RESUMO
Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.
Assuntos
Adenoviridae , Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Humanos , Animais , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Neoplasias Renais/patologia , Neoplasias Renais/genética , Camundongos , Adenoviridae/genética , Adenoviridae/imunologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Terapia Viral Oncolítica/métodos , Imunoterapia/métodos , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Quimiocina CXCL9/imunologia , Movimento Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/imunologia , Citocinas/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Interleucina-15/genética , Interleucina-15/metabolismo , Interleucina-15/imunologia , Receptores CXCR3/metabolismo , Receptores CXCR3/genética , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Linfócitos T CD8-Positivos/imunologiaRESUMO
INTRODUCTION: The third most prevalent malignant neoplasm involving the urinary tract is renal cell carcinoma (RCC), encompassing nearly 3.5% of the entire cancers afflicting the body. The aim of this research was to explore how the R.E.N.A.L. nephrometry score relates to the decisions made regarding surgery in individuals with localized RCC. METHODS: This prospective study, assessed patients with localized parenchymal renal masses (stages I and II) tentatively diagnosed as RCC. Utilizing preoperative multiphasic renal CT scans and MRI, the R.E.N.A.L. score categorized masses for nephrometry values. Inclusion criteria involved collecting patient data, and data collection utilizing a structured format focusing on the nephrometry grading system. RESULTS: The study included 64 patients aged (mean ± SD) 49.78 ± 12.35 yrs. Undergoing renal mass surgery, there were 17 (26.5%) low, 28 (43.8%) moderate and 19 (29.7%) high-complexity lesions. All patients with a low Nephrometry score (n = 17) underwent partial nephrectomy, and all cases with a high score (n = 19) underwent radical nephrectomy. For those with a moderate Nephrometry score (n = 28), 13 (46.4%) underwent partial nephrectomy, while the remaining 15 (53.6%) cases underwent radical nephrectomy. Morbidity was low, and no mortality occurred at 180 days. Patients who had lesions fully above or below polar lines were less likely to need blood transfusions. A trend towards higher Fuhrman grades in patients receiving transfusions suggests a potential link between tumor aggressiveness and bleeding risk. CONCLUSIONS: Our findings provide insight on the utilization of the R.E.N.A.L. nephrometry score in forecasting perioperative, post-surgical, and oncological results. Such data might help optimize surgical methods and pre-operative patient counseling.
Assuntos
Transfusão de Sangue , Carcinoma de Células Renais , Neoplasias Renais , Nefrectomia , Humanos , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Estudos Prospectivos , Nefrectomia/métodos , Feminino , Masculino , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Transfusão de Sangue/estatística & dados numéricos , Adulto , Hemoglobinas/análise , Idoso , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios XRESUMO
Renal clear cell carcinoma (ccRCC) is a common parenchymal tumor of the kidney, and the discovery of biomarkers for early and effective diagnosis of ccRCC can improve the early diagnosis of patients and thus improve long-term survival. Erb-b2 receptor tyrosine kinase 2 (ERBB2) mediates the processes of cell proliferation, differentiation, and apoptosis inhibition. The purpose of this study was to investigate the diagnostic and prognostic role of ERBB2 in ccRCC. We analyzed the expression levels of ERBB2 in various cancers from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RNA-seq data were analyzed using R packages to identify differentially expressed genes between the high and low ERBB2 expression groups in the TCGA-KIRC dataset. Spearman correlation analysis was performed to determine the correlation between ERBB2 expression and immune cell infiltration, immune checkpoint expression, and PTEN expression. DNA methylation changes and genetic alterations in ERBB2 were assessed using the MethSurv and cBioPortal databases. Logistic regression analysis was performed to determine the correlation between ERBB2 expression and the clinicopathological characteristics of ccRCC patients. The diagnostic and prognostic value of ERBB2 was assessed using KaplanâMeier (KâM) survival curves, diagnostic ROC curves, time-dependent ROC curves, nomogram models, and Cox regression models. The expression level of ERBB2 is lower in tumor tissues of ccRCC patients than in the corresponding control tissues. Differentially expressed genes associated with ERBB2 were significantly enriched in the pathways "BMP2WNT4FOXO1 pathway in primary endometrial stromal cell differentiation" and "AMAN pathway". In ccRCC tissues, ERBB2 expression levels were associated with immune cell infiltration, immune checkpoints, and PTEN. The DNA methylation status of 10 CpG islands in the ERBB2 gene was associated with the prognosis of ccRCC. ERBB2 expression levels in ccRCC tissues were associated with race, sex, T stage, M stage, histological grade, and pathological stage. Cox regression analysis showed that ERBB2 was a potential independent predictor of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in ccRCC patients. ROC curve analysis showed that the expression level of ERBB2 could accurately distinguish between ccRCC tissue and adjacent normal renal tissue. Our study showed that ERBB2 expression in ccRCC tissues can be of clinical importance as a potential diagnostic and prognostic biomarker.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais , Receptor ErbB-2 , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Neoplasias Renais/genética , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Prognóstico , Feminino , Masculino , Metilação de DNA , Pessoa de Meia-Idade , Estimativa de Kaplan-Meier , Idoso , Curva ROCRESUMO
BACKGROUND: To date, no meta-analysis has been conducted to compare the effectiveness and safety of adjuvant tyrosine kinase inhibitors (TKIs) and adjuvant immunotherapies (IMTs) in renal cell carcinoma (RCC) patients using reconstructed individual patient data (IPD). This study aims to fill that gap by assessing the efficacy and safety profiles of these treatments in such patients. METHODS: This study employed a systematic approach for identifying relevant literature from the PubMed and EMBASE databases. We included articles published in English from the inception of these databases until November 11, 2023, focusing specifically on appropriate phase III randomized controlled trials (RCTs). To reconstruct survival curves, we utilized a semiautomated tool, WebPlotDigitizer, in conjunction with a novel shiny application integrated with R software. For adverse events (AEs), the summary measures were incidences, expressed as a 95% confidence interval (CI), calculated using a random-effects model with a logit transformation. RESULTS: The analysis included 8 RCTs with a total of 9119 patients. Compared to adjuvant TKIs, adjuvant IMTs showed a similar disease-free survival (DFS) (hazard ratio [HR] 1.03, 95% CI [0.98-1.09], Pâ =â .281). However, the overall survival (OS) rates between the 2 groups couldn't be directly compared due to unmatched control groups in the IMT and TKI studies. Against placebo, adjuvant IMTs demonstrated superior DFS (HR 0.82, 95% CI [0.71-0.94], Pâ =â .004) but comparable OS (HR 0.79, 95% CI [0.59-1.06], Pâ =â .120). Against placebo, adjuvant TKIs showed superior DFS (HR 0.85, 95% CI [0.79-0.92], Pâ <â .0001) and marginally better OS (HR 0.89, 95% CI [0.80-0.996], Pâ =â .042). Regarding severe AEs and discontinuation rates due to AEs, adjuvant IMTs had a significantly lower incidence of severe AEs (25% [320/1282] vs 59% [2192/3716], odds ratio [OR] 0.23, 95% CI [0.20-0.27], Pâ <â .0001) and a markedly better discontinuation rate (39% [499/1282] vs 52% [2068/4018], OR 0.60, 95% CI [0.53-0.68], Pâ <â .0001) compared to TKIs. CONCLUSION: This paper presents a thorough analysis of DFS, OS, and treatment-related AEs across various groups in RCC patients, offering a valuable resource for clinicians in everyday practice. Our findings indicate that while adjuvant IMTs and adjuvant TKIs demonstrate similar DFS, IMTs are notably superior in terms of safety and compliance.
Assuntos
Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Inibidores de Proteínas Quinases , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Quimioterapia Adjuvante/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Intervalo Livre de DoençaRESUMO
BACKGROUND: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort. METHODS: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro. RESULTS: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0ât), AUC(0â∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib. CONCLUSIONS: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.
Assuntos
Interações Medicamentosas , Indóis , Microssomos Hepáticos , Nitrilas , Piridinas , Pirróis , Sunitinibe , Triazóis , Sunitinibe/farmacologia , Sunitinibe/farmacocinética , Animais , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Nitrilas/farmacocinética , Nitrilas/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Pirróis/farmacocinética , Pirróis/farmacologia , Triazóis/farmacocinética , Triazóis/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismoRESUMO
BACKGROUND: Renal epithelioid angiomyolipoma is a rare and unique subtype of classic angiomyolipoma, characterized by the presence of epithelioid cells. It often presents with nonspecific symptoms and can be easily misdiagnosed due to its similarity to renal cell carcinoma and classic angiomyolipoma in clinical and radiological features. This case report is significant for its demonstration of the challenges in diagnosing epithelioid angiomyolipoma and its emphasis on the importance of accurate differentiation from renal cell carcinoma and classic angiomyolipoma. CASE PRESENTATION: A 58-year-old Asian female presented with sudden left flank pain and was initially diagnosed with a malignant renal tumor based on imaging studies. She underwent laparoscopic radical nephrectomy, and postoperative histopathology confirmed the diagnosis of epithelioid angiomyolipoma. The patient recovered well and is currently in good health with regular follow-ups. This case highlights the diagnostic challenges, with a focus on the clinical, radiological, and histopathological features that eventually led to the identification of epithelioid angiomyolipoma. CONCLUSIONS: Epithelioid angiomyolipoma is easily misdiagnosed in clinical work. When dealing with these patients, it is necessary to make a comprehensive diagnosis based on clinical symptoms, imaging manifestations, and pathological characteristics.
Assuntos
Angiomiolipoma , Carcinoma de Células Renais , Erros de Diagnóstico , Neoplasias Renais , Nefrectomia , Humanos , Feminino , Angiomiolipoma/diagnóstico , Angiomiolipoma/patologia , Angiomiolipoma/diagnóstico por imagem , Pessoa de Meia-Idade , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Ruptura Espontânea , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/diagnóstico por imagem , Hemorragia , Tomografia Computadorizada por Raios X , Diagnóstico Diferencial , Dor no Flanco/etiologia , LaparoscopiaRESUMO
BACKGROUND: Open partial nephrectomy (OPN) has previously been considered the gold standard procedure for treatment of T1 localized renal tumors. After introduction of robot assisted partial nephrectomy (RAPN) as an alternative method to OPN, OPN was gradually abandoned at our department. The aim of the study was to retrospectively compare the results of patients treated with either OPN or RAPN for suspected renal carcinoma. METHODS: Patients who underwent either open or robotic assisted partial nephrectomy between January 1st 2010 and December 31st 2020 were retrospectively included in the study. Each tumor subjected to surgery was scored preoperatively by the RENAL nephrometry score. Complications within 30 days were assessed according to the Clavien-Dindo classification system. RESULTS: A total of 197 patients who underwent partial nephrectomy were identified; 75 were subjected to OPN and 122 were treated with RAPN. There were no significant differences between the groups with respect to age (OPN: 63 years ± 11, RAPN: 62 years ± 10), gender (OPN: 71/29%, RAPN: 67/33%), body mass index (OPN: 28 ± 5, RAPN: 28 ± 5), ASA score (OPN: 2.4 ± 0.6, RAPN: 2.2 ± 0.5), or nephrometry score (OPN: 6.6 ± 1.7, RAPN: 6.9 ± 1.7, p = 0.2). The operative time was significantly shorter in the OPN group (81 min) compared to the RAPN group (144.5 min, p < 0.001). Mean perioperative blood loss was 227 ± 162 ml in the OPN group compared to 189 ± 152 ml in the RAPN group (p = 0.1). Mean length of stay was shorter in the RAPN group (3 days) compared to the OPN group (6, days, p < 0.001). Positive surgical margin rate was significantly higher in the OPN group (21.6%) compared to the RAPN group (4.2%, p < 0.001). There were no differences in the number of Clavien-Dindo graded complications between the groups (p = 0.6). CONCLUSIONS: The introduction of RAPN at our department resulted in shorter length of stay and fewer positive surgical margins, without increasing complications.
Assuntos
Neoplasias Renais , Nefrectomia , Procedimentos Cirúrgicos Robóticos , Humanos , Nefrectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Pessoa de Meia-Idade , Feminino , Masculino , Estudos Retrospectivos , Neoplasias Renais/cirurgia , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Carcinoma de Células Renais/cirurgia , Resultado do TratamentoRESUMO
Objectives: To identify the cooperation of authors, countries, institutions and explore the hot spots regarding research of renal cell carcinoma with venous tumor thrombus. Methods: Relevant articles were obtained from the Web of Science Core database (WoSC) from 1999 to 2024. CiteSpace was used to perform the analysis and visualization of scientific productivity and emerging trends. Network maps were generated to evaluate the collaborations between different authors, countries, institutions, and keywords. Results: A total of 2180 related articles were identified. We observed an increased enthusiasm in related fields during the past two decades. The USA dominated the field in all countries, and the University of Miami was the core institution. Ciancio G might have a significant influence with more publications and co-citations. Current research hotspots in this field mainly included thrombectomy, tyrosine kinase inhibitors, immune checkpoint inhibitors, vena cava inferior, and microvascular invasion. Thrombectomy complications, thrombectomy survival outcome, and preoperative neoadjuvant immunotherapy represented the frontiers of research in this field, undergoing an explosive phase. Conclusion: This is the first bibliometric study that comprehensively visualize the research trends and status of RCC with VTT. We hope that this work will provide new ideas for advancing the scientific research and clinical application.
Assuntos
Bibliometria , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Neoplasias Renais/cirurgia , Trombose Venosa/patologia , Trombose Venosa/cirurgia , Trombectomia/métodosRESUMO
Background: Protein information is often replaced by RNA data in studies to understand cancer-related biological processes or molecular functions, and proteins of prognostic significance in Kidney clear cell carcinoma (KIRC) remain to be mined. Methods: The cancer genome atlas program (TCGA) data was utilized to screen for proteins that are prognostically significant in KIRC. Machine learning algorithms were employed to develop protein prognostic models. Additionally, immune infiltration abundance, somatic mutation differences, and immunotherapeutic responses were analyzed in various protein risk subgroups. Ultimately, the validation of protein-coding genes was confirmed by utilizing an online database and implementing quantitative real-time PCR (qRT-PCR). Results: The patients were divided into two risk categories based on prognostic proteins, and notable disparities in both overall survival (OS) and progression free interval (PFI) were observed between the two groups. The OS was more unfavorable in the high-risk group, and there was a noteworthy disparity in the level of immune infiltration observed between the two groups. In addition, the nomogram showed high accuracy in predicting survival in KIRC patients. Conclusion: In this research, we elucidated the core proteins associated with prognosis in terms of survival prediction, immunotherapeutic response, somatic mutation, and immune microenvironment. Additionally, we have developed a reliable prognostic model with excellent predictive capabilities.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Nomogramas , Proteômica , Transcriptoma , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/imunologia , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/imunologia , Prognóstico , Proteômica/métodos , Biomarcadores Tumorais/genética , Feminino , Masculino , Transcriptoma/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Pessoa de Meia-Idade , Aprendizado de MáquinaRESUMO
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) remains one of the most lethal urological malignancies even though a great number of improvements in diagnosis and management have achieved over the past few decades. Accumulated evidence revealed that histone deacetylases (HDACs) play vital role in cell proliferation, differentiation and apoptosis. Nevertheless, the biological functions of histone deacetylation modification related genes in ccRCC remains poorly understood. METHOD: Bulk transcriptomic data and clinical information of ccRCC patients were obtained from the TCGA database and collected from the Chinese PLA General Hospital. A total of 36 histone deacetylation genes were selected and studied in our research. Univariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, random forest (RF) analysis, and protein-protein interaction (PPI) network analysis were applied to identify key genes affecting the prognosis of ccRCC. The 'oncoPredict' algorithm was utilized for drug-sensitive analysis. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the potential biological function. The ssGSEA algorithm was used for tumor immune microenvironment analysis. The expression levels of HDAC10 were validated by RT-PCR and immunohistochemistry (IHC). 5-ethynyl-2'-deoxyuridine (EdU assay), CCK-8 assay, cell transwell migration and invasion assay and colony formation assay were performed to detect the proliferation and invasion ability of ccRCC cells. A nomogram incorporating HDAC10 and clinicopathological characteristics was established to predict the prognosis of ccRCC patients. RESULT: Two machine learning algorithms and PPI analysis identified four histone deacetylation genes that have a significant association with the prognosis of ccRCC, with HDAC10 being the key gene among them. HDAC10 is highly expressed in ccRCC and its high expression is associated with poor prognosis for ccRCC patients. Pathway enrichment and the experiments of EdU staining, CCK-8 assay, cell transwell migration and invasion assay and colony formation assay demonstrated that HDAC10 mediated the proliferation and metastasis of ccRCC cells and involved in reshaping the tumor microenvironment (TME) of ccRCC. A clinically reliable prognostic predictive model was established by incorporating HDAC10 and other clinicopathological characteristics ( https://nomogramhdac10.shinyapps.io/HDAC10_Nomogram/ ). CONCLUSION: Our study found the increased expression of HDAC10 was closely associated with poor prognosis of ccRCC patients. HDAC10 showed a pro-tumorigenic effect on ccRCC and promote the proliferation and metastasis of ccRCC, which may provide new light on targeted therapy for ccRCC.
Assuntos
Carcinoma de Células Renais , Proliferação de Células , Histona Desacetilases , Neoplasias Renais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proliferação de Células/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Prognóstico , Microambiente Tumoral/genética , Linhagem Celular Tumoral , Mapas de Interação de Proteínas , Oncogenes/genética , IdosoRESUMO
INTRODUCTION: Renal cell carcinoma (RCC) is a common malignancy known for its potential to invade the venous system, particularly the inferior vena cava (IVC), leading to tumor thrombus (TT) formation. While the presence of TT in RCC isn't unique, extension of TT above the diaphragm is rare. This case highlights the challenges encountered in diagnosing and managing RCC with extensive TT involvement. CASE REPORT: A 69-year-old man presents with 3-month history of dyspnea and increasing fatigue in the setting of 30 pounds weight loss. Laboratory studies showed anemia and acute kidney injury. CT abdomen and pelvis revealed 6.8cm solid mass within the left perinephric space, enlarged IVC with large thrombus. Kidney biopsy returned positive for clear cell renal carcinoma with metastasis to the liver. Several days into the hospitalization the patient began to experience increased abdominal pain. Repeat ultrasound showed tumor thrombus with extension within the intrahepatic IVC and hepatic veins and reversal of portal venous flow. During the imaging study, the patient suffered a cardiac arrest and expired. Postmortem examination revealed diffuse showering of tumor emboli within the pulmonary arteries, likely contributing to the patient's rapidly progressive respiratory failure, and subsequent cardiovascular collapse. CONCLUSION: This case illustrates the complexity of treating patients with extensive TT. In patients with RCC associated TT, the risk for thromboembolism is increased substantially, however the full benefit of anticoagulation remains controversial. Understanding the intricacies of TT involvement and its potential complications is crucial in guiding treatment decisions in patients with significant tumor thrombus burden.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Veia Cava Inferior , Humanos , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/secundário , Masculino , Idoso , Neoplasias Renais/patologia , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Evolução Fatal , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/patologia , Trombose/etiologia , Trombose/diagnóstico , Células Neoplásicas Circulantes/patologia , Trombose Venosa/etiologia , Trombose Venosa/diagnósticoRESUMO
In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.
Assuntos
Carcinoma de Células Renais , Dano ao DNA , Neoplasias Renais , Proteína-Arginina N-Metiltransferases , Proteínas Repressoras , Animais , Humanos , Camundongos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteômica , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/antagonistas & inibidores , RNA/metabolismo , RNA/genética , MasculinoRESUMO
The treatment landscape for metastatic renal cell carcinoma (RCC) has advanced significantly with first-line immunotargeted therapy combinations. However, no statistically significant differences were observed in the cohort of patients with favorable risk and some oncologists continue to use sunitinib in these patients. PD-L1 expression has emerged as a negative prognostic factor in RCC, particularly in sunitinib-treated patients, where higher PD-L1 levels are linked to worse outcomes. This article discusses the potential risks associated with the use of sunitinib in PD-L1-positive patients.
Assuntos
Antígeno B7-H1 , Carcinoma de Células Renais , Neoplasias Renais , Sunitinibe , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Sunitinibe/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Antineoplásicos/uso terapêutico , PrognósticoRESUMO
This study aimed to assess the prognostic role of body mass index (BMI) in patients with metastatic renal cell carcinoma (mRCC) treated with first-line immune checkpoint inhibitor (ICI)-based therapy. We searched for relevant studies in the MEDLINE, Embase, and Cochrane Library databases. The initial search yielded 599 records, of which seven articles (2,517 patients) were selected for analysis. Patients with a high BMI had a favorable overall survival (OS) based on hazard ratio (HR) (crude HR 0.69, 95% confidence interval [CI] 0.57-0.83, p<0.0001; adjusted (a)HR 0.75, 95% CI 0.59-0.95, p=0.02), but not relative risk (RR 0.88, 95% CI 0.67-1.16, p=0.37). In the subgroup analysis, patients with a high BMI had better OS in the ICI with tyrosine kinase inhibitor (TKI) subgroup (aHR 0.71, 95% CI 0.55-0.92, p=0.01), while no significant difference was found in the ICI-only subgroup (aHR 1.02, 95% CI 0.56-1.87, p=0.95). Adjusted statistics for progression-free survival (PFS) were assessable in predominantly ICI-only studies and demonstrated a favorable outcome for patients with a low BMI (aHR 1.67, 95% CI 1.14-2.45, p=0.01). In conclusion, the impact of high BMI varies depending on the treatment type, exhibiting a favorable correlation with OS within ICI with TKI subgroup, but indicating an adverse association with PFS in the ICI-only subgroup. Further research is needed to clarify the influence of BMI by stratifying patients into ICI-only and ICI with TKI treatment to provide more insights.
Assuntos
Índice de Massa Corporal , Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Prognóstico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Background: Clear cell renal cell carcinoma (ccRCC) poses substantial treatment challenges, especially in advanced stages where the efficacy of immune checkpoint blockade (ICB) therapy varies significantly. Elevated expression of the oncogene TUBA1C has been correlated with poor prognosis in various cancers, however, its role in ccRCC is unclear, especially concerning ICB resistance. Methods: Single-cell analysis was used to examine gene expression variations in malignant cells post-ICB therapy. This included investigating TUBA1C expression across different ICB response groups and its relationship with CD274. A general module of action was identified through pan-cancer and pan-tissue analysis. TUBA1C expression and its association with clinical characteristics and prognosis was further validated. Multiple algorithms were employed to explore immune cell infiltration levels, and the DepMap database was utilized to assess gene dependency and mutation status in kidney cancer cell lines. The in silico knockout of TUBA1C was performed using deep learning model, complemented by immunohistochemical assays, clinical cohort and functional assays validations. Results: TUBA1C expression is elevated in malignant cells following ICB therapy and is correlated with ICB resistance in ccRCC. High TUBA1C expression activates PI3K/AKT pathway and is associated with increased infiltration of regulatory T cells and myeloid-derived suppressor cells, which contributes to an immunosuppressive microenvironment in ccRCC. Patients with high TUBA1C expression exhibit a greater tumor mutation burden and increased genetic variation, which causes a worse prognosis. Additionally, TUBA1C dependency and its effects were evident in kidney cancer cell lines, where mutations conferred resistance to anti-PD-L1 therapy. In silico knockout analyses indicated that treatment targeting TUBA1C shifted malignant cells to a state responsive to ICB therapy. Immunohistochemistry, RT-qPCR and clinical cohort validation further confirmed that TUBA1C expression was upregulated and contributed to poorer outcome in ccRCC. Finaly, wound healing and CCK-8 assays demonstrated the potent oncogenic function of TUBA1C. Conclusions: TUBA1C is a pivotal regulator in ccRCC, affecting both disease progression and the effectiveness of ICB therapy by fostering an immunosuppressive microenvironment mediated by the PI3K/AKT pathway. Additionally, TUBA1C holds promise, both as a prognostic biomarker and a therapeutic target, for enhancing responsiveness to ICB.
Assuntos
Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Microambiente Tumoral , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Microambiente Tumoral/imunologia , Neoplasias Renais/imunologia , Neoplasias Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Prognóstico , Masculino , Feminino , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: This study aimed to investigate the prognostic value of the geriatric nutritional risk index (GNRI) in patients with non-metastatic clear cell renal cell carcinoma (ccRCC) who underwent nephrectomy. METHODS: Patients with non-metastatic ccRCC who underwent nephrectomy between 2013 and 2021 were analyzed retrospectively. The GNRI was calculated within one week before surgery. The optimal cut-off value of GNRI was determined using X-tile software, and the patients were divided into a low GNRI group and a high GNRI group. The Kaplan-Meier method was used to compare the overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) between the two groups. Univariate and multivariate Cox proportional hazard models were used to determine prognostic factors. In addition, propensity score matching (PSM) was performed with a matching ratio of 1:3 to minimize the influence of confounding factors. Variables entered into the PSM model were as follows: sex, age, history of hypertension, history of diabetes, smoking history, BMI, tumor sidedness, pT stage, Fuhrman grade, surgical method, surgical approach, and tumor size. RESULTS: A total of 645 patients were included in the final analysis, with a median follow-up period of 37 months (range: 1-112 months). The optimal cut-off value of GNRI was 98, based on which patients were divided into two groups: a low GNRI group (≤ 98) and a high GNRI group (> 98). Kaplan-Meier analysis showed that OS (P < 0.001), CSS (P < 0.001) and RFS (P < 0.001) in the low GNRI group were significantly worse than those in the high GNRI group. Univariate and multivariate Cox analysis showed that GNRI was an independent prognostic factor of OS, CSS and RFS. Even after PSM, OS (P < 0.05), CSS (P < 0.05) and RFS (P < 0.05) in the low GNRI group were still worse than those in the high GNRI group. In addition, we observed that a low GNRI was associated with poor clinical outcomes in elderly subgroup (> 65) and young subgroup (≤ 65), as well as in patients with early (pT1-T2) and low-grade (Fuhrman I-II) ccRCC. CONCLUSION: As a simple and practical tool for nutrition screening, the preoperative GNRI can be used as an independent prognostic indicator for postoperative patients with non-metastatic ccRCC. However, larger prospective studies are necessary to validate these findings.
Assuntos
Carcinoma de Células Renais , Avaliação Geriátrica , Neoplasias Renais , Avaliação Nutricional , Estado Nutricional , Pontuação de Propensão , Humanos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Masculino , Feminino , Idoso , Prognóstico , Estudos Retrospectivos , Neoplasias Renais/cirurgia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Avaliação Geriátrica/métodos , Avaliação Geriátrica/estatística & dados numéricos , Nefrectomia/métodos , Estimativa de Kaplan-Meier , Fatores de Risco , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Idoso de 80 Anos ou maisRESUMO
To our knowledge, this is the first report of percutaneous endoscopic intragastric surgery (PEIGS) for gastric metastases from other organs. A 70-year-old male with a history of renal cell carcinoma (RCC) was referred to our department for the treatment of gastric metastasis of RCC. Partial gastrectomy was performed using single-incision PEIGS. Two years after the surgery, a follow-up esophagogastroduodenoscopy revealed a tumor located on the middle greater curvature of the stomach. The diagnosis was metastatic renal cell carcinoma, prompting a similar surgery. No recurrence was observed after the second surgery. PEIGS is a minimally invasive option for the treatment of metastatic gastric tumors.
Assuntos
Carcinoma de Células Renais , Gastrectomia , Neoplasias Renais , Neoplasias Gástricas , Humanos , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/secundário , Masculino , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Idoso , Gastrectomia/métodos , GastroscopiaRESUMO
PANoptosis has been shown to play an important role in tumorigenesis and gain more attention. Yet, the prognostic significance of PANoptosis-related genes has not been investigated more in clear cell renal cell carcinoma (ccRCC). The aim of this research was designed to identify and create a signature of PANoptosis-related genes which was expected to predict prognosis of ccRCC more effectively. The transcriptome data and clinical information were collected from The Cancer Genome Atlas database and the Gene Expression Omnibus database. Optimal differentially expressed PANoptosis-related genes, which were closely associated with prognosis and employed to construct a risk score, were extracted by univariate Cox analysis, least absolute shrinkage and selection operator Cox regression and multivariate Cox analysis. We performed Kaplan-Meier survival analysis and time-dependent receiver operating characteristic curves to complete this process. By adopting univariate and multivariate analysis, the constructed risk score was assessed to verify whether it could be taken as an independent contributor for prognosis. Moreover, we created a nomogram in order to predict overall survival (OS) of ccRCC. Five differentially expressed PANoptosis-related genes were screened out and used to construct a risk score. Our results showed that ccRCC patients with high risk score had a poor prognosis and shorter OS. The results of Kaplan-Meier curves and the area under the receiver operating characteristic curves of 1-, 3-, and 5-year OS indicated that the prediction performance was satisfactory. Additionally, the risk model could be taken as an independent prognostic factor in training and validation cohorts. The nomogram exhibited excellent reliability in predicting OS, which was validated by calibration curves. We identified 5 PANoptosis-related genes, which were used to construct a risk score and a nomogram for prognostic prediction with reliable predictive capability. The present study may provide new potential therapeutic targets and precise treatment strategies for ccRCC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Nomogramas , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Prognóstico , Masculino , Feminino , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Curva ROC , Transcriptoma , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica/métodosRESUMO
Clear cell renal cell carcinoma (ccRCC) continues to pose a significant global health concern, with rising incidence and high mortality rate. Accordingly, identifying molecular alternations associated with ccRCC is crucial to boost our understanding of its onset, persistence, and progression as well as developing prognostic biomarkers and novel therapies. Bulk RNA sequencing data and its associated clinicopathological variables of ccRCC were obtained from The Cancer Genome Atlas Program. Atypical differential gene expression analysis of advanced disease states using the extreme categories of staging and grading components was performed. Upregulated differentially expressed genes shared across the aforementioned components were selected. The risk-score construction pipeline started with univariate Cox logistic regression analysis, least absolute shrinkage and selection operator, and multivariate Cox logistic regression analysis in sequence. The generated risk score classified patients into low- vs high-risk groups. The predictive power of the constructed risk score was assessed using Kaplan-Meier curves analysis, multivariate Cox logistic regression analysis, and receiver operator curve of the overall survival. External validation of the risk score was performed using the E-MTAB-1980 cohort. The analysis work scheme established a novel nine-gene prognostic risk score composed of the following genes: ZIC2, TNNT1, SAA1, OTX1, C20orf141, CDHR4, HOXB13, IGFL2, and IGFN1. The high-risk group was associated with shortened overall survival and possessed an independent predictive power (hazard ratio: 1.942, 95% CI: 1.367-2.758, Pâ <â .0001, area under the curveâ =â 0.719). In addition, the high-risk score was associated with advance clinicopathological parameters. The same pattern was observed within the external validation dataset (E-MTAB-1980 cohort), in which the high-risk score held a poor prognostic signature as well as independent predictive potential (hazard ratio: 5.121, 95% CI: 1.412-18.568, Pâ =â .013, area under the curveâ =â 0.787). In the present work, a novel nine-gene prognostic risk score was constructed and validated. The risk score correlated with tumor immune microenvironment, somatic mutation patterns, and altered molecular pathways involved in tumorigenesis. Further experimental data are warranted to expand the work.
Assuntos
Carcinoma de Células Renais , Perfilação da Expressão Gênica , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Idoso , Medição de Risco/métodos , Estimativa de Kaplan-Meier , Regulação Neoplásica da Expressão Gênica , Estadiamento de Neoplasias , TranscriptomaRESUMO
The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel-Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1ß, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein-protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.