The Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Small Renal Cell Carcinomas after Image-Guided Cryoablation or Radio-Frequency Ablation.

There is a lack of cheap and effective biomarkers for the prediction of renal cancer outcomes post-image-guided ablation. This is a retrospective study of patients with localised small renal cell cancer (T1a or T1b) undergoing cryoablation or radiofrequency ablation (RFA) at our institution from 2003 to 2016. A total of 203 patients were included in the analysis. In the multivariable analysis, patients with raised neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) pre-operatively, post-operatively and peri-operatively are associated with significantly worsened cancer-specific survival, overall survival and metastasis-free survival. Furthermore, an increased PLR pre-operatively is also associated with increased odds of a larger than 25% drop in renal function post-operatively. In conclusion, NLR and PLR are effective prognostic factors in predicting oncological outcomes and peri-operative outcomes; however, larger external datasets should be used to validate the findings prior to clinical application.

Long-term outcomes of image-guided ablation and laparoscopic partial nephrectomy for T1 renal cell carcinoma.

OBJECTIVE: To compare long-term outcomes and peri-operative outcomes of image-guided ablation (IGA) and laparoscopic partial nephrectomy (LPN). MATERIAL AND METHODS: This is a retrospective cohort study of localised RCC (T1a/bN0M0) patients undergoing cryoablation (CRYO), radio-frequency ablation (RFA), or LPN at our institution from 2003 to 2016. Oncological outcomes were compared using Cox regression and log-rank analysis. eGFR changes were compared using Kruskal-Wallis and Wilcoxon-rank tests. RESULTS: A total of 296 (238 T1a, 58 T1b) consecutive patients were identified; 103, 100, and 93 patients underwent CRYO, RFA, and LPN, respectively. Median follow-up time was 75, 98, and 71 months, respectively. On univariate analysis, all oncological outcomes were comparable amongst CRYO, RFA, and LPN (p > 0.05). On multivariate analysis, T1a patients undergoing RFA had improved local recurrence-free survival (LRFS) (HR 0.002, 95% CI 0.00-0.11, p = 0.003) and metastasis-free survival (HR 0.002, 95% CI 0.00-0.52, p = 0.029) compared to LPN. In T1a and T1b patients combined, both CRYO (HR 0.07, 95% CI 0.01-0.73, p = 0.026) and RFA (HR 0.04, 95% CI 0.03-0.48, p = 0.011) had improved LRFS rates. Patients undergoing CRYO and RFA had a significantly smaller median decrease in eGFR post-operatively compared to LPN (T1a: p < 0.001; T1b: p = 0.047). Limitations include retrospective design and limited statistical power. CONCLUSIONS: IGA is potentially as good as LPN in oncological durability. IGA preserves kidney function significantly better than LPN. More studies with larger sample size should be performed to establish IGA as a first-line treatment alongside LPN. KEY POINTS: • Ablative therapies are alternatives to partial nephrectomy for managing small renal cell carcinomas. • This study reports long-term outcomes of image-guided ablation versus partial nephrectomy. • Ablative therapies have comparable oncological durability and better renal function preservation compared to partial nephrectomy.

Multimodal image-guided ablation on management of renal cancer in Von-Hippel-Lindau syndrome patients from 2004 to 2021 at a specialist centre: A longitudinal observational study.

OBJECTIVES: To analyse the safety, technical feasibility, long-term renal function and oncological outcome of multimodal technologies in image-guided ablation (IGA) for renal cancer in Von-Hippel-Lindau (VHL) patients, and to evaluate factors that may influence the outcome. METHODS: Retrospective analysis of a prospective database of VHL patients who underwent IGA at a specialist centre. Patient's demographics, treatment energy, peri-operative outcome and oncological outcomes were recorded. Statistical analysis was performed to determine factors associated with complication and renal function reduction. The overall, 5 and 10-year cancer specific (CS), local recurrence-free (LRF) and metastasis-free (MF) survival rates were presented with Kaplan-Meier Curves. RESULTS: From 2004 to 2021, 17 VHL patients (age 21-68.2) with a mean (±SD) RCC size of 2.06 ± 0.92 cm received IGA. Median (IQR) RCCs per patient was 3 (2-4) over the course of follow up. Fifty-four RCCs were treated using radiofrequency ablation (n = 11), cryoablation (n = 38) and irreversible electroporation (n = 8) in 50 sessions. Primary and overall technical success rate were 94.4% (51/54) and 98% (53/54). One CD-III complication with proximal ureteric injury. Five patients in seven treatment sessions experienced a >25% reduction of eGFR immediately post-IGA. All patients have preservation of renal function at a median follow-up of 79 (51-134) months. The 5 and 10-year CS, LRF and MF survival rates are 100%, 97.8% and 100%. Whilst, the 5 and 10-year overall survival rate are100% and 90%. CONCLUSION: Multimodal IGA of de novo RCC for VHL patients is safe and has provided long term preservation of renal function and robust oncological durability.

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Iatrogenic ureteric stricture post image guided renal cryoablation in a patient with von hippel-lindau syndrome.

A 53-year-old lady is known to have Von Hippel-Lindau syndrome with a long history of previous renal cell carcinomas (RCCs) in both kidneys. She was treated by partial nephrectomy for a right peripheral RCC and subsequently image guided radiofrequency ablation (RFA) of a left central RCC. She developed another de novo RCC adjacent to the right pelvic-ureteric junction (PUJ) 4 years after the initial RFA. Due to the close proximity to the PUJ and visibility of an ice ball with cryoablation (CRYO), the consensus from the MDT was that CRYO would be safer than RFA and she subsequently underwent percutaneous image guided CRYO to treat the small de novo RCC. Unfortunately, during the 1-month imaging follow up, she developed moderate hydronephrosis and a ureteric stricture needing long-term ureteric stent management. This case highlights the risk of ureteric injury caused by the thermal effect of the ice ball during image guided renal CRYO. Therefore, it is vital that all interventional radiologists adopt various manoeuvres to protect the ureter from the ice ball during CRYO in order to avoid the development of latent ureteric stricture.

Irreversible electroporation (IRE) in renal cell carcinoma (RCC): a mid-term clinical experience.

OBJECTIVES: To evaluate the safety and efficacy of CT-guided IRE of clinical T1a (cT1a) renal tumours close to vital structures and to assess factors that may influence the technical success and early oncological durability. METHODS: CT-guided IRE (2015-2020) was prospectively evaluated. Patients' demographics, technical details/success, Clavien-Dindo (CD) classification of complications (I-V) and oncological outcome were collated. Statistical analysis was performed to determine variables associated with complications. The overall 2- and 3-year cancer-specific (CS), local recurrence-free (LRF) and metastasis-free (MF) survival rates are presented using the Kaplan-Meier curves. RESULTS: Thirty cT1a RCCs (biopsy-proven/known VHL disease) in 26 patients (age 32-81 years) were treated with IRE. The mean tumour size was 2.5 cm and the median follow-up was 37 months. The primary technical success rate was 73.3%, where 22 RCCs were completely IRE ablated. Seven residual diseases were successfully ablated with cryoablation, achieving an overall technical success rate of 97%. One patient did not have repeat treatment as he died from unexpected stroke at 4-month post-IRE. One patient had CD-III complication with a proximal ureteric injury. Five patients developed > 25% reduction of eGFR immediately post-IRE. All patients have preservation of renal function without the requirement for renal dialysis. The overall 2- and 3-year CS, LRF and MF survival rates are 89%, 96%, 91% and 87%. CONCLUSION: CT-guided IRE in cT1a RCC is safe with acceptable complications. The primary technical success rate was suboptimal due to the early operator's learning curve, and long-term follow-up is required to validate the IRE oncological durability. KEY POINTS: • Irreversible electroporation should only be considered when surgery or image-guided thermal ablation is not an option for small renal cancer. • This non-thermal technique is safe in the treatment of small renal cancer and the primary technical success rate was 73.3%. • This can be used when renal cancer is close to important structure.

Urinothorax following percutaneous image-guided renal cryoablation.

A 69-year-old lady with 2 renal cell carcinomas, one sited at the upper pole of her solitary right kidney, underwent percutaneous image-guided cryoablation and developed urinothorax as a complication. This was diagnosed from pleural fluid analysis and radiology imaging with computed tomography (CT). Management included image-guided chest drain and retrograde ureteric stent insertion to divert the urine from entering the pleural cavity. CT images demonstrated a fistula between the site of renal puncture and the pleural cavity, indicating that the cryoprobes traversed the diaphragm during the procedure. This case highlights urinothorax as an unusual complication of cryoablation of renal cell carcinoma. Prompt diagnosis by interventional radiologists is crucial to avert from this potentially life-threatening complication.

Dysregulation at multiple points of the kynurenine pathway is a ubiquitous feature of renal cancer: implications for tumour immune evasion.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO), the first step in the kynurenine pathway (KP), is upregulated in some cancers and represents an attractive therapeutic target given its role in tumour immune evasion. However, the recent failure of an IDO inhibitor in a late phase trial raises questions about this strategy. METHODS: Matched renal cell carcinoma (RCC) and normal kidney tissues were subject to proteomic profiling. Tissue immunohistochemistry and gene expression data were used to validate findings. Phenotypic effects of loss/gain of expression were examined in vitro. RESULTS: Quinolate phosphoribosyltransferase (QPRT), the final and rate-limiting enzyme in the KP, was identified as being downregulated in RCC. Loss of QPRT expression led to increased potential for anchorage-independent growth. Gene expression, mass spectrometry (clear cell and chromophobe RCC) and tissue immunohistochemistry (clear cell, papillary and chromophobe), confirmed loss or decreased expression of QPRT and showed downregulation of other KP enzymes, including kynurenine 3-monoxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO), with a concomitant maintenance or upregulation of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the NAD+ salvage pathway. CONCLUSIONS: Widespread dysregulation of the KP is common in RCC and is likely to contribute to tumour immune evasion, carrying implications for effective therapeutic targeting of this critical pathway.

The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression.

OBJECTIVE: To test the hypothesis that the baseline clinico-pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10-year median follow-up were different from those of men with stable disease (n = 1409). PATIENTS AND METHODS: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models. RESULTS: The findings showed that 34% of participants (n = 505) had intermediate- or high-risk PCa, and 66% (n = 973) had low-risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low- and intermediate-/high-risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65-69 vs 50-64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins. CONCLUSIONS: We demonstrate that one-third of the ProtecT cohort consists of people with intermediate-/high-risk disease, and the outcomes data at an average of 10 years' follow-up are generalizable beyond men with low-risk PCa.

UK Multicenter Prospective Evaluation of the Leibovich Score in Localized Renal Cell Carcinoma: Performance has Altered Over Time.

OBJECTIVE: To examine changes in outcome by the Leibovich score using contemporary and historic cohorts of patients presenting with renal cell carcinoma (RCC) PATIENTS AND METHODS: Prospective observational multicenter cohort study, recruiting patients with suspected newly diagnosed RCC. A historical cohort of patients was examined for comparison. Metastasis-free survival (MFS) formed the primary outcome measure. Model discrimination and calibration were evaluated using Cox proportional hazard regression and the Kaplan-Meier method. Overall performance of the Leibovich model was assessed by estimating explained variation. RESULTS: Seven hundred and six patients were recruited between 2011 and 2014 and RCC confirmed in 608 (86%) patients. Application of the Leibovich score to patients with localized clear cell RCC in this contemporary cohort demonstrated good model discrimination (c-index = 0.77) but suboptimal calibration, with improved MFS for intermediate- and high-risk patients (5-year MFS 85% and 50%, respectively) compared to the original Leibovich cohort (74% and 31%) and a historic (1998-2006) UK cohort (76% and 37%). The proportion of variation in outcome explained by the model is low and has declined over time (28% historic vs 22% contemporary UK cohort). CONCLUSION: Prognostic models are widely employed in patients with localized RCC to guide surveillance intensity and clinical trial selection. However, the majority of the variation in outcome remains unexplained by the Leibovich model and, over time, MFS rates among intermediate- and high-risk classified patients have altered. These findings are likely to have implications for all such models used in this setting.

MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer.

PURPOSE: Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. There are currently no biomarkers to inform management decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome after radiation therapy, but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from 2 major clinical trials. METHODS AND MATERIALS: Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom. RESULTS: Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival. CONCLUSIONS: Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods or a reassessment of how DNA-damage response relates to clinical outcomes.

Harnessing citizen science through mobile phone technology to screen for immunohistochemical biomarkers in bladder cancer.

BACKGROUND: Immunohistochemistry (IHC) is often used in personalisation of cancer treatments. Analysis of large data sets to uncover predictive biomarkers by specialists can be enormously time-consuming. Here we investigated crowdsourcing as a means of reliably analysing immunostained cancer samples to discover biomarkers predictive of cancer survival. METHODS: We crowdsourced the analysis of bladder cancer TMA core samples through the smartphone app 'Reverse the Odds'. Scores from members of the public were pooled and compared to a gold standard set scored by appropriate specialists. We also used crowdsourced scores to assess associations with disease-specific survival. RESULTS: Data were collected over 721 days, with 4,744,339 classifications performed. The average time per classification was approximately 15 s, with approximately 20,000 h total non-gaming time contributed. The correlation between crowdsourced and expert H-scores (staining intensity × proportion) varied from 0.65 to 0.92 across the markers tested, with six of 10 correlation coefficients at least 0.80. At least two markers (MRE11 and CK20) were significantly associated with survival in patients with bladder cancer, and a further three markers showed results warranting expert follow-up. CONCLUSIONS: Crowdsourcing through a smartphone app has the potential to accurately screen IHC data and greatly increase the speed of biomarker discovery.

Bacteraemia during Transurethral Resection of the Prostate: What Are the Risk Factors and Is It More Common than We Think?

The aim of this work was to investigate the microbial causes, incidence, duration, risk factors and clinical implications of bacteraemia occurring during transurethral resection of the prostate (TURP) surgery to better inform prophylaxis strategies. An ethically approved, prospective, cohort study of patients undergoing TURP was conducted. Clinical information and follow-up details were collected using standardized data collection sheets. Blood was obtained for culture at 6 different time points peri-procedure. Standard of care antibiotic prophylaxis was given prior to surgery. Bacteriuria was assessed in a pre-procedure urine sample. Histopathology from all prostate chips was assessed for inflammation and malignancy. 73 patients were consented and 276 blood samples obtained. No patients developed symptomatic bacteraemia during the procedure, 17 patients developed asymptomatic bacteraemia (23.2%). Enterococcus faecalis and Pseudomonas aeruginosa were the most common organisms cultured. 10 minutes after the start of the TURP, the odds ratio (OR) of developing bacteraemia was 5.38 (CI 0.97-29.87 p = 0.05), and 20 minutes after the start of the procedure, the OR was 6.46 (CI 1.12-37.24, p = 0.03), compared to before the procedure. We also found an association between the development of intra-operative bacteraemia and recent antibiotic use (OR 4.34, CI 1.14-16.62, p = 0.032), the presence of a urinary catheter (OR 4.92, CI 1.13-21.51, p = 0.034) and a malignant histology (OR 4.90, CI 1.30-18.46, p = 0.019). There was no statistical relationship between pre-operative urine culture results and blood culture results. This study shows that asymptomatic bacteraemia is commonly caused by TURP and occurs in spite of antibiotic prophylaxis. Our findings challenge the commonly held view that urine is the primary source of bacteraemia in TURP-associated sepsis and raise the possibility of occult prostatic infection as a cause of bacteraemia. More work will be needed to determine the significance of transient bacteraemia in relation to more serious complications like infective endocarditis and malignancy.

The accuracy of magnetic resonance imaging (MRI) in predicting the invasion of the tunica albuginea and the urethra during the primary staging of penile cancer.

OBJECTIVES: To assess the accuracy of magnetic resonance imaging (MRI) in predicting invasion of the tunica albuginea (TA) and the urethra during the primary staging of penile cancer. PATIENTS AND METHODS: In all, 104 consecutive patients with clinical T1-T3 penile cancer had a penile MRI as a part of local staging protocol. An artificial erection was induced before MRI by injecting alprostadil (prostaglandin E1 ). Four men with poor quality MRI images were excluded from the study. The preoperative MRI was compared with final histology to assess its accuracy in predicting the invasion of the TA and urethra. RESULTS: Data of 100 patients who underwent penile MRI before definitive surgery for invasive penile carcinoma were available for analysis. The mean age was 65 years and number of patients with pathological stage T1, T2 and T3 was 32, 52, and 16, respectively. The sensitivity and specificity of MRI in predicting the invasion of TA and urethra was 82.1% and 73.6%, and 62.5% and 82.1%, respectively. There were no MRI-related complications. CONCLUSIONS: This study shows that penile MRI is an accurate method for assessing TA invasion but is less sensitive in assessing urethral invasion. These results support the use of MRI in the local staging of penile cancer.

Yolk sac tumor of the seminal vesicles: A rare malignant cause of hematospermia.

Extra-gonadal yolk sac tumors (YSTs) are rare and generally associated with poor outcomes. Involvement of the seminal vesicles is extremely rare with only one previously described case. We report a case of a primary YST of the seminal vesicles and discuss the management strategy.

Gleason drift in the NIHR ProtecT study.

AIMS: There is increasing evidence of Gleason score (GS) drift in prostatic core biopsies during the last two decades. The ProtecT study is a randomized controlled study and provides an excellent cohort to study the effect of time, prostate-specific antigen (PSA) level, perineural invasion, tumour length and age on GS. METHODS AND RESULTS: The ProtecT study recruited men in the United Kingdom between 1999 and 2010. The Gleason scores were grouped into four categories ≤ 3 + 3, 3 + 4, 4 + 3 and ≥ 4 + 4 for analysis. Data from England between 2000 and 2012 were also available. A total of 3282 biopsies containing cancer were analysed. For each year of the ProtecT study, the odds of being diagnosed with a higher GS category increased by 4.9%. Higher GS was also associated with perineural invasion, increasing tumour length, age and PSA level. While biopsy GS from England was incomplete, it also showed a marked decrease in GS five and six tumours during the same period. CONCLUSION: There was GS drift from 3 + 3 to 3 + 4 with time in the ProtecT study, but there appeared to be no significant change in percentage of GS 4 + 3 or higher. This drift was less dramatic when compared to GS in the rest of England.

Post-transcriptional regulation of MRE11 expression in muscle-invasive bladder tumours.

Predictive assays are needed to help optimise treatment in muscle-invasive bladder cancer, where patients can be treated by either cystectomy or radical radiotherapy. Our finding that low tumour MRE11 expression is predictive of poor response to radiotherapy but not cystectomy was recently independently validated. Here we investigated further the mechanism underlying low MRE11 expression seen in poorly-responding patients. MRE11 RNA and protein levels were measured in 88 bladder tumour patient samples, by real-time PCR and immunohistochemistry respectively, and a panel of eight bladder cancer cell lines was screened for MRE11, RAD50 and NBS1 mRNA and protein expression. There was no correlation between bladder tumour MRE11 protein and RNA scores (Spearman's rho 0.064, p=0.65), suggesting MRE11 is controlled post-transcriptionally, a pattern confirmed in eight bladder cancer cell lines. In contrast, NBS1 and RAD50 mRNA and protein levels were correlated (p=0.01 and p=0.03, respectively), suggesting primary regulation at the level of transcription. MRE11 protein levels were correlated with NBS1 and RAD50 mRNA and protein levels, implicating MRN complex formation as an important determinant of MRE11 expression, driven by RAD50 and NBS1 expression. Our findings of the post-transcriptional nature of the control of MRE11 imply that any predictive assays used in patients need to be performed at the protein level rather than the mRNA level.

Lymphoepithelioma-like carcinoma of the renal pelvis: Pathological and therapeutic implications.

A 75-year-old woman presented with a presumed urothelial carcinoma of the right renal pelvis. A radical nephroureterectomy was carried out and histological analysis of the specimen revealed lymphoepithelioma-like carcinoma. This is the seventh reported case of this normally nasopharyngeal tumour found in the renal pelvis. These tumours have a distinct histological appearance comprising sheets of undifferentiated syncytial cells on a background of lymphoid stroma. We review the pathological features of lymphoepithelioma-like carcinoma and make arguments for managing these tumours in a similar way to urothelial carcinoma.

MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer.

Radical radiotherapy and surgery achieve similar cure rates in muscle-invasive bladder cancer, but the choice of which treatment would be most beneficial cannot currently be predicted for individual patients. The primary aim of this study was to assess whether expression of any of a panel of DNA damage signaling proteins in tumor samples taken before irradiation could be used as a predictive marker of radiotherapy response, or rather was prognostic. Protein expression of MRE11, RAD50, NBS1, ATM, and H2AX was studied by immunohistochemistry in pretreatment tumor specimens from two cohorts of bladder cancer patients (validation cohort prospectively acquired) treated with radical radiotherapy and one cohort of cystectomy patients. In the radiotherapy test cohort (n = 86), low tumor MRE11 expression was associated with worse cancer-specific survival compared with high expression [43.1% versus 68.7% 3-year cause-specific survival (CSS), P = 0.012] by Kaplan-Meier analysis. This was confirmed in the radiotherapy validation cohort (n = 93; 43.0% versus 71.2%, P = 0.020). However, in the cystectomy cohort (n = 88), MRE11 expression was not associated with cancer-specific survival, commensurate with MRE11 being a predictive marker. High MRE11 expression in the combined radiotherapy cohort had a significantly better cancer-specific survival compared with the high-expression cystectomy cohort (69.9% versus 53.8% 3-year CSS, P = 0.021). In this validated immunohistochemistry study, MRE11 protein expression was shown and confirmed as a predictive factor associated with survival following bladder cancer radiotherapy, justifying its inclusion in subsequent trial designs. MRE11 expression may ultimately allow patient selection for radiotherapy or cystectomy, thus improving overall cure rates.