EZH2-regulated immune risk score prognostic model predicts outcome of clear cell renal cell carcinoma

BackgroundThe enhancer of zeste homolog 2 (EZH2) plays an important role in the tumor microenvironment (TME), and EZH2 in shaping the epigenetic landscape of CD8⁺ T cell fate and function, with a particular emphasis on cancer. Here, high EZH2 expression always leads to less CD8⁺ T cell infiltration. However, clear cell renal cell carcinoma (ccRCC) is reportedly a “hot” tumor, with contradictory high EZH2 expression. Our goal was to construct a EZH2-regulated immune risk score prognostic model to predict ccRCC outcomes, and provide a prospect of clinical EZH2 inhibitors in fine-tuning T cell responses with immune therapy.MethodsWe downloaded and analyzed The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), TISIDB database, and WebGestalt for ccRCC patients, EZH2-related tumor-infiltrating lymphocytes and immunomodulators. R packages “limma”, “BiocManager”, and “preprocessCore”, etc. were downloaded to prepare CIBERSORT files, immune cells heatmap, multivariable Cox model and survival analysis. The EZH2-regulated immune risk model’s prognostic ability was calculated by receiver operating characteristic (ROC) and area under the curve (AUC) analyses in R studio.ResultsEZH2 was highly expressed and related to poor outcome in ccRCC. However, high-expression EZH2 was not related to a “cool” tumor. Of the 49 immunomodulators significantly regulated by EZH2, forest plot showed 26 immunomodulators signatures independently associated with overall survival. The EZH2-regulated immune-risk score prognostic model was an independent prognostic factor (AUC =0.816), especially combined with clinicopathologic parameters in ccRCC overall survival prediction.ConclusionsThe EZH2-regulated immune-risk score prognostic model was an independent prognostic factor, with good accuracy and predictability, and could provide experimental data to the clinical area.     

Metastatic chromophobe renal cell carcinoma treated with targeted therapies: A Renal Cross Channel Group study

BackgroundTreatment of non–clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vascular Endothelial growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC.MethodsWe performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan–Meier method.Results91 mChRCC patients from 26 centres were included. Median follow-up from the date of first metastasis was 6.1 years (range: 0–13.9). Median OS was 37.9 months (95% confidence interval [CI]: 21.4–46.8) from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months (95% CI: 5.2–10.9) and 22.9 months (95% CI: 17.8–49.2) versus 1.9 months (95% CI: 1.0–6.0) and 3.2 months (95% CI: 2.3–not evaluable) with mTOR inhibitors, respectively. A stratified log-rank test was used to compare AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (p = 0.26) or for OS (p = 0.55).ConclusionWe report the largest retrospective cohort of patients with mChRCC treated with TT and no significant difference between AA and mTOR inhibitors was observed for TTF and OS.     

肾癌早期诊断与治疗

目的:探讨肾癌的临床特征、早期诊断治疗情况及对预后的影响。方法:回顾性分析120例肾癌患者的临床资料、诊疗方法和预后。结果:120例平均年龄55.4岁,男性78例,女性42例。体检或因其他部位不适在检查过程中偶然发现者74例(61.7%),无痛性血尿26例(21.7%),腰背部疼痛19例(15.8%),因慢性肾功能不全,经B超、CT检查发现1例。临床分期为T1N0M074例,T2N0M038例,T3期以上8例。行肾癌根治性切除术119例。术后接受α-干扰素和白介素-2治疗36例。随访79例,平均随访时间39个月。结论:彩色多普勒超声、CT是目前早期诊断肾癌的重要手段。早期行根治性切除术是最有效的治疗方法。作为手术、放疗、化疗的补充,生物免疫治疗也逐渐成为一种治疗方法。     

肾细胞癌癌组织和血清中血管内皮生长因子的表达

目的　通过观察VEGF在肾细胞癌患者癌组织和血清中的表达 ,观察其在肿瘤发生、发展中的作用。方法　应用免疫组化和原位杂交技术对 1 4例肾细胞癌患者癌组织行VEGF蛋白和VEGFmRNA表达测定 ,定量SABC -ELISA法对 2 4例肾细胞癌患者血清和 2 0例健康对照行血清中VEGF测定。结果　VEGF在 1 4例肾细胞癌癌组织中 ,不论是免疫组化染色还是原位杂交均为强表达 ,而在肾细胞癌癌周组织中 ,两者均为弱表达或不表达。肾细胞癌患者血清VEGF中值 (476ng·L- 1 )较对照组 (3 1 2ng·L- 1 )明显增高 (P <0 .0 1 )。肾细胞癌分级、分期中 ,高级和高期VEGF阳性表达者与低级、低期者相同。结论　肾细胞癌患者不论是癌组织中还是血清中VEGF表达明显增强 ,相应的癌周组织中无VEGF表达或为弱表达 ,VEGF在肾细胞癌的发生中可能起重要作用 ,可能与其起始相关     

Pilot study of salvage laparoscopic prostatectomy for the treatment of recurrent prostate cancer

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? After primary radiation therapy or cryotherapy for prostate cancer, a biochemical‐only recurrence poses a diagnostic and therapeutic dilemma for clinicians and patients alike. Open radical prostatectomy (ORP) represents the most effective curative treatment option for these patients. Salvage laparoscopic radical prostatectomy seems to offer a safe therapeutic alternative for patients failing primary radiation or cryotherapy.

OBJECTIVE

? To evaluate feasibility, safety and oncological efficacy of salvage laparoscopic radical prostatectomy for pathology‐proven biochemical recurrence after primary radiation therapy or cryotherapy for prostate cancer.

MATERIALS AND METHODS

? This retrospective pilot study examined 15 patients from 2004 to 2010 with biochemical recurrence after external beam radiation therapy (N= 8), brachytherapy (N= 6) or cryotherapy (N= 1). ? Patients were treated with salvage laparoscopic radical prostatectomy (11 conventional, four robotic‐assisted) with bilateral pelvic dissection.

RESULTS

? Median duration of surgery was 235 min. None of the following occurred: conversion to open surgery, transfusion, urethrovesical stenosis or perioperative or postoperative mortality. One patient presented with a rectal injury, repaired using uninterrupted sutures and a colostomy. One patient had anastomotic leak treated with prolonged Foley catheterization. ? Pathological stage was pT2a in three, pT2b in three, pT3a in four, pT3b in three and pT4 in two patients; two patients had nodal metastasis. Within an 8‐month median follow‐up, 11 patients were disease‐free and three had persistent postoperative prostate‐specific antigen (PSA) elevation; the remaining patient experienced PSA recurrence after 21 months. ? Seven patients achieved continence (no pads) by 8.4 months (median), one patient manifested severe incontinence corrected by implanting an artificial sphincter, and seven patients with a 12.6‐month mean follow‐up continued to need one or two pads per day. ? Erectile dysfunction was present in five patients before surgery and in 14 patients after surgery.

CONCLUSION

? Salvage laparoscopic radical prostatectomy seems to offer a safe therapeutic alternative for patients failing primary radiation or cryotherapy. However, larger studies with longer‐term data are required.     

Differential gene expression identifies subgroups of renal cell carcinoma

Clear cell carcinoma of the kidney, the most common subtype of renal cell cancer, displays different biological behavior in different patients. This heterogeneity cannot be recognized by light microscopy. In this study, gene expression in 16 clear cell renal cell carcinoma samples and 17 non-malignant tissue types comprising 539 samples was determined using oligonucleotide microarrays representing approximately 40,000 known genes and ESTs. Differences in gene expression were quantified as the fold change in gene expression between the various sets of samples. A set of genes was identified that was overexpressed in the renal cell carcinoma samples compared with the normal kidney samples. Principle component analysis of the set of renal cell carcinomas using this set of genes overexpressed in renal cell cancer revealed the existence of 2 major subgroups among the renal carcinomas. A series of principle component analyses of the set of renal cell carcinomas using different gene sets composed of genes involved in different metabolic pathways also revealed the same 2 major subgroups of the renal cell cancers. Eisen clustering using the same genes also revealed the same 2 major renal cell cancer subsets. Review of the pathology suggested that these 2 subgroups differed in pathologic grade. Genes differentially expressed between the 2 renal cell cancer subsets were identified. Examination of gene expression in each renal cell cancer subset and the pool of renal cell carcinoma samples compared with that in 17 different normal tissues revealed genes specifically overexpressed in renal cell cancer compared with these normal tissues. The authors conclude that gene expression patterns may be useful in helping to further classify subtypes of renal cell carcinoma that may have clinical significance. In addition, the genes identified as overexpressed in each set of clear cell renal cell carcinomas compared with normal tissues may represent useful targets for therapy.     

MMP-13 is over-expressed in renal cell carcinoma bone metastasis and is induced by TGF-β1

Bone metastasis occurs frequently in renal cell carcinoma (RCC) patients causing significant morbidity by stimulating excessive osteolysis, yet the mechanisms responsible have been little studied. Matrix metalloproteinases (MMPs) are over-expressed in many cancer types and are believed to play a role in bone metastasis, however, the expression of MMPs in RCC bone metastasis (RBM) has not been investigated. Due to their ability to degrade the main component of organic bone matrix, type I collagen, we investigated the expression of MMP-1, -2, -8, -9, and -13 in RBM. By quantitative (q)RT-PCR, expression of MMP-13 was significantly increased in RBM tissues relative to that in RCC and adjacent normal kidney while no differences in the expression of MMP-1, -2, -8, or -9 mRNA were observed. Correspondingly, increased expression of MMP-13 protein was also observed in RBM relative to RCC by immunohistochemical analysis. Intriguingly, the expression of MMP-13 in the human RBM cell line RBM1-IT4 was stimulated by TGF-β1, a growth factor abundant in the bone microenvironment and known to promote RBM-induced osteolysis in animals. Exposure of RBM1-IT4 cells to TGF-β1 increased MMP-13 mRNA levels as well as the latent and active forms of MMP-13 protein. Further, stable expression of a dominant-negative TGF-β type II receptor in RBM1-IT4 cells inhibited MMP-13 expression following TGF-β1 exposure. These data suggest that MMP-13 expression is elevated in RBM relative to primary RCC and adjacent normal kidney, and is regulated at the cellular level by TGF-β1.     

Trends in the treatment of clinical T1 renal cell carcinoma for octogenarians: Analysis of the National Cancer Database

Objective

Treatment of renal cell carcinoma has evolved with emphasis on nephron preservation for small renal masses. Our objective was to evaluate the proportions of treatment types for octogenarians with clinical stage 1 renal cell carcinoma.