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1.
Medicine (Baltimore) ; 99(46): e23181, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181696

RESUMO

Renal cell carcinoma (RCC) is the leading cancer affecting humans; however, the relationship between tumour-infiltrating lymphocytes (TILs) and patient prognosis in RCC is relatively unreported. This study aimed to investigate the relationships among factors (TIL, clinicopathological characteristics, and patient prognosis in RCC).This retrospective study evaluated 533 patients with clear cell renal cell carcinoma (ccRCC) deposited in the the Cancer Genome Atlas between 2004 and 2015. We downloaded immune cell type absolute fraction data for ccRCC patients from the Cancer Immunome Atlas database. The CIBERSORT method was used to transform RNA-sequencing data into microarray data for the cancer genome atlas -ccRCC samples for which microarray and RNA-sequencing data were available on the the Cancer Immunome Atlas website.The overall survival (OS) and disease free survival (DFS) analyses of ccRCC patients showed that M1 macrophages (OS, P = .00000134; DFS, P = .00958) and neutrophils (OS, P = .00000723; DFS, P = .0255) were significant. Age at diagnosis (P < .0001, c-index = 0.59), tumour stage (P < .0001, c-index = 0.667), stage (P < .0001, c-index = 0.729), neoplasm histological grade (P < .0001, c-index = 0.624), and haemoglobin level (P < .0001, c-index = 0.583) were independent predictors of OS. Similarly, the stage, haemoglobin level, and serum calcium level were independent predictors of DFS. There were significant correlations between the M1 macrophage fraction and tumour stage, stage, and neoplasm histological grade. Stage and neoplasm histological grade showed associations with the neutrophil fraction.The correlations between TILs and prognosis and clinicopathological characteristics in ccRCC were demonstrated. The prognosis of ccRCC patients may differ according to the TIL fractions.


Assuntos
Carcinoma de Células Renais/sangue , Linfócitos do Interstício Tumoral/patologia , Valor Preditivo dos Testes , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Prognóstico , Estudos Retrospectivos
2.
Anticancer Res ; 40(11): 6525-6530, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109593

RESUMO

BACKGROUND/AIM: End-stage kidney disease is characterized by chronic inflammation and frequent development of cancer. The level of circulating vitamin D is generally low in patients with end-stage renal disease (ESRD). Experimental studies have implicated the role of dysfunctional vitamin D metabolism in tumorigenesis. PATIENTS AND METHODS: We analyzed the expression of vitamin D receptor (VDR), cytochrome P450 family 27 subfamily B member 1 (CYP27B1) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), the key genes involved in vitamin D signaling, in kidneys from patients with ESRD, tissue microarrays containing ESRD-associated renal cell tumors, as well as in their precursor lesions by immunohistochemistry. RESULTS: Kidneys from patients with ESRD showed strong structural rearrangement with only few tubules and epithelial cell groups embedded in fibrotic-inflammatory stroma. Only an estimated 1-3% of the epithelial cells showed positive staining with antibodies to VDR, CYP27B1 and CYP24A1, which contrasted with the 100%, 40-50% and 40-50% of positively stained cells, respectively, found in normal kidneys. Down-regulation of the vitamin D signaling proteins was found in patients with renal cancer, with the exception of tumors and their precursors occurring exclusively in ESRD. CONCLUSION: The significantly reduced activity of CYP27B1 in kidney from patients with ESRD explains the low level of circulating vitamin D. We suggest that the lack of anti-tumorigenic effect of vitamin D is a crucial factor in the frequent development of unique types of renal cell cancer in in patients with ESRD.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Carcinoma de Células Renais/genética , Falência Renal Crônica/genética , Receptores de Calcitriol/genética , Vitamina D3 24-Hidroxilase/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Redes e Vias Metabólicas/genética , Vitamina D/sangue
3.
Am J Clin Oncol ; 43(9): 621-627, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889831

RESUMO

OBJECTIVES: Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. MATERIALS AND METHODS: mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. RESULTS: Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). CONCLUSION: Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/secundário , Quimiocina CXCL12/sangue , Progressão da Doença , Selectina E/sangue , Feminino , Fator de Crescimento de Hepatócito/sangue , Humanos , Interleucina-6/sangue , Interleucina-8/sangue , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Osteopontina/sangue , Intervalo Livre de Progressão , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Pesquisa Médica Translacional , Fator A de Crescimento do Endotélio Vascular/sangue
4.
Oncology ; 98(10): 734-742, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726790

RESUMO

BACKGROUND: There has been no clinically useful diagnostic or prognostic biomarker for renal cell carcinoma (RCC). Serum γ-glutamyltransferase (GGT) activity has been reported to be a prognostic marker for several types of cancer including RCC. Exosomes or small extracellular vesicles present in body fluids have potential as a biomarker. We have recently demonstrated that GGT activity on exosomes isolated from serum is useful for the differential diagnosis of prostate cancer and benign prostate hyperplasia. In this study, we aimed to examine if serum exosomal GGT activity could be a marker for RCC. METHODS: We examined GGT1 expression and GGT activity in cell lysates and exosomes from culture medium of HK-2 proximal tubule epithelial and RCC cell lines. GGT activity was measured using a fluorescent probe for GGT, γ-glutamyl hydroxymethyl rhodamine green. Serum and serum exosomal GGT activities were measured in patients with RCC. GGT1 expression in RCC tissues was evaluated by immunohistochemical staining. RESULTS: GGT1 levels in exosomes from KMRC-1, OS-RC-2 and 786-O cells were elevated compared with those from HK-2 cells. In exosomes, GGT1 expression correlated with GGT activity determined using a fluorescent probe for GGT. In RCC patients, serum exosomal GGT activity was elevated in those with advanced stages (III/IV vs. I/II, p = 0.037) and those with microvascular invasion (with vs. without, p = 0.034). Immunohistochemical analysis showed that membranous GGT1 expression was increased in RCC with microvascular invasion. Notably, preoperative serum exosomal GGT activity could predict the likelihood of having microvascular invasion diagnosed by pathological examination of surgically resected specimens. CONCLUSIONS: Our results suggest that serum exosomal GGT activity could be a clinically useful marker for advanced clinicopathological features of RCC patients, and its combined use with conventional diagnostic modalities may improve the diagnosis and treatment of patients.


Assuntos
Carcinoma de Células Renais/enzimologia , Exossomos/enzimologia , Neoplasias Renais/enzimologia , gama-Glutamiltransferase/sangue , Idoso , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , gama-Glutamiltransferase/biossíntese
5.
Nat Med ; 26(7): 1041-1043, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32572266

RESUMO

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Metilação de DNA/genética , Detecção Precoce de Câncer , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/urina , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/urina , Epigenoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
6.
Oncol Res Treat ; 43(7-8): 340-345, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32554963

RESUMO

BACKGROUND: The aim of this study was to assess the prognostic value of the preoperative apolipoprotein B (ApoB) level in surgical patients with clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: The study included 307 ccRCC patients receiving radical or partial nephrectomy between 2003 and 2012 in our center. The correlations among the preoperative ApoB, clinicopathological parameters, and overall survival (OS) were evaluated. RESULTS: A total of 193 males (62.9%) and 114 females (37.1%) with ccRCC who underwent radical or partial nephrectomy were enrolled in the present study. The OS at 5 years after the operation was 90.6% for all patients, 87.4% for the lower ApoB group, and 97.0% for the higher-ApoB group. The cause-specific survival (CSS) at 5 years after surgery was 90.2% for all patients, 86.7% for the lower-ApoB group, and 97.0% for the higher-ApoB group. A higher-ApoB level was related to a better OS and CSS in ccRCC patients (p = 0.001 and p < 0.001, respectively). In multivariate analysis, age >60 years (p = 0.008 and p = 0.023) and a lower Apo B level (p = 0.019 and p = 0.018) were independent prognostic factors for OS and CSS, respectively. CONCLUSIONS: In the Apo apolipoprotein family, the preoperative ApoB level had an important clinical significance for predicting the prognosis and survival rate of ccRCC patients.


Assuntos
Apolipoproteína B-100/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Nefrectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Taxa de Sobrevida , Adulto Jovem
7.
Int J Exp Pathol ; 101(3-4): 87-95, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32496656

RESUMO

There are many unknown aspects of the pathogenesis of renal cell carcinoma (RCC). The aim of the current study was to define new RCC-related genes and measure their associations with RCC and clinical parameters, especially platelet/lymphocyte ratio which may be an independent predictor of prognosis in patients with RCC and other forms of cancer. Via in silico analysis upon RCC-specific deleted genes in chromosome 3, four possible ceRNAs (ATXN3, ABI2, GOLGB1 and SMAD2) were identified. Then, the expression levels of these genes in tumour and adjacent healthy kidney tissues of 19 RCC patients were determined by real-time PCR. ATXN3 and GOLGB1 gene expression levels increased but ABI2 gene expression level decreased in tumour kidney tissues when compared to normal ones. ATXN3, ABI2 and GOLGB1 gene expression levels were significantly higher in Fuhrman grade 4 than other grades (P < .001). ABI2 gene expression levels were significantly associated with higher platelet/lymphocyte ratio of the patients with RCC (P < .05). ATXN3, ABI2 and GOLGB1 may predict higher RCC grades. Also, ABI2 may regulate platelet/lymphocyte ratio which may be an independent predictor of RCC and other forms of cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Plaquetas , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Linfócitos , MicroRNAs/genética , Idoso , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Projetos Piloto , Contagem de Plaquetas
8.
BMC Urol ; 20(1): 7, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32013938

RESUMO

BACKGROUND: RNA sequencing data is providing abundant information about the levels of dysregulation of genes in various tumors. These data, as well as data based on older microarray technologies have enabled the identification of many genes which are upregulated in clear cell renal cell carcinoma (ccRCC) compared to matched normal tissue. Here we use RNA sequencing data in order to construct a panel of highly overexpressed genes in ccRCC so as to evaluate their RNA levels in whole blood and determine any diagnostic potential of these levels for renal cell carcinoma patients. METHODS: A bioinformatics analysis with Python was performed using TCGA, GEO and other databases to identify genes which are upregulated in ccRCC while being absent in the blood of healthy individuals. Quantitative Real Time PCR (RT-qPCR) was subsequently used to measure the levels of candidate genes in whole blood (PAX gene) of 16 ccRCC patients versus 11 healthy individuals. PCR results were processed in qBase and GraphPadPrism and statistics was done with Mann-Whitney U test. RESULTS: While most analyzed genes were either undetectable or did not show any dysregulated expression, two genes, CDK18 and CCND1, were paradoxically downregulated in the blood of ccRCC patients compared to healthy controls. Furthermore, LOX showed a tendency towards upregulation in metastatic ccRCC samples compared to non-metastatic. CONCLUSIONS: This analysis illustrates the difficulty of detecting tumor regulated genes in blood and the possible influence of interference from expression in blood cells even for genes conditionally absent in normal blood. Testing in plasma samples indicated that tumor specific mRNAs were not detectable. While CDK18, CCND1 and LOX mRNAs might carry biomarker potential, this would require validation in an independent, larger patient cohort.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Células Neoplásicas Circulantes , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Feminino , Estudos de Associação Genética/métodos , Humanos , Neoplasias Renais/sangue , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , RNA Mensageiro/sangue
9.
EBioMedicine ; 51: 102622, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901870

RESUMO

BACKGROUND: Lipid accumulation has been highlighted in cancer development and progression, but the exact mechanism remains unclear in renal cell carcinoma (RCC). MicroRNAs (miRNAs) have been confirmed to participate in the pathological processes of cancers, including tumour occurrence and inhibition. However, the role and mechanism of miR-765 have not been elucidated in clear cell renal cell carcinoma (ccRCC). METHODS: Using The Cancer Genome Atlas (TCGA) database and qRT-PCR, we investigated differences in miR-765 and proteolipid protein 2 (PLP2) expression, as well as their clinical relevance. To investigate the function of miR-765 and PLP2 in ccRCC, we performed in vitro and in vivo experiments to explore their biological functions in ccRCC. FINDINGS: In this study, we showed that miR-765 was upregulated in the plasma of ccRCC patients after tumour resection. Consistently, ccRCC tissues had low expression of miR-765 when compared with corresponding non-cancerous tissues. Overexpression of miR-765 suppressed cell proliferation and metastasis in vitro and in vivo. Mechanistic studies demonstrated that PLP2 was a direct target gene of miR-765. PLP2 was highly expressed in ccRCC tissues, and high PLP2 levels were positively correlated with higher tumour stage and grade and poor prognosis. PLP2 expression was negatively correlated with the miR-765 level in patient samples. We further showed that PLP2 restrained the cell metastasis and proliferation induced by miR-765 and reduced the lipid-eliminating effects of miR-765 in renal cancer cells. INTERPRETATION: Our findings suggest that miR-765 may function as a tumour suppressor and eliminate lipids in clear cell renal cell carcinoma by targeting PLP2. FUNDING: This work was funded the grants from the National Natural Scientific Foundation of China (Grant No. 81672528, 81672524, 81602218, 31741032, 81902588).


Assuntos
Carcinoma de Células Renais/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Lipídeos/química , Proteínas com Domínio MARVEL/metabolismo , MicroRNAs/metabolismo , Proteolipídeos/metabolismo , Animais , Sequência de Bases , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Proteínas com Domínio MARVEL/genética , Masculino , Camundongos Nus , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Proteolipídeos/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/genética
10.
Int J Biol Markers ; 35(1): 57-64, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31973613

RESUMO

BACKGROUND: Changes in circulating adiponectin have been related to the risks of various cancers. However, the association between circulating adiponectin and the risk of renal cell carcinoma has not been fully determined. A meta-analysis was performed to evaluate the relationship between circulating adiponectin and renal cell carcinoma risk. METHODS: Observational studies that evaluated the association between circulating adiponectin and renal cell carcinoma risk were identified via a systematic search of PubMed and Embase databases. The difference between circulating adiponectin in renal cell carcinoma cases and healthy controls, and the multivariable adjusted association between circulating adiponectin and renal cell carcinoma risk were evaluated. A random effects model was used if significant heterogeneity existed; otherwise a fixed effects model was applied. RESULTS: Eight case-control studies with 2624 renal cell carcinoma cases and 2904 healthy controls were included. Pooled results showed that circulating adiponectin was significantly lower in renal cell carcinoma cases than in healthy controls (mean difference = -1.08 ug/mL; 95% confidence interval (CI) -1.62, -0.54; P < 0.001). Higher circulating adiponectin was independently associated with a significantly lowered risk of renal cell carcinoma (adjusted odds ratio for 1 SD increment of adiponectin = 0.78; 95% CI: 0.63, 0.96; P = 0.02). Subgroup analyses according to characteristics including study design, ethnics of participants, blood samples, numbers of participants, mean ages of participants, and study quality showed consistent results. CONCLUSIONS: Lower circulating adiponectin is associated with increased risk of renal cell carcinoma. The potential pathophysiological mechanisms underlying the role of circulating adiponectin in the pathogenesis of renal cell carcinoma deserve further investigation.


Assuntos
Adiponectina/sangue , Carcinoma de Células Renais/sangue , Neoplasias Renais/sangue , Carcinoma de Células Renais/genética , Estudos de Casos e Controles , Humanos , Neoplasias Renais/genética , Estudos Observacionais como Assunto , Fatores de Risco
11.
Technol Cancer Res Treat ; 19: 1533033819901114, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994979

RESUMO

Increasing studies have suggested that circular RNAs play an important function in the process of numerous cancers. We aimed to investigate the possible role of cir-CCDC66 in renal carcinoma cancer. As cancer stem cells are responsible for the renal carcinoma cancer tumor growth and resistance to conventional therapy, we focus on the cir-CCDC66 influence on renal carcinoma cancer stem cells. In this study, we performed experiments in human renal tubular epithelial cell HK2 cells and several renal carcinoma cancer cancer cell lines. The results showed that cir-CCDC66 was upregulated not only in renal carcinoma cancer cancer cell lines but also in cancer stem cell spheres. What's more, the results showed that cir-CCDC66 enhanced the cancer stem cell enrichment. Further mechanistic studies showed that hepatocyte growth factor/c-Met pathway was activated in cancer stem cell enrichment and responsible for the cir-CCDC66 upregulation. Inhibition of hepatocyte growth factor/c-Met could block cir-CCDC66-induced cancer stem cell enrichment. In conclusion, our research revealed a novel mechanism between hepatocyte growth factor/c-Met/cir-CCDC66 and cancer stem cell enrichment. We verified that cir-CCDC66 could be a promising biomarker and therapy target for renal carcinoma cancer treatment.


Assuntos
Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/metabolismo , Proteínas do Olho/genética , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Circular , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Suscetibilidade a Doenças , Fator de Crescimento de Hepatócito/genética , Humanos , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-met/genética
12.
Int Braz J Urol ; 46(2): 158-168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31961621

RESUMO

PURPOSE: Several studies have demonstrated the strong correlation between the levels of preoperative serum total cholesterol (TC) and the survival of patients with surgically treated renal cell carcinoma (RCC). However, this association remains controversial. We performed a meta-analysis of published reports to evaluate the prognostic signifi cance of the preoperative serum TC levels for patients with surgically treated RCC. MATERIAL AND METHODS: The databases from MEDLINE (via PubMed), Embase, Web of Science and Cochrane Library were systematically searched to identify the eligible studies published before August 2019. Multivariate adjusted hazard ratios (HRs) with 95% confi dence intervals (CIs) were calculated through inverse variance by using random effects models. RESULTS: Nine cohort studies comprising 15.609 patients were identifi ed. Low preopera- tive serum TC levels were associated with poor cancer-specifi c survival (CSS; HR=0.98, 95% CI: 0.97-0.99; P=0.005; I2=74.2%) and progression-free survival (PFS; HR=0.69, 95% CI: 0.49-0.98; P=0.036; I2=80%) in patients with surgically treated RCC. However, no signifi cant association was observed between low preoperative serum TC levels and shorter overall survival (HR=0.93, 95% CI: 0.87-1.00; P=0.057; I2=86.2%). Sensitivity analyses validated the reliability and rationality of the results. CONCLUSIONS: Preoperative serum TC level is an independent poor prognostic factor for patients with surgically treated RCC, with lower levels associated with worse CSS and PFS. Hence, this parameter may provide additional guidance in the selection of therapeutic strategies to improve prognosis, considering that cholesterol is a broadly applied routine marker in clinical practice.


Assuntos
Carcinoma de Células Renais/sangue , Colesterol/sangue , Neoplasias Renais/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/cirurgia , Estudos Observacionais como Assunto , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Reprodutibilidade dos Testes , Análise de Sobrevida
13.
Jpn J Clin Oncol ; 50(2): 214-220, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31755525

RESUMO

BACKGROUND: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma. However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic renal-cell carcinoma. METHODS: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic renal-cell carcinoma and who received nivolumab. Inflammation-based prognostic scores, including neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, lymphocyte/monocyte ratio, and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific survival were compared using Cox proportional-hazards regression models. RESULTS: Univariate analysis showed that Memorial Sloan-Kettering Cancer Center risk score (P = 0.0052), lactate dehydrogenase (P = 0.0266), lymphocyte/monocyte ratio (P = 0.0113), and platelet/lymphocyte ratio (P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that platelet/lymphocyte ratio and lactate dehydrogenase were found to be independent prognostic factors for disease-specific survival (P = 0.0008, risk ratio (RR) = 7.95, 95% confidence interval, 2.16-51.64 and P = 0.0123, RR = 3.92, 95% confidence interval, 1.37-10.80, respectively). The combination of platelet/lymphocyte ratio and lactate dehydrogenase was the most significant prognostic biomarker in metastatic renal-cell carcinoma (P < 0.0001). Changes in lymphocyte/monocyte ratio and platelet/lymphocyte ratio in response to nivolumab were significant prognostic factors for disease-specific survival (P < 0.0001 and P = 0.0477, respectively). CONCLUSIONS: The combination of platelet/lymphocyte ratio and lactate dehydrogenase may be a potential biomarker for estimating disease-specific survival in Japanese patients with metastatic renal-cell carcinoma treated by nivolumab.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Plaquetas/patologia , Carcinoma de Células Renais/patologia , Feminino , Humanos , Inflamação/sangue , Japão , Neoplasias Renais/patologia , L-Lactato Desidrogenase/sangue , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco
14.
Int J Clin Oncol ; 25(1): 135-144, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31512006

RESUMO

BACKGROUND: Association between systemic inflammation and clinical outcome of immune checkpoint inhibitors (ICIs) has received focus. Our objective was to evaluate the utility of the neutrophil-to-lymphocyte ratio (NLR) in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab as well as the prognostic impact of the C-reactive protein (CRP) level. MATERIALS AND METHODS: Sixty-five mRCC patients treated with nivolumab were enrolled. We retrospectively investigated several factors, including the NLR and the CRP level, for their association with progression-free survival (PFS) and overall survival (OS). In addition, we evaluated their impact on the objective response. RESULTS: The CRP level was confirmed to be positively correlated with the NLR in a correlation analysis. An NLR ≥ 5 was significantly associated with a worse PFS (hazard ratio [HR]: 4.54, 95% confidence interval [CI] 1.93-10.7; p < 0.001), and an NLR ≥ 5 and a CRP ≥ 2.1 mg/dL were identified as a significant factors predicting worse OS with HRs of 4.88 (95% CI 1.35-17.7; p < 0.016) and 3.89 (95% CI 1.01-15.0; p = 0.049), respectively. In addition, patients with a ≥ 25% decrease in the NLR and CRP level showed a significantly better response to nivolumab than those without a ≥ 25% decrease in the NLR and CRP level, with odds ratios of 9.54 (95% CI 2.09-49.8, p = 0.001) and 4.36 (95% CI 1.03-18.9, p = 0.032), respectively. CONCLUSION: Both the NLR and CRP levels were significantly associated with the clinical outcome of nivolumab in mRCC patients. The potential prognostic impact of those markers needs to be further prospectively investigated.


Assuntos
Biomarcadores Tumorais/sangue , Proteína C-Reativa/análise , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
15.
J Clin Lab Anal ; 34(1): e23017, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31441128

RESUMO

BACKGROUND: Thromboelastography (TEG) has been established as a sensitive method to assess the whole coagulation process. The aim of the study was to evaluate the diagnosis significance of TEG on hypercoagulability in patients suffering renal mass. METHODS: A total of 478 patients were diagnosed with renal tumor by histolopathologic examination and were assigned to three groups. Group A: 79 patients with benign renal tumor; Group B: 317 patients with renal cell carcinoma (RCC, Fuhrman grades I and II); Group C: 82 patients with high-risk RCC (Fuhrman grades III and IV). Subgroup analysis was performed in malignant renal tumor patients according to the TMN classification. The clinical data, whole blood TEG, and conventional coagulation tests were reviewed. RESULTS: There was no statistically significant difference between subgroups in respect to conventional coagulation tests. Hypercoagulablity was marked in Group C according to the TEG parameters. The elevated platelets and fibrinogen is linked with hypercoagulability in renal tumor. The positive correlation was between fibrinogen and MA value (r = .663, P < .05). The pathologic tumor stages were also associated with the TEG parameters. CONCLUSION: Patients suffering advanced RCC are hypercoagulable which can be identified by TEG. MA value could be potential diagnosis indicators for detecting high-grade RCC.


Assuntos
Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Tromboelastografia , Trombofilia/diagnóstico por imagem , Trombofilia/diagnóstico , Coagulação Sanguínea , Feminino , Humanos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutrófilos/patologia , Trombofilia/sangue
16.
Acta Oncol ; 59(1): 13-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31448981

RESUMO

Background: Elevated neutrophil-lymphocyte ratio (NLR) and hyponatremia each predict poor prognosis in renal cell carcinoma (RCC). Since no previous studies have looked at the combined effect of these two prognostic markers, we examined how NLR and hyponatremia combined associates with mortality and hypothesized that elevated NLR and hyponatremia at RCC diagnosis and at RCC recurrence indicate poorer prognosis.Material and methods: Using Danish medical registries 1999-2015, we included 970 patients from two regions with incident RCC and a measurement of NLR and sodium. NLR was categorized as ≤3.0 and >3.0 and sodium as < lower limit of normal (LLN) and ≥ LLN. Outcomes were survival after RCC diagnosis and first recurrence, respectively. We estimated absolute survival and hazard ratios (HR) using multivariate Cox regression.Results: At RCC diagnosis, 559 (57.6%) had NLR >3.0 and 240 (24.7%) had hyponatremia, the 5 year-survival rate was 35.2% in NLR > 3.0 vs. 69.2% in NLR ≤3.0, adjusted HR 1.8 (95% confidence intervals (CI), 1.4; 2.2). In patients with NLR >3.0 and concomitant hyponatremia vs. NLR ≤3.0 and normal sodium the 5-year survival rate was 21.7% vs. 73.2%, adjusted HR 2.8 (95% CI, 2.1; 3.8). At RCC recurrence, patients with NLR >3.0 and hyponatremia similarly had poorest survival, adjusted HR 3.6 (95% CI, 1.0; 12.8).Conclusion: Elevated NLR alone and in combination with hyponatremia at time of initial RCC diagnosis and at time of RCC recurrence are associated with poor prognosis. Combining these two prognostic markers yield a stronger association than NLR considered alone. This may impact prognostic prediction and its related therapeutic strategy.


Assuntos
Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Hiponatremia/patologia , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Linfócitos/patologia , Neutrófilos/patologia , Feminino , Humanos , Hiponatremia/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
17.
Urol J ; 17(1): 30-35, 2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31087321

RESUMO

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR), as an indicator of the systemic inflammatory response, predicts adverse outcomes in many malignancies. We investigated its prognostic significance in patients with non-metastatic renal cell carcinoma. MATERIALS AND METHODS: We retrospectively evaluated data of 196 consecutive non-metastatic RCC patients who underwent radical or partial nephrectomy between 2010 and 2012 at a single center. Overall survival (OS) was assessed using the Kaplan-Meier method and compared using the log-rank test. We applied univariate and multivariate Cox regression models to evaluate the prognostic value of dichotomized NLR for OS.   Results: At a median follow up of 68 months, high NLR (? 2,69) correlated with worse survival outcome (P = .006 in log-rank test) and higher tumor stage (P = .035). Univariate and multivariate analysis identified elevated NLR (P = .039), as well as age (P = .002), high Fuhrmann grade (P = .002) and high pathologic T stage (P < .001), as significantly associated with overall survival. CONCLUSION: In our cohort, an elevated neutrophil-to-lymphocyte ratio is significantly associated with worse OS on univariate and multivariate analysis. Consequently, the NLR is an easily acquired biomarker, which may be useful in pretreatment patient risk stratification.


Assuntos
Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/sangue , Neoplasias Renais/cirurgia , Linfócitos , Neutrófilos , Fatores Etários , Idoso , Carcinoma de Células Renais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nefrectomia , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida
18.
Acta Oncol ; 59(1): 20-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31462137

RESUMO

Background: An elevated neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis in advanced renal cell carcinoma (RCC). We examined whether the addition of NLR improves the risk reclassification of advanced RCC using current prognostic tools from the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).Methods: Using randomised data from the COMPARZ trial of first-line pazopanib vs. sunitinib in advanced RCC, we constructed multivariable models containing MSKCC and IMDC predictor variables with and without NLR. We evaluated model discrimination using the concordance index (C-index). We computed net reclassification improvement to quantify patient reclassification into low/intermediate/poor risk groups with the addition of NLR.Results: Of 1102 patients, NLR ≥ 5 (16%) was associated with shorter survival adjusting for MSKCC variables (adjusted HR 1.89, p < .001). Adding NLR to MSKCC variables increased the C-index by 0.01. Among patients who died before 24 months (N = 415), adding NLR reclassified 8% and 2% to a higher and lower risk category, respectively. Among those alive at 24 months (N = 636), adding NLR reclassified 4% and 1% to a higher and lower risk category, respectively. This finding translates to a net benefit of eight additional patients who die within 24 months correctly identified as poor risk per 1000 patients tested. We obtained similar results when evaluating NLR with IMDC variables.Conclusions: NLR does not substantially improve risk reclassification over pre-existing prognostic tools. MSKCC and IMDC classifications remain the standard for guiding risk-directed therapy and trial stratification of patients with advanced RCC.


Assuntos
Carcinoma de Células Renais/classificação , Neoplasias Renais/classificação , Linfócitos/patologia , Neutrófilos/patologia , Nomogramas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Risco , Adulto Jovem
19.
Int J Mol Sci ; 20(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816951

RESUMO

In renal cell carcinoma (RCC), interleukin (IL)-1ß may be a pro-metastatic cytokine. However, we have not yet noted the clinical association between tumoral expression or serum level of IL-1ß and RCC in our patient cohort. Herein, we investigate molecular mechanisms elicited by IL-1ß in RCC. We found that IL-1ß stimulates substantial monocyte chemoattractant protein (MCP)-1 production in RCC cells by activating NF-kB and AP-1. In our xenograft RCC model, intra-tumoral MCP-1 injection down-regulated Ki67 expression and reduced tumor size. Microarray analysis revealed that MCP-1 treatment altered protein-folding processes in RCC cells. MCP-1-treated RCC cells and xenograft tumors expressed MCP-1-induced protein (MCPIP) and molecules involved in endoplasmic reticulum (ER) stress-mediated apoptosis, namely C/EBP Homologous Protein (CHOP), protein kinase-like ER kinase (PERK), and calnexin (CNX). ER stress-mediated apoptosis in MCP-1-treated RCC cells was confirmed using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Moreover, ectopic MCPIP expression increased PERK expression in Human embryonic kidney (HEK)293 cells. Our meta-analysis revealed that low MCP-1 levels reduce 1-year post-nephrectomy survival in patients with RCC. Immunohistochemistry indicated that in some RCC biopsy samples, the correlation between MCP-1 or MCPIP expression and tumor stages was inverse. Thus, MCP-1 and MCPIP potentially reduce the IL-1ß-mediated oncogenic effect in RCC; our findings suggest that ER stress is a potential RCC treatment target.


Assuntos
Apoptose , Carcinoma de Células Renais/metabolismo , Quimiocina CCL2/metabolismo , Estresse do Retículo Endoplasmático , Interleucina-1beta/metabolismo , Neoplasias Renais/metabolismo , Ribonucleases/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Animais , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-1beta/sangue , Neoplasias Renais/sangue , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos , Proteínas de Neoplasias/metabolismo , Prognóstico , Dobramento de Proteína , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Immunother Cancer ; 7(1): 334, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783776

RESUMO

BACKGROUND: Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. With the exception of a few candidate biomarkers, the prognostic role of soluble immune checkpoint-related proteins in clear cell renal cell cancer (ccRCC) patients is largely uninvestigated. METHODS: We profiled the circulating levels of 14 immune checkpoint-related proteins panel (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, Tim-3, CD28, CD80, CD137, CD27 and CTLA-4) and their associations with the risk of recurrence and death in 182 ccRCC patients using a multiplex Luminex assay. Gene expression in tumors from a subset of participating patients (n = 47) and another 533 primary ccRCC from TCGA were analyzed to elucidate potential mechanisms. Our primary endpoint is overall survival; secondary endpoint is recurrence-free survival. Multivariate Cox proportional hazard model, unconditional logistic regression model, and Kaplan-Meier analysis were applied in the study. RESULTS: sTIM3 and sLAG3 were significantly associated with advanced (stage III) disease (P < 0.05). sPD-L2 was the strongest predictor of recurrence (HR 2.51, 95%CI 1.46-4.34, P = 9.33E-04), whereas high sBTLA and sTIM3 was associated with decreased survival (HR 6.02, 95%CI 2.0-18.1, P = 1.39E-03 and HR 3.12, 95%CI 1.44-6.75, P = 3.94E-03, respectively). Risk scores based on sTIM3 and sBTLA indicated that the soluble immune checkpoint-related proteins jointly predicted recurrence and death risks of ccRCC (P = 0.01 and 4.44E-04, respectively). Moreover, sLAG3 and sCD28 were found negatively correlated with cytolytic activity of T cells in tumors (rho = -0.31 and - 0.33, respectively). CONCLUSIONS: Our study provides evidence that soluble immune checkpoint-related proteins may associate with advanced disease, recurrence and survival in ccRCC patients, which highlights the prognostic values of soluble immune checkpoint-related proteins. Future independent validation in prospective studies is warranted.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Fenótipo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Citotoxicidade Imunológica , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Recidiva
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