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1.
Anticancer Res ; 41(5): 2511-2521, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952479

RESUMO

BACKGROUND/AIM: This study aimed to elucidate the detailed characteristics of CYP3A5 expression and the association between CYP3A5 expression and clinical outcomes in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: This study retrospectively enrolled 124 Japanese patients with RCC treated at the Okayama University Hospital. The commonest CYP3A5 gene polymorphism, CYP3A5*3, and expression levels of CYP3A5 mRNA and protein in each tissue were examined. RESULTS: Expression of CYP3A5 mRNA and protein in RCC tissues was significantly down-regulated compared to that in adjacent normal tissues. High level of CYP3A5 mRNA expression significantly extended cancer-specific survival (p=0.004) and overall survival (p=0.002). The CYP3A5 mRNA expression level was identified as a significant independent prognostic factor for both cancer-specific survival and overall survival. CONCLUSION: CYP3A5 could serve as a potential marker for prognostication and treatment planning for patients with RCC.


Assuntos
Carcinoma de Células Renais/terapia , Citocromo P-450 CYP3A/genética , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
2.
Adv Exp Med Biol ; 1311: 117-126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014538

RESUMO

According to data from the American Cancer Society, cancer is one of the deadliest health problems globally. Annually, renal cell carcinoma (RCC) causes more than 100,000 deaths worldwide [1-4], posing an urgent need to develop effective treatments to increase patient survival outcomes. New therapies are expected to address a major factor contributing to cancer's resistance to standard therapies: oncogenic heterogeneity. Gene expression can vary tremendously among different types of cancers, different patients of the same tumor type, and even within individual tumors; various metabolic phenotypes can emerge, making singletherapy approaches insufficient. Novel strategies targeting the diverse metabolism of cancers aim to overcome this obstacle. Though some have yielded positive results, it remains a challenge to uncover all of the distinct metabolic profiles of RCC. In the quest to overcome this obstacle, the metabolic oriented research focusing on these cancers has offered freshly new perspectives, which are expected to contribute heavily to the development of new treatments.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Fenótipo
3.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923219

RESUMO

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies.


Assuntos
Carcinoma de Células Renais/terapia , Imunoterapia/métodos , Neoplasias Renais/terapia , Microambiente Tumoral/imunologia , Animais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia
4.
Asia Pac J Clin Oncol ; 17 Suppl 3: 27-38, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33860644

RESUMO

BACKGROUND: To establish a set of consensus statements for the management of metastatic renal cell carcinoma, a total of 12 urologists and clinical oncologists from two professional associations in Hong Kong formed an expert consensus panel. METHODS: Through a series of meetings and using the modified Delphi method, the panelists presented recent evidence, discussed clinical experiences, and drafted consensus statements on several areas of focus regarding the management of metastatic renal cell carcinoma. Each statement was eventually voted upon by every panelist based on the practicability of recommendation. RESULTS: A total of 46 consensus statements were ultimately accepted and established by panel voting. CONCLUSIONS: Derived from recent evidence and expert insights, these consensus statements were aimed at providing practical guidance to optimize metastatic renal cell carcinoma management and promote a higher standard of clinical care.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Urologia/métodos , Consenso , Hong Kong , Humanos , Metástase Neoplásica
6.
Cancer Sci ; 112(6): 2126-2139, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33735492

RESUMO

The tumor microenvironment, comprised of tumor cells and tumor-infiltrating immune cells, is closely associated with the clinical outcome of clear cell renal cell carcinoma (ccRCC) patients. However, the landscape of immune infiltration in ccRCC has not been fully elucidated. Herein, we applied multiple computational methods and various datasets to reveal the immune infiltrative landscape of ccRCC patients. The tumor immune infiltration (TII) levels of 525 ccRCC patients using a single-sample gene were examined and further categorized into immune infiltration subgroups. The TII score was characterized by distinct clinical traits and showed a significant divergence based on gender, grade, and stage. A high TII score was associated with the ERBB signaling pathway, the TGF-ß signaling pathway, and the MTOR signaling pathway, as well as a better prognosis. Furthermore, patients with high TII scores exhibited greater sensitivity to pazopanib. The low TII score was characterized by a high immune infiltration level of CD8+ T cells, T follicular helper cells, and regulatory T cells (Tregs). Moreover, the immune check point genes, including CTLA-4, LAG3, PD-1, and IDO1, presented a high expression level in the low TII score group. Patients in the high TII score group demonstrated significant therapeutic advantages and clinical benefits. The findings in this study have the potential to assist in the strategic design of immunotherapeutic treatments for ccRCC.


Assuntos
Carcinoma de Células Renais/imunologia , Imunoterapia , Neoplasias Renais/imunologia , Microambiente Tumoral/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Checkpoint Imunológico/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Linfócitos do Interstício Tumoral/imunologia , Prognóstico , Transdução de Sinais/imunologia , Análise de Sobrevida , Subpopulações de Linfócitos T/imunologia
7.
Cancer Sci ; 112(4): 1417-1428, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33539630

RESUMO

Chimeric antigen receptor (CAR)-T cell therapy has shown salient efficacy in cancer immunotherapy, particularly in the treatment of B cell malignancies. However, the efficacy of CAR-T for solid tumors remains inadequate. In this study, we displayed that c-met is an appropriate therapeutic target for papillary renal cell carcinoma (PRCC) using clinical samples, developed an anti-human c-met CAR-T cells, and investigated the anti-tumor efficacy of the CAR-T cells using an orthotopic mouse model as pre-clinical research. Administration of the anti-c-met CAR-T cells induced marked infiltration of the CAR-T cells into the tumor tissue and unambiguous suppression of tumor growth. Furthermore, in combination with axitinib, the anti-tumor efficacy of the CAR-T cells was synergistically augmented. Taken together, our current study demonstrated the potential for clinical application of anti-c-met CAR-T cells in the treatment of patients with PRCC.


Assuntos
Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Proteínas Proto-Oncogênicas c-met/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Idoso , Animais , Anticorpos/imunologia , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572811

RESUMO

The development of new technologies and industry is conducive to the increase in the number and variety of electromagnetic field (EMF) sources in our environment. The main sources of EMF are high-voltage lines, household appliances, audio/video devices, mobile phones, radio stations, and radar devices. In the growing use of electronic devices, scientists are increasingly interested in the effects of EMF on human health. Even though many studies on the effects of EMF have already been carried out, none of them has shown a significant effect on mammals, including humans. Moreover, it is not entirely clear how EMF influences cell behavior. The International Agency for Research on Cancer on 31 May 2011, classified PEM as a possible carcinogenic factor. This study aimed to investigate the effect of the electromagnetic field on morphological and functional changes in clear cell renal carcinoma. The research was carried out on in vitro cultures of four cell lines: HEK293, 786-O 769-P, and Caki1. The results of the research showed that the EMF of low frequency had a slight effect on the viability of cells. EMF, which induced cell arrest in the G1 phase, increased the number of early apoptotic cells and decreased the number of viable cells in the 786-O line. EMF did not affect the proliferation and viability of HEK293 cells. Extreme low-frequency EMF (ELF-EMF) also showed an inhibitory effect on the migration and metastatic properties of clear cell kidney cancer cells. Moreover, shortly after the end of ELF-EMF exposure, significant increases in ROS levels were observed in all tested cell lines. As part of the work, it was shown that low-frequency EMF shows an inhibitory effect on the proliferation of primary cancer cells, diminishing their migratory, invasive, and metastatic abilities. It also increases the apoptosis of cancer cells and the amount of reactive oxygen species. Based on the results of our research, we want to point up that the effect of ELF-EMF depends on a specific metabolic state or at a specific stage in the cell cycle of the cells under study.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Terapia de Campo Magnético , Apoptose , Carcinoma de Células Renais/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Campos Eletromagnéticos , Células HEK293 , Humanos , Neoplasias Renais/patologia , Terapia de Campo Magnético/métodos
9.
Med Sci Monit ; 27: e930634, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33507885

RESUMO

BACKGROUND The bluetongue virus (BTV) is the prototype virus in the genus Orbivirus within the family Reoviridae. Recent studies indicate that BTVs are capable of infecting and selectively lysing human hepatic carcinoma cells (Hep-3B) and prostate carcinoma cells (pc-3). This study was designed to evaluate the oncolytic potential of BTV in experimental models of human renal cancer in vitro and in vivo. MATERIAL AND METHODS Five human renal cancer cell lines, ACHN, CAKI-1, OS-RC-2, 786-O, and A498, were used in this study to analyze BTV replication. These cells were lysed by oncolysis compared to normal control. Xenograft models were used to assess the efficacy and toxicity of BTVs in vivo. Data were analyzed by one-way ANOVA or two-sided unpaired t tests. RESULTS The results showed HPTEC cells to be relatively resistant to cytotoxic effects of BTVs and exhibited normal growth rate even at high dose of BTVs. Nonetheless, the renal cancer cells showed a remarkably higher sensitivity to BTVs. Moreover, the ultramicroscopic subcellular changes were also detected in the renal cells. The viral particles were observed in all the RCC cell lines, but not in HPTEC cells. Intratumoral injections of BTVs significantly decreased the tumor volume as compared to animals that received no virus treatment. Infection with BTVs significantly increased the percentage of apoptotic renal cancer cells but not the HPTEC cells. Moreover, BTV triggered apoptosis in renal cancer cells via a mitochondria-mediated pathway. CONCLUSIONS This study for the first time demonstrated the oncolytic potential of BTV in experimental models of human renal cancer. BTV exhibits the potential to inhibit human renal cancer cell growth in vitro and in vivo.


Assuntos
Vírus Bluetongue/metabolismo , Neoplasias Renais/terapia , Neoplasias Renais/virologia , Animais , Apoptose/fisiologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/virologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Humanos , Neoplasias Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Vírus Oncolíticos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Expert Rev Clin Pharmacol ; 14(2): 261-268, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33472450

RESUMO

Background: The RESORT trial showed no longer relapse free survival (RFS) with sorafenib following radical metastasectomy in metastatic renal cell carcinoma. We present the updated 42-month follow-up data.Methods: The phase II RESORT trial randomized patients to sorafenib or observation within 12 weeks from surgery. RFS was the primary endpoint.Results: We analyzed 68 patients (32 in sorafenib and 36 in the observation arm), randomized between November 2012 and November 2017. Eighty-one percent in the sorafenib arm and 80% in the observation arm had one metastasis . At a median follow-up of 42 months (interquartile range 31-58), in the observation arm the median RFS was 35 months, RFS probability was 57% (95% CI 42-76%) at 24 and 44% (95% CI 30-65%) at 48 months. In the sorafenib arm, median RFS was 21 months, RFS probability was 50% (95% CI 34-71%) at 24 and 32% (95% CI 18-57%) at 48 months (p = 0.342;HR 1.35;95% CI 0.72-2.54). Forty-seven percent and 37.5% of the patients in the two arms, respectively, are disease free. The site of relapses was independent of the previous metastasectomy site.Expert commentary: Sorafenib after metastasectomy did not improve RFS, but surgery in selected patients should be considered in order to potentially improve survival.Clinical trial registration: www.clinicaltrials.gov identifier is NCT0144480.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Metastasectomia/métodos , Sorafenibe/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Seguimentos , Humanos , Neoplasias Renais/patologia , Recidiva Local de Neoplasia , Probabilidade
11.
Cancer Sci ; 112(3): 1038-1047, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33410234

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan-kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3-dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. In our analysis of RCC tissue samples, tissue Kyn levels were elevated in advanced-stage RCC and correlated well with TDO expression levels in RCC tumor cells. In patients with mRCC, TDO rather than IDO1 was expressed in RCC tumor cells, showing a strong association with Kyn expression. Furthermore, immunohistochemical staining of TDO was strongly associated with the staining intensity of forkhead box P3, as well as ICI therapy response and survival in patients with mRCC. Our study is the first to show that TDO expression in tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. Our findings suggest that strategies aimed at inhibiting TDO, rather than IDO1, in combination with ICI therapy may aid in the control of mRCC progression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Rim/patologia , Triptofano Oxigenase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imuno-Histoquímica , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Rim/cirurgia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Cinurenina/análise , Cinurenina/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrectomia , Intervalo Livre de Progressão , Triptofano/metabolismo , Triptofano Oxigenase/análise , Triptofano Oxigenase/antagonistas & inibidores
12.
JAMA Netw Open ; 4(1): e2021869, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33475752

RESUMO

Importance: There exists considerable biological and clinical variability between histologic variants of metastatic renal cell carcinoma (mRCC). Data reporting on patterns of metastasis in histologic variants of mRCC are sparse. Objective: To characterize sites of metastasis and their association with survival across the 3 most common histologic variants of mRCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). Design, Setting, and Participants: In this multicenter, international cohort study, the International mRCC Database Consortium (IMDC) database was used to identify consecutive patients starting systemic therapy for mRCC between 2002 and 2019. Patients with mixed histologic subtype were excluded. Statistical analysis was performed from February to June 2020. Exposures: Data regarding histologic subtype and sites of metastatic involvement at the time of first systemic therapy initiation were collected. Main Outcomes and Measures: The primary outcomes were prevalence of metastatic site involvement and overall survival (OS) from time of systemic therapy initiation. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. Results: A total of 10 105 patients were eligible for analysis. Median (interquartile range) age at diagnosis was 60 (53-67) years, 7310 (72.4%) were men and 8526 (84.5%) underwent nephrectomy. Of these, 9252 (92%) had ccRCC, 667 (7%) had pRCC, and 186 (2%) had chrRCC. The median number of sites of metastasis was 2 (range, 0-7). In ccRCC, the most common sites of metastasis were lung (70%; 6189 of 8804 patients [448 missing]), lymph nodes (45%; 3874 of 8655 patients [597 missing]), bone (32%; 2847 of 8817 patients [435 missing]), liver (18%; 1560 of 8804 [448 missing]), and adrenal gland (10%; 678 of 6673 patients [2579 missing]). Sites of metastasis varied between subtypes. Lung, adrenal, brain, and pancreatic metastases were more frequent in ccRCC, lymph node involvement was more common in pRCC, and liver metastases were more frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (95% CI, 13.7-18.8 months) for the pleura and 50 months (95% CI, 41.1-55.5 months) for the pancreas. Compared with ccRCC, patients with pRCC tended to have lower OS, regardless of metastatic site. Conclusions and Relevance: Sites of metastatic involvement differ according to histologic subtype in mRCC and are associated with OS. These data highlight the clinical and biological variability between histologic subtypes of mRCC. Patterns of metastatic spread may reflect differences in underlying disease biology. Further work to investigate differences in immune, molecular, and genetic profiles between metastatic sites and histologic subtypes is encouraged.


Assuntos
Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Idoso , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/terapia , Estudos de Coortes , Feminino , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nefrectomia
13.
Oncology ; 99(3): 192-202, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33440374

RESUMO

BACKGROUND: The approved doses of the single agent nivolumab - an anti-programmed cell death protein 1 (PD-1) monoclonal antibody - for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. METHODS: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. RESULTS: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05-1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25-1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48-6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. CONCLUSION: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.


Assuntos
Carcinoma de Células Renais/terapia , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoterapia/efeitos adversos , Neoplasias Renais/terapia , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Estudos Retrospectivos
14.
Anticancer Res ; 40(9): 4875-4883, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878775

RESUMO

BACKGROUND/AIM: Some reports showed encouraging efficacy of immune checkpoint inhibitors among patients who experienced immune-related adverse events (irAEs). Thus, characterization of T-cell repertoire and immune signatures in peripheral blood mononuclear cells (PBMCs) and tumors before and after immune checkpoint inhibitors treatment should contribute to better understanding of irAE-provoked anticancer immune responses. MATERIALS AND METHODS: We applied expression analysis of immune-related genes and T-cell receptor sequencing in tumor and PBMCs from five patients with renal cell carcinoma before combined immunotherapy and at the onset of severe irAEs. RESULTS: We found that the cluster of differentiation 8 (CD8)/forkhead box P3(FOXP3), granzyme B(GZMB)/CD3, perforin 1(PRF1)/CD3 and programmed cell death 1(PD1)/CD8 expression ratios were significantly elevated in PBMCs at the onset of irAEs. In addition, we found expansion of certain T-cell clones in metastatic tissue after irAEs, which were already increased in peripheral blood at the onset of irAEs. CONCLUSION: irAE-provoked T-cells may also circulate and attack distant tumors, leading to durable response in patients with irAEs.


Assuntos
Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Imunoterapia/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Perfilação da Expressão Gênica , Genes Codificadores dos Receptores de Linfócitos T/genética , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia
15.
Nat Commun ; 11(1): 4168, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820162

RESUMO

There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.


Assuntos
Carcinoma de Células Renais/terapia , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Imunoterapia/métodos , Neoplasias Renais/terapia , Mutação , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/patologia , Pessoa de Meia-Idade
16.
Am J Med Sci ; 360(3): 279-286, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32829780

RESUMO

BACKGROUND: The essential role of 6-phosphogluconate dehydrogenase (6PGD), the enzyme catalyzing the oxidative pentose phosphate pathway, in tumor growth and metabolism has garnered attention in recent years. In this work, we are the first to demonstrate that aberrant activation of 6PGD is a feature in renal cell carcinoma (RCC) and is critically involved in renal carcinogenesis and chemo- and immuno-resistance. MATERIALS AND METHODS: 6PGD expression and activity were systematically analyzed in normal and malignant renal cells and tissues. The roles of 6PGD and its downstream mechanism were investigated using gain-of-function and loss-of-function approaches. RESULTS: 6PGD expression and enzyme activity were increased in RCC cells and patients' samples. Activation of 6PGD via gain-of-function approach promoted growth of normal kidney but not RCC cells, and alleviated the efficacy of chemotherapeutic (e.g., 5-FU) and immunotherapeutic (e.g., IFN-α) agents. In contrast, 6PGD inhibition using siRNA knockdown and pharmacological inhibitor physcion augmented the inhibitory effects of 5-FU and IFN-α in RCC. Mechanistic studies demonstrated that 6PGD inhibition activated AMPK signaling, leading to ACC1 enzyme inhibition and reduction of lipid synthesis. In addition, 6PGD inhibition disrupted NADPH and NADH homeostasis in RCC cells as shown by the decreased level of NADPH and NADH, and suppressed SIRT-1 activity. AMPK inhibition by siRNA knockdown reversed the inhibitory effects of physcion, demonstrating that the effect of 6PGD inhibition is AMPK activation dependent. CONCLUSIONS: Our work provides preclinical evidence that 6PGD inhibition may represent a potential therapeutic strategy to augment the efficacy of RCC standard of care drugs.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma de Células Renais/terapia , Reprogramação Celular/fisiologia , Neoplasias Renais/terapia , Fosfogluconato Desidrogenase/metabolismo , Transdução de Sinais/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Linhagem Celular , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Fluoruracila/uso terapêutico , Técnicas de Silenciamento de Genes , Humanos , Imunoterapia , Interferon-alfa/uso terapêutico , Rim/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , NADP/fisiologia , Fosfogluconato Desidrogenase/antagonistas & inibidores , Fosfogluconato Desidrogenase/genética , RNA Interferente Pequeno , Regulação para Cima
17.
Zhonghua Zhong Liu Za Zhi ; 42(7): 537-542, 2020 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-32842439

RESUMO

Bone is the second most common metastatic site of renal cell carcinoma (RCC), about 35-40% of metastatic RCC patients are associated with bone metastasis. Bone metastasis can cause pain, pathological fracture, spinal cord compression, hypercalcemia and other skeletal related events (SREs), which may seriously affect patients' quality of life. RCC patients with bone metastasis, for whom drug therapy alone is less effective and the prognosis is poor, required multi-disciplinary team (MDT) and individualized comprehensive treatment to reduce or delay the onset of SRE, to maintain the quality of life and to extend the time of disease control and survival. In order to update the worldwide treatment progress in RCC with bone metastasis timely, and to improve the standardized diagnosis and treatment of such patients in China, the diagnosis and therapy for bone metastasis of malignant tumor and skeletal-related event expert group formulates "Expert consensus on renal cell carcinoma with bone metastasis (2020 Edition)" .


Assuntos
Neoplasias Ósseas , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Ósseas/secundário , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , China , Consenso , Humanos , Neoplasias Renais/patologia , Qualidade de Vida
18.
Urol Clin North Am ; 47(3): 271-280, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32600530

RESUMO

Advanced renal cell carcinoma is not uncommon, but necessitates a multidisciplinary approach for optimal treatment. Targeted therapy has increased the likelihood of urologists managing patients in all disease stages. Neoadjuvant therapy is currently experimental. Systemic therapy for metastatic disease demonstrates survival benefits. The role of cytoreductive nephrectomy and adjuvant therapy is dependent on patient selection. Management of advanced renal cell carcinoma involves continued optimization of available agents and biomarker development. This article reviews the role of the urologist in medical and surgical therapies, including prognostication, management of locally advanced and metastatic disease, and provides the most recent clinical trial data.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Papel do Médico , Antineoplásicos/administração & dosagem , Biópsia , Carcinoma de Células Renais/patologia , Terapia Combinada , Humanos , Neoplasias Renais/patologia , Nefrectomia , Prognóstico , Medição de Risco , Urologistas
19.
Urol Clin North Am ; 47(3): 319-327, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32600534

RESUMO

Variant histology renal cell carcinoma (vRCC) encompasses rare non-clear cell subtypes that have long been associated with poor prognosis and minimal response to therapies targeting vascular endothelial growth factor and its receptor. Molecular advances have helped classify vRCC into distinct entities and identify putative targetable driver alterations, such as MET in papillary subtypes. More have since been identified in other vRCC subtypes, including alterations of tumor metabolism, chromatin remodeling genes, cell-cycle genes, and inactivation of tumor suppressors such as TP53 or NF2. New targeted therapies, as well as immune checkpoint inhibitors, have been in development and yielded encouraging results. Collaborative clinical trials will be an essential step toward better implementation of these regimens in clinical practice.


Assuntos
Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Humanos , Terapia de Alvo Molecular , Nefrectomia
20.
Urol Clin North Am ; 47(3): 329-343, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32600535

RESUMO

There has been strong interest in using neoadjuvant therapy to decrease recurrence rates and facilitate surgical resection in locally advanced renal cell carcinoma. To date, no evidence exists to support improvement in oncologic outcomes with neoadjuvant therapy. Likewise, although targeted therapies have shown efficacy in tumor downsizing, this does not often translate to downstaging. Use of presurgical therapy for the purpose of downstaging inferior vena cava tumor thrombi is currently not supported. Future studies evaluating the benefit of newer immune checkpoint inhibitors will determine if there is a larger role for neoadjuvant therapy in locally advanced renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Terapia Neoadjuvante
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