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Background: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined., Objective: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity., Design, Setting, and Participants: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10-12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and adequate organ function., Intervention: Intravenous nivolumab 8 × 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4-2 regimen) or pazopanib 800 mg once daily orally., Outcome Measurements and Statistical Analyses: The primary endpoint was overall survival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported outcomes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis., Results and Limitations: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35-79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence interval 1.36-4.89; p = 0.003). Grade ≥3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study., Conclusions: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC., Patient Summary: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyrosine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolumab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The field of immunotherapy combinations for advanced renal cell carcinoma (aRCC) has been expanded in recent years. However, the treatment response varies widely among individual patients. It is still a challenge to predict oncological outcome in clinical practice. We assessed the impact of an activated immune system reflected by changes in C-reactive protein (CRP) levels and the early onset of treatment-related adverse events (TRAEs) on the treatment response., Methods: In this retrospective analysis of 57 aRCC patients, CRP kinetics based on previous descriptions of CRP flare-response, CRP response or CRP non-response, and the TRAEs, which occurred within a month after therapy initiation, were obtained for this study. According to logistic regression analysis of both factors, we stratified the patients into risk groups: the presence of CRP flare-response/response and early onset of TRAE (low-risk group); the presence of a single factor (intermediate-risk group); and without both factors (high-risk group)., Results: Ten patients (17%) experienced primary disease progression. No progressive disease was observed in the low-risk group, while 60% (n = 6/10) of the high-risk group showed a primary disease progression. Significantly, an increased risk of disease progression was observed by patients without CRP response and TRAEs (p < 0.001)., Conclusion: The present analysis displays the predictive value of the on-treatment risk model based on CRP kinetics and the early onset of TRAEs, which can be easy to implement in clinical practice to optimize the treatment monitoring., (© 2023. The Author(s).)

Background: Nivolumab monotherapy is approved for the treatment of advanced renal cell carcinoma (aRCC) after prior therapy on the basis of results from CheckMate 025., Objective: The NORA (NivOlumab in Renal cell cArcinoma) noninterventional study (NIS) aims to capture real-world data to complement the pivotal CheckMate 025 clinical trial., Design, Setting, and Participants: NORA is a prospective, multicenter NIS in Germany. Consenting patients with aRCC of any subtype who started nivolumab after previous therapy were eligible., Outcome Measurements and Statistical Analysis: The primary objective was to estimate overall survival (OS) in the overall population and relevant subgroups. Secondary objectives included progression-free survival (PFS), the objective response rate (ORR), the duration of response (DOR), safety, and patient-reported outcomes (PROs). Baseline characteristics were summarized using descriptive statistics. OS and PFS were estimated via the Kaplan-Meier-method., Results and Limitations: A total of 228 patients with aRCC were eligible. The median age was 70 yr, 71% were male, 14% had favorable, 58% had intermediate, and 15% had poor International Metastatic RCC Database Consortium risk (12% missing information). The median follow-up was 37 mo. In the overall population, median OS was 24 mo (95% confidence interval [CI] 19-28) and median PFS was 5.3 mo (95% CI 3.9-6.7). The ORR was 20% and the median DOR was 28 mo (95% CI 16-not estimable). No new safety signals emerged (46% and 15% of patients had treatment-related adverse events of all grades and grade 3-4, respectively; there was 1 treatment-related death due to liver failure). PROs did not reveal detriments during the study duration. Limitations include the lack of central pathology review and no standardization for imaging evaluation and toxicity assessment., Conclusions: Effectiveness and safety in this real-world population were in line with the pivotal clinical trial and support the use of nivolumab after prior systemic therapy in a broad aRCC population., Patient Summary: Nivolumab is an antibody treatment approved for patients with advanced kidney cancer who have already received systemic therapy. Its approval was based on results from a clinical trial. Our study demonstrates its effectiveness and safety in "real-world" patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Sunitinib and pazopanib are both standard first-line therapies for clear-cell metastatic renal-cell carcinoma (mRCC). Everolimus is a well-established second-line treatment., Objective: To estimate the efficacy and safety of second-line everolimus following pazopanib or sunitinib., Methods: SUNPAZ was an open-label, phase 4 clinical trial of everolimus in patients with clear-cell mRCC progressing after first-line sunitinib or pazopanib. The primary end point was the number of patients without progression 6 months after starting everolimus. Secondary end points included progression-free survival (PFS), overall survival (OS), and overall response rate. Enrollment was terminated early due to slow recruitment; all analyses are descriptive., Results: Patients who received prior sunitinib (n = 16) or pazopanib (n = 13) were enrolled. One of 12 patients in the sunitinib group and 6/13 patients in the pazopanib group were progression-free by month 6 in the full analysis set. Median PFS in the sunitinib and pazopanib groups was 2.8 and 8.0 months, and median OS was 14.8 months and 20.4 months, respectively. Fifteen patients in the sunitinib group and 13 in the pazopanib group experienced adverse events., Conclusions: Safety and efficacy results confirm the second-line everolimus profile. However, baseline differences in patient populations should be taken into consideration., (© 2019 S. Karger AG, Basel.)

The incidence of renal cell carcinoma has been rising for years. At the same time there is an increasing prevalence of chronic renal failure with subsequent higher morbidity and shorter life expectancy in those affected. In the last decades the gold standard has thus shifted from radical to partial nephrectomy or tumor enucleation. A treatment alternative can be advantageous for selected patients with high morbidity and an increased risk of complications in anesthesia or surgery. Active surveillance represents a controlled delay in the initiation of treatment with a curative intention. Percutaneous radiofrequency ablation and laparoscopic cryoablation are currently the most commonly used treatment alternatives. Newer ablation procedures, such as high-intensity focused ultrasound, irreversible electroporation, microwave ablation, stereotactic ablative radiotherapy and high-dose brachytherapy have a high potential in some cases but are still considered experimental for the treatment.

Objective: To assess the efficacy of irreversible electroporation (IRE) ablation of pT1a renal cell carcinoma (RCC) in the first prospective, monocentric phase 2a pilot ablate-and-resect study (Irreversible Electroporation of Kidney Tumors Before Partial Nephrectomy [IRENE] trial). It has been postulated that focal IRE can bring about complete ablation of soft-tissue tumors with protection of healthy peritumoral tissue and anatomic structures., Patients and Methods: The first 7 study patients with biopsy-proven pT1a RCC (15-39 mm) underwent IRE. Percutaneous computed tomography-guided IRE was performed with electrocardiographic triggering under general anesthesia and deep muscle paralysis with 3-6 monopolar electrodes positioned within the renal tumor. Twenty-eight days later, the tumor region was completely resected to confirm tumor destruction pathologically. Individual results for these patients are displayed, described, and discussed., Results: Technical feasibility was attained in all patients, but electrode placement and ablation were complex, with a mean overall procedure time of 129 minutes. There were no major complications. Partial kidney resection was performed in 5 patients, and radical nephrectomy was performed in 2 patients because of central tumor location and ablation areas. Resections revealed by tumor, node, and metastasis classification of the International Union for Cancer Control 2017 no residual tumor as complete ablation in 4 cases (ypT0V0N0Pn0R0) and microscopic residual tumor cells as incomplete ablation in the other 3 cases (ypT1aV0N0Pn0R1)., Conclusion: Renal percutaneous IRE appears to be a safe treatment for pT1a RCC but requires substantial procedural effort. Resection specimens of the ablation zone revealed a high rate of microscopic incomplete ablation 4 weeks after IRE. According to these initial study results, curative, kidney-sparing ablation of T1a RCC appears possible but needs technical improvement to ensure complete ablation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Irreversible electroporation (IRE) is a new potential ablation modality for small renal masses. Animal experiments have shown preservation of the urine-collecting system (UCS). The purpose of this clinical study was to perform the first evaluation and comparison of IRE's effects on the renal UCS by using urinary cytology, magnetic-resonance imaging, and resection histology in men after IRE of pT1a renal-cell carcinoma (RCC)., Methods: Seven patients with biopsy-proven RCC pT1a cN0cM0 underwent IRE in a phase 2a pilot ablate-and-resect study (IRENE trial). A contrast-enhanced, diffusion-weighted MRI and urinary cytology was performed 1 day before and 2, 7, and 27 days after IRE. Twenty-eight days after IRE the tumour region was completely resected surgically., Results: Technical feasibility was demonstrated in all patients. In all cases, MRI revealed complete coverage of the tumour area by the ablation zone with degenerative change. The urographic late venous MRI phase (urogram scans) demonstrated normal morphological appearances. Urine cytology showed a temporary vacuolisation of the cyto- and caryoplasmas after IRE. Whereas the urothelium showed signs of regeneration 28 days after IRE-ablation, the tumour and parenchyma below it showed necrosis and permanent tissue destruction., Conclusions: Renal percutaneous IRE appears to be a safe treatment for pT1a RCC. The preservation of the UCS with unaltered normal morphology as well as urothelial regeneration and a phenomenon (new in urinary cytology) of temporary degeneration with vacuolisation of detached transitional epithelium cells were demonstrated in this clinical pilot study.

Objective: To identify the clinicopathological association of PBRM1 (Polybromo-1 gene) and VHL (von Hippel-Lindau gene) expression at mRNA and protein levels in clear cell renal cell carcinoma (ccRCC) and its role in tumor progression., Patients and Methods: Immunohistochemical analysis, Western blotting and qPCR analysis of PBRM1 and VHL were performed on fresh-frozen ccRCC and adjacent normal tissue obtained from 70 patients who underwent radical nephrectomy. In addition, a tissue microarray (TMA) from specimens of 326 ccRCC patients was used to evaluate the effect of loss of PBRM1 and VHL immunohistological expression on clinicopathological features as well as patient survival., Results: In frozen tissue, PBRM1 and VHL mRNA were significantly down-regulated in most ccRCC tumors (77.6%/80.6%). Simultaneous weak PBRM1 and VHL protein expression was observed in 21.4% of frozen tumors. In the TMA samples, weak PBRM1 and VHL immunohistochemical staining was observed in 60.4% of the cases and was correlated (P<0.001). The association of PBRM1 and VHL immunohistochemical expression with clinicopathological parameters depicts a variable picture: predominantly weak PBRM1 and VHL expression were significantly associated with higher Fuhrman grade (P = 0.012 and 0.024, respectively) but only weak VHL expression was associated with a higher pT stage (P = 0.023). PBRM1 expression did not affect the overall survival, whereas weak VHL expression was associated with decreased patient overall survival (P = 0.013)., Conclusions: Our data suggest that reduced expression of PBRM1 and VHL is correlated with an increased tumor aggressiveness. Low VHL expression was identified as a risk factor for worse patient overall survival, independently from PBRM1 expression pattern., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: If technically feasible, organ-preservation is indicated for T1 renal cell carcinoma (RCC), since partial nephrectomy (PN) is equivalent to radical nephrectomy with regard to tumor-specific survival and probably achieves better overall survival. Treatment results of a training clinic were assessed with regard to guideline adherence and treatment quality., Methods: Based on 220 open interventions in the time periods 2006-2009 (TP1) and 2010-2013 (TP2), a retrospective single center examination was performed to determine the influence of patient-age, sex, BMI, ASA-score, preoperative eGFR, PADUA-score and surgeon's experience on PN-rate and trifecta-outcome (R0 resection, warm ischemia time ≤25 min, no intraoperative complications and no blood-transfusion and postoperative complications grade ≤1 Clavien and Dindo)., Results: PN-rate increased from 36.1 % in TP1 to 72.4 % in TP2. Despite significantly higher PADUA-scores in TP2 than in TP1 (p = 0.0038), the trifecta-rate did not differ significantly (TP1 65.7 %; TP2 70.8 %; p = 0.666). Only the PADUA-score exerted an independent influence on the endpoints "organ-preservation" and "trifecta-outcome"., Conclusions: This study again demonstrated that the PADUA-score is a robust predictor of technical feasibility and treatment outcome for open PN. Consistent implementation of guidelines for nephron sparing surgery in RCC ≤7 cm is possible even in the setting of a training clinic and need not be associated with compromised treatment quality despite the increasing level of difficulty. Depending on the author, there are various definitions of trifecta-outcome. A uniform trifecta-concept would be desirable.

Primary tumor resection in patients with synchronous metastatic renal cell carcinoma and a good performance status corresponds to a guideline recommendation which, however, is based on weak data from the era of cytokine therapy. This article presents arguments that weigh heavily against cytoreductive nephrectomy. From a molecular genetic viewpoint, the intervention eliminates only the easiest adversary but cannot prevent cancer-related death. Therefore, benefits and risks must be carefully and critically considered. Cytoreductive nephrectomy is not beneficial if treatment-induced morbidity will substantially affect the patient's quality of life and/or life expectancy or if the size and topography of the primary tumor renders it less dangerous than the metastases.

Purpose: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC)., Methods: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing., Results: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited., Conclusions: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy., Competing Interests: AH: consultancies, honoraria or study participation from Pierre Fabre, BMS, GSK and Novartis. JB: consultancies, honoraria or study participation from Bayer, BMS, GSK, Immatics, Novartis, Pfizer and Roche. EH: consultancies, honoraria or study participation from Bayer, BMS, GSK, Novartis and Pfizer. JJ: Consultancies and honoraria of study participation from: Roche, Pfizer, GSK, Bayer, Lilly, Janssen-Cilag, Amgen, Celgene, Sanofi, Pharma Mar, Puma, Teva, Merck Sereno, Novartis. MS: consultancies, honoraria or study participation from Bayer, BMS, Novartis and Roche. SH: consultancies, honoraria from Novartis. SS: consultancies, honoraria or study participation from Amgen, Janssen-Cilag, Celgene, Novartis und MSD Sharp & Dohme. TG: consultancies or honoraria: Bayer, BMS, GSK, Novartis, Roche. VG: consultancies, honoraria or travel support: Bayer, BMS; Novartis, Pfizer.

Background: The rising incidence of renal cell carcinoma, its more frequent early detection (stage T1a) and the increasing prevalence of chronic renal failure with higher morbidity and shorter life expectancy underscore the need for multimodal focal nephron-sparing therapy., Discussion: During the past decade, the gold standard shifted from radical to partial nephrectomy. Depending on the surgeon's experience, the patient's constitution and the tumor's location, the intervention can be performed laparoscopically with the corresponding advantages of lower invasiveness. A treatment alternative can be advantageous for selected patients with high morbidity and/or an increased risk of complications associated with anesthesia or surgery. Corresponding risk stratification necessitates previous confirmation of the small renal mass (cT1a) by histological examination of biopsy samples. Active surveillance represents a controlled delay in the initiation of treatment., Results: Percutaneous radiofrequency ablation (RFA) and laparoscopic cryoablation are currently the most common treatment alternatives, although there are limitations particularly for renal tumors located centrally near the hilum. More recent ablation procedures such as high intensity focused ultrasound (HIFU), irreversible electroporation, microwave ablation, percutaneous stereotactic ablative radiotherapy and high-dose brachytherapy have high potential in some cases but are currently regarded as experimental for the treatment of renal cell carcinoma.

Introduction: It is postulated that focal IRE affords complete ablation of soft-tissue tumours while protecting the healthy peritumoral tissue. Therefore, IRE may be an interesting option for minimally invasive, kidney-tissue-sparing, non-thermal ablation of renal tumours., Aim: With this current pilot study ("IRENE trial"), we present the first detailed histopathological data of IRE of human RCC followed by delayed tumour resection. The aim of this interim analysis of the first three patients was to investigate the ablation efficiency of percutaneous image-guided focal IRE in RCC, to assess whether a complete ablation of T1a RCC and tissue preservation with the NanoKnife system is possible and to decide whether the ablation parameters need to be altered., Methods: Following resection 4 weeks after percutaneous IRE, the success of ablation and detailed histopathological description were used to check the ablation parameters., Results: The IRE led to a high degree of damage to the renal tumours (1 central, 2 peripheral; size range 15-17 mm). The postulated homogeneous, isomorphic damage was only partly confirmed. We found a zonal structuring of the ablation zone, negative margins and, enclosed within the ablation zone, very small tumour residues of unclear malignancy., Conclusion: According to these initial, preliminary study results of the first three renal cases, a new zonal distribution of IRE damage was described and the curative intended, renal saving focal ablation of localised RCC below <3 cm by percutaneous IRE by the NanoKnife system appears to be possible, but needs further, systematic evaluation for this treatment method and treatment protocol.

Introduction: Focal ablation therapy is playing an increasing role in oncology and may reduce the toxicity of current surgical treatments while achieving adequate oncological benefit. Irreversible electroporation (IRE) has been proposed to be tissue-selective with potential advantages compared with current thermal-ablation technologies or radiotherapy. The aim of this pilot trial is to determine the effectiveness and feasibility of focal percutaneous IRE in patients with localised renal cell cancer as a uro-oncological tumour model., Methods: Prospective, monocentric Phase 2a pilot study following current recommendations, including those of the International Working Group on Image-Guided Tumor Ablation. Twenty patients with kidney tumour (T1aN0M0) will be recruited. This sample permits an appropriate evaluation of the feasibility and effectiveness of image-guided percutaneous IRE ablation of locally confined kidney tumours as well as functional outcomes. Percutaneous biopsy for histopathology will be performed before IRE, with magnetic-resonance imaging one day before and 2, 7, 27 and 112 days after IRE; at 28 days after IRE the tumour region will be completely resected and analysed by ultra-thin-layer histology., Discussion: The IRENE study will investigate over a short-term observation period (by magnetic-resonance imaging, post-resection histology and assessment of technical feasibility) whether focal IRE, as a new ablation procedure for soft tissue, is feasible as a percutaneous, tissue-sparing method for complete ablation and cure of localised kidney tumours. Results from the kidney-tumour model can provide guidance for designing an effectiveness and feasibility trial to assess this new ablative technology, particularly in uro-oncology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Metabolic adaptations, such as increases in glucose and energy metabolism, play a pivotal role in the biology of RCC. PDK-1 and DJ-1/PARK7 are thought to control metabolic pathways in cancer. We investigated the expression of PDK-1 and DJ-1/PARK7 in RCC and their prognostic relevance., Methods: RCC tumor tissue and corresponding normal parenchyma samples were obtained from 91 patients with clear cell RCC. Expression of PDK-1 and DJ-1/PARK7 was determined on the mRNA and protein levels using quantitative RT-PCR and immunohistochemistry. Expression ratios tumor/normal were analyzed for associations with pathological stage and grade (Kruskal-Wallis ANOVA, chi-square test). Potential associations with progression-free and overall survival were analyzed using Cox regression models., Results: PDK-1 mRNA expression was up-regulated as compared to normal tissue (p < 0.001). Differences were observed by tumor stage (p < 0.05) with a trend toward lower expression with increasing stage (p > 0.01). Expression ratio tumor/normal also showed differences by tumor stage with the lowest ratio observed in advanced (pT3) disease. MRNA expression data were confirmed on the protein level with the lowest protein expression in pT3 tumors. PDK-1 expression ratio tumor/normal was inversely associated with outcome after adjustment for stage and grade (HR, 0.54; 95 % CI, 0.31-0.94). No associations observed for DJ-1/PARK7 expression., Conclusions: PDK is up-regulated in RCC, but down-regulation may be associated with progression toward a metastasizing behavior. Given the role of PDK-1 in the control of glucose metabolism, aerobic glycolysis via up-regulation of PDK-1 may be an early event in RCC development, but less relevant for the progression toward an aggressive phenotype.

Background: Local ablation techniques are a major focus of current developments in oncology. The primary aim is to retain organs and preserve organ functions without compromising the oncological outcome., Method: Irreversible electroporation (IRE) is a novel ablation technique that involves the application of high-voltage pulses to induce cell apoptosis without causing thermal damage to the target tissue or adjacent structures., Aim: First published in 2005 IRE is currently undergoing preclinical and clinical trials in several areas of oncology and the initial results have been promising. The IRE technique could be a significant development in ablation treatment for renal cell carcinoma (RCC) but decisive proof of its effectiveness for local RCC has not yet been provided. This study presents the results of preclinical and initial clinical trials which are discussed and compared with those of other ablation techniques in order to demonstrate the current value of IRE.

Background/aims: Altered expression of the Bcl-2 family member Mcl-1 has been linked to the progression and outcome of various malignancies, but its expression and potential prognostic value has yet not been investigated in clear-cell renal cell carcinomas (ccRCC)., Methods: In this study, dual-colour real-time RT-PCR was used to quantify the expression of Mcl-1 splicing variants in malignant and paired normal renal tissue samples, obtained from 93 ccRCC patients (median follow-up: 45 months) undergoing radical nephrectomy., Results: Over-expression of the anti-apoptotic Mcl-1L variant in ccRCC occurred in nearly 60% of the paired samples (p = 0.004). Decreased expression, however, was related to poor tumour differentiation (p = 0.013) and independently predicted a higher risk for relapse (hazard rate 3.99; 95% CI 1.32-12.04; p = 0.014). Kaplan-Meier analyses revealed down-regulation of Mcl-1L in ccRCC to be associated with a markedly shortened recurrence-free and disease-specific survival, particularly in patients with locally advanced (p < 0.001 and p = 0.003) and poorly differentiated tumours (p = 0.004 and p = 0.011)., Conclusion: These findings suggest Mcl-1L to provide a molecular parameter for outcome prediction in ccRCC patients, down-regulation indicating exceptionally aggressive tumour phenotypes., (Copyright 2009 S. Karger AG, Basel.)

Purpose: Numerous molecular parameters are thought to be implicated in renal cell carcinoma (RCC) tumor biology and may therefore reflect the malignant potential of individual tumors. Their investigation may thus help to improve the postoperative management of RCC patients. This study characterized the mRNA expression levels and evaluated the prognostic effect of the mitochondrial inhibitor of apoptosis antagonists Smac/DIABLO and Omi/HtrA2 in tumor tissue from clear-cell RCC patients., Methods: The relative gene expression (RGE) was analyzed by real-time RT-PCR in tumor tissue obtained from 85 patients (median follow-up: 47 months) following surgical treatment. Expression data was correlated to clinico-pathological variables and outcome., Results: The RGE of Smac/DIABLO was lowest in patients with primary metastases, intermediate in those who progressed to metastatic disease, and highest in those who did not develop metastases during follow-up (P=0.006). Expression levels of Smac/DIABLO and Omi/HtrA2 were strongly correlated with each other (Pearson coefficient 0.90). Recurrence-free and tumor-specific survival was shorter in patients with low Smac/DIABLO levels (P=0.019 and P=0.001) as well as in those with low Omi/HtrA2 tumor expression (P=0.033 and P=0.032). Contrary to Omi/HtrA2, low Smac/DIABLO levels were still predictive of a reduced time to recurrence (hazard rate 5.31; 95% CI: 1.16-24.21) and tumor-specific survival (hazard rate 4.24; 95% CI: 1.22-14.77) in explorative multivariate analysis., Conclusions: The mRNA expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 are strongly inter-correlated, but do not relate to tumor stage or grade of RCC. Our data suggest that expression of Smac/DIABLO, but not Omi/HtrA2, is inversely associated with outcome of RCC patients.

Purpose: We determined the relation between promoter methylation and mRNA expression of the p53 target genes APAF-1 and DAPK-1 in 55 consecutive tumor and corresponding normal tissue samples., Materials and Methods: Tissue was taken from nonmetastatic clear cell renal cell carcinoma at a median followup of 75 months. Quantitative methylation specific real-time polymerase chain reaction and quantitative real-time reverse transcriptase-polymerase chain reaction were used., Results: The mRNA expression levels of APAF-1 and DAPK-1 were significantly higher in tumor vs nontumor tissue from the same kidney (p = 0.003 and 0.0001, respectively). Expression levels of the 2 genes did not correlate with tumor stage but they were significantly lower in high grade (G3) tumors (p = 0.018 and 0.05, respectively). In patients with positive lymph node staging mRNA expression of APAF-1 and DAPK-1 was significantly lower. On matched pair analysis of tumor tissue the methylation level of the APAF-1 gene correlated inversely with the mRNA expression level (p = 0.02). In tumor and normal kidney tissue from patients with lesions 4 cm or greater mRNA expression levels of DAPK-1 were significantly lower in those who later had metastatic disease (p = 0.04 and 0.02, respectively)., Conclusions: These data demonstrate decreased tumor suppressor gene expression in more aggressive subtypes of clear cell renal cell carcinoma. The lower mRNA level of the DAPK-1 gene in tumor and normal tissue from patients with an unfavorable clinical outcome suggests the organ specific loss of tumor suppressor gene expression, predisposing to metastatic tumor disease and shorter overall survival.

Transcriptional downregulation of the putative tumor suppressor gene XIAP-associated Factor 1 (XAF1) by promoter methylation has been shown to relate to tumor progression of gastric and bladder cancer. This study determined the mRNA expression levels and the methylation status of XAF1 by real-time RT-PCR and quantitative methylation specific PCR in tumor tissue obtained from 91 renal cell carcinoma (RCC) patients (median follow-up 50.5 months) following surgical treatment. Expression data was correlated to histopathological variables and outcome. XAF1 expression levels were not related to standard pathological parameters for outcome prediction but results from crude and explorative multivariable-adjusted analyses revealed low XAF1 levels to significantly increase the relative risk (RR) for tumor recurrence (RR 4.6; CI 95%: 1.4-14.6) and tumor-related death (RR 3.6; CI 95%: 1.4-9.7). The association of low XAF1 expression with an abbreviated recurrence-free (p=0.009) and disease-specific survival (p=0.005) was most pronounced in patients with locally advanced (pT3) tumors. XAF1 promoter methylation was rarely detected (10%) but, if present, XAF1 mRNA expression levels correlated inversely to the normalized index of methylation (p=0.01). Our findings suggest that low XAF1 mRNA expression levels relate to an unfavorable clinical course in RCC patients. Promoter methylation may be one, but probably not the essential mechanism for transcriptional downregulation of the XAF1 gene in RCC.

The expression of the inhibitor of apoptosis (IAP) family members cIAP1 and cIAP2 have been shown to be altered in various cancer entities. This study was done to characterize the tumor-related expression profile of cIAP1 and cIAP2 in patients with renal cell carcinomas (RCC) and to evaluate its potential predictive value after curative resection. Expression of cIAP1 and cIAP2 was analyzed by real-time RT-PCR in RCC and corresponding normal tissue samples obtained from a cohort of 127 RCC patients (median follow-up: 48 months) undergoing surgical treatment. Expression data was correlated to histopathological variables and outcome. Overexpression of cIAP1 and cIAP2 occurred in most RCC specimens (p < 0.001), but 20% of the patients had lower cIAP levels in malignant than in normal tissue. The cIAP1 expression correlated with the tumor stage, levels being higher in pT1 tumors than in advanced pathological stages (p = 0.002). Decreased cIAP1 expression in RCC relative to paired normal samples predicted an abbreviated time to recurrence (hazard rate 2.96; 95% CI: 1.23-7.09) and tumor-specific survival (hazard rate 2.78; 95% CI: 1.22-6.38) irrespective of the tumor stage and grade. The prognostic effect of cIAP1 was most pronounced in patients with pT3 disease (log rank test p = 0.001). The results of uni- and multivariate analysis suggest a prognostic value of cIAP1 expression for RCC patients, downregulation indicating an aggressive, potentially lethal phenotype., (Copyright 2006 Wiley-Liss, Inc.)

Livin has recently been identified as a member of the inhibitor of apoptosis family expressed in several types of cancer but not in most benign tissues. Expression levels of livin were associated with prognosis in various malignancies, but livin expression and its prognostic relevance have not been evaluated in renal cell carcinomas (RCC). In a cohort of 152 RCC patients, we analyzed the relative expression of livin and its splicing variants by real-time RT-PCR and Western blot in tumor and adjacent normal renal tissue specimens. Livin expression was detected in 59 (38.8%) of 152 RCC specimens but in none of the normal samples. Both splicing variants were present in the livin-positive RCC specimens. Livin expression levels did not correlate with pathological or clinical parameters and were not predictive of patient outcome. Our findings suggest that livin expression in RCC is not of prognostic relevance. Further studies to clarify the role of livin expression in RCC and its potential value as a target for immune-mediated tumor destruction are warranted., (Copyright 2007 S. Karger AG, Basel.)

Purpose: Risk stratification of renal cell carcinoma is based on the histopathologic classification. Promoter hypermethylation as a mechanism of gene inactivation in renal cell carcinoma has been shown for only a small number of genes. We examined the usefulness of quantitative methylation analysis with a new set of p53 target genes for determining the clinical outcome and aggressiveness of the tumor disease., Experimental Design: The genes selected were APAF-1, CASPASE-8, DAPK-1, IGFBP-3, and PML. The tissue samples analyzed were taken from tumor specimens obtained from 90 consecutive patients with clear cell renal carcinoma and from 20 normal kidney specimens. Quantitative methylation analysis of CpG sites in the promoter region was done by methylation-specific real-time PCR and the normalized index of methylation (NIM) was determined for each sample., Results: Hypermethylation of the promoter region was common for APAF-1 (97%) and DAPK-1 (41%) but not for IGFBP-3 (3%), PML (3%), or CASP-8 (0%). The tumor patients had a median follow-up of 55 months. A correlation was found between the methylation level of APAF-1 and tumor size and nodal status, but not for tumor stage, grade, and age of patient. Kaplan-Meier analysis was able to identify patients with a higher risk of recurrence and tumor-related death by using APAF-1 (>or=56% NIM) and DAPK-1 (>or=10% NIM) methylation levels. In multivariate analysis, APAF-1 and DAPK-1 methylation levels were independent prognostic markers for metastatic disease and death from renal cell carcinoma., Conclusions: Our findings indicate that promoter hypermethylation of APAF-1 and DAPK-1 is a marker of aggressive renal cell carcinoma and provides independent prognostic information on disease outcome.