealed novel, potentially promising DNA methylation biomarkers of ccRCC with the possibility to be applied for non-invasive urine-based ccRCC detection and follow-up.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Metilação de DNA , Neoplasias Renais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/urina , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Transcriptoma
17.
Int Urol Nephrol ; 54(1): 63-69, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34783981

RESUMO

PURPOSE: The prognosis of patients undergoing 2-sided radical nephroureterectomies (RNUs) with a residual bladder due to bilateral upper tract urothelial carcinoma (UTUC) is poorly understood. This study was aimed toward surveying the oncology outcomes and prognostic factors that may help in shared decision-making related to bladder preservation in patients preparing to receive 2-sided RNUs. METHODS: Patients with synchronous or metachronous bilateral UTUC who received bilateral RNUs with a residual bladder in our hospital were retrospectively reviewed. Clinical and pathological data were analyzed for potential variables affecting the oncology outcomes. RESULTS: A total of 50 patients were included. The average age at completion of the 2-sided RNU was 62.7 ± 12.4 years, with a mean follow-up of 88.4 ± 59.3 months after the 2-sided RNUs. The medium overall survival was 13.4 ± 1.8 years. Twenty-six patients (52%) had cancer recurrence in the residual bladder, but only 2 (8%) of the recurrences were muscle invasive. The highest UTUC stage was the only predictive factor for cancer-specific survival (CSS) rather than intravesical recurrence. The 5 year CSS rates in patients with the highest UTUC stage ≦ pT2 and ≧ pT3 were 90% and 51%, respectively (p = 0.007). CONCLUSIONS: Risk of cancer recurrence in the residual bladder is high, but does not affect survival outcomes. The highest UTUC stage plays a significant role in cancer-specific survival. With a careful patient surveillance, bladder preservation may be reasonable in patients with bilateral UTUC preparing for 2-sided RNUs.


Assuntos
Carcinoma de Células de Transição/cirurgia , Neoplasias Renais/cirurgia , Nefroureterectomia/métodos , Tratamentos com Preservação do Órgão , Neoplasias Ureterais/cirurgia , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Tratamentos com Preservação do Órgão/efeitos adversos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias Ureterais/mortalidade , Neoplasias Ureterais/patologia , Bexiga Urinária
18.
Urology ; 159: 146-151, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34492287

RESUMO

OBJECTIVE: To understand the influence of histologic subtypes on the survival outcomes of intermediate-high and high-risk renal cell carcinoma (RCC) following nephrectomy. METHODS: This study employed data files from the SEER Program to identify patients diagnosed with intermediate-high or high risk RCC and treated with nephrectomy. Unadjusted Kaplan Meier curves, and multivariable Cox regression analyses were applied to estimate the hazards of histologic types for overall survival (OS) and cancer-specific survival (CSS). RESULTS: OS was higher for chromophobe (HR=0.58, 95% CI 0.47-0.70; P<.0001), similar for papillary (HR=0.90, 95% CI 0.80-1.02; P=.11) and worse for sarcomatoid (HR=3.17, 95% CI 2.70-3.72; P<.0001) subtypes relative to the clear cell subtype. OS was lower in the high-risk disease (HR=2.35, 95% CI 2.01-2.74; P <.0001) versus intermediate-high risk disease. CSS was higher for chromophobe (HR=0.47, 95% CI 0.35-0.63; P<.0001), similar for papillary (HR=0.91, 95% CI 0.77-1.08; P=.28) and worse for sarcomatoid (HR=4.19, 95% CI 3.50-5.02; P<.0001) subtypes relative to the clear cell subtype. CSS was lower for the high-risk disease (HR=2.86, 95%CI 2.39-3.43; P <.0001) relative to intermediate-high risk disease.


Assuntos
Biópsia , Carcinoma de Células Renais , Neoplasias Renais , Nefrectomia , Programa de SEER/estatística & dados numéricos , Idoso , Biópsia/métodos , Biópsia/estatística & dados numéricos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Estados Unidos/epidemiologia
19.
Urol Int ; 106(2): 186-194, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34492655

RESUMO

OBJECTIVE: The aim of this study was to investigate whether diagnostic ureteroscopy (URS) biopsy is unfavourable for bladder tumour recurrence in upper urinary tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: We performed a retrospective analysis of 195 patients diagnosed with UTUC, who were divided into a diagnostic URS group (URS+) and a nondiagnostic URS group (URS-) according to whether diagnostic ureteroscopic biopsy was performed. A Cox regression model was used to analyse the risk factors for intravesical recurrence (IVR)-free survival (IRFS) and overall survival (OS) in UTUC after radical nephroureterectomy (RNU). Kaplan-Meier analysis was used to estimate the influence of factors on the incidence of IVR and the cumulative survival rate of UTUC. RESULTS: Patients with a maximum tumour diameter of less than 3.1 cm, low-stage tumours, and ureteral tumours were more likely to undergo diagnostic URS before radical surgery. Multivariate Cox regression analysis showed that tumour pathological stage and diagnostic ureteroscopic biopsy can be used as predictors of IVR after RNU (p = 0.019, 0.033). Kaplan-Meier survival analysis found that diagnostic ureteroscopic biopsy was a high-risk factor for IRFS (p = 0.034). Subcomponent analysis showed that pTa/Tis/T1, pT2, pT3/pT4 stage, and diagnostic ureteroscopic biopsy with pTa/Tis/T1 stage were unfavourable for IVR (p = 0.047). CONCLUSION: Diagnostic ureteroscopic biopsy before RNU should be carefully selected for patients with atypical preoperative UTUC. We believe that intravesical chemotherapy drug perfusion can be used after surgery to prevent IVR if biopsy is unavoidable, but this still requires further prospective studies.


Assuntos
Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia/patologia , Nefroureterectomia , Neoplasias Ureterais/patologia , Neoplasias Ureterais/cirurgia , Ureteroscopia , Neoplasias da Bexiga Urinária/patologia , Idoso , Biópsia/métodos , Carcinoma de Células de Transição/mortalidade , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Ureterais/mortalidade , Neoplasias da Bexiga Urinária/mortalidade
20.
Clin Cancer Res ; 28(3): 441-445, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34417198

RESUMO

On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75-1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Aprovação de Drogas , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe/administração & dosagem , Sorafenibe/uso terapêutico , Taxa de Sobrevida , Resultado do Tratamento
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