Validation of a 2-gene mRNA urine test for the detection of ≥GG2 prostate cancer in an opportunistic screening population.

BACKGROUND: A 2-gene urine-based molecular test that targets messenger RNAs known to be overexpressed in aggressive prostate cancer (PCa) has been described as a helpful method for detecting clinically significant prostate cancer (grade group [GG] ≥2). We performed an external validation of this test in men undergoing initial prostate biopsy (Bx) within a Spanish opportunistic screening scenario. METHODS: We analyzed archived samples from 492 men who underwent prostate Bx in an opportunistic screening scenario, with prostate-specific antigen (PSA) 3 to 10 ng/mL and/or suspicious digital rectal exploration (DRE) and without previous multi-parametric magnetic resonance imaging (mpMRI). Urinary biomarker measurements were combined with clinical risk factors to determine a risk score, and accuracy for GG ≥ 2 PCa detection was compared with PCA3, European randomized screening in prostate cancer (ERSPC), and prostate biopsy collaborative group (PBCG) risk calculators in a validation workup that included calibration, discrimination, and clinical utility analysis. RESULTS: In our cohort, the detection rates for GG1 and GG ≥ 2 PCa were 20.3% and 14.0%, respectively. The median PSA level was 3.9 ng/mL and 13.4% of subjects had suspicious DRE findings. The median risk score for men with GG ≥ 2 PCa was 21 (interquartile range: 14-28), significantly higher than benign+GG1 PCa (10, 6-18), P < .001, achieving the highest area under the curve among the models tested, 0.749 (95% confidence interval: 0.690-0.807). The urine test was well-calibrated, while ERSPC showed a slight underestimation and PBCG a slight overestimation of risk. Assuming a GG2 non-detection rate of 11% without using mpMRI, use of the urinary biomarker-based clinical model could have helped avoid 37.2% of excess biopsies while delaying the diagnosis of eight patients (1.6% of the entire cohort) with GG ≥ 2 PCa. CONCLUSIONS: In this first evaluation in an opportunistic screening population, the urinary biomarker-based test improved the detection of clinically significant PCa. Facing men with elevated PSA and/or suspicious DRE, it could be a useful tool to help avoid excess initial Bx and to identify patients most likely to benefit from Bx.

Insulin-like growth factor 1 receptor affects the survival of primary prostate cancer patients depending on TMPRSS2-ERG status.

BACKGROUND: Prostate cancer (PCa) is characterized by clinical and biological heterogeneity and has differential outcomes and mortality rates. Therefore, it is necessary to identify molecular alterations to define new therapeutic strategies based on the risk of progression. In this study, the prognostic relevance of the insulin-like growth factor (IGF) system was examined in molecular subtypes defined by TMPRSS2-ERG (T2E) gene fusion within a series of patients with primary localized PCa. METHODS: A cohort of 270 formalin-fixed and paraffin-embedded (FFPE) primary PCa samples from patients with more than 5 years' follow-up was collected. IGF-1R, IGF-1, IGFBP-3 and INSR expression was analyzed using quantitative RT-PCR. The T2E status and immunohistochemical ERG findings were considered in the analyses. The association with both biochemical and clinical progression-free survival (BPFS and PFS, respectively) was evaluated for the different molecular subtypes using the Kaplan-Meier proportional risk log-rank test and the Cox proportional hazards model. RESULTS: An association between IGF-1R overexpression and better BPFS was found in T2E-negative patients (35.3% BPFS, p-value = 0.016). Multivariate analysis demonstrated that IGF-1R expression constitutes an independent variable in T2E-negative patients [HR: 0.41. CI 95% (0.2-0.82), p = 0.013]. These data were confirmed using immunohistochemistry of ERG as subrogate of T2E. High IGF-1 expression correlated with prolonged BPFS and PFS independent of the T2E status. CONCLUSIONS: IGF-1R, a reported target of T2E, constitutes an independent factor for good prognosis in T2E-negative PCa. Quantitative evaluation of IGF-1/IGF-1R expression combined with molecular assessment of T2E status or ERG protein expression represents a useful marker for tumor progression in localized PCa.

Optimizing the clinical utility of PCA3 to diagnose prostate cancer in initial prostate biopsy.

BACKGROUND: PCA3 has been included in a nomogram outperforming previous clinical models for the prediction of any prostate cancer (PCa) and high grade PCa (HGPCa) at the initial prostate biopsy (IBx). Our objective is to validate such IBx-specific PCA3-based nomogram. We also aim to optimize the use of this nomogram in clinical practice through the definition of risk groups. METHODS: Independent external validation. Clinical and biopsy data from a contemporary cohort of 401 men with the same inclusion criteria to those used to build up the reference's nomogram in IBx. The predictive value of the nomogram was assessed by means of calibration curves and discrimination ability through the area under the curve (AUC). Clinical utility of the nomogram was analyzed by choosing thresholds points that minimize the overlapping between probability density functions (PDF) in PCa and no PCa and HGPCa and no HGPCa groups, and net benefit was assessed by decision curves. RESULTS: We detect 28% of PCa and 11 % of HGPCa in IBx, contrasting to the 46 and 20% at the reference series. Due to this, there is an overestimation of the nomogram probabilities shown in the calibration curve for PCa. The AUC values are 0.736 for PCa (C.I.95%:0.68-0.79) and 0.786 for HGPCa (C.I.95%:0.71-0.87) showing an adequate discrimination ability. PDF show differences in the distributions of nomogram probabilities in PCa and not PCa patient groups. A minimization of the overlapping between these curves confirms the threshold probability of harboring PCa >30 % proposed by Hansen is useful to indicate a IBx, but a cut-off > 40% could be better in series of opportunistic screening like ours. Similar results appear in HGPCa analysis. The decision curve also shows a net benefit of 6.31% for the threshold probability of 40%. CONCLUSIONS: PCA3 is an useful tool to select patients for IBx. Patients with a calculated probability of having PCa over 40% should be counseled to undergo an IBx if opportunistic screening is required.

Identification of miR-187 and miR-182 as biomarkers of early diagnosis and prognosis in patients with prostate cancer treated with radical prostatectomy.

PURPOSE: miRNAs are noncoding RNAs that negatively regulate target mRNA gene expression. Aberrant miRNA expression is associated with prostate cancer pathogenesis. We identified miRNAs as potential biomarkers for prostate cancer diagnosis and prognosis. MATERIALS AND METHODS: Total RNA was obtained from 10 normal prostate and 50 prostate cancer samples, and analyzed using the GeneChip® miRNA 2.0 Array. At a median followup of 92 months (range 2 to 189) an independent cohort of 273 paraffin embedded prostate cancer samples was used for validation by quantitative reverse transcriptase-polymerase chain reaction. Another 92 urine samples from patients undergoing prostate biopsy were evaluated for these miRNAs. RESULTS: miR-182 and 187, the miRNAs most differentially expressed between normal and tumor tissue, were selected for further validation. miR-187 inversely correlated with cT (p = 0.125) and pT (p = 0.0002) stages, Gleason score (p = 0.003) and TMPRSS2-ERG status (p = 0.003). The log rank test showed associations of miR-182 with biochemical (p = 0.026) and clinical (p = 0.043) progression-free survival, as also noted on multivariate analysis. A significant independent improvement in the definition of risk of progression was achieved by combining miR-182 expression with Gleason score (p <0.0001). miR-187 detection in urine provided an independent predictive value for positive biopsy. A prediction model including serum prostate specific antigen, urine PCA3 and miR-187 provided 88.6% sensitivity and 50% specificity (AUC 0.711, p = 0.001). CONCLUSIONS: Results show that miR-182 and 187 are promising biomarkers for prostate cancer prognosis to identify patients at risk for progression and for diagnosis to improve the predictive capability of existing biomarkers.

Implementing the use of nomograms by choosing threshold points in predictive models: 2012 updated Partin Tables vs a European predictive nomogram for organ-confined disease in prostate cancer.

OBJECTIVES: To implement the use of nomograms in clinical practice showing how to choose thresholds in nomograms' predictions to select risk groups. To validate and compare the predictive ability and clinical utility of the Hospital Universitario 'Miguel Servet' (HUMS) and the updated Partin Tables 2012 (PT-2012) nomograms to predict organ-confined disease (OCD) after radical prostatectomy (RP). PATIENTS AND METHODS: Cohort of 1285 patients with prostate cancer treated with RP at Instituto Valenciano de Oncología (IVO) between 1986 and 2011. The predictive value of the nomograms was assessed by means of calibration curves, discrimination ability (area under the receiver operating characteristic (ROC) curve (AUC) and probability density functions). The clinical utility was evaluated through Vickers' decision curves and thresholds were chosen through probability density functions. RESULTS: The calibration curves showed a minimal underestimation in low probabilities (<20%), a minimal overestimation in high probabilities (>50%) in the HUMS nomogram and a regular minimal overestimation in the PT-2012. Their AUC of 0.7285 (95% confidence interval [CI] 0.7010-0.7559) and 0.7288 (95%CI 0.7013-0.7562) respectively, show an adequate discrimination ability for both predictive models in the IVO cohort. The decision curves show similar net benefits for both models. In this study we advocate for a threshold of 53% for the identification of OCD. CONCLUSIONS: The HUMS-nomogram and the PT-2012 predictions of OCD confirm their utility in a contemporary cohort of patients. Patients with a probability of OCD >53% should be classified as OCD, helping physicians to better counsel their patients. A selection of adequate thresholds, as presented in this paper, makes nomograms more accessible tools.

[New biomarkers to optimize the selection and follow up of patients with prostate cancer on active surveillance]. / Nuevos biomarcadroes para optimizar selección y seguimiento de pacientes con cáncer de prostata en vigilancia activa.

Identification of biomarkers that, at the time of diagnosis of prostate cancer (PCa), are associated with presence of disease or a more aggressive behavior will transform the clinical management of this disease. If both patients and clinicians would have reproducible and valid tools to estimate the specific risk of morbidity associated with PCa, then many patients would opt to and join active surveillance (AS) protocols, and consequently costs and comorbidities associated with the current overtreatment of prostate cancer would be reduced. Thus, a biomarker, or a panel of biomarkers, with high specificity to identify patients at risk for progression in AS protocols, would identify those men who could benefit from less intensive AS protocols with less repeated biopsies, so reducing the risk and cost of these invasive procedures. In this review we try to offer an overview of the new markers identified by genomic techniques and to discuss their potential role in an AS context. Moreover, the AS protocol offers an adequate setting for validation of biomarkers associated to disease progression.

Second TURB, restaging TURB or repeat TURB in primary T1 non-muscle invasive bladder cancer: impact on prognosis?

PURPOSE: A re-transurethral resection of the bladder (re-TURB) is a well-established approach in managing non-muscle invasive bladder cancer (NMIBC) for various reasons: repeat-TURB is recommended for a macroscopically incomplete initial resection, restaging-TURB is required if the first resection was macroscopically complete but contained no detrusor muscle (DM) and second-TURB is advised for all completely resected T1-tumors with DM in the resection specimen. This study assessed the long-term outcomes after repeat-, second-, and restaging-TURB in T1-NMIBC patients. METHODS: Individual patient data with tumor characteristics of 1660 primary T1-patients (muscle-invasion at re-TURB omitted) diagnosed from 1990 to 2018 in 17 hospitals were analyzed. Time to recurrence, progression, death due to bladder cancer (BC), and all causes (OS) were visualized with cumulative incidence functions and analyzed by log-rank tests and multivariable Cox-regression models stratified by institution. RESULTS: Median follow-up was 45.3 (IQR 22.7-81.1) months. There were no differences in time to recurrence, progression, or OS between patients undergoing restaging (135 patients), second (644 patients), or repeat-TURB (84 patients), nor between patients who did or who did not undergo second or restaging-TURB. However, patients who underwent repeat-TURB had a shorter time to BC death compared to those who had second- or restaging-TURB (multivariable HR 3.58, P = 0.004). CONCLUSION: Prognosis did not significantly differ between patients who underwent restaging- or second-TURB. However, a worse prognosis in terms of death due to bladder cancer was found in patients who underwent repeat-TURB compared to second-TURB and restaging-TURB, highlighting the importance of separately evaluating different indications for re-TURB.

Each Cellular Compartment Has a Characteristic Protein Reactive Cysteine Ratio Determining Its Sensitivity to Oxidation.

Signaling and detoxification of Reactive Oxygen Species (ROS) are important patho-physiologcal processes. Despite this, we lack comprehensive information on individual cells and cellular structures and functions affected by ROS, which is essential to build quantitative models of the effects of ROS. The thiol groups from cysteines (Cys) in proteins play a major role in redox defense, signaling, and protein function. In this study, we show that the proteins in each subcellular compartment contain a characteristic Cys amount. Using a fluorescent assay for -SH in thiolate form and amino groups in proteins, we show that the thiolate content correlates with ROS sensitivity and signaling properties of each compartment. The highest absolute thiolate concentration was found in the nucleolus, followed by the nucleoplasm and cytoplasm whereas protein thiolate groups per protein showed an inverse pattern. In the nucleoplasm, protein reactive thiols concentrated in SC35 speckles, SMN, and the IBODY that accumulated oxidized RNA. Our findings have important functional consequences, and explain differential sensitivity to ROS.

Phase II Trial Evaluating Olaparib Maintenance in Patients with Metastatic Castration-Resistant Prostate Cancer Responsive or Stabilized on Docetaxel Treatment: SOGUG-IMANOL Study.

The SOGUG-IMANOL trial was a phase 2, uncontrolled, Spanish multicenter study to assess the effect of maintenance treatment with olaparib on radiographic progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who achieved partial or complete response or disease stabilization on docetaxel treatment and had a documented germline/somatic mutation in any of the homologous recombination repair (HRR) genes. Patients received olaparib 300 mg orally twice daily. From the screened population (n = 134), 26 (19.4%) somatic mutations were found, and 14 patients were included in the study. The median radiographic PFS was 11.1 (95%CI, 5.7 to 16.5) months. The median PSA-PFS was 3.5 (95%CI, 1.0 to 6.0) months, and the median clinical PFS was 14.7 (95%CI, 1.8 to 27.5 months). Clinical benefit was observed in 12 patients (85.7%, 95%CI 67.4% to 100%), including two patients with partial response and 10 with stable disease. Six patients reported grade 3-5 adverse events: asthenia (n = 3), anemia (n = 2) and neutropenia (n = 1). In this setting, olaparib has been shown to be an efficacious maintenance treatment in terms of radiographic PFS and clinical benefit, becoming a therapeutic option for some patients harboring an HRR gene mutation and in scenarios where further investigation is needed.

Impact of concurrent tumour events on the prostate cancer outcomes of germline BRCA2 mutation carriers.

BACKGROUND: Several studies have reported the association of germline BRCA2 (gBRCA2) mutations with poor clinical outcomes in prostate cancer (PCa), but the impact of concurrent somatic events on gBRCA2 carriers survival and disease progression is unknown. PATIENTS AND METHODS: To ascertain the role of frequent somatic genomic alterations and histology subtypes in the outcomes of gBRCA2 mutation carriers and non-carriers, we correlated the tumour characteristics and clinical outcomes of 73 gBRCA2 and 127 non-carriers. Fluorescent in-situ hybridisation and next-generation sequencing were used to detect copy number variations in BRCA2, RB1, MYC and PTEN. Presence of intraductal and cribriform subtypes was also assessed. The independent impact of these events on cause-specific survival (CSS), metastasis-free survival and time to castration-resistant disease was assessed using cox-regression models. RESULTS: Somatic BRCA2-RB1 co-deletion (41% versus 12%, p < 0.001) and MYC amplification (53.4% versus 18.8%, p < 0.001) were enriched in gBRCA2 compared to sporadic tumours. Median CSS from diagnosis of PCa was 9.1 versus 17.6 years in gBRCA2 carriers and non-carriers, respectively (HR 2.12; p = 0.002), Median CSS in gBRCA2 carriers increased to 11.3 and 13.4 years in the absence of BRCA2-RB1 deletion or MYC amplification, respectively. Median CSS of non-carriers decreased to 8 and 2.6 years if BRCA2-RB1 deletion or MYC amplification were detected. CONCLUSIONS: gBRCA2-related prostate tumours are enriched for aggressive genomic features, such as BRCA2-RB1 co-deletion and MYC amplification. The presence or absence of these events modify the outcomes of gBRCA2 carriers.

Prognosis of Primary Papillary Ta Grade 3 Bladder Cancer in the Non-muscle-invasive Spectrum.

BACKGROUND: Ta grade 3 (G3) non-muscle-invasive bladder cancer (NMIBC) is a relatively rare diagnosis with an ambiguous character owing to the presence of an aggressive G3 component together with the lower malignant potential of the Ta component. The European Association of Urology (EAU) NMIBC guidelines recently changed the risk stratification for Ta G3 from high risk to intermediate, high, or very high risk. However, prognostic studies on Ta G3 carcinomas are limited and inconclusive. OBJECTIVE: To evaluate the prognostic value of categorizing Ta G3 compared to Ta G2 and T1 G3 carcinomas. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for 5170 primary Ta-T1 bladder tumors from 17 hospitals were analyzed. Transurethral resection of the tumor was performed between 1990 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to recurrence and time to progression were analyzed using cumulative incidence functions, log-rank tests, and multivariable Cox-regression models with interaction terms stratified by institution. RESULTS AND LIMITATIONS: Ta G3 represented 7.5% (387/5170) of Ta-T1 carcinomas of which 42% were classified as intermediate risk. Time to recurrence did not differ between Ta G3 and Ta G2 (p = 0.9) or T1 G3 (p = 0.4). Progression at 5 yr occurred for 3.6% (95% confidence interval [CI] 2.7-4.8%) of Ta G2, 13% (95% CI 9.3-17%) of Ta G3, and 20% (95% CI 17-23%) of T1 G3 carcinomas. Time to progression for Ta G3 was shorter than for Ta G2 (p < 0.001) and longer than for T1 G3 (p = 0.002). Patients with Ta G3 NMIBC with concomitant carcinoma in situ (CIS) had worse prognosis and a similar time to progression as for patients with T1 G3 NMIBC with CIS (p = 0.5). Multivariable analyses for recurrence and progression showed similar results. CONCLUSIONS: The prognosis of Ta G3 tumors in terms of progression appears to be in between that of Ta G2 and T1 G3. However, patients with Ta G3 NMIBC with concomitant CIS have worse prognosis that is comparable to that of T1 G3 with CIS. Our results support the recent EAU NMIBC guideline changes for more refined risk stratification of Ta G3 tumors because many of these patients have better prognosis than previously thought. PATIENT SUMMARY: We used data from 17 centers in Europe and Canada to assess the prognosis for patients with stage Ta grade 3 (G3) non-muscle-invasive bladder cancer (NMIBC). Time to cancer progression for Ta G3 cancer differed from both Ta G2 and T1 G3 tumors. Our results support the recent change in the European Association of Urology guidelines for more refined risk stratification of Ta G3 NMIBC because many patients with this tumor have better prognosis than previously thought.

T1G1 Bladder Cancer: Prognosis for this Rare Pathological Diagnosis Within the Non-muscle-invasive Bladder Cancer Spectrum.

BACKGROUND: The pathological existence and clinical consequence of stage T1 grade 1 (T1G1) bladder cancer are the subject of debate. Even though the diagnosis of T1G1 is controversial, several reports have consistently found a prevalence of 2-6% G1 in their T1 series. However, it remains unclear if T1G1 carcinomas have added value as a separate category to predict prognosis within the non-muscle-invasive bladder cancer (NMIBC) spectrum. OBJECTIVE: To evaluate the prognostic value of T1G1 carcinomas compared to TaG1 and T1G2 carcinomas within the NMIBC spectrum. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for 5170 primary Ta and T1 bladder tumors from 17 hospitals in Europe and Canada were analyzed. Transurethral resection (TUR) was performed between 1990 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to recurrence and progression were analyzed using cumulative incidence functions, log-rank tests, and multivariable Cox regression models stratified by institution. RESULTS AND LIMITATIONS: T1G1 represented 1.9% (99/5170) of all carcinomas and 5.3% (99/1859) of T1 carcinomas. According to primary TUR dates, the proportion of T1G1 varied between 0.9% and 3.5% per year, with similar percentages in the early and later calendar years. We found no difference in time to recurrence between T1G1 and TaG1 (p = 0.91) or between T1G1 and T1G2 (p = 0.30). Time to progression significantly differed between TaG1 and T1G1 (p < 0.001) but not between T1G1 and T1G2 (p = 0.30). Multivariable analyses for recurrence and progression showed similar results. CONCLUSIONS: The relative prevalence of T1G1 diagnosis was low and remained constant over the past three decades. Time to recurrence of T1G1 NMIBC was comparable to that for other stage/grade NMIBC combinations. Time to progression of T1G1 NMIBC was comparable to that for T1G2 but not for TaG1, suggesting that treatment and surveillance of T1G1 carcinomas should be more like the approaches for T1G2 NMIBC in accordance with the intermediate and/or high risk categories of the European Association of Urology NMIBC guidelines. PATIENT SUMMARY: Although rare, stage T1 grade 1 (T1G1) bladder cancer is still diagnosed in daily clinical practice. Using individual patient data from 17 centers in Europe and Canada, we found that time to progression of T1G1 cancer was comparable to that for T1G2 but not TaG1 cancer. Therefore, our results suggest that primary T1G1 bladder cancers should be managed with more aggressive treatment and more frequent follow-up than for low-risk bladder cancer.

Evaluation of Fluorescent Confocal Microscopy for Intraoperative Analysis of Prostate Biopsy Cores.

BACKGROUND: Diagnosis of prostate cancer is based on histopathological evaluation, which is time-consuming. Fluorescent confocal microscopy (FCM) is a novel technique that allows rapid tissue analysis. OBJECTIVE: To determine if FCM could be used for real-time diagnosis of prostate cancer and evaluate concordance with traditional analysis. DESIGN, SETTING, AND PARTICIPANTS: From January 2019 to March 2020, 182 magnetic resonance imaging-targeted prostate biopsy cores from 57 consecutive biopsy-naïve men with suspected prostate cancer were taken. These were intraoperatively stained with acridine orange for analysis using FCM (VivaScope; MAVIG, Munich, Germany) and subsequently sent for traditional haematoxylin-eosin histopathological (HEH) examination. Two expert uropathologists analysed the FCM and HEH cores blinded to the counterpart results in a single institution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement between FCM and HEH analysis in terms of the presence of cancer was analysed at biopsy core and region of interest (ROI) levels, considering HEH as the reference test. RESULTS AND LIMITATIONS: FCM allowed intraoperative assessment of prostate biopsy cores with strong histopathological evaluation agreement: Cohen's κ for agreement was 0.81 at the biopsy core level and 0.69 for the ROI level. Positive predictive values (85% and 83.78%) and negative predictive values (95.1% and 85.71%) were high at the biopsy core and ROI levels. These initial results are encouraging, but given the single-centre and preliminary nature of the study, further confirmation is required. CONCLUSIONS: FCM allowed rapid evaluation of prostate biopsy cores. This technique is feasible and achieves rapid closure with a reliable diagnosis, parallel to the gold standard analysis. Initial results are promising but further studies are needed to validate and define the role of this technique. PATIENT SUMMARY: A novel microscopic technique reduces the time needed to obtain a prostate cancer diagnosis by speeding up biopsy processing. Although the initial results are promising; this development needs to be confirmed in further studies.

One-Step Nucleic Acid Amplification (OSNA) of Sentinel Lymph Node in Early-Stage Endometrial Cancer: Spanish Multicenter Study (ENDO-OSNA).

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 µm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/µL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.

European Association of Urology (EAU) Prognostic Factor Risk Groups for Non-muscle-invasive Bladder Cancer (NMIBC) Incorporating the WHO 2004/2016 and WHO 1973 Classification Systems for Grade: An Update from the EAU NMIBC Guidelines Panel.

BACKGROUND: The European Association of Urology (EAU) prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC) are used to provide recommendations for patient treatment after transurethral resection of bladder tumor (TURBT). They do not, however, take into account the widely used World Health Organization (WHO) 2004/2016 grading classification and are based on patients treated in the 1980s. OBJECTIVE: To update EAU prognostic factor risk groups using the WHO 1973 and 2004/2016 grading classifications and identify patients with the lowest and highest probabilities of progression. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for primary NMIBC patients were collected from the institutions of the members of the EAU NMIBC guidelines panel. INTERVENTION: Patients underwent TURBT followed by intravesical instillations at the physician's discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox proportional-hazards regression models were fitted to the primary endpoint, the time to progression to muscle-invasive disease or distant metastases. Patients were divided into four risk groups: low-, intermediate-, high-, and a new, very high-risk group. The probabilities of progression were estimated using Kaplan-Meier curves. RESULTS AND LIMITATIONS: A total of 3401 patients treated with TURBT ± intravesical chemotherapy were included. From the multivariable analyses, tumor stage, WHO 1973/2004-2016 grade, concomitant carcinoma in situ, number of tumors, tumor size, and age were used to form four risk groups for which the probability of progression at 5 yr varied from <1% to >40%. Limitations include the retrospective collection of data and the lack of central pathology review. CONCLUSIONS: This study provides updated EAU prognostic factor risk groups that can be used to inform patient treatment and follow-up. Incorporating the WHO 2004/2016 and 1973 grading classifications, a new, very high-risk group has been identified for which urologists should be prompt to assess and adapt their therapeutic strategy when necessary. PATIENT SUMMARY: The newly updated European Association of Urology prognostic factor risk groups for non-muscle-invasive bladder cancer provide an improved basis for recommending a patient's treatment and follow-up schedule.

Feasibility of radical transurethral resection as monotherapy for selected patients with muscle invasive bladder cancer.

PURPOSE: We proved the feasibility of radical transurethral bladder tumor resection in selected patients with muscle invasive bladder cancer with a minimum followup of more than 15 years and investigated the impact of patient age on survival. A followup schedule was developed based on progression and recurrence during this period. MATERIALS AND METHODS: A phase II nonrandomized trial was designed including patients with muscle invasive bladder cancer with negative biopsies of tumor bed who were apparently healthy after undergoing complete transurethral bladder tumor resection. Patients with positive biopsies, or with macroscopically residual tumor, hydronephrosis or metastasis were excluded from study. In this trial 133 patients fulfilled the inclusion criteria and had a minimum followup of more than 15 years. RESULTS: Cancer specific survival was 81.9%, 79.5% and 76.7%, and progression-free survival with bladder preservation was 75.5%, 64.9% and 57.8% at 5, 10 and 15 years, respectively. Patient age had a negative impact on overall survival on univariate (HR 0.842, p = 0.049) and multivariate analyses (HR 1.062, p = 0.000), and according to median and quartile age stratifications (p = 0.000 and p = 0.000, respectively). However, age did not have a negative impact on cancer specific survival even when following the same stratifications. Although progression and recurrence were concentrated during the first 3 years (70% and 65%, respectively), both steadily increased afterward. A followup schedule was developed according to this sequence of events. CONCLUSIONS: Radical transurethral bladder tumor resection is a reliable therapeutic approach for patients with muscle invasive bladder cancer after complete tumor resection and with negative biopsies of the tumor bed. These results are consistent in all age ranges.

Clinical implications of TMPRSS2-ERG gene fusion expression in patients with prostate cancer treated with radical prostatectomy.

PURPOSE: Molecular prognostic factors may be useful tools for prostate cancer that complement classic clinicopathological factors. Genetic rearrangements between TMPRSS2 and ETS have been described for prostate cancer but their clinical significance is still unclear. We analyzed the association of the TMPRSS2-ERG fusion gene with prostate cancer outcome in patients treated with radical prostatectomy. MATERIAL AND METHODS: We analyzed prostate cancer samples from 226 patients treated with radical prostatectomy from 1996 to 2002 with a median followup of 84 months (range 9 to 153). TMPRSS2-ERG fusion gene expression was determined by reverse transcriptase-polymerase chain reaction. Clinicopathological and molecular variables were related to biochemical and clinical progression-free survival by the Kaplan-Meier proportional risk log rank test. A Cox proportional hazards model using stepwise selection was used to identify independent predictors of poor outcome. RESULTS: TMPRSS2-ERG fusion was detected in 114 cases (50.4%). We noted no association between fusion gene status and prostate cancer clinicopathological characteristics. However, when patients were grouped by TMPRSS2-ERG fusion gene status, different clinicopathological prognostic factors defined each group for biochemical and clinical progression-free survival. Prostate specific antigen, specimen Gleason score and margin status were independent prognostic factors in patients with prostate cancer expressing the fusion gene. In the nonexpressing TMPRSS2-ERG group the prognostic factors were cT, Gleason score and margins. CONCLUSIONS: TMPRSS2-ERG fusion gene status classifies patients with prostate cancer treated with radical prostatectomy into groups defined by different prognostic factors. This could be the basis for designing more refined treatment strategies.

A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole.

BACKGROUND: Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC. METHODS: We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood. RESULTS: Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009). CONCLUSIONS: Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients.

Ex-vivo confocal fluorescence microscopy for rapid evaluation of renal core biopsy.

Small renal mass incidentally diagnosed are common findings nowadays due to the widespread of imaging. Renal mass biopsy is still underutilized by urologists due to its non-diagnostic rates. Confocal microscopy allows for rapid imaging of fresh tissue samples. We report the feasibility of using confocal technology for determining the quality of the renal core at renal mass biopsy on 4 consecutive cases at our institution.

Papillary urothelial neoplasm of low malignant potential (PUN-LMP): Still a meaningful histo-pathological grade category for Ta, noninvasive bladder tumors in 2019?

BACKGROUND: Papillary urothelial neoplasm of low malignant potential (PUN-LMP) was introduced as a noninvasive, noncancerous lesion and a separate grade category in 1998. Subsequently, PUN-LMP was reconfirmed by World Health Organization (WHO) 2004 and WHO 2016 classifications for urothelial bladder tumors. OBJECTIVES: To analyze the proportion of PUN-LMP diagnosis over time and to determine its prognostic value compared to Ta-LG (low-grade) and Ta-HG (high-grade) carcinomas. To assess the intraobserver variability of an experienced uropathologist assigning (WHO) 2004/2016 grades at 2 time points. MATERIALS AND METHODS: Individual patient data of 3,311 primary Ta bladder tumors from 17 hospitals in Europe and Canada were available. Transurethral resection of the tumor was performed between 1990 and 2018. Time to recurrence and progression were analyzed with cumulative incidence functions, log-rank tests and multivariable Cox-regression stratified by institution. Intraobserver variability was assessed by examining the same 314 transurethral resection of the tumorslides twice, in 2004 and again in 2018. RESULTS: PUN-LMP represented 3.8% (127/3,311) of Ta tumors. The same pathologist found 71/314 (22.6%) PUN-LMPs in 2004 and only 20/314 (6.4%) in 2018. Overall, the proportion of PUN-LMP diagnosis substantially decreased over time from 31.3% (1990-2000) to 3.2% (2000-2010) and to 1.1% (2010-2018). We found no difference in time to recurrence between the three WHO 2004/2016 Ta-grade categories (log-rank, P = 0.381), nor for LG vs. PUN-LMP (log-rank, P = 0.238). Time to progression was different for all grade categories (log-rank, P < 0.001), but not between LG and PUN-LMP (log-rank, P = 0.096). Multivariable analyses on recurrence and progression showed similar results for all 3 grade categories and for LG vs. PUN-LMP. CONCLUSIONS: The proportion of PUN-LMP has decreased to very low levels in the last decade. Contrary to its reconfirmation in the WHO 2016 classification, our results do not support the continued use of PUN-LMP as a separate grade category in Ta tumors because of the similar prognosis for PUN-LMP and Ta-LG carcinomas.