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1.
Urol Clin North Am ; 47(4): 419-431, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008493

RESUMO

The management of metastatic renal cell carcinoma (RCC) has evolved rapidly in recent years with several immunotherapy-based combinations of strategies approved as first-line therapies. Targeted strategies, including systemic antiangiogenesis agents and immune checkpoint blockade, form the basis of a therapeutic approach. With rising rates of recurrence after first-line treatment, it is increasingly important to not only adopt a personalized treatment plan with minimal adverse events but also develop predictive biomarkers for response. This review discusses currently available first-line and second-line therapies in RCC and their pivotal data, with specific focus on ongoing clinical trials in the adjuvant setting, including those involving novel agents.


Assuntos
Produtos Biológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Quimioterapia Combinada , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Nefrectomia/métodos , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos
2.
Adv Exp Med Biol ; 1255: 153-164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949398

RESUMO

Single-cell sequencing (SCS) is a powerful new tool that applies Next Generation Sequencing at the cellular level. SCS has revolutionized our understanding of tumor heterogeneity and the tumor microenvironment, immune infiltration, cancer stem cells (CSCs), circulating tumor cells (CTCs), and clonal evolution. The following chapter highlights the current literature on SCS in genitourinary (GU) malignancies and discusses future applications of SCS technology. The renal cell carcinoma (RCC) section highlights the use of SCS in characterizing the initial cells driving tumorigenesis, the intercellular mutational landscape of RCC, intratumoral heterogeneity (ITH) between primary and metastatic lesions, and genes driving RCC cancer stem cells (CSCs). The bladder cancer section will also illustrate molecular drivers of bladder cancer stem cells (BCSCs), SCS use in reconstructing tumor developmental history and underlying subclones, and understanding the effect of cisplatin on intratumoral heterogeneity in vitro and potential mechanisms behind platinum resistance. The final section featuring prostate cancer will discuss how SCS can be used to identify the cellular origins of benign prostatic hyperplasia and prostate cancer, the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, and the use of SCS in CTCs to understand chemotherapy resistance and gene expression changes after androgen deprivation therapy (ADT). The studies listed in this chapter illustrate many translational applications of SCS in GU malignancies, including diagnostic, prognostic, and treatment-related approaches. The ability of SCS to resolve intratumor heterogeneity and better define the genomic landscape of tumors and CTCs will be fundamental in the new era of precision-based care.


Assuntos
Neoplasias Renais/genética , Neoplasias da Próstata/genética , Análise de Sequência , Análise de Célula Única , Androgênios , Humanos , Neoplasias Renais/patologia , Masculino , Neoplasias da Próstata/patologia
3.
Nature ; 585(7826): 603-608, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32939090

RESUMO

Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2-5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.


Assuntos
Éteres/metabolismo , Ferroptose , Peroxissomos/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Linhagem Celular , Éteres/química , Feminino , Edição de Genes , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Peroxidação de Lipídeos , Masculino , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Peroxissomos/genética
4.
Yonsei Med J ; 61(10): 837-843, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32975057

RESUMO

PURPOSE: The standard schedule for sunitinib treatment is 4 weeks on and 2 weeks off (4/2) in first-line treatment for metastatic renal cell carcinoma (mRCC). Schedule modifications, including 2 weeks on and 1 week off (2/1), appear to reduce the total number of treatment-related adverse events (TRAEs) without compromising efficacy. Even though TRAEs can qualitatively differ from each other, it is not clear as to what effects a 2/1 schedule has on individual TRAEs. MATERIALS AND METHODS: This meta-analysis included one randomized controlled trial (RCT) and four non-randomized controlled studies (non-RCTs) that compared the two schedules in parallel. The primary objective was to estimate risk of individual adverse events (AEs) with a sunitinib 2/1 schedule versus a 4/2 schedule. Seven representative AEs were evaluated as standard data for the RCT and as weighted pooling data of the non-RCTs. Random effects modelling with Review Manager v5.3 was used to pool study-level data using the inverse-variance of each study as the weight. RESULTS: The five selected studies included a total of 484 patients with mRCC. Risk ratios for fatigue for a 2/1 schedule were significantly lower than those for a 4/2 schedule {0.69 [95% confidence intervals (CI), 0.51, 0.95] in the RCT and 0.77 (95% CI, 0.63, 0.94) in the non-RCTs}. Other TRAEs, except diarrhea and anorexia, also tended to decrease in both sets. Efficacy outcomes were comparable between 2/1 and standard schedules. CONCLUSION: This meta-analysis suggests that a 2/1 schedule of sunitinib lowers the risk of fatigue and the occurrence other AEs without compromising efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Carcinoma de Células Renais/patologia , Esquema de Medicação , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
5.
Int Heart J ; 61(5): 1070-1074, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921673

RESUMO

We report a case of lethal myocarditis and myositis after pembrolizumab treatment for advanced upper urinary tract urothelial carcinoma. A 69-year-old man underwent pembrolizumab therapy as a second-line treatment. He had myalgia and a slightly elevated creatinine kinase (CK) on the day of the second administration of pembrolizumab. Five days later, the patient was admitted with severe fatigue and an abnormal gait. Physical examination revealed reduced muscle reflexes and proximal muscle weakness. An electrocardiogram (ECG) demonstrated a wide QRS complex ventricular rhythm. A marked elevation of cardiac enzymes, including CK, myoglobin, and cardiac troponin I, was detected. Myocardial biopsy revealed inflammatory cell infiltration and the partial impairment of myocardial tissue. The electromyogram was normal, but inflammation in myofibers was noted in a muscle biopsy. Myocarditis and myositis as immune-related adverse events (irAEs) were suspected, and the patient began intravenous steroid therapy and plasma exchange. However, the patient underwent cardiac arrest three days after admission and began extracorporeal membrane oxygenation and intra-aortic balloon pumping therapy. Despite steroid pulse therapy, the patient demonstrated no sign of improvement and subsequently died 17 days after admission. Immune-mediated myocarditis is a rare but fatal irAE of an immune checkpoint inhibitor (ICI). The present case suggests that myositis precedes myocarditis. Therefore, if myositis is suspected, subsequent myocarditis may need attention. In conclusion, we found that myositis and myocarditis developed in a patient with advanced urothelial carcinoma after pembrolizumab treatment. A routine follow-up of CK and cardiac troponin I, as well as an ECG, should be performed to identify any possible ICI-induced myocarditis and myositis quickly.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Miocardite/induzido quimicamente , Miosite/induzido quimicamente , Idoso , Carcinoma de Células de Transição/secundário , Creatina Quinase/sangue , Creatina Quinase Forma MB/sangue , Ecocardiografia , Eletromiografia , Oxigenação por Membrana Extracorpórea , Evolução Fatal , Glucocorticoides/uso terapêutico , Parada Cardíaca , Humanos , Balão Intra-Aórtico , Pelve Renal , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Músculo Esquelético/patologia , Miocardite/sangue , Miocardite/diagnóstico por imagem , Miocardite/patologia , Miocárdio/patologia , Mioglobina/sangue , Miosite/sangue , Miosite/patologia , Miosite/fisiopatologia , Troca Plasmática , Troponina I/sangue
6.
Medicine (Baltimore) ; 99(36): e22057, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899070

RESUMO

INTRODUCTION: Based on existing literature, the juxtaglomerular cell tumor (JGCT) is a rare renal tumor, typically present with hypertension and hypokalemia. Nonfunctioning JGCT, without hypertension or hypokalemia, is extremely rare. PATIENT CONCERNS: Herein, we report a case of nonfunctioning JGCT mimicking renal cell carcinoma. The 29-year-old woman with an unremarkable past medical history presented with a left renal tumor without hypertension or hypokalemia. DIAGNOSIS: Both CT and 18F-FDG-PET/CT suggested a malignancy, possibly renal cell carcinoma. INTERVENTIONS: The tumor was then removed completely via robotic assistant laparoscopic partial nephrectomy; and pathology result was JGCT. Since the patient had no hypertension or hypokalemia, a nonfunctional JGCT was diagnosed. OUTCOMES: The patient recovered uneventfully, and was in good health in 6-months' follow-up period. CONCLUSION: Preoperative identification of JGCT is very difficult due to the lack of specific clinical manifestations. This case teaches us that for young patients with renal tumors whose CT enhancement is not obvious at the early phase, JGCT should be considered as a differential diagnosis. Radical nephrectomy should be avoided for JGCT in consideration of its relatively good prognosis.


Assuntos
Carcinoma de Células Renais/diagnóstico , Sistema Justaglomerular/patologia , Neoplasias Renais/patologia , Neoplasias/cirurgia , Adulto , Assistência ao Convalescente , Diagnóstico Diferencial , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Neoplasias Renais/diagnóstico por imagem , Laparoscopia/instrumentação , Nefrectomia/métodos , Nefrectomia/tendências , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do Tratamento
7.
Croat Med J ; 61(4): 326-332, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32881430

RESUMO

AIM: To assess diseases outcomes and tolerability of real-life second-line nivolumab in a series of metastatic renal cell carcinoma (mRCC) patients. METHODS: This retrospective chart review involved prospectively monitored patients (named patient program) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from February 2016 to March 2018. RESULTS: The study enrolled 30 patients, 5 of whom (16.7%) had a complete response. The mean ± standard deviation therapeutic response time to nivolumab treatment was 14.07 ± 8.92 months, with a minimum treatment duration of 2 months and a maximum of 24 months. The median duration of therapy was 17 months (mean: 15.8 months; range: 3-24 months), and 50% (n=15/30) of patients remained alive at the end of follow up. The most common adverse events associated with nivolumab were fatigue (26.67%; n=8/30), anemia (10.0%; n=3/30), adrenal insufficiency (6.67%; n=2/30: G1=1, G2=1), grade 2 pneumonitis (6.67%; n=2/30), grade 2 neuropathy (6.67%; n=2/30), rash (6.67%; n = 2/30: G1=1, G2=1), and hepatitis (3.33%; n=1/30). CONCLUSION: The present study indicates acceptable patient responses and tolerability of nivolumab in mRCC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
8.
Anticancer Res ; 40(10): 5445-5456, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988866

RESUMO

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.


Assuntos
Jejum , Neoplasias Renais/tratamento farmacológico , Obesidade/tratamento farmacológico , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos , Obesidade/complicações , Obesidade/genética
9.
Medicine (Baltimore) ; 99(38): e22329, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957401

RESUMO

RATIONALE: A supernumerary kidney is an extremely rare renal anomaly. Currently, <100 cases are reported in the literature. There are only 2 right unilateral supernumerary kidneys reported in the literature thus far, but no confirmed cases of urothelial carcinoma in supernumerary kidneys. We report a case of a right supernumerary with urothelial carcinoma, which is, to the best of our knowledge, reported for the first time. PATIENT CONCERNS: A 73-year-old female patient presented with intermittent, painless, whole course and gross hematuria for about 3 months. Her physical and laboratory examinations did not reveal any significant findings except positive occult blood in routine urine examination. Contrast-enhanced spiral computed tomography revealed a dysplastic supernumerary kidney under the normal right kidney. DIAGNOSES: The ureteroscopy showed that the ureter was Y-shaped in the middle part. The medial ureter led to a normal kidney. The lateral ureter was just 2 cm and led to a small cavity in which there was a mass whose biopsy showed urothelial carcinoma. The patient was subsequently diagnosed with a right supernumerary kidney with urothelial carcinoma. INTERVENTION: Nephroureterectomy, including the right normal and supernumerary kidneys, and partial cystectomy by laparoscopy were performed after the ureteroscopy. The patient then received 6 cycles of gemcitabine and cisplatin regimen chemotherapy and regular intravesical epirubicin chemotherapy. OUTCOMES: No recurrence or metastasis was found on follow-up computed tomography performed 13 months postoperatively. LESSONS: A supernumerary kidney is an extremely rare renal anomaly. Malignancy can occur in supernumerary kidneys.


Assuntos
Carcinoma de Células de Transição/terapia , Neoplasias Renais/terapia , Rim/anormalidades , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/diagnóstico por imagem , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Humanos , Rim/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Nefroureterectomia , Ureter/anormalidades
10.
Nat Commun ; 11(1): 4111, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807776

RESUMO

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Células 3T3 , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Inflamação/genética , Inflamação/metabolismo , Neoplasias Renais/genética , Espectrometria de Massas , Camundongos , Proteômica/métodos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
12.
Radiol Clin North Am ; 58(5): 875-884, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32792120

RESUMO

Indeterminate renal masses remain a diagnostic challenge for lesions not initially characterized as angiomyolipoma or Bosniak I/II cysts. Differential for indeterminate renal masses include oncocytoma, fat-poor angiomyolipoma, and clear cell, papillary, and chromophobe renal cell carcinoma. Qualitative and quantitative techniques using data derived from multiphase contrast-enhanced imaging have provided methods for specific differentiation and subtyping of indeterminate renal masses, with emerging applications such as radiocytogenetics. Early and accurate characterization of indeterminate renal masses by multiphase contrast-enhanced imaging will optimize triage of these lesions into surgical, ablative, and active surveillance treatment plans.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Imagem por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Meios de Contraste , Diagnóstico Diferencial , Humanos , Aumento da Imagem/métodos , Rim/diagnóstico por imagem , Rim/patologia , Triagem
13.
Yakugaku Zasshi ; 140(8): 963-968, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741869

RESUMO

Metabolome analysis is an approach to investigate cell characteristics from the metabolites that are constantly produced and changed by those cells. We conducted a metabolome analysis of the response of 786-O renal cell carcinoma (RCC) cells to histone deacetylase (HDAC) inhibitors, which are expected to increase anticancer drug sensitivity, and compared the response with that of drug-resistant cells. Trichostatin A (TSA), an HDAC inhibitor, increased the sensitivity of 786-O cells to sunitinib. Moreover, TCA cycle and nucleotide metabolism of the cells were promoted. The findings that acetylated p53 (active form) and early apoptotic cells were increased suggests that the mechanism involved enhancement of mitochondrial metabolism and function. In addition, established sunitinib-resistant RCC cells were exposed to a combination of sunitinib and TSA, resulting in significant growth inhibition. Principal component analysis revealed that the parent and resistant cells were obviously different, but approximately half their fluctuations were illustrated by the same pathways. In summary, it was suggested that TSA reduced sunitinib resistance by triggering intracellular metabolome shifts in energy metabolism. This was the first recognized mechanism of action of TSA as an HDAC inhibitor.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metaboloma , Metabolômica , Sunitinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo
14.
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
15.
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
16.
Lancet Oncol ; 21(6): 776-785, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631491

RESUMO

BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma/tratamento farmacológico , Portadores de Fármacos , Neoplasias Renais/tratamento farmacológico , Mitomicina/administração & dosagem , Urotélio/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Carcinoma/patologia , Composição de Medicamentos , Feminino , Humanos , Hidrogéis , Israel , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mitomicina/efeitos adversos , Gradação de Tumores , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Urotélio/patologia
17.
ESMO Open ; 5(Suppl 3)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669298

RESUMO

BACKGROUND: The coronavirus pandemic has provoked discussions among healthcare providers how to manage cancer patients when faced with the threat of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) infection. Immune checkpoint inhibitor (ICI) containing regimens are standard of care in the majority of metastatic clear cell renal cell carcinoma (mccRCC) patients. It remains unclear whether therapies should be modified in response to the COVID-19 pandemic. METHODS: We performed an online survey among physicians involved in the treatment of mccRCC, and 41 experts responded. Questions focused on criteria relevant for treatment decision outside the pandemic and the modifications of systemic therapy during COVID-19. FINDINGS: For the majority of experts (73%), the combination of International metastatic renal cell carcinoma Database Consortium (IMDC) risk category and patient fitness are two important factors for decision-making. The main treatment choice in fit, favourable risk patients outside the pandemic is pembrolizumab/axitinib for 53%, avelumab/axitinib, sunitinib or pazopanib for 13% of experts each. During the pandemic, ICI-containing regimens are chosen less often in favour of a tyrosine kinase inhibitors (TKI) monotherapy, mainly sunitinib or pazopanib (35%).In fit, intermediate/poor-risk patients outside the pandemic, over 80% of experts choose ipilimumab/nivolumab, in contrast to only 41% of physicians during COVID-19, instead more TKI monotherapies are given. In patients responding to established therapies with ICI/ICI or ICI/TKI combinations, most participants modify treatment regimen by extending cycle length, holding one ICI or even both. CONCLUSION: mccRCC treatment modifications in light of the coronavirus pandemic are variable, with a shift from ICI/ICI to ICI/TKI or TKI monotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Neoplasias Renais/tratamento farmacológico , Pneumonia Viral/epidemiologia , Padrões de Prática Médica/estatística & dados numéricos , Betacoronavirus , Carcinoma de Células Renais/secundário , Tomada de Decisão Clínica , Infecções por Coronavirus/prevenção & controle , Humanos , Fatores Imunológicos/uso terapêutico , Neoplasias Renais/patologia , Oncologia/estatística & dados numéricos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Inibidores de Proteínas Quinases/uso terapêutico , Urologia/estatística & dados numéricos
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): 281-291, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32600531

RESUMO

Patients with renal cell carcinoma may develop metastases after radical nephrectomy, and therefore monitoring with imaging for recurrent or metastatic disease is critical. Imaging varies with specific suspected site of disease. Computed tomography/MRI of the abdomen and pelvis are mainstay modalities. Osseous and central nervous system imaging is reserved for symptomatic patients. Radiologic reporting is evolving to reflect effects of systemic therapy on lesion morphology. Nuclear medicine studies compliment routine imaging as newer agents are evaluated for more accurate tumor staging. Imaging research aims to fill gaps in treatment selection and monitoring of treatment response in metastatic renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Carcinoma de Células Renais/secundário , Humanos , Neoplasias Renais/patologia
20.
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
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