Preoperative red blood cell distribution width as an independent prognostic factor in metastatic renal cell carcinoma

ObjectiveThis study aimed to explore the prognostic value of preoperative red blood cell distribution width (RDW) in patients with metastatic renal cell carcinoma (mRCC).MethodsClinicopathological data of 230 patients with mRCC treated at the First Affiliated Hospital of Chongqing Medical University and the Chinese PLA General Hospital from January 2008 to December 2018 were retrospectively analyzed. Patients were stratified according to the optimal cut-off value of RDW calculated using X-tile software. The prognostic value of RDW was analyzed using the Kaplan-Meier curve with log-rank test and univariate and multivariate Cox proportional hazards models.ResultsA total of 230 patients were included. The optimal cut-off value of RDW obtained using X-tile software was 13.1%. The median Progression-free survival (PFS) and Overall survival (OS) of all populations were 12.06 months (IQR: 4.73–36.9) and 32.20 months (IQR: 13.73–69.46), respectively. Kaplan–Meier curves showed that patients with high RDW had worse PFS and OS than those with low RDW (median PFS of 9.7 months vs. 17.9 months, P = 0.002, and median OS of 27.8 months vs. 45.1 months, P = 0.012, respectively). Multivariate analysis showed that RDW was an independent risk factor for PFS (HR: 1.505; 95% CI: 1.111–2.037; P = 0.008) and OS (HR: 1.626; 95% CI: 1.164–2.272; P = 0.004) in mRCC after cytoreductive nephrectomy.ConclusionPreoperative RDW was independently associated with PFS and OS in patients with mRCC and may be a potential predictor of survival outcomes in mRCC.     

Integrated 18F-fluorodeoxyglucose-positron emission tomography/dynamic contrast-enhanced computed tomography to phenotype non-small cell lung carcinoma

AbstractWe applied modern molecular and functional imaging to the pretreatment assessment of lung cancer using combined dynamic contrast-enhanced computed tomography (DCE-CT) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) to phenotype tumors. Seventy-four lung cancer patients were prospectively recruited for 18F-FDG-PET/DCE-CT using PET/64-detector CT. After technical failures, there were 64 patients (35 males, 29 females; mean age [± SD] 67.5 ± 7.9 years). DCE-CT yielded tumor peak enhancement (PE) and standardized perfusion value (SPV). The uptake of 18F-FDG quantified on PET as the standardized uptake value (SUVmax) assessed tumor metabolism. The median values for SUVmax and SPV were used to define four vascular-metabolic phenotypes. There were associations (Spearman rank correlation [rs]) between tumor size and vascular-metabolic parameters: SUVmax versus size (rs = .40, p = .001) and SUV/PE versus size (r = .43, p < .001). Patients with earlier-stage (I-IIA, n = 30) disease had mean (± SD) SUV/PE 0.36 ± 0.28 versus 0.56 ± 0.32 in later-stage (stage IIB-IV, n = 34) disease (p = .007). The low metabolism with high vascularity phenotype was significantly more common among adenocarcinomas (p = .018), whereas the high metabolism with high vascularity phenotype was more common among squamous cell carcinomas (p = .024). Other non-small cell lung carcinoma tumor types demonstrated a high prevalence of the high metabolism with low vascularity phenotype (p = .028). We show that tumor subtypes have different vascular-metabolic associations, which can be helpful clinically in managing lung cancer patients to hone targeted therapy.     

Proteomics identified nuclear N-myc downstream-regulated gene 1 as a prognostic tissue biomarker candidate in renal cell carcinoma

The aim of this study was to identify proteins with aberrant expression in clear cell renal cell carcinoma (ccRCC), and elucidate their clinical utilities. The protein expression profiles of primary ccRCC tumor tissues and neighboring non-tumor tissues were obtained from 9 patients by two-dimensional difference gel electrophoresis and mass spectrometry. Comparative analysis of 3771 protein spots led to the identification of 73 proteins that were expressed at aberrant levels in tumor tissues compared with non-tumor tissues. Among these 73 proteins, we further focused on N-myc downstream-regulated gene 1 protein (NDRG1). NDRG1 expression is regulated by members of myc family as well as by p53, HIF1A, and SGK1. The biological and clinical significance of NDRG1 is controversial for various malignancies and no detailed studies on NDRG1 have been reported in ccRCC until our study. For the 82 newly enrolled ccRCC patients, immunohistochemical analysis revealed a significant association between nuclear NDRG1 and favorable prognosis (p < 0.05). Multivariate analysis demonstrated the role of NDRG1 as an independent factor of progression-free survival (p = 0.01). Subsequent in vitro gene suppression assay demonstrated that NDRG1 silencing significantly enhanced cell proliferation and invasion of RCC cells. The cytotoxic effects of NDRG1 up-regulation induced by an iron chelator were also confirmed. These findings suggest that nuclear NDRG1 has tumor suppressive effects, and the NDRG1 expression may have clinical values in ccRCC. Nuclear NDRG1 may provide additional insights on molecular backgrounds of ccRCC progression, and contribute to the development of novel therapeutic strategy.     

A large-scale transcriptome analysis identified ELANE and PRTN3 as novel methylation prognostic signatures for clear cell renal cell carcinoma

DNA methylation was involved in the progress of many types of cancer including clear cell renal cell carcinomas (ccRCCs). This study aimed to identify the prognostic DNA methylation biomarkers for the ccRCCs by a large-scale RNA-seq analysis. The DNA methylation data and the corresponding clinical information of the patients with ccRCCs were extracted from TCGA database and randomly divided into the training group and the validation group. The differentially expressed CpG sites and the survival-related CpG sites were further identified, which was combined into CpG sites pair and followed by screening the survival-related pairs. The C-index and the forward search algorithms were constructed to identify the prognostic signatures for the patients with ccRCCs. The prognostic signatures were verified by the validation dataset and the protein–protein interactions (PPI) network analysis was performed on the CPG sites of the signature. A total of 9,861 differentially expressed CPG sites were identified and 567 CpG sites were found to relate to the overall survival (OS) of the patients with ccRCCs. Besides, 1,146 CPG sites pairs were found to be related to the OS of the ccRCCs samples and the signature composed of seven CpG sites pairs were obtained to predict the prognosis of patients with ccRCCs and the results were verified in the validation dataset. Besides, the PPI network analysis showed that ELANE and PRTN3 gene may be associated with the invasion and metastasis of ccRCCs and could function as potential prognostic and therapeutic signatures for ccRCCs.     

Tissue expression of VEGF as a prognostic factor in early cervical squamous cell carcinoma

The purpose of this retrospective study was to determine whether the intensity of tumor angiogenesis, expressed as microvessel density (MD), is indeed an important parameter predicting lymph node metastasis and survival rate in 73 women operated on for early invasive squamous cell carcinoma of the uterine cervix in stages Ib and IIa (FIGO). Angiogenesis was quantified by light microscope (LM) using an assay for vascular endothelial growth factor (VEGF). In the study, differences were revealed by comparing the MD between both groups. The patient survival with high MD was significantly worse than for those with low MD (p<0.01). A correlation was found between MD and the incidence of lymph node metastases. Hence, quantitative analysis of MD used as the expression of VEGF in the each cervical squamous cell carcinomas could be useful as a significant prognostic indicator.     

Identification of a three-miRNA signature as a novel potential prognostic biomarker in patients with clear cell renal cell carcinoma

Current studies suggest that some microRNAs (miRNAs) are associated with prognosis in clear cell renal cell carcinoma (ccRCC). In this paper, we aimed to identify a miRNAs signature to improve prognostic prediction for ccRCC patients. Using ccRCC RNA-Seq data of The Cancer Genome Atlas (TCGA) database, we identified 177 differentially expressed miRNAs between ccRCC and paracancerous tissue. Then all the ccRCC tumor samples were divided into training set and validation set randomly. Three-miRNA signature including miR130b, miR-18a, and miR-223 were constructed by the least absolute shrinkage and selection operator (LASSO) Cox regression model in training set. According to optimal cut-off value of three-miRNA signature risk score, all the patients could be classified into high-risk group and low-risk group significantly. Survival of patients was significantly different between two groups (hazard ratio, 5.58, 95% confidence interval, 3.17-9.80; P < 0.0001), and three-miRNA signature performed favorably prognostic and predictive accuracy. The results were further validated in the validation set and total set. Multivariate Cox regression analyses and subgroup analyses showed that three-miRNA signature was an independent prognostic factor. Two nomograms that integrated three-miRNA signature and three clinicopathological risk factors were constructed to predict overall survival and disease-free survival after surgery for ccRCC patients. Functional enrichment analysis showed the possible roles of three-miRNA signature in some cancer-associated biological processes and pathways. In conclusion, we developed a novel three-miRNA signature that performed reliable prognostic for patient survival with ccRCC, it might facilitate ccRCC patients counseling and individualize management.     

Pinin acts as a poor prognostic indicator for renal cell carcinoma by reducing apoptosis and promoting cell migration and invasion

Pinin (PNN) was originally characterized as a desmosome-associated molecule. Its function and the mechanism of its regulation in renal cell carcinoma (RCC) are still undefined. Data on PNN expression, clinicopathological features, and prognosis of patients with RCC were obtained from The Cancer Genome Atlas (TCGA) database. Immunohistochemistry revealed high PNN expression in tumour cells. PNN expression showed negative correlation with survival in patients with RCC, acting as an independent prognostic factor in RCC. PNN up-regulation might be attributed to epigenetic alterations in RCC. Immunofluorescence revealed PNN expression mainly in the nucleus of RCC cells. The transfection of siRNA targeting the PNN gene resulted in enhanced apoptosis, which was detected by flow cytometry, and reduced cell migration and invasion, which were assessed using wound healing and transwell migration assay. Gene set enrichment analysis revealed associations between PNN expression and several signalling pathways involved in cancer progression, as a potential mechanism underlying the carcinogenicity of PNN. The analyses of the Tumor Immune Estimation Resource platform showed significant positive associations between high PNN expression and tumour immune infiltrating cells. PNN may function as an oncogenic factor by reducing apoptosis and promoting cell migration and invasion in RCC.     

HSP 27 as possible prognostic factor in patients with oral squamous cell carcinoma

HSP27 belongs to the Heat shock protein (HSP) family, which plays essential functions in cells under physiological conditions and prevents stress-induced cellular damage. The aim of this study was to investigate the biological role of HSP27 in oral tumorigenesis. MATERIALS AND METHODS: Seventy-nine cases of oral squamous cell carcinoma and 10 cases of normal mucosa were analysed for HSP27 expression by immunohistochemistry. Moreover, the western blot analysis was performed on two cases of normal mucosa and five cases of OSCC. RESULTS: Normal oral mucosa showed a suprabasal expression of HSP27. Twenty-four cases of SCC (30.7%) showed a diffuse staining for HSP27, and 48 cases (60.3%) showed instead a decrease in staining, which was diffuse, homogeneous, or with alternation of positive and negative areas in a single tumor ("mosaic" pattern). Only 7 cases of OSCC (7.5%) were completely negative for HSP27. Frequency of lymph node metastases was higher in HSP27-negative tumours (3/7, 42.8%) than in HSP-reduced (16/48, 33.3%) or positive ones (5/26, 19.2%). Regard staging, stages I and II had a higher score than stages III and IV (stage I > stage II > stage III > stage IV). There was also a statistically significant correlation between HSP27 expression and grade: HSP27 expression was reduced in poorly differentiated tumours (P < 0.05). When analysed for prognostic significance, patients with negative/reduced HSP27 expression had poorer survival rates than the group with positive HSP27 expression (P < 0.05). The statistical analysis of these findings showed no significant correlation between HSP27 expression, sex, and tumour size. CONCLUSION: Cases with reduced expression were more aggressive and poorly differentiated. These data suggest that HSP27 expression may be useful in order to identify cases of oral squamous cell carcinoma with more aggressive and invasive phenotype providing novel diagnostic and prognostic information on individual patient survival with oral cancers.     

Semaphorin 6D as an independent predictor for better prognosis in clear cell renal cell carcinoma

IntroductionClear cell renal cell carcinoma (ccRCC) is the most common type of RCC and is associated with poor survival. However, the mechanisms underlying its development have not been thoroughly investigated. Semaphorin 6D (SEMA6D) is differentially expressed in various cancers, including lung adenocarcinoma and colorectal cancer. However, the role and mechanism of SEMA6D in ccRCC remain unexplored.Materials and methodsWe obtained 25 pairs of ccRCC tissue samples and 57 urine samples from patients with ccRCC and 52 urine samples from healthy volunteers. We performed RNA sequencing and compared the results with data from The Cancer Genome Atlas database to identify our gene of interest, SEMA6D. To verify the differential expression of SEMA6D, we used real-time quantitative polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Finally, we conducted in vitro proliferation, migration and invasion experiments.ResultsSEMA6D expression was significantly lower in ccRCC tissue compared to that in normal tissue. Comparative analysis of our results with data from online databases revealed that the expression level of SEMA6D in ccRCC tissue correlated with the clinical stage and pathological grade of ccRCC. Furthermore, higher SEMA6D expression was associated with improved quality of life of patients with ccRCC. In addition, the diagnostic value of SEMA6D was confirmed using data from two Gene Expression Omnibus ccRCC databases. The results showed that SEMA6D can be used as a predictor for ccRCC diagnosis, with an area under the curve of 0.9642.ConclusionSEMA6D may serve as a diagnostic and prognostic biomarker for ccRCC.     

Serum antibodies against Saccharomyces cerevisiae: a new prognostic indicator in metastatic renal-cell carcinoma

PURPOSE: A recent study reported that a diet rich in bread and refined cereals might have an unfavorable role in the development of renal cell carcinoma (RCC). To test whether an underlying intolerance of bread ingredients is responsible for the unfavorable influence of bread on RCC, we examined patient sera for the presence of food-specific IgG. EXPERIMENTAL DESIGN: A commercial test was used to detect food-specific IgG directed against a panel of 113 food antigens in sera of 54 patients with metastatic RCC. Kaplan-Meier estimates were used for univariate survival analysis, and differences in survival curves were assessed with the log-rank test. Multivariate survival analysis was done using a Cox regression model. RESULTS: We found that RCC patients with elevated serum levels of IgG antibodies against S. cerevisiae, commonly known as baker's yeast and yet another bread component, have an unfavorable clinical course. Median survival of patients with high levels of S. cerevisiae IgG was only 17.8 months, whereas median survival of patients with low S. cerevisiae IgG was 43.8 months (P = 0.0022; log-rank). Multivariate survival analysis identified high levels of S. cerevisiae IgG as a strong and independent prognostic risk factor (risk ratio 4.6, P = 0.001; 95% CI 1.61-13.08). CONCLUSIONS: Our findings indicate that serum levels of IgG against S. cerevisiae may predict survival in patients with metastatic RCC. The data suggest not cereals but baker's yeast being the critical component of bread that may cause immune deviation and impaired immunosurveillance in predisposed RCC patients.     

原发性肝癌:CT血液供应、P53抗体和血管内皮生长因子

目的:分析原发性肝癌(primary hepatic carcinoma,简称肝癌)血液供应(blood supply,简称血供)CT类型与患者血清P53抗体、血管内皮生长因子(vascular endothelial growth factor,VEGF)的关系,以及血清P53抗体与VEGF的相关性.方法:用酶联免疫吸附法定量检测首诊肝癌患者血清P53抗体和VEGF,与CT诊断的血供类型结果进行对比,分析不同血供类型的肝癌是否存在血清P53抗体差异(单因素分析),并分析不同血供类型的肝癌血清VEGF是否存在差异(单因素分析),然后分析血清P53抗体和VEGF之间的相关性.结果:四种不同血供类型的肝癌之间血清P53抗体滴度有差异(P<0.05).值得注意的是,富血供型与混合型之间、动-静脉漏型(AVS)与混合型之间血清P53抗体有显著差异(P<0.05),富血供型与AVS型之间血清P53抗体没有显著差异(P>0.05).不同血供类型的肝癌中,富血供型和混合型血清P53抗体与VEGF呈正相关(P<0.05),而AVS型和乏血供型中,血清P53抗体与VEGF不呈直线相关(P>0.05).结论:血清P53抗体和血清VEGF滴度在血供不同肝癌中滴度有差异,在富血供型和混合型中血清P53抗体与VEGF滴度呈正相关.     

Lymphatic microvessel density as a prognostic factor in non-small cell lung carcinoma: a meta-analysis of the literature

The role of lymphatic microvessel density (LVD) as a prognostic factor for survival of patients with non-small cell lung carcinoma (NSCLC) remains controversial. To evaluate this potential role, we performed a systematic review of the electronic databases PubMed and EMBASE for relevant literature to review and compile available survival results. To be eligible, a study had to assess LVD in patients with NSCLC and to compare survival based on LVD stratification. Among 12 eligible trials, all dealt with NSCLC, and 10 trials provided results for the meta-analysis of survival data (evaluable trials). In terms of survival, high LVD was reported to be an unfavorable prognostic factor for overall survival in 8 studies, whereas it was not in 4 studies. The overall survival hazard ratio for the 10 evaluable studies (1,426 patients) was calculated to be 1.41 (95% CI: 1.14–1.75) using a random effects model, indicating a poorer survival for NSCLC patients with high LVD. The hazard ratio was 1.52 (95% CI: 1.10–2.11) in 5 NSCLC studies where LVD was assessed based on D2-40 and 1.31 (95% CI: 1.08–1.60) in 4 studies where LVD was measured based on vascular endothelial growth factor receptor-3. This study supports the hypothesis that the lymphatic microvessel count or LVD, which reflects levels of lymphangiogenesis, is a poor prognostic factor for patient survival in surgically treated NSCLC. However, the present findings may overestimate the prognostic capacity of LVD because of publication and report bias. In addition, the standardization of lymphangiogenesis assessment by the lymphatic microvessel count is necessary.     

Angiogenesis as a prognostic factor in invasive carcinoma of the uterine cervix

The aim of the study was to evaluate angiogenesis as an independent prognostic factor and to determine the correlation between the angiogenic index (AI) and histologic grade of the neoplastic process in patients operated on for invasive carcinoma of the uterine cervix. Angiogenesis was assessed with immunohistochemical technique using a monoclonal antibody against human factor VIII--(F8/86 M0616, DAKO, Denmark). A positive correlation was revealed between the intensification of angiogenesis and the incidence of lymph node involvement and survival rate.     

Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma

Tumor-associated macrophages (TAMs) derived from peripheral blood monocytes recruited into the renal cell carcinoma (RCC) microenvironment. In response to inflammatory stimuli, macrophages undergo M1 (classical) or M2 (alternative) activation. M1 cells produce high levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-12, IL-23 and IL-6, while M2 cells produce anti-inflammatory cytokines, such as IL-10, thus contributing to RCC-related immune dysfunction. The presence of extensive TAM infiltration in RCC microenvironment contributes to cancer progression and metastasis by stimulating angiogenesis, tumor growth, and cellular migration and invasion. Moreover, TAMs are involved in epithelial–mesenchymal transition of RCC cancer cells and in the development of tumor resistance to targeted agents. Interestingly, macrophage autophagy seems to play an important role in RCC. Based on this scenario, TAMs represent a promising and effective target for cancer therapy in RCC. Several strategies have been proposed to suppress TAM recruitment, to deplete their number, to switch M2 TAMs into antitumor M1 phenotype and to inhibit TAM-associated molecules. In this review, we summarize current data on the essential role of TAMs in RCC angiogenesis, invasion, impaired anti-tumor immune response and development of drug resistance, thus describing the emerging TAM-centered therapies for RCC patients.     

Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma

With the objective of evaluating leukocyte orchestration in situ, serial blood samples and tumour tissue core needle biopsies were obtained at baseline and repeated after 1 month of therapy, among 49 consecutive single-institution patients with metastatic renal cell carcinoma (mRCC). Patients were treated with outpatient low-dose subcutaneous interleukin 2 (IL-2) and interferon (IFN-) alone (n=23) or in combination with histamine dihydrochloride (n=26). Objective responses were achieved in ten of 49 patients (20%) with an overall median survival of 14 months and an estimated 1- to 4-year survival rate of 57, 35, 24 and 22%, respectively. Toxicity was mild to moderate with no treatment-related deaths. High numbers of blood monocytes and neutrophils were significantly correlated to short survival. By contrast, high numbers of intratumoural CD3⁺, CD4⁺, CD8⁺ and CD57⁺ lymphocytes were positively correlated to objective response and/or long-term survival. Intratumoural lymphocytes showed low expression, whereas blood lymphocytes showed almost normal levels of expression. Neutrophils, the most frequent peripheral blood leukocyte subset, were scarce within the tumour tissue. Intratumoural eosinophils were not observed. In progressing patients, both the absolute number and the relative composition of leukocyte subsets in blood and tumour tissue remained unaffected by cytokine therapy. However, in responding patients, cytokine therapy was followed by an absolute and relative increase in T cells in blood as well as tumour tissue, an absolute and relative reduction in neutrophils in peripheral blood and a relative reduction of intratumoural macrophages. Histamine did not influence levels of intratumoural or blood leukocyte numbers, -chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN- in mRCC should attract interest based on response, survival and toxicity. In responding patients, cytokine therapy was followed by substantial changes in the blood and tumour tissue leukocyte composition, correlated to response and survival. No discernable differences in immunologic parameters studied could be detected between histamine- and nonhistamine-treated patients.