Modified immunoscore improves the prediction of progression-free survival in patients with non-muscle-invasive bladder cancer: A digital pathology study

Tumour-infiltrating lymphocytes (TIL), known to be of prognostic value in various solid tumours, have been in the focus of research in the last years. TIL are often quantified via IMMUNOSCORE ® (IS), a scoring system based on TIL cell densities. Recent studies were able to replicate these findings for muscle-invasive bladder cancer (MIBC), however data regarding non-muscle-invasive bladder cancer (NMIBC) are scarce. This study aimed to evaluate the value of a modified Immunoscore (mIS) as a predictive marker for NMIBC prognosis using tissue-micro-arrays (TMAs). We analysed two TMAs containing 316 samples from 158 patients with NMIBC, stained for CD3, CD8, CD45RO and FOXP3. Stained TIL were captured by digital pathology, cumulated, averaged, and reported as density (stained cells per mm²). The mIS was then constructed based on density of all four immune-cell types. Clinical, pathological and follow-up data were collected retrospectively. Univariable and multivariable cox regression analysis was performed to assess the potential value of mIS as a predictor for progression free survival (PFS) and recurrence-free-survival (RFS). Patients within "European Organisation for Research and Treatment of Cancer" (EORTC) risk groups were further substratified in high mIS and low mIS subgroups. Finally log-rank test was used to compare the different survival curves. The median age in our cohort was 68 years (Interquartile Range (IQR): 60 - 76), and 117 (74%) patients were male. A total of 26 patients (16.5%) were classified as EORTC low risk, 45 (28.5%) as intermediate risk and 87 (55.1%) as high risk. Patients in the EORTC high risk group with low mIS showed a shorter PFS in comparison to high mIS (HR 2.9, CI 0.79 - 11.0, p=0.082). In contrast, no predictive potential regarding PFS was observed in intermediate or low risk groups. Furthermore, mIS was not able to predict RFS in any EORTC risk group. mIS could be utilized to predict prognosis more accurately in high-risk patients with NMIBC by identifying those with higher or lower risk of progression. Therefore, mIS could be used to allocate these highrisk patients to more streamlined follow-up or more aggressive treatment strategies. Keywords: biomarker; bladder cancer; digital pathology; immunoscore; prognosis; progressio

Contrast media kinetics in multiparametric magnetic resonance imaging before radical prostatectomy predicts the probability of postoperative incontinence.

PURPOSE To evaluate the role of preoperative multiparametric magnetic resonance imaging (MRI) as predictor of post-prostatectomy incontinence (PPI). METHODS We analyzed patients who underwent robot-assisted radical prostatectomy for localized prostate cancer at our institution between July 2015 and April 2017. In these patients, we measured the perfusion quality of the pelvic floor with contrast media kinetics in the preoperative MRI of the prostate and compared the levator ani muscle (region of interest) to the surrounding pelvic muscle structures (reference). Prospectively collected questionnaires regarding urinary incontinence were then evaluated 1 year postoperatively. Outcomes were dichotomized into "continent" (ICIQ-Score = 0-5) and "incontinent" (ICIQ-Score ≥ 6). In each patient, we determined the perfusion ratio of the levator ani muscle divided by the surrounding pelvic muscle structures and compared them among the groups. RESULTS Forty-two patients were included in the study (n = 22 in "continent", n = 20 in "incontinent" group). The median perfusion ratio from the continent group was significantly higher compared to the incontinent group (1.61 vs. 1.15; 95% CI 0.09-0.81, p = 0.015). The median perfusion ratio in "excellent" (ICIQ-Score = 0) was significantly higher than in "poor" (ICIQ-Score ≥ 11) outcomes (1.48 vs. 0.94; 95% CI 0.04-1.03, p = 0.036). Further, a higher perfusion ratio was negatively correlated with ICIQ-Score (r = - 0.33; 95% CI - 0.58 to 0.03; p = 0.031). CONCLUSIONS Our data demonstrate a promising new strategy to predict PPI through the perfusion quality of pelvic muscle structures with contrast media kinetics. This may facilitate preoperative patient consulting and decision-making

Limited Value of Bladder Wash Cytology During Follow-Up of Patients With Non-muscle Invasive Bladder Cancer

Aims We aimed to assess the performance of bladder wash cytology (BWC) in daily clinical practice in a pure follow-up cohort of patients previously diagnosed with non-muscle invasive bladder cancer (NMIBC). Materials and methods We analyzed 2064 BWCs derived from 314 patients followed for NMIBC (2003-2016). Follow-up investigations were performed using cystoscopy (CS) in combination with BWC. Patients with suspicious CS and/or positive BWC underwent bladder biopsy or transurethral resection. BWC was considered positive if malignant or suspicious cells were reported. Sensitivity (Sn) and specificity (Sp) were calculated for the entire cohort and separately for low-grade (LG) and high-grade (HG) tumors, and carcinoma in situ (CIS) subgroups. Results A total of 95 recurrences were detected, of which only three were detected by BWC alone. Overall, Sn and Sp of BWC were 17.9% and 99.5%, respectively. For LG disease, these numbers were 14.0% and 100%, and for HG disease, these were 22.2% and 99.1%, respectively. For patients with CIS at initial diagnosis, Sn and Sp were 11.0% and 71.4%, respectively. For isolated primary CIS, Sn was 50.0%, and Sp was 98.2%. Conclusion Routine use of BWC in the follow-up for NMIBC is of limited value even in HG tumors. In the presence of isolated primary CIS, adjunct BWC might be justified

Risk Factors and Treatment Outcomes of 1,375 Patients with Testicular Leydig Cell Tumors: Analysis of Published Case Series Data

AIMS Leydig cell tumors (LCTs) are rare but the most common non-germ cell testicular tumors. Only limited evidence exists for reliably differentiating between benign and malignant LCTs and for optimally managing the different types and stages of this rare disease. This review aims to synthesize the available evidence regarding the clinical presentation and clinicopathological characteristics associated with LCT malignancy and management. METHODS We analyzed published case series with LCTs patients. The association between clinicopathological variables and the presence of metastatic disease was assessed using regression analyses. RESULTS We included 357 reports, reviewing available data from 1,375 patients (median age: 34y). Testis-sparing surgery (TSS) was performed in 463 patients. Local recurrence after TSS occurred in 8 of 121 (7%) patients with available follow-up information. Metastases were found in 101 patients and were most often located in the retroperitoneal lymph nodes (60%), lungs (38%), and/or liver (29%). The multivariable models with or without multiple imputation predicting metastatic disease included older age, larger tumor size, the presence of any adverse factor (larger tumor diameter, necrosis, angiolymphatic invasion, pleomorphism, high mitotic index, atypia), and any protective factor (Reinke crystals, lipofuscin pigments, gynecomastia) with model AUCs of 0.93. Durable remission after resection of metastases or platinum-based chemotherapy was rarely seen. CONCLUSION Our risk tables using clinicopathological parameters can help identify patients harboring malignant tumors. These patients should undergo staging and either be followed or receive further treatment. In metastatic disease surgical and systemic treatment might result in disease control in in some patients

External Validation and Comparison of Prostate Cancer Risk Calculators Incorporating Multiparametric Magnetic Resonance Imaging for Prediction of Clinically Significant Prostate Cancer

PURPOSE: To externally validate recently published prostate cancer risk calculators (PCa-RCs) incorporating multiparametric magnetic resonance imaging (mpMRI) for the prediction of clinically significant prostate cancer (csPCa) and compare their performance to mpMRI-naïve PCa-RCs. MATERIAL AND METHODS: Men without previous PCa diagnosis undergoing transperineal template saturation prostate biopsy with fusion-guided targeted biopsy between 11/2014 and 03/2018 in our academic tertiary referral center were identified. Any Gleason pattern ≥4 was defined to be csPCa. Predictors (age, PSA, DRE, prostate volume, family history, previous prostate biopsy and highest region of interest according to PIRADS) were retrospectively collected. Four mpMRI-PCa-RCs and two mpMRI-naïve PCa-RCs were evaluated for their discrimination, calibration and clinical net benefit using a ROC analysis, calibration plots and a decision curve analysis, respectively. RESULTS: Out of 468 men, 193 (41%) were diagnosed with csPCa. Three mpMRI-PCa-RCs showed similar discrimination with area-underneath-the-receiver-operating-characteristic-curves (AUC) from 0.83 to 0.85, which was significantly higher than the other PCa-RCs (AUCs: 0.69-0.74). Calibration-in-the-large showed minimal deviation from the true amount of csPCa by 2% for two mpMRI-PCa-RCs, while the other PCa-RCs showed worse calibration (11-27%). A clinical net benefit could only be observed for three mpMRI-PCa-RCs at biopsy thresholds ≥15%, while none of the six investigated PCa-RCs demonstrated clinical utility against a biopsy all strategy at thresholds <15%. CONCLUSIONS: Performance of the mpMRI-PCa-RCs varies, but they generally outperform mpMRI-naïve PCa-RCs in regard to discrimination, calibration and clinical usefulness. External validation in other biopsy settings is highly encouraged

Long-Term Oncological Efficacy of Retroperitoneoscopic Radical Nephrectomy of Localized Renal Cell Cancer pT1-3 (≤12 cm)

Investigation of oncological efficacy in retroperitoneoscopic radical nephrectomy (RRN) of patients with localized renal cell carcinoma (RCC). Consecutive patients undergoing RRN for localized stage pT1-3 RCC in 2 tertiary care centers in Switzerland were evaluated. Excellent long-term oncological efficacy was found. Our long-term follow-up validates the survival outcome from comparable literature after conventional open or laparoscopic radical nephrectomy

Systematic review and meta-analysis on trimodal therapy versus radical cystectomy for muscle-invasive bladder cancer: Does the current quality of evidence justify definitive conclusions?

OBJECTIVES To systematically review and meta-analyze the current literature in a methodologically rigorous and transparent manner for quantitative evidence on survival outcomes among patients diagnosed with muscle-invasive bladder cancer that were treated by either trimodal therapy or radical cystectomy. MATERIALS AND METHODS MEDLINE, EMBASE, CENTRAL were systematically searched for comparative observational studies reporting disease-specific survival and/or overall survival on adult patients diagnosed with localized muscle-invasive bladder cancer that were exposed to either trimodal therapy or radical cystectomy. Studies qualified for meta-analysis (random effects model) if they were not at critical risk of bias (RoB). RESULTS The literature search identified 12 eligible studies. Three (all rated as "moderate RoB") out of 6 studies reporting on disease-specific survival qualified for quantitative analysis and yielded a pooled hazard ratio (trimodal therapy versus radical cystectomy) of 1.39 (95% confidence interval: 1.03-1.88). Four (mainly rated as "serious RoB") out of 12 studies were included in the meta-analysis of overall survival and estimated a hazard ratio of 1.39 (1.20-1.59). CONCLUSION Pooled results were significant in favor of radical cystectomy. The conclusion is mainly driven by large population-based studies that are at high RoB. Hence, the certainty of these treatment estimates can be considered very low and further research will likely have an important impact on these estimates. At present, the ultimate decision between trimodal therapy and radical cystectomy should be left to the patient based on individual preferences and on the recommendation of a multidisciplinary provider team experienced with both approaches

BioPrev-C – development and validation of a contemporary prostate cancer risk calculator

ObjectivesTo develop a novel biopsy prostate cancer (PCa) prevention calculator (BioPrev-C) using data from a prospective cohort all undergoing mpMRI targeted and transperineal template saturation biopsy.Materials and methodsData of all men who underwent prostate biopsy in our academic tertiary care center between 11/2016 and 10/2019 was prospectively collected. We developed a clinical prediction model for the detection of high-grade PCa (Gleason score ≥7) based on a multivariable logistic regression model incorporating age, PSA, prostate volume, digital rectal examination, family history, previous negative biopsy, 5-alpha-reductase inhibitor use and MRI PI-RADS score. BioPrev-C performance was externally validated in another prospective Swiss cohort and compared with two other PCa risk-calculators (SWOP-RC and PBCG-RC).ResultsOf 391 men in the development cohort, 157 (40.2%) were diagnosed with high-grade PCa. Validation of the BioPrev C revealed good discrimination with an area under the curve for high-grade PCa of 0.88 (95% Confidence Interval 0.82-0.93), which was higher compared to the other two risk calculators (0.71 for PBCG and 0.84 for SWOP). The BioPrev-C revealed good calibration in the low-risk range (0 - 0.25) and moderate overestimation in the intermediate risk range (0.25 - 0.75). The PBCG-RC showed good calibration and the SWOP-RC constant underestimation of high-grade PCa over the whole prediction range. Decision curve analyses revealed a clinical net benefit for the BioPrev-C at a clinical meaningful threshold probability range (≥4%), whereas PBCG and SWOP calculators only showed clinical net benefit above a 30% threshold probability.ConclusionBiopPrev-C is a novel contemporary risk calculator for the prediction of high-grade PCa. External validation of the BioPrev-C revealed relevant clinical benefit, which was superior compared to other well-known risk calculators. The BioPrev-C has the potential to significantly and safely reduce the number of men who should undergo a prostate biopsy

Required efficacy for novel therapies in BCG-unresponsive non-muscle invasive bladder cancer: Do current recommendations really reflect clinically meaningful outcomes?

BACKGROUND Single-arm trials are currently an accepted study design to investigate the efficacy of novel therapies (NT) in non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette-Guérin (BCG) immunotherapy as randomized controlled trials are either unfeasible (comparator: early radical cystectomy; ERC), or unethical (comparator: placebo). To guide the design of such single-arm trials, expert groups published recommendations for clinically meaningful outcomes. The aim of this study was to quantitatively verify the appropriateness of these recommendations. METHODS We used a discrete event simulation framework in combination with a supercomputer to find the required efficacy at which a NT can compete with ERC when it comes to quality-adjusted life expectancy (QALE). In total, 24 different efficacy thresholds (including the recommendations) were investigated. RESULTS After ascertaining face validity with content experts, repeated verification, external validation, and calibration we considered our model valid. Both recommendations rarely showed an incremental benefit of the NT over ERC. In the most optimistic scenario, an increase in the IBCG recommendation by 10% and an increase in the FDA/AUA recommendation by 5% would yield results at which a NT could compete with ERC from a QALE perspective. CONCLUSIONS This simulation study demonstrated that the current recommendations regarding clinically meaningful outcomes for single-arm trials evaluating the efficacy of NT in BCG-unresponsive NMIBC may be too low. Based on our quantitative approach, we propose increasing these thresholds to at least 45%-55% at 6 months and 35% at 18-24 months (complete response rates/recurrence-free survival) to promote the development of clinically truly meaningful NT

External evaluation of a novel prostate cancer risk calculator (ProstateCheck) based on data of the Swiss arm of the ERSPC

PURPOSE: To externally validate a novel prostate cancer (PCa) risk-calculator (RC), based on data of the Swiss arm of the European Randomize Study of Screening for Prostate Cancer (ERSPC), and to assess whether the RC (ProstateCheck) is superior to the PCPT RC and SWOP RC in an independent Swiss cohort. MATERIALS AND METHODS: Data of all men who underwent prostate biopsy in an academic tertiary care center between 2004 and 2012 were retrospectively analyzed. The probability of having any PCa or high-grade PCa (Gleason score ≥7) upon prostate biopsy was calculated using the ProstateCheck-RC. The RC's performance was assessed using calibration and discrimination and additionally compared with the PCPT- and SWOP-RC by decision curve analyses. RESULTS: Of 1615 men, 401 (25%) were diagnosed with any PCa and 196 (12%) with high-grade PCa. Our analyses of the ProstateCheck-RC revealed good calibration in the low risk range (0 to 0.4) and moderate overestimation in the higher risk range (0.4 to 1) for any and high-grade PCa. The AUC for the discrimination of any PCa and high-grade PCa was 0.69 and 0.72, respectively, which was slightly but significantly higher compared to the PCPT-RC (0.66 and 0.69, respectively) and SWOP-RC (0.64 and 0.70, respectively). Decision analysis taking into account the harms of transrectal ultrasound measurements of prostate volume, found little benefit for ProstateCheck-RC, with inferior properties to the PCPT- and SWOP-RC. CONCLUSION: Our independent external evaluation revealed moderate performance of the ProstateCheck-RC. Its clinical benefit is limited and inferior to the PCPT- and SWOP-RC