Renal cell carcinoma: The role of radical surgery on different patterns of local or distant recurrence

IntroductionWith the increasing reliance on targeted therapies and immunotherapy, no standard management strategy is today available for the treatment of locally, distant, or both renal cell carcinoma (RCC) recurrences, and their surgical treatment seems to play a crucial role. We report the 20-year experience of our center evaluating the short- and long-term outcomes of patients undergone surgical resection of RCC recurrences, and the possible role of repeated surgical resections of RCC recurrences.Materials and methodsFrom January 1999 to January 2019, 40 patients underwent surgical resection of isolated locally recurrent RCC (iLR-RCC-group), locally recurrent RCC associated with the presence of distant recurrence (LR-DR-RCC-group), and distant-only recurrent RCC (DR-RCC-group). Data regarding pre-, intra-, post-operative course, and follow-up, prospectively collected in an institutional database, were retrospectively analyzed and compared.ResultsiLR-RCC-group was composed of 9 patients, LR-DR-RCC-group of 6 patients, and DR-RCC-group of 25 patients. The recurrence rate was 55.6% (5/9 patients) in iLR-RCC-group, 50% (3/6 patients) in LR-DR-RCC-group, and 44% (11/25) patients in DR-RCC-group, p = 0.830. 3/5 (60%) patients in iLR-RCC-group, 2/3 (66.7%) patients in LR-DR-RCC-group, and 7/11 (63.6%) patients in DR-RCC group underwent to almost one further local treatments of their recurrences, respectively (p = 0.981). No differences in the mean disease-free survival (p = 0.384), overall survival (OS) (p = 0.881), and cancer-specific survival (p = 0.265) were reported between the three groups. In DR-RCC-group, patients who underwent further local treatments of new recurrences presented a longer OS: 150.7 versus 66.5 months (p = 0.004).ConclusionsA surgical resection of RCC recurrences should be always taken in consideration, also in metastatic patients and/or in those who have already undergone surgery of previous RCC recurrence, whenever radicality is still possible, because this approach may offer a potentially long survival.     

Clinicopathologic Patterns of Adult Renal Tumors in Pakistan

Background: Renal cancer is a serious public health problem which may be under reported and registeredin our setup, since the Karachi cancer registry documented only 43 cases out of 4,268 incident cancer cases over3 year duration. Therefore we aimed to determine the clinicopathologic characteristics of adult renal tumors inour setup. Materials and Methods: The study was conducted in histopathology department, Liaquat NationalHospital and included total of 68 cases of adult renal tumors over 4 years. Detailed histopathologic characteristicsof tumors were analyzed. Results: Mean age of patients was 56.4 (18-84) years. Renal cell carcinoma (RCC) wasthe most common cell type (78%) cases; followed by transitional/urothelial carcinoma (12.5%), leiomyosarcoma(4.7%), oncocytoma (1.6%), squamous cell carcinoma (1.6%) and high grade pleomorphic undifferentiatedsarcoma (1.6%). Among 50 RCC cases; 62% were conventional/clear cell RCC (CCRCC) type followed bypapillary RCC(PRCC), 24%; chromophobe RCC(CRCC), 6% and sarcomatoid RCC(SRCC), 8%. Mean tumorsize for RCC was 7.2 cm. Most RCCs were intermediate to high grade (60% and 40% respectively). Capsularinvasion, renal sinus invasion, adrenal gland involvement and renal vein invasion was seen in 40%, 18%, 2% and10% of cases respectively. Conclusions: We found that RCC presents at an earlier age in our setup compared toWestern populations. Tumor size was significantly larger and most of the tumors were of intermediate to highgrade. This reflects late presentation of patients after disease progression which necessitates effective measuresto be taken in primary care setup to diagnose this disease at an early stage.     

Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis

BackgroundPapillary histology accounts for 10–15% of renal cell carcinoma (RCC), and treatment options for patients with this subtype are limited. The RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) study evaluated first-line everolimus in patients with papillary metastatic RCC (mRCC).MethodsThis phase 2 trial enrolled previously untreated patients with type 1 or type 2 papillary mRCC. Papillary histology was confirmed by central review and was performed for every patient. Patients received oral everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS) rate at 6 months among the first 44 patients of the per protocol (PP) population. Secondary end-points included PFS, tumour response, overall survival (OS), and safety.FindingsAnalysis sets included safety (N = 92; 100%), intent-to-treat (ITT) (n = 88), and PP populations (n = 46). In the safety population, most patients were men (78%) and the mean age was 60 years (range 23–84). Papillary histology was confirmed in 78% of patients (type 1, 32%; type 2, 64%; missing information, 4%). PFS rate at 6 months was 34% (80% confidence interval [CI] 25–45). In the ITT population, median PFS was 4.1 months (95% CI 3.6–5.5), 65% of patients achieved stable disease, and median OS was 21.4 months (95% CI 15.4–28.4). Among patients with type 1 or type 2 histology, median PFS was 7.9 months (95% CI 2.1–11.0) and 5.1 months (95% CI 3.3–5.5), respectively, and median OS was 28.0 months (95% CI 7.6–not estimable) and 24.2 months (95% CI 15.8–32.8), respectively. Common grade >2 adverse events were asthenia (13%), anaemia (7%), and fatigue (5%).InterpretationResults of this large prospective study in papillary mRCC demonstrated that everolimus provides some clinical benefit to this patient population and highlight the need for central pathological review of this rare tumour.     

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.     

Physical activity and renal cell cancer risk in a cohort of male smokers

Few studies have examined exercise in relation to risk of renal cell cancer. We examined the association between leisure-time and occupational physical activity and renal cell cancer in a cohort of 29,133 male smokers 50-69 years of age in the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study. Physical activity was assessed at baseline using a self-administered questionnaire that inquired about usual level of physical activity during leisure-time and at work during the past year. Cox proportional hazards modeling was used to adjust simultaneously for known or suspected risk factors for renal cell cancer. During 12 years (354,407 person-years) of follow-up, 210 incident cases of renal cell cancer were identified. In age-adjusted analysis, the RRs of renal cell cancer in increasing categories of leisure-time physical activity (light, moderate and heavy) were 1.0, 0.89 (95% CI = 0.67-1.17) and 0.38 (95% CI = 0.15-0.94), respectively (p-value for trend = 0.06). After adjustment for body mass index, energy intake, smoking, hypertension, education and fruit and vegetable intake, the multivariate RRs of renal cell cancer in increasing categories of leisure-time physical activity (light, moderate and heavy), were 1.0, 0.89 (95% CI = 0.66-1.19), and 0.46 (95% CI = 0.18-1.13) (p-value for trend = 0.12). Occupational physical activity was unrelated to renal cell cancer risk. These data suggest that recreational physical activity may play a role in the prevention of renal cell cancer in men.     

Phase 2 Trial of Capecitabine,Gemcitabine, and Bevacizumab in Sarcomatoid Renal-Cell Carcinoma

Background

Patients with sarcomatoid renal-cell carcinomas (sRCC) have poor outcomes and limited treatment options. Preclinical and clinical data suggest susceptibility to cytotoxic agents and vascular endothelial growth factor–targeted therapies. We designed a phase 2 trial to evaluate the efficacy and safety of capecitabine, gemcitabine, and bevacizumab in sRCC.

MicroRNA expression signatures of stage,grade, and progression in clear cell RCC

Clear cell RCC is the most common, and more likely to metastasize, of the three main histological types of RCC. Pathologic stage is the most important prognostic indicator and nuclear grade can predict outcome within stages of localized RCC. Epithelial tumors are thought to accumulate a series of genetic and epigenetic changes as they progress through well-defined clinical and histopathological changes. MicroRNAs (miRNAs) are involved in the regulation of mRNA expression from many human genes and miRNA expression is dysregulated in cancer. To better understand the contribution of dysregulated miRNA expression to the progression and biology of ccRCC, we examined the differences in expression levels of 723 human miRNAs through a series of analyses by stage, grade, and disease progression status in a large series of 94 ccRCC. We found a consistent signature that included significant upregulation of miR-21-5p, 142-3p, let-7g-5p, let-7i-5p and 424-5p, as well as downregulation of miR-204-5p, to be associated with ccRCC of high stage, or high grade, or progression. Discrete signatures associated with each of stage, grade, or progression were also identified. The let-7 family was significantly downregulated in ccRCC compared with normal renal parenchyma. Expression of the 6 most significantly differentially expressed miRNAs between ccRCC was verified by stem-loop qRT-PCR. Pathways predicted as targets of the most significantly dysregulated miRNAs included signaling, epithelial cancers, metabolism, and epithelial to mesenchymal transition. Our studies help to further elucidate the biology underlying the progression of ccRCC and identify miRNAs for potential translational application.     

Addressing the best treatment for non-clear cell renal cell carcinoma: A meta-analysis of randomised clinical trials comparing VEGFR-TKis versus mTORi-targeted therapies

AimNon-clear cell renal cell carcinoma (nccRCC) tumours include a heterogeneous group of malignancies that profoundly differ in terms of morphology, genetic profile, clinical behaviour and prognosis. The optimal treatment algorithm for nccRCC is still unknown and derived mainly from evidence available for ccRCC, being therefore represented by targeted agents against vascular endothelial growth factor and mammalian target of rapamycin (mTOR) pathways.We aimed to compare the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKis) and mTOR inhibitors (mTORi) for the treatment of nccRCC patients.MethodsSearching the MEDLINE/PubMed, Cochrane Library and American Society of Clinical Oncology Meeting abstracts prospective studies were identified. Data extraction was conduced according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.The measured outcomes were progression-free survival (PFS), overall survival (OS) and the overall response rate (ORR).ResultsFour randomised controlled trials were selected for final analysis, with a total of 332 patients evaluable for PFS. Treatment with TKi significantly reduced the risk of progression compared with mTORi (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.60–0.84; p < 0.0001). This difference remained significant when sunitinib was compared with everolimus in first-line setting (HR = 0.67; 95% CI, 0.56–0.80; p < 0.00001). In the 332 patients evaluable for OS, no significant difference was found between TKi and mTORi (HR = 0.86; 95% CI, 0.67–1.12; p = 0.27). In the 176 evaluable patients, TKis therapy did not improve the ORR when compared with mTORi (relative risk [RR] = 2.21; 95% CI, 0.87–5.60; p = 0.09), even if treatment with sunitinib doubled the probability of achieving a tumour response.ConclusionsTreatment with TKis significantly improves PFS, but not OS, when compared with mTORi. Moreover, sunitinib as first-line therapy reduces the risk of progression compared with everolimus; therefore, supporting the standard treatment paradigm broadly used for ccRCC patients. The relatively modest efficacy of available targeted therapies reinforces the need of future histology based, molecular driven therapeutic paradigm.     

Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma

We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (P_{meta-analysis} = 9.15 × 10⁻⁴, P_{heterogeneity} = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman''s rank r = −0.59, p = 5.61 × 10⁻⁶). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.     

CTLA-4基因多态性与肾癌易感性的相关性研究

目的探讨CTLA-4基因rs5742909、rs231775位点单核苷酸多态性与中国汉族人群肾癌易感性的关系。方法收集96例肾癌患者和96名健康对照人群的基线资料,采集研究对象5 ml外周血用于提取全血DNA,应用imLDR技术对rs5742909、rs231775位点进行基因分型,观察其基因型在病例组和对照组之间的分布差异,使用条件Logistic回归分析各基因型与肾癌发病风险的关系;根据连锁不平衡结果构建单倍型,分析各单倍型在病例组和对照组中分布频率。结果对照组中rs5742909、rs231775位点的基因型频率均符合Hardy-Weinberg平衡(P>0.05)。CTLA-4 rs5742909、rs231775位点基因型和等位基因频率在两组的分布差异均有统计学意义(P<0.05),但与患肾癌的风险关系均未达到统计学意义(P>0.05);rs5742909位点C等位基因可能与肾癌患病风险降低有关[P=0.006,OR(95%CI)为0.443(0.237~0.792)],rs231775位点A等位基因可能与肾癌患病风险增加有关[P=0.009,OR(95%CI)为1.781(1.154~2.749)]。单倍型rs5742909C-rs231775G可能是肾癌患病的保护因素[OR(95%CI)为0.556(0.360~0.858)],而rs5742909T-rs231775A或为肾癌患病的危险因素[OR(95%CI)为2.230(1.216~4.089)]。结论CTLA-4基因rs5742909、rs231775位点多态性与中国人群肾癌患病风险可能无关。     

肾细胞癌靶向治疗的临床研究进展

肾细胞癌（RCC ）是难治的恶性肿瘤之一,对放化疗不敏感,免疫治疗方式有效率一直徘徊于10% ～15% 。随着对肿瘤分子机制的深入以及多种分子靶向药物的深入研究,靶向治疗取得了重大进展。肾癌的发病机制与VHL 、Ras、PTEN等抑癌基因的突变有关,可诱导其下游的蛋白激酶受体表达异常。而蛋白激酶抑制剂可以通过干扰细胞内信号传导通路及改变肿瘤细胞微环境而影响肿瘤细胞的存活和增殖,是当前研发最集中的靶向治疗药物之一。近年来,多项靶向药物临床试验的可喜结果为转移性肾细胞癌（mRCC）治疗带来了新希望。本文就2009年NCCN 肿瘤治疗指南中介绍的舒尼替尼、索拉非尼、Temsirolimus、贝伐单抗等四种药物在肾细胞癌靶向治疗方面的临床研究最新进展展开综述。     

Genome‐wide profiling of chromosomal alterations in renal cell carcinoma using high‐density single nucleotide polymorphism arrays

The identification of genetic aberrations may help understand the mechanisms of tumorigenesis and has important implications in diagnosis, prognosis and treatment. We applied Illumina's 317K high‐density single nucleotide polymorphism (SNP) arrays to profile chromosomal aberrations in clear cell renal cell carcinoma (ccRCC) from 80 patients and analyzed the association of LOH/amplification events with clinicopathological characteristics and telomere length. The most common loss of heterozygosity (LOH) were 3p (69 cases) including 38 whole 3p arm losses, 30 large fragment LOH (spanning 3p21‐36), and 1 interstitial LOH (spanning 3p12‐14, 3p21‐22, 3p24.1‐24.2 and 3p24.3), followed by chromosome losses at 8p12‐pter, 6q23.3‐27, 14q24.1‐qter, 9q32‐qter, 10q22.3‐qter, 9p13.3‐pter, 4q28.3‐qter and 13q12.1‐21.1. We also found several smallest overlapping regions of LOH that contained tumor suppressor genes. One smallest LOH in 8p12 had a size of 0.29 Mb and only contained one gene (NRG1). The most frequent chromosome gains were at 5q (32 cases), including 10 whole 5q amplification, 21 large amplifications encompassing 5q32‐ter and 1 focal amplification in 5q35.3 (0.42 Mb). The other common chromosome gains were 1q25.1‐qter, 7q21.13‐qter, 8q24.12‐qter and whole 7p arm. Significant associations of LOH at 9p, 9q, 14q and 18q were observed with higher nuclear grade. Significant associations with tumor stage were observed for LOH at 14q, 18p and 21q. Finally, we found that tumors with LOH at 2q, 6p, 6q, 9p, 9q and 17p had significantly shorter telomere length than those without LOH. This is the first study to use Illumina's SNP–CGH array that provides a close estimate of the size and frequency of chromosome LOH and amplifications of ccRCC. The identified regions and genes may become diagnostic and prognostic biomarkers as well as potential targets of therapy. © 2009 UICC     

Nucleostemin mRNA is expressed in both normal and malignant renal tissues

Nucleostemin (NS), a p53-binding protein, has been shown essential for stem and cancer cell proliferation and implicated in oncogenesis. To explore potential contributions of NS to the development of clear cell renal cell carcinomas (ccRCCs), we determined NS expression in ccRCC cell lines, and in paired normal and malignant renal tissues from 31 patients with ccRCC. Nucleostemin mRNA and/or protein expression was observed in all four cell lines and 27 of 31 (87%) tumour specimens. Surprisingly, 16 of 31 (52%) adjacent normal renal samples also expressed NS mRNA and its levels in four of them were comparable with those in paired tumour tissues. Three of the patients had detectable NS mRNA in their normal renal tissues whereas lacked its expression in the matched tumours. Compared to the oncogene c-MYC expression in these same samples, NS expression showed a much less specificity for ccRCC. We further demonstrated that NS mRNA expression was closely associated with cellular proliferation in normal fibroblasts or T lymphocytes and renal cell carcinoma cell lines. Collectively, NS expression widely occurs in normal and malignant renal tissues, and is likely a proliferation marker rather than a unique regulator of cell proliferation and survival in stem and cancer cells.     

Simultaneous targeting of Src kinase and receptor tyrosine kinase results in synergistic inhibition of renal cell carcinoma proliferation and migration

There have been recent improvements in the treatment for metastatic renal cell carcinoma (RCC) with receptor tyrosine kinase (RTK) inhibitors being one of newer treatment options. We hypothesized that simultaneous targeting of Src kinase and the RTK may have synergistic effects to further improve therapies on metastatic RCC. The effects of Src kinase inhibitor saracatinib and multiple RTK inhibitor sunitinib on RCC cell line (ACHN) and Caki-1 were studied. Saracatinib alone or in combination with sunitinib inhibited the migration of ACHN and Caki-1 cells in vitro. Activation of migration related components FAK, P130Cas and Paxillin were blocked by saracatinib at 0.05- to 3-μM concentrations. Combined treatment resulted in improved growth inhibition, greater loss of the S phase cell population and decreased clonogenic colony formation compared to sunitinib alone in the metastatic Caki-1 line. Molecular studies in Caki-1 showed that saracatinib alone and in combination with sunitinib inhibited phosphorylation of the cell progression regulator c-Myc in a dose-dependent manner. Sunitinib alone or in combination suppressed cyclin-D1 expression with the combination showing greater dose-dependent effect. Sunitinib inhibited vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 signaling and VEGF biosynthesis. HIF1-α expression in normoxic and hypoxic conditions in Caki-1 cells was inhibited by either saracatinib or sunitinib when administered alone, however, a greater reduction occurred when these compounds were given in combination. Targeting Src kinase and RTK simultaneously with saracatinib and sunitinib resulted in 70-80% blockade of RCC cell migration, synergistic inhibition of cell growth and reduction of acquired drug resistance in Caki-1 cells. The results show promise for combination targeted therapy of RCC.     

Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells

Background:

Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth.

Methods:

We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib – a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC.

Results:

NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays.

Conclusions:

Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.     

Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma

Clear cell Renal Cell Carcinoma (ccRCC) is due to loss of von Hippel–Lindau (VHL) gene and at least one out of three chromatin regulating genes BRCA1-associated protein-1 (BAP1), Polybromo-1 (PBRM1) and Set domain-containing 2 (SETD2). More than 350, 700 and 500 mutations are known respectively for BAP1, PBRM1 and SETD2 genes. Each variation damages these genes with different severity levels. Unfortunately for most of these mutations the molecular effect is unknown, so precluding a severity classification. Moreover, the huge number of these gene mutations does not allow to perform experimental assays for each of them. By bioinformatic tools, we performed predictions of the molecular effects of all mutations lying in BAP1, PBRM1 and SETD2 genes. Our results allow to distinguish whether a mutation alters protein function directly or by splicing pattern destruction and how much severely. This classification could be useful to reveal correlation with patients’ outcome, to guide experiments, to select the variations that are worth to be included in translational/association studies, and to direct gene therapies.     

Functional polymorphisms in cell death pathway genes and risk of renal cell carcinoma

The FAS/FAS ligand (FASL) system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumorigenesis. However, the effects of functional promoter polymorphisms of the CASP8, FAS, and FASL genes on risk of renal cell carcinoma (RCC) are unknown. In this study, we genotyped CASP8 ‐652 6N ins/del, FAS ‐1377 G > A, FAS ‐670 A > G, and FASL ‐844 C > T polymorphisms in a hospital‐based case–control study of 353 patients diagnosed with RCC and 365 cancer‐free controls in a Chinese population. Compared with CASP8 ‐652 ins/ins genotype, the del/del genotype had a significantly decreased RCC risk [adjusted odds ratio (OR) = 0.36, 95% confidence interval (CI) = 0.16–0.84]. For FAS ‐1377 G > A polymorphism, a significantly increased risk of RCC was found for AA (adjusted OR = 1.65, 95% CI = 1.03–2.64) and GA (adjusted OR = 1.41, 95% CI = 1.02–1.94) genotypes compared with GG genotype. When we combined these two polymorphisms together, we found that individuals carrying CASP8 ‐652 6N ins/del and FAS ‐1377 GG genotypes or CASP8 ‐652 6N del/del and FAS ‐1377 GG genotypes were associated with a statistically significantly decreased risk of RCC (adjusted OR = 0.46, 95% CI = 0.24–0.88 and OR = 0.12, 95% CI = 0.02–0.58, respectively) compared with individuals carrying CASP8 ‐652 6N ins/ins and FAS ‐1377 AA genotypes. These results suggest that the CASP8 ‐652 6N ins/del and FAS ‐1377 G > A polymorphisms are involved in the susceptibility to developing RCC in Chinese populations. © 2010 Wiley‐Liss, Inc.     

Review and prospect of immune checkpoint blockade therapy represented by PD-1/PD-L1 in the treatment of clear cell renal cell carcinoma

As a common tumor of the urinary system, the morbidity and mortality related to renal carcinoma, are increasing annually. Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell carcinoma, accounting for approximately 75% of the total number of patients with renal cell carcinoma. Currently, the clinical treatment of ccRCC involves targeted therapy, immunotherapy, and a combination of the two. In immunotherapy, PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment. However, as treatment progresses, some patients gradually develop resistance to immunotherapy. Meanwhile, other patients experience great side effects after immunotherapy, resulting in a survival status far lower than the expected survival rate. Based on these clinical problems, many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results. We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.     

Improving the accuracy of pre-operative survival prediction in renal cell carcinoma with C-reactive protein

Background:

Validated objective biomarkers are needed for patients with renal cell carcinoma (RCC) to guide patient management and define high-risk populations for follow-up or for therapeutic purposes.

Methods:

Patients undergoing nephrectomy for RCC (n=286 all stages, 84% with conventional clear cell type) were included with a median duration follow-up of 5 years. The prognostic significance of pre-operative haematological and biochemical variables, including C-reactive protein (CRP) values were examined and whether they added additional information to a recently published pre-operative scoring system was determined.

Results:

C-reactive protein was the most significant predictor of overall survival (OS; χ²=50.9, P<0.001). Five-year OS for patients with CRP⩽15 mg l⁻¹ vs >15 mg l⁻¹ was 72% (95% CI 65–78%) and 33% (95% CI 23–44%), respectively. Similar results were seen for cancer-specific survival (CSS) and disease-free survival. On multivariate analysis, CRP remained highly significant for CSS (χ²=17.3, P<0.0001) and OS (χ²=9.8, P<0.002), in addition to other pre-operative variables including log of neutrophil/lymphocyte ratio, red blood cell count and white cell count. C-reactive protein was significant in addition to the pre-operative nomogram score (χ²=12.5, P=0.0004 for OS, χ²=16.2, P=0.0001 for CSS and χ²=8.6, P=0.003 for DFS) and was still significant when other pre-operative variables were included.

Conclusion:

C-reactive protein and other haematological and biochemical variables have independent prognostic significance in RCC and may enhance pre-operative scoring systems.