Juxtatumoral perinephric fat analysis in clear cell renal cell carcinoma

Purpose

The purpose of the study was to evaluate the feasibility of using contrast-enhanced computed tomography (CECT)-based texture analysis (CTTA) metrics to differentiate between juxtatumoral perinephric fat (JPF) surrounding low-grade (ISUP 1–2) versus high-grade (ISUP 3–4) clear cell renal cell carcinoma (ccRCC).

Methods

In this IRB-approved study, we retrospectively queried the surgical database between June 2009 and April 2016 and identified 83 patients with pathologically confirmed ccRCC (low grade: n = 54, mean age = 61.5 years, 18F/35M; high grade n = 30, mean age = 61.7 years, 8F/22M) who also had pre-operative multiphase CT acquisitions. CT images were transferred to a 3D workstation, and nephrographic phase JPF regions were manually segmented. Using an in-house developed Matlab program, a CTTA panel comprising of texture metrics extracted using six different methods, histogram, 2D- and 3D-Gray-level co-occurrence matrix (GLCM) and Gray-level difference matrix (GLDM), and 2D-Fast Fourier Transform (FFT) analyses, was applied to the segmented images to assess JPF textural heterogeneity in low- versus high-grade ccRCC. Univariate analysis and receiver-operator characteristics (ROC) analysis were used to assess interclass differences in texture metrics and their prediction accuracy, respectively.

Results

All methods except GLCM consistently revealed increased heterogeneity in the JPF surrounding high- versus low-grade ccRCC. FFT showed increased complexity index (p < 0.01). Histogram analysis showed increased kurtosis and positive skewness in (p < 0.03), and GLDM analysis showed decreased measure of correlation coefficient (MCC) (p < 0.04). Several of the GLCM metrics showed statistically significant (p < 0.04) textural differences between the two groups, but with no consistent trend. ROC analysis showed that MCC in GLCM analysis had an area under the curve of 0.75.

Conclusions

Our study suggests that CTTA of ccRCC shows statistically significant textural differences in JPF surrounding high- versus low-grade ccRCC.

     

基于增强CT影像组学模型鉴别肾透明细胞癌与非透明细胞癌

目的 建立基于增强CT的影像组学模型,评估其鉴别肾透明细胞癌（ccRCC）与非透明细胞癌（non-ccRCC）的应用价值。方法 将147例ccRCC及32例non-ccRCC患者随机分为训练集125例和测试集54例。将所有患者的增强CT资料导入ITK-SNAP软件,手动勾画ROI,获得16个特征,分别建立基于特征的随机森林（RF）模型和逻辑回归（LR）模型,采用ROC曲线观察模型对ccRCC的诊断效能。结果 训练集RF模型诊断ccRCC的AUC为0.96（P<0.05）,特异度为1.00,敏感度0.83;LR模型诊断ccRCC的AUC为0.96（P<0.05）,特异度为1.00,敏感度为0.83。测试集RF模型诊断ccRCC的AUC为0.96（P<0.05）,特异度为1.00,敏感度为0.89;LR模型诊断ccRCC的AUC为0.88（P<0.05）,特异度为0.90,敏感度为0.77。结论 基于增强CT影像组学模型可用于鉴别ccRCC与non-ccRCC;RF模型诊断价值较LR模型更高。     

定量CT纹理分析鉴别诊断透明细胞型与非透明细胞型肾癌

目的 探讨定量CT纹理分析鉴别透明细胞型肾癌和非透明细胞型肾癌的可行性。方法 回顾性分析100个透明细胞型肾癌和27个非透明细胞型肾癌病灶的CT图像,应用TexRAD软件分析各扫描期相两种类型肾癌的纹理特征。结果 增强图像上,非透明细胞型肾癌的平均灰度值、标准差、熵、正像素的平均值明显低于透明细胞型肾癌,而峰度高于透明细胞型肾癌（P均<0.001）,偏度差异无统计学意义（P>0.05）。在皮髓质期的粗糙纹理上,正像素的平均值鉴别两种类型肾癌的ROC曲线下面积为0.92±0.04,敏感度为0.85,特异度为0.93,准确率为0.87。结论 透明细胞型肾癌与非透明细胞型肾癌的CT纹理特征间存在显著差异,定量CT纹理分析鉴别诊断这两种类型肾癌具有临床价值。     

LINC01232 serves as a novel biomarker and promotes tumour progression by sponging miR-204-5p and upregulating RAB22A in clear cell renal cell carcinoma

BackgroundLong non-coding RNAs (lncRNAs) are involved in the progression of various cancers, including clear cell renal cell carcinoma (ccRCC). This study aimed to investigate the expression and prognostic value of long intergenic non-protein coding RNA (LINC) 01232 in ccRCC and preliminary explore the molecular mechanism underlying the role of LINC01232 in ccRCC progression.MethodsTumour tissues and adjacent normal tissues of 122 patients with ccRCC were collected in this study. The levels of LINC01232, microRNA (miR)-204-5p and RAB22A were measured by quantitative real-time PCR. The proliferation, migration and invasion of ccRCC cells were detected by cell counting kit-8 assay and Transwell assay, respectively. The interaction among LINC01232, miR-204-5p and RAB22A was confirmed by bioinformatics analysis, dual-luciferase reporter assay and Pearson correlation analysis. The association of LINC01232 and miR-204-5p with ccRCC patient survival was verified by the Kaplan–Meier method and log-rank test. The prognostic value of LINC01232 in ccRCC was confirmed by Cox regression analysis.ResultsLINC01232 expression was increased in ccRCC tumour tissues and ccRCC cells and independently predicted the prognosis of ccRCC patients. In addition, LINC01232 silencing inhibited ccRCC cell proliferation, migration and invasion. Moreover, LINC01232 served as a sponge for miR-204-5p, and miR-204-5p reduction reversed the inhibitory effect of LINC01232 silencing on ccRCC cell function. Furthermore, LINC01232 could sponge miR-204-5p, causing the elevation of RAB22A in ccRCC, thereby promoting ccRCC cell function.ConclusionLINC01232 may be an independent prognostic biomarker in ccRCC and plays an oncogenic role in ccRCC progression by sponging miR-204-5p and upregulating RAB22A.     

Baseline perfusion CT parameters as potential biomarkers in predicting long-term prognosis of localized clear cell renal cell carcinoma

Purpose

We aimed to explore the relationship among baseline perfusion CT parameters, clinical, and pathological factors with post-nephrectomy long-term progression-free survival in localized clear cell renal cell carcinoma.

Materials and methods

This study retrospectively collected 127 patients from March 2005 to May 2007 who undertook perfusion CT. 61 patients were confirmed of pT1N0M0 or pT2N0M0 ccRCC. The mean follow-up time is 118.8 months (± 13.1 m, range 72–135 m). We compared clinical, pathological factors (gender, T stage, age, Fuhrmann grade, VEGF level, and MVD), and perfusion parameters before treatment [blood flow (BF), blood volume, mean transition time, and permeability surface-area product] between groups with post-nephrectomy metastasis and without metastasis. Association between covariates and progression-free survival (PFS) were analyzed using Cox proportional regression.

Results

Among 61 patients, 11 developed distant metastasis (10 in the lung, one in the bone). BF in metastatic group [429.1 (233.8, 570.1) ml/min/100 g] was significantly higher than non-metastatic group [214.3 (153.3, 376.5) ml/min/100 g] (p = 0.011). Metastatic group also had more patients with higher Fuhrmann grade. Multi-covariant Cox regression demonstrated T staging, Fuhrmann grade, and BF were significantly associated with PFS [hazard ratio (HR) 3.35, 3.08, and 1.006]. In another model, BF > 230 ml/min/100 g was associated with PFS (HR 12.90), along with T staging and Fuhrmann grade (HR 4.73, 3.69).

Conclusion

Baseline tumor BF is a potential biomarker in prediction long-term metastasis of localized ccRCC and may help screening for higher risk localized ccRCC patients who need personalized surveillance strategy after nephrectomy.

     

Expression and clinical significance of PTPN12 in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is a common urological disease. Expression of the protein tyrosine phosphatase 12 gene (PTPN12) is decreased in many cancers; however, the relationship between PTPN12 gene function and renal cancer remains unclear.MethodsWe detected PTPN12 protein expression in ccRCC and corresponding normal tissues from 64 patients with ccRCC by immunohistochemistry, and relative PTPN12 mRNA levels by real-time quantitative polymerase chain reaction. The relationships between the relative expression levels of PTPN12 mRNA and the patients’ clinical data were analyzed.ResultsPTPN12 protein and mRNA expression levels were significantly lower in ccRCC compared with the corresponding normal tissues. The mRNA expression levels in the ccRCC and corresponding normal tissues from the 64 patients with ccRCC were 0.459±0.445 and 1.001±0.128, respectively, compared with the control (glyceraldehyde 3-phosphate dehydrogenase). There was a significant correlation between relative expression of PTPN12 mRNA in ccRCC tissues and tumor diameter and clinical stage.ConclusionThe expression levels of PTPN12 protein and mRNA were significantly lower in ccRCC tissues compared with normal tissues. The role of PTPN12 may provide new insights and evidence to aid the diagnosis and targeted therapy of ccRCC.     

Role of metabolomics-derived biomarkers to identify renal cell carcinoma: a comprehensive perspective of the past ten years and advancements

ABSTRACT

Introduction: Renal cell carcinoma (RCC) is one of the most prevalent metabolic diseases and a leading cause of utmost mortality among men globally. In spite of extensive development in technology for biomarker discovery during the last 10 years, the currently used clinical biomarkers are still unable to detect RCC at early and progression stages. Hence, the development of new and precise biomarkers is most important to improve the clinical management of RCC and reduce the level of mortality.

Area covered: For the detection of RCC at an early stage; a new branch of omics technology – metabolomics – has been introduced. Mainly two techniques (mass spectrometry and nuclear magnetic resonance spectroscopy) have been exploited to execute metabolomics. Precisely, metabolomics showed promising and powerful approach to identify novel RCC biomarker. The present review discussed and the literature search to narrate the outcomes of the past 10 years of studies related to RCC pathophysiology, metabolomics, advancements, and shortcomings.

Expert opinion: Although, compared to mass spectrometric tactic, nuclear magnetic resonance is moving fast to achieve the aim and in vivo application for diagnosis and management of RCC, metabolomics-based research in RCC is still in its infancy stage.     

Association of qualitative and quantitative imaging features on multiphasic multidetector CT with tumor grade in clear cell renal cell carcinoma

Purpose

The purpose of the study was to determine if enhancement features and qualitative imaging features on multiphasic multidetector computed tomography (MDCT) were associated with tumor grade in patients with clear cell renal cell carcinoma (ccRCC).

Methods

In this retrospective, IRB approved, HIPAA-compliant, institutional review board-approved study with waiver of informed consent, 127 consecutive patients with 89 low grade (LG) and 43 high grade (HG) ccRCCs underwent preoperative four-phase MDCT in unenhanced (UN), corticomedullary (CM), nephrographic (NP), and excretory (EX) phases. Previously published quantitative (absolute peak lesion enhancement, absolute peak lesion enhancement relative to normal enhancing renal cortex, 3D whole lesion enhancement and the wash-in/wash-out of enhancement within the 3D whole lesion ROI) and qualitative (enhancement pattern; presence of necrosis; pattern of; tumor margin; tumor–parenchymal interface, tumor–parenchymal interaction; intratumoral vascularity; collecting system infiltration; renal vein invasion; and calcification) assessments were obtained for each lesion independently by two fellowship-trained genitourinary radiologists. Comparisons between variables included χ², ANOVA, and student t test. p values less than 0.05 were considered to be significant. Inter-reader agreement was obtained with the Gwet agreement coefficient (AC1) and standard error (SE) was reported.

Results

No significant differences were observed between the LG and HG ccRCC cohorts with respect to absolute peak lesion enhancement and relative lesion enhancement ratio. There was a significant inverse correlation between low and high grade ccRCC and tumor enhancement the NP (71 HU vs. 54 HU, p < 0.001) and EX (52 HU vs. 39 HU, p < 0.001) phases using the 3D whole lesion ROI method. The percent wash-in of 3D enhancement from the UN to the CM phase was also significantly different between LG and HG ccRCCs (352% vs. 255%, p = 0.003). HG lesions showed significantly more calcification, necrosis, collecting system infiltration and ill-defined tumor margins (p < 0.05). Overall agreement between the two readers had a mean AC1 of 0.8172 (SE 0.0235).

Conclusions

Quantitatively, high grade ccRCC had significantly lower whole lesion enhancement in the NP and EX phases on MDCT. Qualitatively, high grade ccRCC were significantly more likely to be associated with calcifications, necrosis, collecting system infiltration, and an ill-defined tumor margin.

     

Can diffusion-weighted magnetic resonance imaging of clear cell renal carcinoma predict low from high nuclear grade tumors

Objective

To assess the diagnostic performance of the apparent diffusion coefficient (ADC) in predicting the Fuhrman nuclear grading of clear cell renal cell carcinomas (ccRCC).

Materials and methods

A total of 129 patients who underwent partial and radical nephrectomies with pathology-proven ccRCC were retrospectively evaluated. Histopathological characteristics and nuclear grades were analyzed. In addition, conventional magnetic resonance imaging (MRI) features were assessed in consensus by two radiologists to discriminate nuclear grading. ADC values were obtained from a region of interest (ROI) measurement in the ADC maps calculated from diffusion-weighted imaging (DWI) using b values of 50, 500, and 800 s/mm². The threshold values for predicting and differentiating low-grade cancers (Fuhrman I–II) from high grade (Fuhrman III–IV) was obtained using binary logistic regression. The ADC cut-off value for differentiating low- and high-grade tumors was determined using classification analysis.

Results

Significant associations (P < 0.001) were found between nuclear grading, conventional MR features, and DWI. Hemorrhage, necrosis, perirenal fat invasion, enhancement homogeneity, and cystic component were identified as independent predictors of tumor grade. High-grade ccRCC had significantly lower mean ADC values compared to low-grade tumors. An ADC cut-off value of 1.6 × 10⁻³ mm²/s had an optimal predictive percentage of 65.5% for low-grade tumors above this threshold and 81% for high-grade ccRCC below this threshold. Overall predictive accuracy was 70.5%.

Conclusion

The addition of ADC values to a model based on MRI conventional features demonstrates increased sensitivity and high specificity improving the distinguishing accuracy between both high-grade and low-grade ccRCC.

     

Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer

ABSTRACT

Introduction: The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC.

Areas covered: In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated.

Expert opinion: Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.     

Deciphering metabonomics biomarkers-targets interactions for psoriasis vulgaris by network pharmacology

Objectives: Psoriasis vulgaris is a chronic inflammatory and immune-mediated skin disease. 44 metabonomics biomarkers were identified by high-throughput liquid chromatography coupled to mass spectrometry in our previous work, but the roles of metabonomics biomarkers in the pathogenesis of psoriasis is unclear.

Methods: The metabonomics biomarker-enzyme network was constructed. The key metabonomics biomarkers and enzymes were screened out by network analysis. The binding affinity between each metabonomics biomarker and target was calculated by molecular docking. A binding energy-weighted polypharmacological index was introduced to evaluate the importance of target-related pathways.

Results: Long-chain fatty acids, phospholipids, Estradiol and NADH were the most important metabonomics biomarkers. Most key enzymes belonged hydrolase, thioesterase and acyltransferase. Six proteins (TNF-alpha, MAPK3, iNOS, eNOS, COX2 and mTOR) were extensively involved in inflammatory reaction, immune response and cell proliferation, and might be drug targets for psoriasis. PI3K-Akt signaling pathway and five other pathways had close correlation with the pathogenesis of psoriasis and could deserve further research.

Conclusions: The inflammatory reaction, immune response and cell proliferation are mainly involved in psoriasis. Network pharmacology provide a new insight into the relationships between metabonomics biomarkers and the pathogenesis of psoriasis.

• KEY MESSAGES

• ??Network pharmacology was adopted to identify key metabonomics biomarkers and enzymes.

• ??Six proteins were screened out as important drug targets for psoriasis.

• ??A binding energy-weighted polypharmacological index was introduced to evaluate the importance of target-related pathways.

     

Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis

ObjectiveWe seek to identify the differentially expressed miRNAs in the clear cell subtype (ccRCC) of kidney cancer.Design and methodsWe performed a miRNA microarray analysis to compare the miRNA expression levels between ccRCC tissues and their normal counterpart. The top dysregulated miRNAs were validated by quantitative RT-PCR analysis. Bioinformatics analysis was also performed.ResultsA total of 33 dysregulated miRNAs were identified in ccRCC, including 21 upregulated miRNAs and many of these miRNAs have been reported to be dysregulated in other malignancies and have a potential role in cancer pathogenesis. The miRNAs showed a significant correlation with reported chromosomal aberration sites. We also utilized target prediction algorithms to identify gene targets. Preliminary analyses showed these targets can be directly involved in RCC pathogenesis.ConclusionWe identified miRNAs that are dysregulated in ccRCC and bioinformatics analysis suggests that these miRNAs may be involved in cancer pathogenesis and have the potential to be biomarkers.     

mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation

Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4⁺ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8⁺ T cell effector and memory populations. Evaluation of mice with a T cell–specific deletion of the gene encoding the negative regulator of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic and potent effector CD8⁺ T cells; however, due to constitutive mTORC1 activation, these cells retained a terminally differentiated effector phenotype and were incapable of transitioning into a memory state. In contrast, CD8⁺ T cells deficient in mTORC1 activity due to loss of RAS homolog enriched in brain (RHEB) failed to differentiate into effector cells but retained memory characteristics, such as surface marker expression, a lower metabolic rate, and increased longevity. However, these RHEB-deficient memory-like T cells failed to generate recall responses as the result of metabolic defects. While mTORC1 influenced CD8⁺ T cell effector responses, mTORC2 activity regulated CD8⁺ T cell memory. mTORC2 inhibition resulted in metabolic reprogramming, which enhanced the generation of CD8⁺ memory cells. Overall, these results define specific roles for mTORC1 and mTORC2 that link metabolism and CD8⁺ T cell effector and memory generation and suggest that these functions have the potential to be targeted for enhancing vaccine efficacy and antitumor immunity.     

Molecular markers related to immunosurveillance as predictive and monitoring tools in non-small cell lung cancer: recent accomplishments and future promises

ABSTRACT

Introduction: The landscape of systemic treatment options for lung cancer has rapidly evolved with the emergence of immunomodulatory agents such as neutralizing antibodies targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1). Another major breakthrough was the introduction of biomarkers, such as PD-L1 expression and tumor mutational burden (TMB), predicting response to immunotherapy. However, markers for monitoring treatment response are still lacking.

Areas covered: PD-L1 and TMB represent static pre-treatment evaluations. Dynamic biomarkers are required, along with static ones, to accurately predict and monitor immunotherapy response and to discriminate between responders and non-responders early in the course of treatment. The tumor immune contexture offers potential candidates that can be tested through the liquid biopsy approach, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, microRNAs (miRNAs), circular RNAs (circRNAs), RNA splice variants, and immune cell subsets.

Expert opinion: A holistic approach combining information from tissue at the time of diagnosis and serial liquid biopsy data could lead to a novel combinatorial biomarker panel with enhanced treatment monitoring potential. Incorporating information from additional parts of the tumor-host ecosystem, such as metabolic markers and the microbiome is expected to provide added value to this strategy.     

探究PODXL在肾透明细胞癌中的表达及相关意义

目的：研究PODXL在透明细胞肾细胞癌(ccRCC)组织与正常组织中的表达差异,并初步分析PODXL对肾透明细胞癌的临床诊断和患者预后的关系。实验方法：运用癌症基因组图谱(TCGA)数据库收集RNA-Seq数据和临床数据,观察ccRCC患者组织与正常组织中PODXL基因表达量的差异,同时分析PODXL与临床病理学之间的关系及与预后之间的关系。结果：在TCGA数据库中总体526例ccRCC样本的癌和癌旁组织中的PODXL的表达水平分别为6.42±1.42和3.61±1.31,差异有统计学意义(P<0.001)。72例配对的ccRCC和癌旁组织中的PODXL表达水平分别为6.55±1.23和3.53±1.35,有统计学意义(P<0.001)。PODXL的表达在患者性别、肾肿瘤分级、T分期、M分期、临床分期等均有不同差异(P<0.001)。生存分析发现PODXL低表达量组和高表达量组的生存时间分别为(1446.75±956.32)d和(1253.81±939.57)d,差异有统计学意义(Log-rank=14.38,P<0.001)。ROC曲线结果显示,PODXL基因可作为一个灵敏度和特异度较高的ccRCC诊断指标：其中AUC为0.805,敏感性为67.26%,特异性为78.17%。结论：PODXL在ccRCC中高表达与临床病理特征呈正相关,是预后不良因素,有望作为肾透明细胞癌患者的生存预后及诊断的潜在生物学标志。     

Noncanonical Wnt as a prognostic marker in prostate cancer: “you can’t always get what you Wnt”

ABSTRACT

Introduction: Wnt signaling is important for normal development, cell proliferation, and cell differentiation. However, aberrations in the pathway can lead to tumorigenesis and cancer progression. Recent genome-wide studies have demonstrated the frequent occurrence of Wnt pathway alterations in prostate cancer. Although alterations in the canonical Wnt pathway in prostate cancer may have an impact on prognosis, recent studies suggest that the noncanonical Wnt pathway also plays an important role in disease progression and treatment resistance.

Areas covered: We review the literature with regard to the potential prognostic significance of noncanonical Wnt signaling in prostate cancer. After a brief overview of the canonical and noncanonical Wnt pathways, we discuss the preclinical and clinical evidence for activation of Wnt signaling in prostate cancer. We focus on clinical evidence for noncanonical Wnt pathway components to serve as potential prognostic biomarkers.

Expert opinion: Although many therapeutic options are available for men with prostate cancer, there remains an unmet need for prognostic and predictive biomarkers to precisely guide clinical management. Early evidence suggests that components of the noncanonical Wnt pathway may serve as prognostic biomarkers. However, prospective validation studies are necessary before these biomarkers can be routinely applied in the clinic.     

精囊蛋白SG1在肾透明细胞癌中的表达和预后意义

目的探讨精囊蛋白SG1在肾透明细胞癌患者癌旁组织和癌组织中的表达差异,结合临床指标,研究其临床意义。方法以qRT-PCR检测24例明确诊断为肾透明细胞癌患者的癌组织和癌旁组织中的SG1表达水平,以免疫组化研究53例肾透明细胞癌标本中的SG1蛋白表达水平,并进一步研究其临床意义。结果 qRT-PCR显示癌组织中的SG1水平明显低于癌旁组织的(P<0.01)。53例癌组织中,抗SG1免疫组化染色30例阳性(57%),明显低于对应癌旁组织的全部阳性(100%)。SG1表达量和肾透明细胞癌临床分期呈负相关(pT1² vs.pT32 vs.pT3⁴,P<0.000 1),且SG1表达阴性的患者复发概率升高(P<0.01)。结论 SG1在肾透明细胞癌中为低表达,SG1可预测肾透明细胞癌的进展和预后。