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2.
J Urol ; 204(1): 42-49, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32073996

RESUMO

PURPOSE: Loss of renal function remains a major limitation of radical nephrectomy. The extent of renal functional compensation by the preserved kidney after radical nephrectomy has not been adequately studied in this elderly population with comorbidities. MATERIALS AND METHODS: A total of 273 patients treated with radical nephrectomy without end stage renal disease with available preoperative nuclear renal scans were included in the analysis. Renal functional compensation was defined as percent change in estimated glomerular filtration rate of the preserved kidney after radical nephrectomy. Estimated glomerular filtration rate was calculated by the Chronic Kidney Disease-Epidemiology Collaboration formula up to 5 years postoperatively. Preoperative/postoperative parenchymal volumes of the preserved kidney were measured from cross-sectional imaging. Multiple regression was used to identify predictive factors for renal functional compensation. RESULTS: Median age was 67 years and 67% of the patients were male. Overall 70% had hypertension, 26% diabetes and 37% preexisting chronic kidney disease. Locally advanced (T3a or greater) tumors were found in 53% of cases. Renal functional compensation was observed at 2 weeks (median 10%) and increased during the first 3 months (median 26%) after radical nephrectomy. Functional stability was then observed to 5 years. Renal parenchymal volume increased a median of 10% at 3 to 12 months but in addition, the functional efficiency per unit of parenchymal volume also increased 8% (estimated glomerular filtration rate units/cm3 of parenchyma was 0.236 postoperatively vs 0.208 preoperatively, p=0.004). Age (-0.85, p <0.01), global preoperative estimated glomerular filtration rate (-0.28, p <0.01) and split renal function of the removed kidney (0.61, p <0.01) were independent predictors of renal functional compensation. CONCLUSIONS: Percent renal functional compensation after radical nephrectomy is greater in younger patients, when preoperative estimated glomerular filtration rate is lower and when the removed kidney has more robust function. Increases in measurable parenchymal mass and functional efficiency contribute substantially to renal functional compensation.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Rim/patologia , Rim/fisiopatologia , Nefrectomia , Complicações Pós-Operatórias , Insuficiência Renal/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/fisiopatologia , Feminino , Humanos , Rim/cirurgia , Testes de Função Renal , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Tamanho do Órgão , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/fisiopatologia , Insuficiência Renal/diagnóstico , Insuficiência Renal/patologia , Insuficiência Renal/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
3.
BMC Cancer ; 20(1): 61, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992244

RESUMO

BACKGROUND: To explore the influencing factors of perioperative renal function change and their relationship with prognosis on renal cell carcinoma (RCC) patients with tumor thrombus after nephrectomy and thrombectomy. METHODS: The clinical and pathological data of 135 patients with RCC and tumor thrombus, who underwent nephrectomy and thrombectomy at Peking University Third Hospital from May 2015 to July 2018, was retrospectively analyzed. Absolute change in estimated glomerular filtration rate (eGFR) (ACE) and percent change in eGFR (PCE) were calculated by preoperative and postoperative renal function. Linear regression analysis was used to explore the influencing factors of ACE and PCE, and logistic regression analysis was used to explore the influencing factors of worse postoperative renal function [eGFR≤60 mL/(min × 1.73 m^2)]. Cancer-specific survival (CSS) was estimated by Kaplan-Meier method and multivariate Cox regression, which were used to explore the effect of ACE and PCE on prognosis. RESULTS: Of all the 135 patients, 101 patients (74.8%) were male and 34 patients (25.2%) were female. The mean preoperative eGFR was 73.9 ± 21.8 mL/(min × 1.73 m^2) and postoperative eGFR was 69.5 ± 25.2 mL/(min × 1.73 m^2). In multivariate linear regression analysis, preoperative eGFR (P < 0.001) and pathological type (P = 0.038) were significant predictive factors of ACE. In aspect of PCE, preoperative eGFR (P < 0.001) and pathological type (P = 0.002) were significant predictors. In multivariate logistic regression analysis, preoperative eGFR (P = 0.016) was the only risk factor of predicting worse postoperative renal function. During follow-up, 22 patients (16.3%) were dead due to RCC. According to ROC analysis, the cut off value of ACE and PCE was 13.9 and 0.16, respectively. ACE> 13.9 and PCE > 0.16 indicated worse CSS (P = 0.006 and P = 0.047, respectively). However, in multivariate Cox regression analysis of several related factors, perinephric tissues invasion (P = 0.001), sarcomatoid differentiation (P = 0.001) and ACE> 13.9 (P = 0.002) were significant prognostic factors for CSS. PCE > 0.16 seemed to be not (P = 0.055). CONCLUSION: We explored several clinicopathological risk factors of predicting renal function change and their relationship with prognosis of RCC patients with tumor thrombus after nephrectomy and thrombectomy. The renal function change, which was associated with preoperative eGFR and pathological type, was prognostic risk factor for CSS and ACE> 13.9 indicated the worse prognosis.


Assuntos
Carcinoma de Células Renais/fisiopatologia , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/fisiopatologia , Neoplasias Renais/cirurgia , Trombose/cirurgia , Idoso , Carcinoma de Células Renais/patologia , China , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Neoplasias Renais/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nefrectomia , Período Perioperatório , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida , Trombectomia , Trombose/fisiopatologia
4.
Hum Pathol ; 97: 1-7, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31857138

RESUMO

Nonfunctioning kidneys secondary to various etiologies display different histopathological features. Studies focused on incidence and types of renal neoplasms using the new World Health Organization and International Society of Urological Pathology classification system in various types of nonfunctioning kidneys are very limited. We identified 311 nephrectomies of nonfunctioning kidneys and categorized them into 5 categories: acquired cystic kidney disease (ACKD, n = 61); end-stage renal disease, nonspecific (ESRD, n = 63); adult polycystic kidney disease (APKD, n = 49); failed transplant kidney (FTK, n = 96); and those caused by obstructive conditions in the kidney (OCK, n = 42). ACKD (70%) and ESRD (43%) had higher cancer incidences than the other 3 groups (APKD = 2%, FTK = 0%, and OCK = 5%). Besides clear cell renal cell carcinoma (RCC) and papillary RCC, clear cell papillary RCC had a much higher incidence within ACKD patients (13/61) compared to other groups. ACKD-associated RCC was only identified in ACKD patients. ACKD patients had significantly longer dialysis duration compared to ESRD, APKD, and FTK. Although they had similar risk for clear cell RCC and papillary RCC, ACKD patients had a much higher risk for ACKD-associated RCC and clear cell papillary RCC than ESRD patients. Although most RCCs arising in these nonfunctioning kidneys were early pT1 stage, 6 ACKD patients and 3 ESRD patients had higher-stage diseases, which can be fatal if not treated appropriately. Therefore, precise clinicopathological classification of these nonfunctioning kidneys is important for predicting kidney cancer risk. These results indicate the need for active monitoring of the patients with high-risk nonfunctioning kidney diseases and appropriate surgical treatment when necessary.


Assuntos
Carcinoma de Células Renais/patologia , Doenças Renais Císticas/patologia , Falência Renal Crônica/patologia , Neoplasias Renais/patologia , Doenças Renais Policísticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/fisiopatologia , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Incidência , Doenças Renais Císticas/epidemiologia , Doenças Renais Císticas/fisiopatologia , Doenças Renais Císticas/terapia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Neoplasias Renais/epidemiologia , Neoplasias Renais/fisiopatologia , Neoplasias Renais/cirurgia , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Nefrectomia , Doenças Renais Policísticas/epidemiologia , Doenças Renais Policísticas/fisiopatologia , Doenças Renais Policísticas/terapia , Prognóstico , Diálise Renal , Medição de Risco , Fatores de Risco , Falha de Tratamento , Adulto Jovem
5.
J Cancer Res Clin Oncol ; 146(1): 261-272, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31677114

RESUMO

PURPOSE: Partial nephrectomy has been persuaded as a widely accepted surgical procedure for T1a (≤ 4 cm) renal tumors. However, when treating T1b (4-7 cm) renal cell carcinoma (RCC), the "optimal" method of surgery is still debatable. The aim of the research is to evaluate the long-term oncological and renal functional outcomes of laparoscopic radical nephrectomy (LRN) versus laparoscopic partial nephrectomy (LPN) for patients with T1b RCC. MATERIALS AND METHODS: From March 1, 2003 to July 1, 2016, 331 patients were included in the current study. Patients presented with unilateral T1b RCC and underwent either LPN (n = 177) or LRN (n = 154). Relevant clinical data including follow-ups were acquired from patients. RESULTS: The operation time of the LPN group patients was longer than that of LRN group (94.3 min vs 88.3 min, p = 0.021) and LPN group patients required shorter stays in hospital (11.5 days vs. 13.4 days, p = 0.009). Contrast to LRN, level of eGFR was superior in LPN at the postoperative time of 1 day, 3 months, 6 months, 12 months and 24 months (all p < 0.001). Kaplan-Meier plots and log-rank tests showed that patients undergoing LPN had a much higher overall survival (OS) (p = 0.007), cancer-specific survival (CSS) (p = 0.006) and metastasis-free survival (MFS) (p = 0.008) than those receiving LRN. In comparison with the LRN group, multivariable Cox analysis indicated that patients of the LPN group had a 1.9-fold OS, 2.9-fold CSS and 2.3-fold MFS. CONCLUSIONS: For patients with T1b RCC, our findings revealed that OS, CSS and MFS are superior in patients receiving LPN than those treated with LRN. With the benefit of preserving renal function of LPN, which leads a less incidence risk of other systematic diseases, LPN may be the preferred option when condition permits for cases involving T1b RCC.


Assuntos
Carcinoma de Células Renais/fisiopatologia , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/fisiopatologia , Neoplasias Renais/cirurgia , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Neoplasias Renais/mortalidade , Laparoscopia/métodos , Laparoscopia/mortalidade , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Nefrectomia/mortalidade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Resultado do Tratamento
6.
Asian J Surg ; 43(1): 257-264, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31324510

RESUMO

BACKGROUND/OBJECTIVES: To investigate the oncological and functional outcomes after partial nephrectomy for clinical stage T1 (cT1) renal cell carcinoma (RCC), and assess the association between excisional volume loss (EVL) and postoperative renal function. METHODS: We retrospectively reviewed 150 patients with cT1 RCC undergoing partial nephrectomy from 2002 to 2016. End-point evaluation was assessed by recurrence free survival (RFS), overall survival (OS), stage III and stage IV chronic kidney disease (CKD). Regression models were used to determine the risk factors of CKD after surgery. The relationship between EVL and renal function decline was evaluated using Spearman correlation method. RESULTS: Ninety patients with clinical stage T1a (cT1a) tumors and 60 patients with clinical stage T1b (cT1b) tumors were included. There were no differences in RFS, OS, and risk of stage III and stage IV CKD between the two groups. In Cox regression models, multivariate analysis showed that preoperative estimated glomerular filtration rate (eGFR) was an independent risk factor for developing stage III (hazard ratio 0.937, P < 0.001) and stage IV CKD (hazard ratio 0.929, P = 0.027). EVL was significantly associated with postoperative eGFR decrease. (Correlation Coefficient = 0.325, P = 0.003). CONCLUSIONS: Patients with cT1a and cT1b RCC have comparable oncological and functional outcome after partial nephrectomy, and preoperative eGFR is an independent factor to predict developing CKD. EVL has influence on the postoperative renal function decline.


Assuntos
Carcinoma de Células Renais/fisiopatologia , Carcinoma de Células Renais/cirurgia , Testes de Função Renal , Neoplasias Renais/fisiopatologia , Neoplasias Renais/cirurgia , Rim/patologia , Rim/cirurgia , Nefrectomia/métodos , Recuperação de Função Fisiológica , Adulto , Idoso , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tamanho do Órgão , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
7.
World J Urol ; 38(1): 151-158, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30937569

RESUMO

PURPOSE: To compare the outcomes of PN to those of RN in very elderly patients treated for clinically localized renal tumor. PATIENTS AND METHODS: A purpose-built multi-institutional international database (RESURGE project) was used for this retrospective analysis. Patients over 75 years old and surgically treated for a suspicious of localized renal with either PN or RN were included in this database. Surgical, renal function and oncological outcomes were analyzed. Propensity scores for the predicted probability to receive PN in each patient were estimated by logistic regression models. Cox proportional hazard models were estimated to determine the relative change in hazard associated with PN vs RN on overall mortality (OM), cancer-specific mortality (CSM) and other-cause mortality (OCM). RESULTS: A total of 613 patients who underwent RN were successfully matched with 613 controls who underwent PN. Higher overall complication rate was recorded in the PN group (33% vs 25%; p = 0.01). Median follow-up for the entire cohort was 35 months (interquartile range [IQR] 13-63 months). There was a significant difference between RN and PN in median decline of eGFR (39% vs 17%; p < 0.01). PN was not correlated with OM (HR = 0.71; p = 0.56), OCM (HR = 0.74; p = 0.5), and showed a protective trend for CSM (HR = 0.19; p = 0.05). PN was found to be a protective factor for surgical CKD (HR = 0.28; p < 0.01) and worsening of eGFR in patients with baseline CKD. Retrospective design represents a limitation of this analysis. CONCLUSIONS: Adoption of PN in very elderly patients with localized renal tumor does not compromise oncological outcomes, and it allows better functional preservation at mid-term (3-year) follow-up, relative to RN. Whether this functional benefit translates into a survival benefit remains to be determined.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Estadiamento de Neoplasias , Nefrectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Pontuação de Propensão , Fatores Etários , Idoso , Ásia/epidemiologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/fisiopatologia , Europa (Continente)/epidemiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Neoplasias Renais/diagnóstico , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento
8.
Eur Rev Med Pharmacol Sci ; 23(23): 10248-10256, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31841179

RESUMO

OBJECTIVE: To investigate whether microRNA-588 was involved in the development and progression of renal cancer, and to explore its possible regulatory mechanisms. PATIENTS AND METHODS: Tumor tissues excised from renal carcinoma and adjacent normal tissues were selected for the experiment. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to analyze the expression level of microRNA-588 in tissue specimens. The relationship between the expression of microRNA-588 and the prognosis of patients with renal cell carcinoma was also evaluated. Subsequently, two renal cancer cell lines, including769-P and 786-O, were selected for functional experiments in vitro. Eukaryotic initiation factor 5A2 (pcDNA-EIF5A2) or microRNA-588 mimics was transfected into 769-P cells, respectively. Meanwhile, si-EIF5A2 or microRNA-588 inhibitor was transfected into 786-O cells. After that, the mRNA expression level of EIF5A2 was detected by qRT-PCR. The invasiveness and metastasis abilities of the two cell lines were evaluated via transwell assay. Furthermore, the levels of EIF5A2 and epithelial-mesenchymal transition (EMT)-related proteins were analyzed using Western blot. Luciferase reporter gene assay was used to confirm that microRNA-588 could directly regulate EIF5A2 expression. QRT-PCR and Western blot were performed to explore the mRNA and protein expressions of EIF5A2 in patients with highly or lowly-expressed microRNA-588. The correlation between the two molecules was evaluated using linear analysis. Through the above experiments, it was verified whether microRNA-588 could enhance the invasiveness and metastasis of renal cancer by targeting EIF5A2. RESULTS: MicroRNA-588 expression in tumor tissues of patients with renal carcinoma was significantly decreased with the increase of tumor diameter and stage. A higher level of microRNA-588 indicated significantly longer overall survival of patients. This suggested that microRNA-588 expression was negatively correlated with the prognosis of patients. Overexpression of microRNA-588 remarkably reduced the invasion and metastasis abilities of 769-P cells, as well as the expressions of EMT-related proteins. However, opposite results were observed in 786-O cells after knockdown of microRNA-588. Reporter gene assay confirmed that microRNA-588 could target bind to EIF5A2. In 769-P cells, up-regulated microRNA-588 significantly inhibited the mRNA and protein expressions of EIF5A2. However, down-regulated microRNA-588 in 786-O cells significantly enhanced the expressions of EIF5A2 at both mRNA and protein levels. Linear analysis verified that microRNA-588 was negatively correlated with EIF5A2 at the mRNA level. Additionally, the up-regulation of EIF5A2 in 769-P cells enhanced the malignancy of cancer cells and the expressions of EMT-related proteins. However, in 786-O cells, opposite results were observed after knockdown of EIF5A2. CONCLUSIONS: MicroRNA-588 was lowly expressed in renal cancer tissues and cell lines. This might lead to an increase in the protein level of EIF5A2, eventually promoting tumor invasion and metastasis.


Assuntos
Carcinoma de Células Renais/fisiopatologia , Movimento Celular/fisiologia , Neoplasias Renais/fisiopatologia , MicroRNAs/fisiologia , Invasividade Neoplásica/fisiopatologia , Fatores de Iniciação de Peptídeos/fisiologia , Proteínas de Ligação a RNA/fisiologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação para Baixo , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/biossíntese , Mimetismo Molecular/fisiologia , Fatores de Iniciação de Peptídeos/biossíntese , Proteínas de Ligação a RNA/biossíntese , Transfecção , Regulação para Cima
9.
Genes Dev ; 33(23-24): 1641-1656, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727773

RESUMO

Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα+ fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8+ T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B-NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.


Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/fisiopatologia , Progressão da Doença , Melanoma/fisiopatologia , Transdução de Sinais , Proteínas Semelhantes a Angiopoietina/deficiência , Proteínas Semelhantes a Angiopoietina/imunologia , Animais , Vacinas Anticâncer/imunologia , Carcinoma de Células Renais/imunologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Melanoma/imunologia , Camundongos , Transdução de Sinais/genética , Células Estromais/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
11.
Jpn J Clin Oncol ; 49(12): 1164-1171, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31665407

RESUMO

OBJECTIVES: The efficacy and safety of sunitinib versus sorafenib in patients with advanced renal cell carcinoma with renal impairment remains poorly documented. PATIENTS AND METHODS: We assessed the efficacy and safety of sunitinib and sorafenib in patients with advanced renal cell carcinoma with an estimated glomerular filtration rate of 15-60 mL/min/1.73 m2 by reviewing the medical records of patients treated at Jichi Medical University Hospital, Japan, between May 2008 and August 2016. RESULTS: Twenty-seven patients were treated with sunitinib and 14 with sorafenib. Median progression-free survival in sunitinib- and sorafenib-treated patients was comparable, at 6.6 vs 5.8 months, respectively (HR, 1.618; 95% CI, 0.689-3.798; P = 0.2691). Median overall survival was also comparable, at 65.9 vs 58.0 months (HR, 0.985; 95% CI, 0.389-2.479; P = 0.9748). Grade 3 or higher adverse events were significantly more frequent in the sunitinib-treated than sorafenib-treated patients (P = 0.0357). Compared to pre-treatment values, estimated glomerular filtration rate at the discontinuation of treatment was not decreased in either group. In contrast, estimated glomerular filtration rate was decreased on long-term treatment, particularly in previously nephrectomized patients. CONCLUSIONS: Sunitinib and sorafenib had similar efficacy in patients with advanced renal cell carcinoma and severe renal impairment. Although renal function was not markedly impaired in either group, close attention to decreased renal function may be necessary in previously nephrectomized patients on long-term treatment.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/fisiopatologia , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular , Humanos , Japão , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Insuficiência Renal/patologia , Insuficiência Renal/fisiopatologia , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico , Análise de Sobrevida
12.
BMC Cancer ; 19(1): 874, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481081

RESUMO

BACKGROUND: The ubiquitous expressed transcript (UXT) plays a key role in various tumors by regulating transcriptional activity of multiple transcription factors, including androgen receptor (AR). However, the role of UXT in clear cell renal cell carcinoma (ccRCC) is still unknown. METHODS: Yeast two-hybrid screening, GST pull-down and co-immunoprecipitation assays were performed to detect the interacting protein of UXT. Chromatin immunoprecipitation (ChIP) was performed to investigate the levels of histone H3 lysine 27 trimethylation at the HOXA9 promoters. CCK-8 assays, colony formation assays and Transwell assays were performed to detect the proliferation, colony formation, migration and invasion of renal cancer cells. Quantitative PCR analysis was performed to detect the expressions of UXT in human ccRCC samples. RESULTS: The enhancer of zeste homolog 2 (EZH2) is a novel UXT interacting protein and UXT interacts with EZH2 in the nucleus. In addition, UXT interacts with the polycomb repressive complex 2 (PRC2) through directly binding to EZH2 and suppressor of zeste 12 homolog (SUZ12), but not to embryonic ectoderm development (EED). Moreover, the UXT activates EZH2 histone methyltransferase activity by facilitating EZH2 binding with SUZ12. We further provided striking evidences that knockdown of UXT inhibits proliferation, colony formation, migration and invasion of renal cancer cells, in an EZH2-dependent manner. Importantly, the upregulation of UXT expression was observed in clinical ccRCC samples, and the high expression level of UXT was associated with advanced stage, distant metastasis and poor overall survival in patients with ccRCC. CONCLUSION: The UXT is a novel regulator of the PRC2 and acts as a renal cancer oncogene that affects the progression and survival of ccRCC patients.


Assuntos
Carcinoma de Células Renais/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Renais/genética , Chaperonas Moleculares/metabolismo , Idoso , Carcinoma de Células Renais/fisiopatologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Núcleo Celular/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Renais/fisiopatologia , Masculino , Metilação , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Mutação , Complexo Repressor Polycomb 2/metabolismo , Prognóstico , Ligação Proteica , Análise de Sobrevida
13.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547602

RESUMO

This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.


Assuntos
Axitinibe , Carcinoma de Células Renais , Hipertensão , Neoplasias Renais , Compostos de Fenilureia , Quinolinas , Sorafenibe , Sunitinibe , Axitinibe/efeitos adversos , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/fisiopatologia , Humanos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico
14.
Med Oncol ; 36(10): 88, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520152

RESUMO

We prospectively validate the efficacy of the frailty discriminant score (FDS) in individuals with urological cancers, as there has been growing importance in evaluating frailty in clinical practice. A prospective, multicenter study was conducted from February 2017 to April 2019. We enrolled 258 patients with urological cancers and 301 community-dwelling participants who were assessed for frailty. Frailty was assessed using FDS that includes ten items, such as physical, mental, and blood biochemical tests. The primary outcome was the non-inferiority (margin 5%) of FDS in discriminating patients with urological cancers from controls (Ctrl). The sensitivity, specificity, and area under the receiver operating characteristic (AUROC) curve for each predictive test were calculated. The secondary endpoints included the prediction of overall survival between patients with urological cancer who have high and low FDS. FDS was significantly higher in patients with urological cancers than that in the Ctrl. The AUROC curves for individuals with non-prostate cancers (such as bladder cancer, upper tract urothelial carcinoma, and renal cell carcinoma; 0.942) and those with prostate cancer (0.943) were within the non-inferior margin. The overall survival values were significantly lower in patients with higher FDS score than in those with lower FDS score. The study met its primary and secondary endpoints. The FDS is a reliable and valid tool for assessing frailty and prognosis in patients with urological cancers.


Assuntos
Fragilidade/fisiopatologia , Neoplasias Urológicas/patologia , Neoplasias Urológicas/fisiopatologia , Idoso , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/fisiopatologia , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/fisiopatologia , Estudos de Avaliação como Assunto , Feminino , Idoso Fragilizado , Avaliação Geriátrica/métodos , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia , Curva ROC , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/fisiopatologia
15.
Biorheology ; 56(2-3): 151-161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256115

RESUMO

BACKGROUND: Previous studies have demonstrated that the glycosaminoglycans (GAGs) heparan sulfate (HS) and hyaluronic acid (HA) are mechanosensors for interstitial flow on cancer cells. The proteins that link the GAGs to the cancer cell for mechanotransduction, however, are not known. OBJECTIVE: To assess whether the HS proteoglycan core proteins, Glypican-1 and Syndecan-1, or the HA receptor, CD44, provides the mechanical linkage to the cell. METHODS: The highly metastatic renal carcinoma cell line (SN12L1) and its companion low metastatic cell line (SN12C) were analyzed by Western blot, siRNA, and a 3-dimensional interstitial flow migration assay. RESULTS: There was significant elevation of Glypican-1 protein expression in the SN12L1 cells relative to the SN12C cells while there were no significant differences in Syndecan-1 or CD44. Knock down of Glypican-1 by siRNA completely blocked flow induced migration in SN12L1 cells. MAPK inhibitors also blocked flow induced migration in SN12L1 cells. CONCLUSIONS: Glypican-1 provides the mechanical linkage from HS (the flow sensor) to the SN12L1 cell where mechanotransduction leading to the enhancement of migration (metastasis) occurs. MAPKs downstream of Glypican-1 propagate the signal. The HS, Glypican-1, MAPK signaling axis suggests opportunities for pharmaceutical intervention.


Assuntos
Movimento Celular/fisiologia , Líquido Extracelular/fisiologia , Glicocálix/metabolismo , Glipicanas/metabolismo , Mecanotransdução Celular/fisiologia , Metástase Neoplásica/fisiopatologia , Carcinoma de Células Renais/fisiopatologia , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Renais/fisiopatologia , Sindecana-1/metabolismo
16.
Medicina (Kaunas) ; 55(6)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216752

RESUMO

Background and objective: We investigated the ability of preoperative serum values of red blood cell distribution width (RDW), neutrophil lymphocyte ratio (NLR) and plateletcrit (PCT) to predict Fuhrman grades (FG) and tumor stages of renal cell carcinoma in patients who underwent radical nephrectomy. Materials and methods: Records of 283 patients that underwent radical or partial nephrectomy of renal masses at our clinic between January 2010 and April 2018, whose pathology results indicated renal cell carcinoma (RCC), and who had their FG and T1-4 N0M0 identified were retrospectively evaluated. The patients were divided into two groups based on their FG as low (I-II) and high (III-IV) and their T stages were similarly grouped as limited to kidney (pT1-pT2) and not limited to kidney (pT3-pT4). Results: Mean RDW, NLR, PCT cut-off values of the patients for FG and T stage were 15.65%, 3.54, 0.28% and 14.35%, 2.69, 0.28%, respectively. The RDW and NLR were determined to be statistically significant predictors of a pathologically high FG, whereas the PCT value was not a statistically significant predictor of high FG (p = 0.003, p = 0.006, p = 0.075, respectively). The relationship of RDW, NLR and PCT values with a limited to the kidney pathological T stage revealed statistically significant correlations for all three values. Conclusions: We determined that only RDW and NLR were markers predicting FG, while PCT had no prognostic value. On the other hand, all three of these values were associated with a limited to the kidney pathological T stage in patients who underwent nephrectomy due to renal masses and whose pathologies suggested RCC.


Assuntos
Carcinoma de Células Renais/diagnóstico , Eritrócitos/patologia , Valor Preditivo dos Testes , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Carcinoma de Células Renais/fisiopatologia , Feminino , Humanos , Contagem de Linfócitos/métodos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neutrófilos/fisiologia , Prognóstico , Curva ROC , Estudos Retrospectivos
17.
Mol Med Rep ; 20(2): 1212-1220, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173226

RESUMO

Renal cell carcinoma (RCC) is a common malignant tumor globally. The overall survival of patients with RCC is poor; one important factor is tumor heterogeneity. Ubiquitin­conjugating enzyme E2T (UBE2T) has been reported to act as an oncogene in various types of cancer; however, its role in RCC has yet to be investigated. In the present study, UBE2T was demonstrated via reverse transcription­quantitative PCR analysis to be significantly upregulated in RCC samples and cell lines compared with in normal tissue and cells. Additionally, UBE2T expression was significantly associated with late tumor stage and high grade in patients with RCC, and patients with high UBE2T expression exhibited poor prognosis compared with patients with low expression. Following knockdown of UBE2T in 786­O cells using RNA interference technology, the proliferation and colony formation of cells were inhibited as determined by an MTT assay and crystal violet staining, respectively; however, the migration and invasion of 786­O cells were not affected, as determined by wound­healing assay and Transwell assays, respectively. Xenograft RCC tumor growth in vivo was also significantly suppressed. The expression levels of two mesenchymal cell markers, N­cadherin and vimentin, were reduced following UBE2T knockdown, whereas E­cadherin and fibronectin levels were increased as determined by western blotting, indicating that epithelial­mesenchymal transition was suppressed. In addition, the phosphorylation levels of PI3K, Akt and mTOR were notably decreased following UBE2T knockdown, but were increased when UBE2T was overexpressed. Wortmannin, an Akt inhibitor, reversed the UBE2T overexpression­induced increase in the phosphorylation of PI3K, Akt and mTOR. Similarly, the UBE2T overexpression­induced promotion of 786­O cell proliferation was also attenuated by wortmannin. In conclusion, UBE2T promoted the proliferation of RCC cells by regulating PI3K/Akt signaling, suggesting it may be a novel target for the treatment of patients with RCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Proliferação de Células , Neoplasias Renais/metabolismo , Transdução de Sinais , Enzimas de Conjugação de Ubiquitina/metabolismo , Adolescente , Adulto , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/fisiopatologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
18.
Medicine (Baltimore) ; 98(17): e15346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027111

RESUMO

To assess whether left and right-sided renal cell carcinoma (RCC) carry side-specific outcomes.Surgically treated RCC patients were included from the United States Surveillance, Epidemiology and End Results database (Surveillance, Epidemiology and End Results database [SEER]; 2013 version) and the German Centre for Cancer Registry Data (ZfKD; 2000-2014). Bilateral RCC, those with missing RCC staging, follow-up time, and survival status were excluded. Cancer-specific survival (CSS) according to RCC side was compared using multivariable Cox regression.Seventeen thousand seven hundred nine SEER patients and 41,967 ZfKD patients were included. In both datasets, patients with left-sided RCC had higher T status and more often presented with nodal positive or metastatic disease. In the SEER dataset 1258 (14.33%) patients with left-sided RCC underwent lymphadenectomy (LAD), compared to 908 (10.17%) LADs in right-sided RCC (P <.001). CSS was inferior for left-sided in both datasets after multivariable adjustment (SEER HR = 1.187, 95% CI 1.048-1.345, P = .007, P = .008; ZfKD HR = 1.155, 95% CI 1.046-1.275, P = .004).In the SEER population, site-specific CSS differences were driven by whether or not a LAD was performed. Among SEER patients with LAD no statistically significant differences in laterality were observed (HR 1.096, 95% CI 0.8977-1.337, P = .396) whereas, in absence of LAD, CSS was shorter for individuals with left-sided tumor (HR = 1.176, 95%CI 1.002-1.38, P = .0468).Although the overall survival difference was only marginal, left-sided RCC in surgically treated patients tends to present at more advanced stage and has in general worse CSS, especially in patients without LAD. Site-specific lymphogenic spread patterns might contribute to these findings. Further prospective studies should evaluate, whether side-adapted LAD protocols influence outcomes in RCC patients.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/diagnóstico , Neoplasias Renais/mortalidade , Idoso , Carcinoma de Células Renais/fisiopatologia , Feminino , Seguimentos , Humanos , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Programa de SEER , Análise de Sobrevida
19.
Eur Urol Oncol ; 2(2): 207-213, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31017098

RESUMO

BACKGROUND: Robot-assisted partial nephrectomy (RAPN) is an established, minimally invasive nephron-sparing technique with excellent perioperative and intermediate oncological outcomes. However, long-term oncological outcomes have not been reported to date. OBJECTIVE: To report oncological and functional outcomes of RAPN among patients with minimum follow-up of 5 yr. DESIGN, SETTING, AND PARTICIPANTS: Data for consecutive patients undergoing RAPN since October 2006 were extracted from a prospectively-maintained institutional PN database. Patients with benign tumors, genetic mutations, prior radical or ipsilateral PN, and those with follow-up of <5 yr were excluded. INTERVENTION: Transperitoneal RAPN for renal cell carcinoma (RCC). OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Demographic, perioperative, postoperative, functional, and oncological data were evaluated. A linear random-effects model was used to estimate the effect of follow-up duration on the estimated glomerular filtration rate (eGFR) after adjustment for potential confounders. Univariable competing-risks regression analyses were performed to evaluate the hazard ratio (HR) for cancer-related events for the variables of interest. RESULTS AND LIMITATIONS: A total of 278 RAPNs for RCC were included. eGFR was significantly lower at follow-up time points than at baseline. At last follow-up (median 46 mo, interquartile range 30-58) the mean eGFR difference was -10.6ml/min (95% confidence interval -12.56 to -8.66; p < 0.0001). There were 28 deaths (10.1%) in the cohort during the follow-up period, of which five (1.8%) were related to metastatic RCC. The 5-yr and 7-yr cumulative incidence of RCC deaths was 1.80% at both 5 and 7 yr, while the cumulative incidence of local recurrence was 3.61% and 4.16%, and that of metastasis was 3.24% and 4.57% at 5 and 7 yr, respectively. Univariable competing-risks regression revealed that higher Fuhrman grade (HR 8.76; p = 0.051), larger tumor size (HR 1.67; p < 0.0001), and tumor necrosis (HR 16.73; p = 0.0019) were independent predictors of RCC death. The retrospective design and potential selection bias due to patient selection in the early RAPN experience may limit the generalizability of the findings. CONCLUSIONS: This is the first study reporting minimum oncological follow-up of 5 yr after RAPN. The results demonstrate excellent long-term oncological outcomes after RAPN in a selected cohort of patients. Our data confirm that the renal functional deterioration after RAPN remains stable over time after the early postoperative decrease. PATIENT SUMMARY: Robot-assisted partial nephrectomy is being more widely used as a standard treatment for small localized renal cell carcinomas. This study reveals excellent long-term cancer control for both local recurrences and distant metastases. Renal function is stable after an initial postoperative deterioration.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Nefrectomia/métodos , Idoso , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/fisiopatologia , Seguimentos , Taxa de Filtração Glomerular , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tratamentos com Preservação do Órgão , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos , Resultado do Tratamento , Carga Tumoral
20.
Actas urol. esp ; 43(3): 118-123, abr. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-181169

RESUMO

Contexto y objetivo: En los últimos años se han producido avances significativos en el conocimiento de la carcinogénesis renal. Hoy en día los tumores renales se clasifican en función de su perfil genético, y además se han desarrollado tratamientos específicos basados en la identificación de dianas terapéuticas. Sin embargo, todavía no se han identificado marcadores pronósticos. El objetivo de esta revisión es analizar la literatura que ha evaluado la expresión de la proteína STAT3 como marcador molecular en el carcinoma renal de célula clara (ccRCC). Adquisición de evidencia: En enero de 2018 se realizó una búsqueda sistemática de la literatura en Pubmed, Cochrane Library y Sciencedirect de las publicaciones realizadas desde 1990. Los términos de búsqueda fueron renal cell carcinoma and STAT3 or STAT-3 and prognostic factor. Se siguieron los principios de la declaración PRISMA y la estrategia de selección PICO, seleccionándose los artículos originales con series de pacientes diagnosticados de ccRCC localizado o metastásico, donde se analiza la actividad de STAT3 como marcador pronóstico. Se identificaron 132 publicaciones de las que finalmente se han revisado 10 por cumplir los criterios de inclusión. Síntesis de evidencia: La activación (fosforilación) de STAT3 (pSTAT3) en el residuo Ser727 es importante en el desarrollo y progresión de ccRCC. La expresión de pSTAT3 parece ser un marcador pronóstico y predictor de resistencia a algunos tratamientos en pacientes con enfermedad diseminada. Existe poca evidencia de su utilidad como un marcador pronóstico en pacientes con enfermedad localizada. Conclusiones: La expresión de pSTAT3(Ser727) en el núcleo de las células del ccRCC puede ser un marcador pronóstico y de respuesta al tratamiento en pacientes con ccRCC. La evidencia científica actual es limitada y son necesarios más estudios que demuestren su utilidad


Context and objective: There have been significant advances in the knowledge of renal carcinogenesis in the last years. Nowadays, renal tumours are classified according to their genetic profile and specific treatments based on the identification of therapeutic targets have also been developed. However, no prognostic markers have yet been identified. The aim of this review is to analyze literature that has evaluated the expression of the STAT3 protein as a molecular marker in clear cell renal carcinoma (ccRCC). Evidence acquisition: In January 2018 a systematic review was conducted in Pubmed, Cochrane library and Sciencedirect databases, from papers published from 1990. Search terms were "renal cell carcinoma" and "STAT3" or "STAT-3" and prognostic factor. Following the principles of the PRISMA declaration and the PICO selection strategy, original articles with series of patients diagnosed with localized or metastatic ccRCC, and where the activity of STAT3 is analyzed as a prognostic marker, were selected. A total of 132 publications were identified, of which 10 were finally revised, for they met the inclusion criteria. Evidence synthesis: STAT3 activation (phosphorylation) through Ser727 is important during ccRCC development and progression. PSTAT3 expression seems to be a prognostic marker and an antiangiogenic-resistance marker in metastatic patients. There is little evidence as prognostic marker in patients with localized disease. Conclusions: STAT3 (Ser 727) expression in the nucleus of the ccRCC cells can be a prognostic marker and an antiangiogenic-resistance marker. Current scientific evidence is limited and more studies are needed to demonstrate its usefulness


Assuntos
Neoplasias Renais/etiologia , Carcinoma de Células Renais/diagnóstico , Fator de Transcrição STAT3/metabolismo , Biomarcadores Tumorais , Carcinoma de Células Renais/fisiopatologia , Prognóstico , Carcinoma de Células Renais/etiologia , Fator de Transcrição STAT3/uso terapêutico
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