The predictive value of the prostate health index vs. multiparametric magnetic resonance imaging for prostate cancer diagnosis in prostate biopsy.

PURPOSE: To compare the ability of Prostate Health Index (PHI) to diagnose csPCa, with that of total PSA, PSA density (PSAD) and the multiparametric magnetic resonance (mpMRI) of the prostate. METHODS: We analysed a group of 395 men planned for a prostate biopsy who underwent a mpMRI of the prostate evaluated using the PIRADS v1 criteria. All patients had their PHI measured before prostate biopsy. In patients with an mpMRI suspicious lesions, an mpMRI/ultrasound software fusion-guided biopsy was performed first, with 12 core systematic biopsy performed in all patients. A ROC analysis was performed for PCa detection for total PSA, PSAD, PIRADS score and PHI; with an AUC curve calculated for all criteria and a combination of PIRADS score and PHI. Subsequent sub-analyses included patients undergoing first and repeat biopsy. RESULTS: The AUC for predicting the presence of csPCa in all patients was 59.5 for total PSA, 69.7 for PHI, 64.9 for PSAD and 62.5 for PIRADS. In biopsy naive patients it was 61.6 for total PSA, 68.9 for PHI, 64.6 for PSAD and 63.1 for PIRADS. In patients with previous negative biopsy the AUC for total PSA, PHI, PSAD and PIRADS was 55.4, 71.2, 64.4 and 69.3, respectively. Adding of PHI to PIRADS increased significantly (p = 0.007) the accuracy for prediction of csPCa. CONCLUSION: Prostate Health Index could serve as a tool in predicting csPCa. When compared to the mpMRI, it shows comparable results. The PHI cannot, however, help us guide prostate biopsies in any way, and its main use may, therefore, be in pre-MRI or pre-biopsy triage.

Preoperative prostate health index predicts adverse pathology and Gleason score upgrading after radical prostatectomy for prostate cancer.

BACKGROUND: We aimed to explore the utility of prostate specific antigen (PSA) isoform [- 2] proPSA and its derivatives for prediction of pathological outcome after radical prostatectomy (RP). METHODS: Preoperative blood samples were prospectively and consecutivelyanalyzed from 472 patients treated with RP for clinically localized prostate cancerat four medical centers. Measured parameters were PSA, free PSA (fPSA), fPSA/PSA ratio, [- 2] proPSA (p2PSA), p2PSA/fPSA ratio and Prostate Health Index (PHI)(p2PSA/fPSA)*√PSA]. Logistic regression models were fitted to determine the accuracy of markers for prediction of pathological Gleason score (GS) ≥7, Gleason score upgrading, extracapsular extension of the tumor (pT3) and the presence of positive surgical margin (PSM). The accuracy of predictive models was compared using area under the receiver operating curve (AUC). RESULTS: Of 472 patients undergoing RP, 339 (72%) were found to have pathologic GS ≥ 7, out of them 178 (53%) experienced an upgrade from their preoperative GS = 6. The findings of pT3 and PSM were present in 132 (28%) and 133 (28%) cases, respectively. At univariable analysis of all the preoperative parameters, PHI was the most accurate predictor of pathological GS ≥7 (OR 1.02, 95% CI 1.01-1.03, p<0.001), GS upgrading (OR 1.02, 95% CI 1.01-1.03, p<0.003), pT3 disease (OR 1.01, 95% CI 1.00-1.02, p<0.007) and the presence of PSM (OR 1.01, 95% CI 1.00-1.02, p<0.002). Adding of PHI into the base multivariable model increased significantly the accuracy for prediction of pathological GS by 4.4% to AUC = 66.6 (p = 0.015) and GS upgrading by 5.0% to AUC = 65.9 (p = 0.025), respectively. CONCLUSIONS: Preoperative PHI levels may contribute significantly to prediction of prostate cancer aggressiveness and expansion of the tumor detected at final pathology.

Prevention of bladder cancer incidence and recurrence: tobacco use.

PURPOSE OF REVIEW: To summarize the current knowledge about smoking carcinogenesis in bladder cancer (BCa), individual susceptibility and impact of smoking on incidence and outcomes of nonmuscle invasive BCa (NMIBC) and muscle-invasive BCa (MIBC). To assess the impact of smoking cessation on oncological outcomes. RECENT FINDINGS: Smoking pattern, intensity, and duration are responsible for an increased risk of developing BCa and for worse tumor features at presentation. Tobacco consumption is associated with a higher risk of recurrence in NMIBC and with an impaired intravesical therapy efficacy. To date, the impact of smoking on oncological outcomes after radical surgery remains unclear. SUMMARY: Smoking cessation decreases the risk of BCa and may also allow benefits on treatment outcomes. Nonetheless, the magnitude of the effect remains unclear and prospective series with the specific aim of weighing smoking cessation on outcomes are needed. Because even a 5-min counseling in the urology setting may be sufficient to significantly enhance smoking cessation rates, adequate knowledge of links between tobacco and BCa, from its molecular pathophysiology and its harms to benefits of cessation is paramount for urologists and for everyday clinical practice.

Comparison of MicroRNA Content in Plasma and Urine Indicates the Existence of a Transrenal Passage of Selected MicroRNAs.

MicroRNAs (miRNAs) in urine are examined as potential biomarkers. We examined the urine samples from 70 individuals (45 males, 25 females, mean age 65 years, range 20-84 years). Of the urine donors, 15 were healthy volunteers, 5 were patients with non-cancer diseases, 50 were patients with different stages of bladder cancer. To examine the spectrum of miRNAs in the cell-free fraction of urine, TaqMan Human miRNA Array Card A v.2.1 was used. A set of 30 miRNAs were found that are constantly present in urine supernatants independently of sex, age and health status of the subjects. We compared this set with miRNAs found in plasma, expressed in kidney and genito-urinary tract. Our results indicate that some miRNA could be transferred from the circulation into urine.

Urinary Cell-Free DNA Quantification as Non-Invasive Biomarker in Patients with Bladder Cancer.

INTRODUCTION: Concentration of urinary cell-free DNA (ucfDNA) belongs to potential bladder cancer markers, but the reported results are inconsistent due to the use of various non-standardised methodologies. The aim of the study was to standardise the methodology for ucfDNA quantification as a potential non-invasive tumour biomarker. MATERIAL AND METHODS: In total, 66 patients and 34 controls were enrolled into the study. Volumes of each urine portion (V) were recorded and ucfDNA concentrations (c) were measured using real-time PCR. Total amounts (TA) of ucfDNA were calculated and compared between patients and controls. Diagnostic accuracy of the TA of ucfDNA was determined. RESULTS: The calculation of TA of ucfDNA in the second urine portion was the most appropriate approach to ucfDNA quantification, as there was logarithmic dependence between the volume and the concentration of a urine portion (p = 0.0001). Using this methodology, we were able to discriminate between bladder cancer patients and subjects without bladder tumours (p = 0.0002) with area under the ROC curve of 0.725. Positive and negative predictive value of the test was 90 and 45%, respectively. CONCLUSION: Quantification of ucf DNA according to our modified method could provide a potential non-invasive biomarker for diagnosis of patients with bladder cancer.

Panel of Urinary Diagnostic Markers for Non-Invasive Detection of Primary and Recurrent Urothelial Urinary Bladder Carcinoma.

OBJECTIVES: To determine the combination of urinary protein markers for noninvasive detection of primary and recurrent urothelial bladder carcinomas. METHODS: Urinary concentrations of 27 biomarkers (NSE, ATT, AFABP, Resistin, Midkine, Clusterin, Uromodulin, ZAG2, HSP27, HSP 60, NCAM1/CD56, Angiogenin, Calreticulin, Chromogranin A, CEACAM1, CXCL1, IL13Ra2, Progranulin, VEGFA, CarbAnhydIX, Annexin-V, TIM4, Galectin1, Cystatin B, Synuclein G, ApoA1 and ApoA2) were assessed by enzyme-linked immunosorbent assay or by electrochemiluminiscence immunoassay. RESULTS: During the primary diagnostics, a group of 70 patients with primary occurrence of bladder cancer and 49 healthy control subjects were compared. For this clinical situation, the most accurate combination proved to be the combination of cytology with markers Midkine and Synuclein G (sensitivity 91.8%, specificity 97.5%). During the monitoring of patients with non-muscle invasive bladder cancer (NMIBC), a group of 44 patients with cancer recurrence was compared with the group of 61 patients with a history of NMIBC without current disease. For this clinical situation, the most accurate combination proved to be the combination of cytology and erythrocytes count in urine sediment with markers Midkine, ZAG2, CEACAM1, and Synuclein G (sensitivity 92.68%, specificity 90.16%). A lower accuracy of the diagnostic panel and the necessity to use more markers in the case of recurrence was connected with a different structure of patients. CONCLUSIONS: Multi-marker test can significantly improve the bladder cancer detection both during the primary diagnostics and monitoring of patients with NMIBC. This outcome should result in other, larger studies.

Diagnostic Importance of Selected Protein Serum Markers in the Primary Diagnostics of Prostate Cancer.

OBJECTIVE: To determine a predictive model for the primary diagnosis of prostate cancer (PC) based on a multiple serum biomarker assay. MATERIAL AND METHODS: Between August 2011 and February 2013, a total of 387 prostate biopsies were performed. Serum or plasma concentrations of 22 biomarkers (neopterin, IGF-1, IGFBP-2, IGFBP-3, sarcosine, endoglin, TGF-ß1, periostin, sPLA2-IIa, chromogranin A, ZAG2, clusterin, PSP94, PSP94bp, leptin, cathepsin D, hepsin, KLK11, PSMA, AMACR, CRISP3 and A1AT) were determined. Biomarker levels were correlated with the prostate biopsy results. Several statistical models for PC detection were created. RESULTS: A total of 167 of the 373 evaluated patients (44.8%) were diagnosed with PC. None of the tested biomarkers reached statistical significance using the univariate analysis. However, the level of serum clusterin was not associated with any other tested parameter. Several basic models showed a higher positive predictive value than individual parameters. Addition of serum clusterin to the base model with prostate-specific antigen, digital rectal exam and prostate size significantly improved the area under curve value (0.723 vs. 0.716). CONCLUSION: Our findings suggested that multiple serum assays based on some promising markers may only have a limited practical benefit for the prediction of PC in the prostate biopsy.

[Circulating tumor cells and prostate cancer prognosis]. / Cirkulující nádorové bunky a prognóza karcinomu prostaty.

Prostate cancer (PC) is the most common malignant disease in men. Prognosis of patients with metastatic PC is generally unfavourable; however there are significant differences in survival at this stage of the disease. The definition of prognosis is essential for the selection of therapy, respecting an individual risk. In recent years, the association between circulating tumor cells (CTC) detection and response to PC treatment has been widely investigated. Detection of CTC is based on a metastatic process theory and uses well-known tumor-specific antigens on the cell surface. Individual methods assess CTC with different sensitivity and are not yet efficient at the localised PC stage. Only the method of immunomagnetic separation and semi-automatic visualisation (CellSearchTM) has been validated and approved for the use in the PC management. Assessment of the CTC count directly correlates with the prognosis of patients with castration-resistant PC. Change in the CTC count during the therapy also considerably improves risk estimation and represents a marker of overall survival. New methods of CTC cultivation and gene profiling may contribute to individualisation of the treatment similarly to breast cancer. The authors present a review article about theory, methods of detection and clinical use of CTC in castration-resistant PC.

Deep-learning-based reconstruction of T2-weighted magnetic resonance imaging of the prostate accelerated by compressed sensing provides improved image quality at half the acquisition time.

Background: Deep-learning-based reconstruction (DLR) improves the quality of magnetic resonance (MR) images which allows faster acquisitions. The aim of this study was to compare the image quality of standard and accelerated T2 weighted turbo-spin-echo (TSE) images of the prostate reconstructed with and without DLR and to find associations between perceived image quality and calculated image characteristics. Methods: In a cohort of 47 prospectively enrolled consecutive patients referred for bi-parametric prostate magnetic resonance imaging (MRI), two T2-TSE acquisitions in the transverse plane were acquired on a 3T scanner-a standard T2-TSE sequence and a short sequence accelerated by a factor of two using compressed sensing (CS). The images were reconstructed with and without DLR in super-resolution mode. The image quality was rated in six domains. Signal-to-noise ratio (SNR), and image sharpness were measured. Results: The mean acquisition time was 281±23 s for the standard and 140±12 s for the short acquisition (P<0.0001). DLR images had higher sharpness compared to non-DLR (P<0.001). Short and short-DLR had lower SNR than the standard and standard-DLR (P<0.001). The perceived image quality of short-DLR was rated better in all categories compared to the standard sequence (P<0.001 to P=0.004). All domains of subjective evaluation were correlated with measured image sharpness (P<0.001). Conclusions: T2-TSE acquisition of the prostate accelerated using CS combined with DLR reconstruction provides images with increased sharpness that have a superior quality as perceived by human readers compared to standard T2-TSE. The perceived image quality is correlated with measured image contrast.

European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ)-A Summary of the 2024 Guidelines Update.

BACKGROUND AND OBJECTIVE: This publication represents a summary of the updated 2024 European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ. The information presented herein is limited to urothelial carcinoma, unless specified otherwise. The aim is to provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation. METHODS: For the 2024 guidelines on NMIBC, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. KEY FINDINGS AND LIMITATIONS: Key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with NMIBC. The guidelines stress the importance of defining patients' risk stratification and treating them appropriately. CONCLUSIONS AND CLINICAL IMPLICATIONS: This overview of the 2024 EAU guidelines offers valuable insights into risk factors, diagnosis, classification, prognostic factors, treatment, and follow-up of NMIBC. These guidelines are designed for effective integration into clinical practice.

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.

Timing of Early Salvage Therapy for Patients With Biochemical Relapse of Prostate Carcinoma.

Between 25% and 33% of patients after radical prostatectomy experience a relapse of the disease. The risk of relapse increases in patients with risk factors up to 50%-80%. For a long time, adjuvant radiotherapy has been considered the standard of care. Four large prospective trials, that compared adjuvant and salvage radiotherapy in patients with biochemical relapse, showed the superiority of the adjuvant approach in biochemical and local relapse-free survival, but no consistent benefit in long-term endpoints (i.e., metastasis-free survival, overall survival, or carcinoma-specific survival) at the expense of increased urinary and bowel toxicity. Three large international studies comparing adjuvant and salvage radiotherapy paved the way toward early salvage radiotherapy. However, the optimal threshold of the PSA level (range of 0.2-0.5 ng/mL) for initiating early salvage radiotherapy remains unresolved and still poses a challenge in everyday clinical practice when balancing the need for early radiotherapy and the associated toxicity. Imprecise stratification of biochemical relaps patients according to the risk of clinical relapse drives efforts to find additional molecular biomarkers that would improve the timing of the salvage therapy.

Quantification and significance of extraprostatic findings on prostate MRI: a retrospective analysis and three-tier classification.

OBJECTIVES: To quantify extraprostatic findings (EPFs) on prostate MRI, estimate the proportion of reported and unreported EPFs, assess their clinical importance, and propose standardized reporting of EPFs. MATERIALS AND METHODS: Prostate 3-T MRI studies, reports, and clinical data from 623 patients (age 67.9 ± 8.2 years) were retrospectively analyzed and re-evaluated for the presence of EPFs and their clinical significance: E1-no finding or findings that have no clinical significance; E2-potentially significant findings; and E3-significant findings. RESULTS: Secondary reading identified 1236 EPFs in 593 patients (1.98 ± 1.13 EPFs per patient, no EPFs in 30 patients), from which 468 (37.8%) were mentioned in the original report. The most common findings included diverticulosis (44% of patients), hydrocele (34%), inguinal fat hernia (16%), and bladder wall trabecular hypertrophy (15%). There were 80 (6.5%) E2 EPFs and 30 (2.4%) E3 EPFs. From E3 EPFs, 10 (33%) were not originally reported. A workup was suggested in 35 (52%) of the 67 originally reported E2 and E3 findings with follow-up and performed in 20 (30%). Fourteen (21%) EPFs in 11 patients influenced their management. Four experienced radiologists originally reported 1.8 to 2.5 findings per patient (p < 0.0001). CONCLUSIONS: EPFs on prostate MRI are frequent, but only 2.4% are clinically significant (E3), and 33% of these are not reported. Only 30% of E2 and E3 findings are further explored, and 21% influence patient management. We suggest that an "E" category should be attached to the PI-RADS system to identify the presence of EPFs that require further workup. CRITICAL RELEVANCE STATEMENT: Extraprostatic findings on prostate MRI are frequent, but only 2.4% are clinically significant (E3), and 33% of these are not reported. We advocate standardized reporting of extraprostatic findings indicating their clinical significance. KEY POINTS: • Extraprostatic findings on prostate MRI are frequent with an average of two findings per patient. • 2.4% of extraprostatic findings are significant, and 33% of these are not reported. • There is a significant variability among experienced radiologists in reporting extraprostatic findings.

Serum Thymidine Kinase 1 - Potential Prostate Cancer Biomarker: A Clinical Study.

BACKGROUND/AIM: Serum thymidine kinase 1 (STK1) is a proliferation biomarker that has been used as a diagnostic marker of several malignant diseases. However, there are limited data for prostate cancer (PCa). PATIENTS AND METHODS: In this study, we retrospectively analysed serum samples from 169 patients with biopsy confirmed PCa, who had been indicated for radical prostatectomy (RP) between 2013-2016. The results were compared with those in serum samples from 39 healthy men. We used commercially available enzymatic immunoassay to determine the levels of STK1. The patients were divided into groups according to the Gleason score (GS) and risk factors for adjuvant radiotherapy (aRT), which were defined as GS 8-10, pT3, and a positive surgical margin. RESULTS: The median serum level of STK1 in PCa patients was 0.289 pmol/l. In the control group, the median value was 0.0116 pmol/l (p<0.001). By comparing the patients with GS≤6 vs. 7 vs. ≥8 (p=0.01), we found statistically significant differences. In the correlation of STK1 values with risk factors, we found statistically significant differences both in comparison of 0 vs. 1 vs. 2 vs. 3 risk factors (p=0.021), as well as ≤1 vs. 2≥ risk factors (p=0.009). CONCLUSION: The levels of STK1 are significantly higher in patients with PCa than those in healthy controls. Furthermore, STK1 values correlate with GS and predefined risk factors for aRT. Therefore, STK1 can be considered as a potential tumour marker of PCa diagnosis and risk stratification.

European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update.

CONTEXT: The European Association of Urology (EAU) guidelines panel on upper urinary tract urothelial carcinoma (UTUC) has updated the guidelines to aid clinicians in evidence-based management of UTUC. OBJECTIVE: To provide an overview of the EAU guidelines on UTUC as an aid to clinicians. EVIDENCE ACQUISITION: The recommendations provided in these guidelines are based on a review of the literature via a systematic search of the PubMed, Ovid, EMBASE, and Cochrane databases. Data were searched using the following keywords: urinary tract cancer, urothelial carcinomas, renal pelvis, ureter, bladder cancer, chemotherapy, ureteroscopy, nephroureterectomy, neoplasm, (neo)adjuvant treatment, instillation, recurrence, risk factors, metastatic, immunotherapy, and survival. The results were assessed by a panel of experts. EVIDENCE SYNTHESIS: Even though data are accruing, for many areas there is still insufficient high-level evidence to provide strong recommendations. Patient stratification on the basis of histology and clinical examination (including imaging) and assessment of patients at risk of Lynch syndrome will aid management. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk UTUC and two functional kidneys. In particular, for patients with high-risk or metastatic UTUC, new treatment options have become available. In high-risk UTUC, platinum-based chemotherapy after radical nephroureterectomy, and adjuvant nivolumab for unfit or patients who decline chemotherapy, are options. For metastatic disease, gemcitabine/carboplatin chemotherapy is recommended as first-line treatment for cisplatin-ineligible patients. Patients with PD-1/PD-L1-positive tumours should be offered a checkpoint inhibitor (pembrolizumab or atezolizumab). CONCLUSIONS: These guidelines contain information on the management of individual patients according to the current best evidence. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen according to the risk stratification of these tumours. PATIENT SUMMARY: Cancer of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis, timely and appropriate diagnosis is most important. A number of known risk factors exist.

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.

Systematic Review of the Incidence of and Risk Factors for Urothelial Cancers and Renal Cell Carcinoma Among Patients with Haematuria.

CONTEXT: The current impact of haematuria investigations on health care organisations is significant. There is currently no consensus on how to investigate patients with haematuria. OBJECTIVE: To evaluate the incidence of bladder cancer, upper tract urothelial carcinoma (UTUC), and renal cell carcinoma (RCC) among patients undergoing investigation for haematuria and identify any risk factors for bladder cancer, UTUC, and RCC (BUR). EVIDENCE ACQUISITION: Medline, Embase, and Cochrane controlled trials databases and ClinicalTrials.gov were searched for all relevant publications from January 1, 2000 to June 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Prospective, retrospective, and cross-sectional studies with a minimum population of 50 patients with haematuria were considered for the review. EVIDENCE SYNTHESIS: A total of 44 studies were included. The total number of participants was 229701. The pooled incidence rate for urothelial bladder cancer was 17% (95% confidence interval [CI] 14-20%) for visible haematuria (VH) and 3.3% (95% CI 2.45-4.3%) for nonvisible haematuria (NVH). The pooled incidence rate for RCC was 2% (95% CI 1-2%) for VH and 0.58% (95% CI 0.42-0.77%) for NVH. The pooled incidence rate for UTUC was 0.75% (95% CI 0.4-1.2%) for VH and 0.17% (95% CI 0.081-0.299%) for NVH. On sensitivity analysis, the proportions of males (risk ratio [RR] 1.14, 95% CI 1.10-1.17 for VH; 1.54, 95% CI 1.34-1.78 for NVH; p < 0.00001; moderate certainty evidence) and individuals with a smoking history (RR 1.41, 95% CI 1.24-1.61 for VH; 1.53, 95% CI 1.36-1.72 for NVH; p < 0.00001; moderate certainty evidence) appeared to be higher in BUR than in non-BUR groups. CONCLUSIONS: Male gender and smoking history are risk factors for BUR cancer in haematuria, with bladder cancer being the commonest cancer. The incidence of RCC and UTUC in NVH is low. The review serves as a reference standard for future policy-making on investigation of haematuria by global organisations. PATIENT SUMMARY: Our review shows that male gender and smoking history are risk factors for cancers of the bladder, kidney, and ureter. The review also provides information on the proportion of patients who have cancer when they have blood in their urine (haematuria) and will allow policy-makers to decide on the most appropriate method for investigating haematuria in patients.

European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ).

CONTEXT: The European Association of Urology (EAU) has released an updated version of the guidelines on non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To present the 2021 EAU guidelines on NMIBC. EVIDENCE ACQUISITION: A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines since the 2020 version was performed. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned. EVIDENCE SYNTHESIS: Tumours staged as Ta, T1 and carcinoma in situ (CIS) are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of tissue obtained via transurethral resection of the bladder (TURB) for papillary tumours or via multiple bladder biopsies for CIS. For papillary lesions, a complete TURB is essential for the patient's prognosis and correct diagnosis. In cases for which the initial resection is incomplete, there is no muscle in the specimen, or a T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risk of progression may be estimated for individual patients using the 2021 EAU scoring model. On the basis of their individual risk of progression, patients are stratified as having low, intermediate, high, or very high risk, which is pivotal to recommending adjuvant treatment. For patients with tumours presumed to be at low risk and for small papillary recurrences detected more than 1 yr after a previous TURB, one immediate chemotherapy instillation is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose intravesical bacillus Calmette-Guérin (BCG) immunotherapy or instillations of chemotherapy for a maximum of 1 yr. For patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. For patients at very high risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is also recommended for BCG-unresponsive tumours. The extended version of the guidelines is available on the EAU website at https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/. CONCLUSIONS: These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. PATIENT SUMMARY: The European Association of Urology has released updated guidelines on the classification, risk factors, diagnosis, prognostic factors, and treatment of non-muscle-invasive bladder cancer. The recommendations are based on the literature up to 2020, with emphasis on the highest level of evidence. Classification of patients as having low, intermediate, or and high risk is essential in deciding on suitable treatment. Surgical removal of the bladder should be considered for tumours that do not respond to bacillus Calmette-Guérin (BCG) treatment and tumours with the highest risk of progression.

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.

Prognostic Value of the WHO1973 and WHO2004/2016 Classification Systems for Grade in Primary Ta/T1 Non-muscle-invasive Bladder Cancer: A Multicenter European Association of Urology Non-muscle-invasive Bladder Cancer Guidelines Panel Study.

BACKGROUND: In the current European Association of Urology (EAU) non-muscle-invasive bladder cancer (NMIBC) guideline, two classification systems for grade are advocated: WHO1973 and WHO2004/2016. OBJECTIVE: To compare the prognostic value of these WHO systems. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for 5145 primary Ta/T1 NMIBC patients from 17 centers were collected between 1990 and 2019. The median follow-up was 3.9 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariate and multivariable analyses of WHO1973 and WHO2004/2016 stratified by center were performed for time to recurrence, progression (primary endpoint), cystectomy, and duration of survival, taking into account age, concomitant carcinoma in situ, gender, multiplicity, tumor size, initial treatment, and tumor stage. Harrell's concordance (C-index) was used for prognostic accuracy of classification systems. RESULTS AND LIMITATIONS: The median age was 68 yr; 3292 (64%) patients had Ta tumors. Neither classification system was prognostic for recurrence. For a four-tier combination of both WHO systems, progression at 5-yr follow-up was 1.4% in low-grade (LG)/G1, 3.8% in LG/G2, 7.7% in high grade (HG)/G2, and 18.8% in HG/G3 (log-rank, p < 0.001). In multivariable analyses with WHO1973 and WHO2004/2016 as independent variables, WHO1973 was a significant prognosticator of progression (p < 0.001), whereas WHO2004/2016 was not anymore (p = 0.067). C-indices for WHO1973, WHO2004, and the WHO systems combined for progression were 0.71, 0.67, and 0.73, respectively. Prognostic analyses for cystectomy and survival showed results similar to those for progression. CONCLUSIONS: In this large prognostic factor study, both classification systems were prognostic for progression but not for recurrence. For progression, the prognostic value of WHO1973 was higher than that of WHO 2004/2016. The four-tier combination (LG/G1, LG/G2, HG/G2, and HG/G3) of both WHO systems proved to be superior, as it divides G2 patients into two subgroups (LG and HG) with different prognoses. Hence, the current EAU-NMIBC guideline recommendation to use both WHO classification systems remains correct. PATIENT SUMMARY: At present, two classification systems are used in parallel to grade non-muscle-invasive bladder tumors. Our data on a large number of patients showed that the older classification system (WHO1973) performed better in terms of assessing progression than the more recent (WHO2004/2016) one. Nevertheless, we conclude that the current guideline recommendation for the use of both classification systems remains correct, since this has the advantage of dividing the large group of WHO1973 G2 patients into two subgroups (low and high grade) with different prognoses.