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1.
Anticancer Res ; 40(3): 1739-1745, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132082

RESUMO

BACKGROUND/AIM: The present study examined the impact of systemic inflammatory markers including C-reactive protein (CRP)/Albumin (Alb) and neutrophil lymphocyte ratio (NLR)/Alb on the prognosis of patients treated with first line molecular targeted therapy for advanced RCC. PATIENTS AND METHODS: A total of 131 patients with advanced RCC treated with molecular targeted therapy as first line treatment from May 2008 to April 2019 were retrospectively analyzed. RESULTS: High CRP, high NLR, low Alb and high CRP/Alb showed significantly worse progression-free survival (PFS) and overall survival (OS) than low CRP, low NLR, high Alb, low CRP/Alb and low NLR/Alb, respectively. In multivariate analyses, prior nephrectomy (p=0.0321) and NLR/Alb ratio (p=0.0327) were independent prognostic factors for PFS. Furthermore, prior nephrectomy (p=0.0013) and CRP/Alb ratio (p=0.0020) were independent prognostic factors for OS. CONCLUSION: CRP/Alb and NLR/Alb ratios are useful and independent prognostic biomarkers in patients with advanced RCC treated with molecular targeted therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/terapia , Terapia de Alvo Molecular/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
2.
Bull Cancer ; 107(2): 272-280, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32044098

RESUMO

MiT family translocation renal cell carcinomas (tRCC) represent a rare subtype of renal cell carcinomas. These tumors have been introduced for the first time in the World Health Classification (WHO) classification of kidney cancers in 2004. tRCC are characterized by reccurent translocations involving members of the MiT family transcription factors, mainly TFE3 and TFEB. The estimated incidence of these tumors is ∼1-5 % among all renal cell carcinomas, with female prodominance. tRCC were initially described in children, and the spectrum has been expanded over time to encompass adolescents and adults. TFE3- and TFEB-rearranged RCC harbor characteristic clinicopathological and immunohistochemical features and fluorescent hybridization in situ is considered the gold standard for their diagnosis, although it has some limitations especially when the partners are located in the vicinity of TFE3. Nephron-sparing surgery is an efficient treatment of localized cases when achievable. In metastatic setting, targeted agents and immunotherapy showed modest efficacy, with response rates and median overall survival inferior to those observed in clear-cell renal cell carcinomas. Management of tRCC necessite a multidisciplinary team and accrual in clinical trials have to be encouraged when possible. Novel biological insights are urgently awaited to better understand the mechanisms associated with kidney oncogenesis in this setting, and ultimately help to identify therapeutic targets.


Assuntos
Adenocarcinoma de Células Claras , Carcinoma de Células Renais , Neoplasias Renais , Translocação Genética , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/terapia , Adolescente , Adulto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Criança , Feminino , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/terapia , Masculino , Fator de Transcrição Associado à Microftalmia/genética
3.
J Korean Med Sci ; 35(5): e31, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32030920

RESUMO

BACKGROUND: Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. METHODS: We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. RESULTS: TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais , Inibidores de Proteínas Quinases , Receptores Tipo I de Fatores de Necrose Tumoral , Transdução de Sinais , Fator de Necrose Tumoral alfa , Adulto , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/diagnóstico , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
5.
Urologe A ; 59(2): 149-154, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32076796

RESUMO

In view of a considerable risk of recurrence especially in patients with a high-risk profile after organ-sparing surgery or nephrectomy, adjuvant treatment seems to make sense in renal cell carcinoma. After the failed attempts using older immunotherapeutics or vaccination therapies, new hope was put in the panel of targeted VEGF/R inhibitors. But the results from these studies published so far are also disappointing. In this context the instruments for selecting the best suitable patients for adjuvant trials have to be discussed. It remains to be seen whether using the same selection criteria as in ongoing trials with checkpoint inhibitors will show better results.


Assuntos
Carcinoma de Células Renais/terapia , Quimioterapia Adjuvante/métodos , Neoplasias Renais/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia , Nefrectomia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
6.
Zhonghua Zhong Liu Za Zhi ; 42(1): 44-49, 2020 Jan 23.
Artigo em Chinês | MEDLINE | ID: mdl-32023768

RESUMO

Objective: To investigate the clinicopathologic features and prognosis of the patients who had clear cell renal cell carcinoma (CCRCC) with metastasis to the pancreas. Methods: From Jan, 2000 to Dec, 2018, 18 patients with clear cell renal cell carcinoma (CCRCC) and had pathologically diagnosed metastasis to the pancreas were enrolled at Peking Union Medical College Hospital. The clinical and pathological data were retrospectively analyzed. Results: 11 out of 18 patients were male, and the other 7 were female. The average age of onset of CCRCC was 51.4 years. 8 cases (44.4%) occurred in the left kidney, and the other 10 cases (55.6%) with right kidney tumor. Three patients had synchronous pancreatic metastasis, and the other 15 patients had metachronous pancreatic metastasis. The median time from CCRCC onset to pancreas metastasis was 156 months. The main complaints of pancreas metastasis were abdominal pain, jaundice, gastrointestinal bleeding, nausea, weakness, loss of weight and so on. Seven patients (38.9%) had single lesion of pancreas, while 11 patients (66.1%) had multiple lesions of pancreas. Nine patients (50%) had other organs metastasis besides pancreatic metastasis at the same time. Five patients underwent pancreatic metastasis resection, while 15 patients received oral tyrosine kinase inhibitor(TKI). The mean follow-up was 171.7 months(1~361.5 months) and 5 patients died. The median overall survival (mOS) was 122 months, and the 5 year-survival rate was 81.4%. In univariate analysis, synchronous metastasis to the pancreas, relapse after 10 years, Memorial Sloan Kettering Cancer Center prognostic index, International Metastatic Renal Cell Carcinoma Database Consortium index were all significant parameters for patients'survival. Conclusions: Metastasis to the pancreas from clear cell renal cell carcinoma were rare. These patients had better survival outcomes, especially those relapsing after ten years. Pancreatic metastasis resection had no significant benefit on patient's survival.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Pancreáticas , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Pancreáticas/secundário , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Retrospectivos
7.
Life Sci ; 243: 117273, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926244

RESUMO

Renal cell carcinoma (RCC) is the ninth most prevalent form of malignancy worldwide. The tumor microenvironment significantly affects gene expression in tumor tissues, which subsequently impacts the prognosis of RCC patients. Available datasets such as The Cancer Genome Atlas (TCGA) can be utilized to improve diagnostic methods and search for novel tumor therapeutic targets and prognostic biomarkers. The current study used the ESTIMATE algorithm to explore the immune and stromal components in RCC. Differentially expressed genes (DEGs) were identified by comparing the gene expression patterns in groups with high and low immune/stromal scores. Functional enrichment analysis was conducted and Kaplan-Meier survival curves were plotted to explore the functions of the DEGs in the tumorigenesis, progression, and prognosis of RCC. Our results revealed that immune and stromal scores are associated with specific clinicopathologic variables in RCC. These variables include gender, tumor grade, tumor stage, tumor size, distant metastasis and prognosis. A total of 48 upregulated and 47 downregulated genes were obtained. Functional enrichment analysis demonstrated a correlation between DEGs and the tumor microenvironment, tumor immune response and RCC tumorigenesis. Kaplan-Meier survival curves showed that 43 out of the 48 identified tumor microenvironment related genes are involved in the prognosis of RCC. Three genes, IL10, IGLL5 and POU2AF1, were selected as the hub genes, and their kinase targets were identified as MAPK1 and PPKCA. A positive correlation was obtained between the expression of IL/POU2AF1 and the abundance of six immune cells. Our study provides potential biomarkers for the therapy and prognosis of RCC.


Assuntos
Biomarcadores/metabolismo , Carcinoma de Células Renais/metabolismo , Biologia Computacional , Neoplasias Renais/metabolismo , Microambiente Tumoral , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Prognóstico
8.
Urology ; 136: 9-18, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31770548

RESUMO

For prostate cancer, we review racial differences in incidence, androgen pathways, growth factors, tumor location, rate of definitive treatment, and outcomes. We review the effect of race on risk-stratification and discuss studies of active surveillance in the African American population. For bladder cancer, race- and gender- associated differences in incidence, sex hormone pathways. For renal cell carcinoma, disparities in incidence, genetic factors, tumor pathology, time to presentation, and disease specific survival have been observed. We evaluate the impact of race and ethnicity on tumor pathology and discuss gaps in our current understanding of renal cell carcinoma pathogenesis.


Assuntos
Carcinoma de Células Renais/terapia , Disparidades em Assistência à Saúde , Neoplasias Renais/terapia , Neoplasias da Próstata/terapia , Neoplasias da Bexiga Urinária/terapia , Feminino , Humanos , Masculino
9.
Int J Cancer ; 146(5): 1307-1315, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31498894

RESUMO

Non-clear cell renal cell carcinoma is a very rare malignancy that includes several histological subtypes. Each subtype may need to be addressed separately regarding prognosis and treatment; however, no Phase III clinical trial data exist. Thus, treatment recommendations for patients with non-clear cell metastatic RCC (mRCC) remain unclear. We present first prospective data on choice of first- and second-line treatment in routine practice and outcome of patients with papillary mRCC. From the prospective German clinical cohort study (RCC-Registry), 99 patients with papillary mRCC treated with systemic first-line therapy between December 2007 and May 2017 were included. Prospectively enrolled patients who had started first-line treatment until May 15, 2016, were included into the outcome analyses (n = 82). Treatment was similar to therapies used for clear cell mRCC and consisted of tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors and recently checkpoint inhibitors. Median progression-free survival from start of first-line treatment was 5.4 months (95% confidence interval [CI], 4.1-9.2) and median overall survival was 12.0 months (95% CI, 8.1-20.0). At data cutoff, 73% of the patients died, 6% were still observed, 12% were lost to follow-up, and 9% were alive at the end of the individual 3-year observation period. Despite the lack of prospective Phase III evidence in patients with papillary mRCC, our real-world data reveal effectiveness of systemic clear cell mRCC therapy in papillary mRCC. The prognosis seems to be inferior for papillary compared to clear cell mRCC. Further studies are needed to identify drivers of effectiveness of systemic therapy for papillary mRCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/mortalidade , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Registros/estatística & dados numéricos , Serina-Treonina Quinases TOR/antagonistas & inibidores
10.
Urology ; 135: 76-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31536739

RESUMO

OBJECTIVE: To determine whether use of renal mass biopsy may be associated with a reduction in surgery for patients with small, localized renal cell carcinoma (cT1aN0M0), especially among older patients and patients with greater comorbidity burden. METHODS: A total of 106,258 patients with cT1aN0M0 renal cell carcinoma from 2004 to 2015 were analyzed in the National Cancer Data Base. Multivariable logistic regression identified independent associations with nonsurgical management, receipt of biopsy, and pathologic upstaging. Marginal effects were derived by age and comorbidity. A sensitivity analysis was conducted in years identifying patients undergoing active surveillance (2010-2015). RESULTS: There was increased use of biopsy (8.0%-15.3%) and nonsurgical management (11.7%-15.6%) over time. Biopsy was significantly associated with use of nonsurgical management (OR 4.80 [95%CI 4.58-5.02], P <.001) as well as active surveillance (OR 1.87 [1.69-2.07], P <.001) in the sensitivity analysis. Individual predicted probability of undergoing nonsurgical management ranged from 3% to 92% (median 31.4% with use of biopsy) and increased with age and comorbidity. Pathologic tumor upstaging (≥pT3a) occurred more frequently for patients receiving biopsy compared to no biopsy (5.8% vs 3.3%, P <.001). After adjustment, biopsy remained a statistically significant predictor of upstaging (OR 1.31 [95%CI 1.24-1.38], P <.001). CONCLUSION: Overall, biopsy demonstrated a strong, independent association with reduced use of surgery for cT1aN0M0 kidney cancer, especially with increasing age and comorbidity. The potential association of renal mass biopsy with upstaging warrants caution, but it is uncertain whether it impacts prognosis relative to true perinephric fat invasion.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Rim/patologia , Nefrectomia/estatística & dados numéricos , Conduta Expectante/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Rim/cirurgia , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nefrectomia/métodos , Prognóstico , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Estados Unidos
12.
Medicine (Baltimore) ; 98(50): e18093, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852068

RESUMO

RATIONALE: Papillary renal cell carcinoma (PRCC) accounts for about 15% to 20% of renal cell carcinoma and is histologically distinguished in type I and type II. The last one is associated with poorer prognosis.Treatment options for PRCC patients are surgery, immunotherapy, revolutionized by Nivolumab, and other target-therapy with an improvement in overall survival. Heterogenous response and a pseudo-progression may be observed in the initial phase of biological treatment that could induce premature discontinuation. PATIENT CONCERNS: We present the case of a 44-year-old woman with left cervical palpable mass increased in size and without concomitant disease or previous surgery. DIAGNOSIS: Neck ultrasonography, contrast-enhanced Computed Tomography, and 18F-FDG PET/CT were performed with the detection of lymph nodes involvement and a left renal lesion. INTERVENTIONS: The patients underwent left radical nephrectomy and homolateral cervical and para-aortic lymphadenectomy, with histological diagnosis of PRCC, type II. After disease relapse, the inter-aortocaval lymph node was laparoscopically removed. Following the detection of further disease relapse in several lymph nodes and the lung, several lines of target-therapy were started; then disease progression and worsening of clinical and hematological status led us to start Nivolumab as last-line therapy. OUTCOMES: A heterogeneous response to therapies was documented with morphological and nuclear medicine imaging, however the concomitant deterioration of performance status and liver function led to discontinuation of Nivolumab; then the patient died, 30 months after diagnosis. LESSONS: Here we describe the clinical case and radiological and nuclear medicine imaging investigations performed by our patient, highlighting that 18F-FDG PET/CT shows greater adequacy in assessing the response to therapy, avoiding premature drug discontinuation, and ensuring better management of a patient with advanced PRCC.


Assuntos
Neoplasias Ósseas/diagnóstico , Carcinoma de Células Renais/diagnóstico , Fluordesoxiglucose F18/farmacologia , Neoplasias Renais/diagnóstico , Imagem Multimodal , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Adulto , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Terapia Combinada , Evolução Fatal , Feminino , Humanos , Neoplasias Renais/terapia , Laparoscopia , Excisão de Linfonodo/métodos , Linfonodos/patologia , Metástase Linfática , Pescoço , Estadiamento de Neoplasias , Nefrectomia/métodos , Compostos Radiofarmacêuticos/farmacologia , Vértebras Torácicas
13.
Cancer Immunol Immunother ; 68(12): 2005-2014, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701161

RESUMO

Checkpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class  (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved through a multivariate model, including age and a centroid of VLCFA-containing lipids prior to first immunotherapy (sensitivity: 0.850, specificity: 0.825, ROC: 0.935). We hypothesize that the association of VLCFA-containing lipids with CPI response is based on enhanced peroxisome signaling in T cells, which results in a switch to fatty acid catabolism. Beyond use as a novel predictive non-invasive biomarker, we envision that nutritional supplementation with VLCFA-containing lipids might serve as an immuno sensitizer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Ácidos Graxos/metabolismo , Imunoterapia/métodos , Linfócitos T/imunologia , Neoplasias Urológicas/terapia , Adulto , Idoso , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/mortalidade , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Feminino , Humanos , Imunização , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Peroxissomos/metabolismo , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Transdução de Sinais , Análise de Sobrevida , Resultado do Tratamento , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/mortalidade
14.
Yakugaku Zasshi ; 139(11): 1357-1363, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685731

RESUMO

The tumor microenvironment plays a key role in cancer progression, drug resistance, metastasis, etc. To establish a new therapeutic strategy based on control of the tumor microenvironment, I have developed a lipid nanoparticle (LNP)-based in vivo small interfering RNA (siRNA) delivery system equipped with a targeting ligand. First, I established an LNP that induces membrane fusion in response to acidification after internalization by cells using the original pH-sensitive cationic lipid YSK05. A modification of polyethylene glycol to YSK05-containing LNPs allowed significant gene silencing in the human renal cell carcinoma model. Then, I attempted to establish a tumor vasculature-targeting LNP because the vasculature is responsible for the tumor microenvironment. Cyclic RGD peptide is known to be a ligand against integrin αVß3, which is highly expressed on tumor endothelial cells (TECs). Optimized cyclic RGD peptide-modified LNP (RGD-LNP) suppressed gene expression in TECs to 50%. The inhibition of vascular endothelial cell growth factor receptor 2 (VEGFR2), which is a dominant factor in angiogenesis, by the injection of RGD-LNP significantly delayed tumor growth. Finally, I examined the effect of RGD-LNP on the tumor microenvironment. The suppression of VEGFR2 increased pericyte coverage and endothelial junctions, which indicate maturation of the vasculature. In RGD-LNP-treated mice, systemically administered nanoparticles encapsulating doxorubicin were distributed in a larger area than in untreated mice. Moreover, the therapeutic effect of doxorubicin-loaded liposomes was significantly enhanced by RGD-LNP. In conclusion, I succeeded in developing a new therapy based on regulation of the tumor microenvironment.


Assuntos
Carcinoma de Células Renais/terapia , Sistemas de Liberação de Medicamentos , Neoplasias Renais/terapia , Lipídeos , Terapia de Alvo Molecular , Piperidinas , RNA Interferente Pequeno/administração & dosagem , Microambiente Tumoral , Inibidores da Angiogênese , Animais , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/genética , Doxorrubicina/administração & dosagem , Inativação Gênica , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/genética , Camundongos , Nanopartículas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
15.
Cancer Immunol Immunother ; 68(12): 1979-1993, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31686124

RESUMO

5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of 5T4-targeted antibody and vaccine therapies. 5T4 also represents a compelling and unexplored target for T-cell receptor (TCR)-engineered T-cell therapy. Our group has previously isolated high-avidity CD8+ T-cell clones specific for an HLA-A2-restricted 5T4 epitope (residues 17-25; 5T4p17). In this report, targeted single-cell RNA sequencing was performed on 5T4p17-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (CDR3) of T-cell receptor α chain (TRA) and ß chain (TRB) genes. Full-length TRA and TRB sequences were cloned into lentiviral vectors and transduced into CD8+ T-cells from healthy donors. Redirected effector T-cell function against 5T4p17 was measured by cytotoxicity and cytokine release assays. Seven unique TRA-TRB pairs were identified. All seven TCRs exhibited high expression on CD8+ T-cells with transduction efficiencies from 59 to 89%. TCR-transduced CD8+ T-cells demonstrated redirected cytotoxicity and cytokine release in response to 5T4p17 on target-cells and killed 5T4+/HLA-A2+ kidney-, breast-, and colorectal-tumor cell lines as well as primary RCC tumor cells in vitro. TCR-transduced CD8+ T-cells also detected presentation of 5T4p17 in TAP1/2-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4p17 epitope from a broadly shared tumor antigen are of interest for future testing as a cellular immunotherapy strategy for HLA-A2+ subjects with 5T4+ tumors.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Vacinas Anticâncer/imunologia , Carcinoma de Células Renais/terapia , Epitopos de Linfócito T/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias Renais/terapia , Glicoproteínas de Membrana/metabolismo , Linfócitos T CD8-Positivos/transplante , Carcinoma de Células Renais/imunologia , Células Clonais , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/metabolismo , Humanos , Neoplasias Renais/imunologia , Glicoproteínas de Membrana/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética
16.
Cancer Treat Rev ; 79: 101891, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491662

RESUMO

Collecting ducts carcinoma (CDC) is a rare and aggressive histological subtype of renal cancer accounting for only 1% of renal tumors. Usually patients present in bad clinical conditions due to a symptomatic disease with synchronous metastasis. Due to the rarity of CDC, data from prospective trials evaluating the best treatment for these patients are limited. The prognosis is poor with a median overall survival of around 11 months for patients with metastatic disease. The best treatment option today is considered a doublet chemotherapy with platinum salt plus gemcitabine as a result from a prospective phase II trial, but survival outcomes remain unsatisfactory. The interest in the in-depth understanding the biology of this orphan disease is growing, leading to find potential new biological-driven treatment approaches. Here we review the up-to-date literature evidences to address the best management of this rare and unfavorable clinical condition.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/terapia , Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Animais , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/mortalidade , Terapia Combinada , Gerenciamento Clínico , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/mortalidade , Prognóstico , Resultado do Tratamento
18.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480348

RESUMO

Immunotherapy has changed the therapeutic scenario of metastatic renal cell carcinoma (mRCC), however the evaluation of disease response to immune-checkpoint inhibitors is still an open challenge. Response evaluation criteria in solid tumors (RECIST) 1.1 criteria are the cornerstone of response assessment to anti-neoplastic treatments, but the use of anti-programmed death receptor 1 (PD1) and other immunotherapeutic agents has shown atypical patterns of response such as pseudoprogression. Therefore, immune-modified criteria have been developed in order to more accurately categorize the disease response, even though their use in the everyday clinical practice is still limited. In this review we summarize the available evidence on this topic, with particular focus on the application of immune-modified criteria in the setting of mRCC.


Assuntos
Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Imunoterapia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Padrões de Prática Médica , Carcinoma de Células Renais/imunologia , Humanos , Neoplasias Renais/imunologia , Metástase Neoplásica , Critérios de Avaliação de Resposta em Tumores Sólidos
19.
Hinyokika Kiyo ; 65(6): 197-201, 2019 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-31501385

RESUMO

The patient underwent laparoscopic left radical nephrectomy for clear cell renal cell carcinoma (ccRCC). After surgery, the patient had multiple lung metastases and underwent the combination therapy of radiofrequency ablation, interferon-alpha, and inteleukin-2. Thereafter, computed tomography showed multiple lymph node and brain metastases. The patient was administered targeted therapy and radiation. Eventually, the patient suddenly complained of dyspnea. An echocardiogram, coronary angiography and magnetic resonance imaging suggested acute heart failure and pericardial effusion due to a metastatic tumor in the cardiac anteroseptal and posterior wall. Nivolumab was administered for cardiac metastases. The patient has been in stable condition with no progression of cardiac metastases after the administration of nivolumab for 22 months.


Assuntos
Carcinoma de Células Renais , Neoplasias Cardíacas , Neoplasias Renais , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Terapia Combinada , Neoplasias Cardíacas/secundário , Neoplasias Cardíacas/terapia , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Nefrectomia
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