PD-L1 expression in tumor and inflammatory cells is associated with favorable tumor features and favorable prognosis in muscle-invasive urothelial carcinoma of the bladder not treated by immune checkpoint inhibitors.

BACKGROUND: A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. METHODS: To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. RESULTS: Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2-4) carcinomas (29.3%; p < 0.0001). However, within pT2-4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). CONCLUSION: It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma.

Transplant nephrectomy: indication, surgical approach and complications-experiences from a single transplantation center.

PURPOSE: Management of a failed kidney allograft, and the question whether it should be removed is a challenging task for clinicians. The reported risks for transplant nephrectomy (TN) vary, and there is no clear recommendation on indications or surgical approach that should be used. This study gives an overview of indications, compares surgical techniques, and identifies risk factors for higher morbidity. METHODS: Retrospective analysis was conducted on all transplant nephrectomies performed between 2005 and 2020 at Charité Hospital Berlin, Department of Urology. Patient demographics, laboratory parameters, graft survival data, indication for TN, and surgical complications were extracted from medical reports. RESULTS: A total of 195 TN were performed, with graft intolerance syndrome being the most common indication in 52 patients (26.7%), acute rejection in 36 (18.5%), acute infection in 30 (15.4%), and other reasons to stop immunosuppression in 26 patients (13.3%). Rare indications were vascular complications in 16 (8.2%) and malignancies in the allograft in six (3.1%) cases. Extracapsular surgical approach was significantly more often used in cases of vascular complications and earlier allograft removal, but there was no difference in complication rates between extra- and intracapsular approach. Acute infection was identified as an independent risk factor for a complication grade IIIb or higher according to Clavien-Dindo classification, with a HR of 12.3 (CI 2.2-67.7; p = 0.004). CONCLUSION: Transplant nephrectomy should only be performed when there is a good indication, and non-elective surgery should be avoided, when possible, as it increases morbidity.

Prognostic Impact and Spatial Interplay of Immune Cells in Urothelial Cancer.

BACKGROUND: Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. OBJECTIVE: To characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Spatial immune parameters were compared with histopathological parameters and overall survival data. RESULTS AND LIMITATIONS: The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. CONCLUSIONS: The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. PATIENT SUMMARY: Quantification of intraepithelial CD8+ T cells, the strongest prognostic feature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology.

Loss of Upk1a and Upk1b expression is linked to stage progression in urothelial carcinoma of the bladder.

BACKGROUND: Uroplakin-1a (Upk1a) and uroplakin-1b (Upk1b) have recently been identified as diagnostic markers for the distinction of urothelial carcinomas from other solid tumor entities. Both proteins play an important role in the stabilization and strengthening of epithelial cells that line the bladder. METHODS: To evaluate the prognostic role of uroplakin expression in urothelial carcinomas, more than 2700 urothelial neoplasms were analyzed in a tissue microarray format by immunohistochemistry. To further assess the diagnostic role of uroplakin immunohistochemistry, results were compared with preexisting GATA3 data. RESULT: The fraction of Upk1a/Upk1b positive cases decreased slightly from pTaG2 low-grade (88% positive for Upk1a/87% positive for Upk1b) and pTaG2 high-grade (92%/89%) to pTaG3 (83%/88%; p > 0.05) and was lower in muscle-invasive (pT2-4) carcinomas (42%/64%; p < 0.0001/p < 0.0001 for pTa vs. pT2-4). Within pT2-4 carcinomas, high expression of Upk1a and Upk1b was linked to nodal metastasis and lymphatic vessel infiltration (p < 0.05) but unrelated to patient outcome. There were significant associations between Upk1a, Upk1b and GATA3 immunostaining (p < 0.0001 each), but 11% of GATA3 negative cancers were Upk1a/b positive and 8% of Upk1a/b negative cancers were GATA3 positive. Absence of GATA3/Upk1a/b staining was significantly linked to poor patient survival in the subgroup of 126 pT4 carcinomas (p = 0.0004) but not in pT2 and pT3 cancers. CONCLUSIONS: In summary, the results of our study demonstrate that Upk1a and/or Upk1b immunohistochemistry can complement GATA3 for the distinction of urothelial carcinomas. Furthermore, a progressive loss of Upk1a/b expression during stage progression and a prognostic role of the combination GATA3/Upk1a/Upk1b in pT4 carcinomas is evident.

Follow-Up of Men Who Have Undergone Focal Therapy for Prostate Cancer with HIFU-A Real-World Experience.

PURPOSE: To determine oncological and functional outcomes and side effects after focal therapy of prostate cancer (PCa) with high-intensity focused ultrasound (HIFU). METHODS: This retrospective single-center study included 57 consecutive patients with localised PCa. Aged 18-80 with ≤2 suspicious lesions on mpMRI (PIRADS ≥ 3), PSA of ≤15 ng/mL, and an ISUP GG of ≤2. HIFU was performed between November 2014 and September 2018. All men had an MRI/US fusion-guided targeted biopsy (TB) combined with a TRUS-guided 10-core systematic biopsy (SB) prior to focal therapy. HIFU treatment was performed as focal, partial, or hemiablative, depending on the prior histopathology. Follow-up included Questionnaires (IIEF-5, ICIQ, and IPSS), prostate-specific antigen (PSA) measurement, follow-up mpMRI, and follow-up biopsies. RESULTS: The median age of the cohort was 72 years (IQR 64-76), and the median PSA value before HIFU was 7.3 ng/mL (IQR 5.75-10.39 ng/mL). The median follow-up was 27.5 (IQR 23-41) months. At the time of the follow-up, the median PSA value was 2.5 ng/mL (IQR 0.94-4.96 ng/mL), which shows a significant decrease (p < 0.001). In 17 (29.8%) men, mpMRI revealed a suspicious lesion, and 19 (33.3%) men had a positive biopsy result. Only IIEF values significantly decreased from 16 (IQR 10.75-20.25) to 11.5 (IQR 4.5-17) (p < 0.001). The rate of post-HIFU complications was low, at 19.3% (11 patients). The limitation of this study is the lack of long-term follow-up. CONCLUSIONS: HIFU as a therapy option for nonmetastatic, significant prostate cancer is effective in the short term for carefully selected patients and shows a low risk of adverse events and side effects.

Altered p53/p16 expression is linked to urothelial carcinoma progression but largely unrelated to prognosis in muscle-invasive tumors.

BACKGROUND: Most inactivating p53 mutations result in a nuclear p53 accumulation - detectable by immunohistochemistry (IHC). p53 alterations leading to a complete lack of p53 protein and absence of immunostaining do also occur - not easily detectable by IHC. p16 is upregulated in p53 inactivated cells. We hypothesized that a positive p16 IHC may help to distinguish p53 inactivation in IHC negative cases. MATERIAL AND METHODS: We investigated p53 and p16 immunostaining on 2710 urothelial bladder carcinomas in a tissue microarray format to understand their impact in relation to clinicopathological parameters of disease progression and patient outcome. RESULTS: p16 immunostaining was absent in normal urothelium but occurred in 63.5% (30.4% strong) of cancers. p16 strongly positive cases increased from pTaG2 low-grade (9.6%) to pTaG3 high-grade tumors (46.5%, p < .0001) but decreased from pTaG3 to pT4 (33.3%; p = .0030). Among pT2-4 carcinomas, p16 positivity was linked to high-grade (p = .0005) but unrelated to overall survival. p53 staining was negative in 8.4%, very weak in 15.4%, weak in 55.3%, strong in 4.7%, and very strong in 16.2% cancers. p53 negative (potentially p53 null phenotype), strong, and very strong p53 positivity increased from pTaG2 low-grade to pTaG3 high-grade tumors (p < .0001) and from pTaG3 to pT2-4 cancers (p = .0007). p53 staining was largely unrelated to histopathological parameters or patient prognosis among pT2-4 carcinomas, except of p53 strong/very strong immunostaining. p16 expression predominated in tumors with very strong, strong, and negative p53 staining and the combination of p53 negative/p16 strongly positive cancers was linked to features of tumor aggressiveness. CONCLUSION: Aberrant p53 and p16 immunostaining increases during grade and stage progression although p53 negative and p16 positive immunostaining lack prognostic significance in pT2-4 carcinomas. Potential diagnostic features are that high level p16 expression is limited to neoplastic urothelium and p53 null phenotype to aggressive cancers (grade 3 and invasive).

BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL as urinary marker for bladder cancer: Final results of a German multicenter study.

INTRODUCTION AND OBJECTIVE: BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL are urinary-based rapid tests. This multicenter study is the first study comparing all available rapid tests on a large cohort of bladder cancer patients and healthy controls in one setting. METHODS: In total 732 urine samples (second morning urine) in a real-world assessment have been analyzed. We evaluated clinical samples from 464 patients with histologically confirmed urothelial tumors of the urinary bladder (17 solitary CIS, 189 low-grade, 187 high-grade nonmuscle invasive, 71 high-grade muscle invasive), 77 patients with No Evidence of Disease (NED), and from 191 healthy controls. Urine samples were analyzed by the BTA stat®, NMP22® BladderChek®, UBC® Rapid Test point-of-care (POC) system using the concile Omega 100 POC reader, and CancerCheck® UBC® rapid VISUAL. Sensitivities and specificities were calculated by contingency analyses. RESULTS: All investigated urinary markers detected more pathological concentrations in urine of bladder cancer patients compared to tumor-free patients. The calculated diagnostic sensitivities for BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, CancerCheck® UBC® rapid VISUAL, and cytology were 62.4%, 13.4%, 58.2%, 28.6%, 36.2% for low-grade, 83.4%, 49.5%, 84.5%, 63.1%, 71.2% for high-grade nonmuscle invasive, and 95.8%, 35.2%, 76.1%, 50.7%, 67.7% for high-grade muscle-invasive bladder cancer. The specificity was 67.9%, 95.5%, 79.4%, 94.4%, and 83.7%, respectively. The area under the curve (AUC) after receiver operating characteristics (ROC) analysis for high-grade non-muscle-invasive tumors was 0.757, 0.725, 0.819, 0.787, and 0.774, respectively. CONCLUSIONS: The analysis of more than 700 urine samples offers an objective view on urine-based rapid diagnostics. Elevated pathological concentrations of markers in urine of bladder cancer patients were detected in all investigated tests. The highest sensitivities for high-grade non-muscle-invasive tumors were calculated for BTA stat® and UBC® Rapid Test, whereas NMP22® BladderChek®, and cytology showed the highest specificities. BTA stat® and UBC® Rapid Test have the potential to be used as a clinical valuable urinary protein biomarker for the detection of high-grade non-muscle-invasive bladder cancer patients and could be included in the management of these tumors.

Interactive Explainable Deep Learning Model Informs Prostate Cancer Diagnosis at MRI.

Background Clinically significant prostate cancer (PCa) diagnosis at MRI requires accurate and efficient radiologic interpretation. Although artificial intelligence may assist in this task, lack of transparency has limited clinical translation. Purpose To develop an explainable artificial intelligence (XAI) model for clinically significant PCa diagnosis at biparametric MRI using Prostate Imaging Reporting and Data System (PI-RADS) features for classification justification. Materials and Methods This retrospective study included consecutive patients with histopathologic analysis-proven prostatic lesions who underwent biparametric MRI and biopsy between January 2012 and December 2017. After image annotation by two radiologists, a deep learning model was trained to detect the index lesion; classify PCa, clinically significant PCa (Gleason score ≥ 7), and benign lesions (eg, prostatitis); and justify classifications using PI-RADS features. Lesion- and patient-based performance were assessed using fivefold cross validation and areas under the receiver operating characteristic curve. Clinical feasibility was tested in a multireader study and by using the external PROSTATEx data set. Statistical evaluation of the multireader study included Mann-Whitney U and exact Fisher-Yates test. Results Overall, 1224 men (median age, 67 years; IQR, 62-73 years) had 3260 prostatic lesions (372 lesions with Gleason score of 6; 743 lesions with Gleason score of ≥ 7; 2145 benign lesions). XAI reliably detected clinically significant PCa in internal (area under the receiver operating characteristic curve, 0.89) and external test sets (area under the receiver operating characteristic curve, 0.87) with a sensitivity of 93% (95% CI: 87, 98) and an average of one false-positive finding per patient. Accuracy of the visual and textual explanations of XAI classifications was 80% (1080 of 1352), confirmed by experts. XAI-assisted readings improved the confidence (4.1 vs 3.4 on a five-point Likert scale; P = .007) of nonexperts in assessing PI-RADS 3 lesions, reducing reading time by 58 seconds (P = .009). Conclusion The explainable AI model reliably detected and classified clinically significant prostate cancer and improved the confidence and reading time of nonexperts while providing visual and textual explanations using well-established imaging features. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Chapiro in this issue.

Cytokeratin 20 expression is linked to stage progression and to poor prognosis in advanced (pT4) urothelial carcinoma of the bladder.

Cytokeratin 20 (CK20) expression is limited to umbrella cells in the normal urothelium. Since CK20 is often upregulated in neoplastic urothelial cells including dysplasia and carcinoma in situ, immunohistochemical CK20 analysis is often used for the assessment of bladder biopsies. CK20 expression is a feature of luminal bladder cancer subtype, but its prognostic relevance is disputed. In this study, we investigated CK20 on >2700 urothelial bladder carcinomas in a tissue microarray format by immunohistochemistry. Cytoplasmic and membranous CK20 staining was seen in 1319 (51.8%) cancers. The fraction of CK20 positive and especially strongly positive cases increased from pTaG2 low grade (44.5% strongly positive) and pTaG2 high grade (57.7%) to pTaG3 high grade (62.3%; p = 0.0006) but was lower in muscle-invasive (pT2-4) carcinomas (51.1% in all pTa vs. 29.6% in pT2-4; p < 0.0001). Within pT2-4 carcinomas, CK20 positivity was linked to nodal metastasis and lymphatic vessel invasion (p < 0.0001 each) and to venous invasion (p = 0.0177). CK20 staining was unrelated to overall patient survival if all 605 pT2-4 carcinomas were jointly analyzed but subgroup analyses revealed a significant association of CK20 positivity with favorable prognosis in 129 pT4 carcinomas (p = 0.0005). CK20 positivity was strongly linked to the expression of GATA3 (p < 0.0001), another feature of luminal bladder cancer. The combined analysis of both parameters showed best prognosis for luminal A (CK20+/GATA3+, CK20+/GATA3-) and worst outcome for luminal B (CK20-/GATA3+) and basal/squamous (CK20-/GATA3-) in pT4 urothelial carcinomas (p = 0.0005). In summary, the results of our study demonstrate a complex role of CK20 expression in urothelial neoplasms including neoexpression in pTa tumors, a subsequent loss of CK20 expression in a subset of tumors progressing to muscle-invasion, and a stage dependent prognostic role in muscle-invasive cancers.

Discrepancy between German S3 Guideline Recommendations and Daily Urologic Practice in the Management of Nonmuscle Invasive Bladder Cancer: Results of a Binational Survey.

INTRODUCTION: Guideline recommendations are meant to help minimize morbidity and to improve the care of nonmuscle invasive bladder cancer (NMIBC) patients but studies have suggested an underuse of guideline-recommended care. The aim of this study was to evaluate the level of adherence of German and Austrian urologists to German guideline recommendations. METHODS: A survey of 27 items evaluating diagnostic and therapeutic recommendations (15 cases of strong consensus and 6 cases of consensus) for NMIBC was administered among 14 urologic training courses. Survey construction and realization followed the checklist for reporting results of internet e-surveys and was approved by an internal review board. RESULTS: Between January 2018 and June 2019, a total of 307 urologists responded to the questionnaire, with a mean response rate of 71%. The data showed a weak role of urine cytology (54%) for initial diagnostics although it is strongly recommended by the guideline. The most frequently used supporting diagnostic tool during transurethral resection of the bladder was hexaminolevulinate (95%). Contrary to the guideline recommendation, 38% of the participants performed a second resection in the case of pTa low-grade NMIBC. Correct monitoring of Bacille Calmette-Guérin (BCG) response with cystoscopy and cytology was performed by only 34% of the urologists. CONCLUSIONS: We found a discrepancy between certain guideline recommendations and daily routine practice concerning the use of urine cytology for initial diagnostics, instillation therapy with a low monitoring rate of BCG response, and follow-up care with unnecessary second resection after pTa low-grade NMIBC in particular. Our survey showed a moderate overall adherence rate of 73%. These results demonstrate the need for sharpening awareness of German guideline recommendations by promoting more intense education of urologists to optimize NMIBC care thus decreasing morbidity and mortality rates.

MRI-targeted biopsy cores from prostate index lesions: assessment and prediction of the number needed.

BACKGROUND: Magnetic resonance imaging (MRI) is used to detect the prostate index lesion before targeted biopsy. However, the number of biopsy cores that should be obtained from the index lesion is unclear. The aim of this study is to analyze how many MRI-targeted biopsy cores are needed to establish the most relevant histopathologic diagnosis of the index lesion and to build a prediction model. METHODS: We retrospectively included 451 patients who underwent 10-core systematic prostate biopsy and MRI-targeted biopsy with sampling of at least three cores from the index lesion. A total of 1587 biopsy cores were analyzed. The core sampling sequence was recorded, and the first biopsy core detecting the most relevant histopathologic diagnosis was identified. In a subgroup of 261 patients in whom exactly three MRI-targeted biopsy cores were obtained from the index lesion, we generated a prediction model. A nonparametric Bayes classifier was trained using the PI-RADS score, prostate-specific antigen (PSA) density, lesion size, zone, and location as covariates. RESULTS: The most relevant histopathologic diagnosis of the index lesion was detected by the first biopsy core in 331 cases (73%), by the second in 66 cases (15%), and by the third in 39 cases (9%), by the fourth in 13 cases (3%), and by the fifth in two cases (<1%). The Bayes classifier correctly predicted which biopsy core yielded the most relevant histopathologic diagnosis in 79% of the subjects. PI-RADS score, PSA density, lesion size, zone, and location did not independently influence the prediction model. CONCLUSION: The most relevant histopathologic diagnosis of the index lesion was made on the basis of three MRI-targeted biopsy cores in 97% of patients. Our classifier can help in predicting the first MRI-targeted biopsy core revealing the most relevant histopathologic diagnosis; however, at least three MRI-targeted biopsy cores should be obtained regardless of the preinterventionally assessed covariates.

Loss of TROP2 and epithelial cell adhesion molecule expression is linked to grade progression in pTa but unrelated to disease outcome in pT2-4 urothelial bladder carcinomas.

Introduction: Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for the antibody-drug conjugate Sacituzumab govitecan (SG; TrodelvyTM) which has been approved for treatment of metastatic urothelial carcinoma by the United States Food and Drug administration (FDA) irrespective of its TROP2 expression status. Methods: To evaluate the potential clinical significance of subtle differences in TROP2 and EpCAM expression in urothelial bladder cancer, both proteins were analyzed by multiplex fluorescence immunohistochemistry in combination with a deep-learning based algorithm for automated cell detection on more than 2,700 urothelial bladder carcinomas in a tissue microarray (TMA) format. Results: The staining pattern of TROP2 and EpCAM were highly similar. For both proteins, the staining intensity gradually decreased from pTa G2 low grade (TROP2: 68.8±36.1; EpCAM: 21.5±11.7) to pTa G2 high grade (64.6±38.0; 19.3±12.2) and pTa G3 (52.1±38.7; 16.0±13.0, p<0.001 each). In pT2-4 carcinomas, the average TROP2 and EpCAM staining intensity was intermediate (61.8±40.9; 18.3±12.3). For both proteins, this was significantly lower than in pTa G2 low grade (p<0.001 each) but also higher than in pTa G3 tumors (p=0.022 for TROP2, p=0.071 for EpCAM). Within pT2-4 carcinomas, the TROP2 and EpCAM staining level was unrelated to pT, grade, UICC-category, and overall or tumor-specific patient survival. The ratio TROP2/EpCAM was unrelated to malignant phenotype and patient prognosis. Conclusion: Our data show that TROP2 and EpCAM expression is common and highly interrelated in urothelial neoplasms. Despite of a progressive loss of TROP2/EpCAM during tumor cell dedifferentiation in pTa tumors, the lack of associations with clinicopathological parameters in pT2-4 cancer argues against a major cancer driving role of both proteins for the progression of urothelial neoplasms.

GATA3 expression loss is linked to stage progression but is unrelated to prognosis in muscle-invasive urothelial carcinoma of the bladder.

The transcription factor GATA binding protein 3 (GATA3) is commonly used in surgical pathology as a diagnostic marker to distinguish urothelial carcinomas from other cancer entities. However, the clinical relevance of GATA3 expression in urothelial bladder cancer is not completely clarified. In this study, we investigated GATA3 immunostaining on 2710 urothelial bladder carcinomas on a tissue microarray platform by using two different antibodies to better understand its impact in relation to pathological parameters of disease progression and patient outcome. Nuclear GATA3 immunostaining was regularly seen in normal urothelium and found in 74%/82% of interpretable urothelial neoplasms depending on the antibody used. Within pTa tumors, the rate of GATA3 positive tumors decreased with advancing grade. GATA3 positivity was seen in 98.6%/99.8% of pTaG2 low-grade, 98.6%/100% of pTaG2 high-grade, and 94.9%/99.2% of pTaG3 high-grade tumors (P = .0002). As compared to pTa tumors, GATA3 positivity was markedly less common in muscle-invasive urothelial carcinoma (59.9%/71.6%; P < .0001). Within pT2-4 cancers, high-level GATA3 immunostaining was associated with the presence of lymph node metastasis (P = .0034), and blood vessel (P = .0290) or lymphatic invasion (P = .0005) but unrelated to pT stage. GATA3 immunostaining results for both antibodies were not associated with overall survival in 586 patients treated by cystectomy for pT2-4 urothelial carcinoma. The results of our study identify GATA3 expression as a frequent event in noninvasive urothelial carcinomas with favorable tumor features. Loss of GATA3 immunostaining is linked with muscle-invasive disease but is largely unrelated to pathological parameters and patient prognosis.

Follow-up of men with a PI-RADS 4/5 lesion after negative MRI/Ultrasound fusion biopsy.

Magnetic resonance imaging/Ultrasound (MRI/US) fusion targeted biopsy (TB) in combination with a systematic biopsy (SB) improves cancer detection but limited data is available how to manage patients with a Prostate Imaging-Reporting and Data System (PI-RADS) ≥ 4 lesion and a negative biopsy. We evaluate the real-world management and the rate of clinically significant Prostate Cancer (csPCa) during follow-up. 1546 patients with a multi-parametric MRI (mpMRI) and a PI-RADS ≥ 3 who underwent SB and TB between January 2012 and May 2017 were retrospectively analyzed. 222 men with a PI-RADS ≥ 4 and a negative biopsy were included until 2019. For 177/222 (80%) complete follow-up data was obtained. 66/84 (78%) had an initial PI-RADS 4 and 18 (22%) a PI-RADS 5 lesion. 48% (84/177) received a repeat mpMRI; in the follow-up mpMRI, 39/84 (46%) lesions were downgraded to PI-RADS 2 and 11 (13%) to PI-RADS 3; three cases were upgraded and 28 lesions remained consistent. 18% (32/177) men underwent repeated TB and csPCa was detected in 44% (14/32). Our study presents real world data on the management of men with a negative TB biopsy. Men with a positive mpMRI and lesions with high suspicion (PI-RADS4/5) and a negative targeted biopsy should be critically reviewed and considered for repeat biopsy or strict surveillance. The optimal clinical risk assessment remains to be further evaluated.

A non-inferiority comparative analysis of micro-ultrasonography and MRI-targeted biopsy in men at risk of prostate cancer.

OBJECTIVE: To compare the efficacy of multiparametric magnetic resonance imaging (mpMRI)-directed and micro-ultrasonography (micro-US)-directed biopsy for detecting clinically significant (Grade Group >1) prostate cancer (csPCa). MATERIALS AND METHODS: A total of 203 patients were prospectively enrolled at three institutions across Germany and Austria in the period from January 2019 to December 2019. During each biopsy, the urologist was blinded to the mpMRI report until after the micro-US targets had been assessed. After unblinding, targets were then sampled using software-assisted fusion, followed by systematic samples. The primary outcome measure was non-inferiority of micro-US to detect csPCa, with a detection ratio of at least 80% that of mpMRI. RESULTS: A total of 79 csPCa cases were detected overall (39%). Micro-US-targeted biopsy detected 58/79 cases (73%), while mpMRI-targeted biopsy detected 60/79 (76%) and non-targeted (completion sampling) samples detected 45/79 cases (57%). mpMRI-targeted samples alone detected 7/79 (9%) csPCa cases which were missed by micro-US-targeted and non-targeted samples. Three of these seven were anterior lesions with 2/7 in the transition zone. Micro-US-targeted samples alone detected 5/79 (6%) and completion sampling alone detected 4/79 cases (5%). Micro-US was non-inferior to mpMRI and detected 97% of the csPCa cases detected by mpMRI-targeted biopsy (95% CI 80-116%; P = 0.023). CONCLUSIONS: This is the first multicentre prospective study comparing micro-US-targeted biopsy with mpMRI-targeted biopsy. The study provides further evidence that micro-US can reliably detect cancer lesions and suggests that micro-US biopsy might be as effective as mpMRI for detection of csPCA. This result has significant implications for increasing accessibility, reducing costs and expediting diagnosis.

Evolution of Targeted Prostate Biopsy by Adding Micro-Ultrasound to the Magnetic Resonance Imaging Pathway.

BACKGROUND: Although multiparametric magnetic resonance imaging (mpMRI) revolutionized the implementation of prostate biopsies, a considerable amount of clinically significant prostate cancer (csPCa) is missed when performing mpMRI-targeted biopsies only. Microultrasound (micro-US) is a new modality that allows real-time targeting of suspicious regions. OBJECTIVE: To evaluate micro-US of the prostate with real-time targeting of suspicious regions in patients suspected to have prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: We examined 159 patients with prior mpMRI and suspicion of PCa with micro-US in the period from February to December 2018. Micro-US lesions were documented according to the prostate risk identification for micro-US (PRI-MUS) protocol, and were blinded to the mpMRI results and targeted independently of the mpMRI lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main outcomes were cancer detection rate, additional detection of csPCa, and International Society of Urological Pathology (ISUP) grade group upgrading via micro-US. RESULTS AND LIMITATIONS: PCa was found in 113/159 (71%) men, with 49% (78/159) having clinically significant cancer (csPCa; ISUP ≥ 2). Micro-US-targeted biopsies resulted in a higher ISUP grade group than the nontargeted biopsies in 26% (42/159), compared with both nontargeted and MRI-targeted biopsies in 16% (26/159). In 17% (27/159) of patients, targeted mpMRI-guided biopsy was negative with cancer identified in the micro-US-guided biopsy, of whom 20 had csPCa. The comparison with only MRI-positive patients is the main limitation of this analysis. CONCLUSIONS: Our data show an added benefit of micro-US in addition to mpMRI-targeted biopsies in a population of men at risk of PCa. A novel biopsy protocol with solely targeted biopsy with micro-US and mpMRI seems possible, replacing conventional ultrasound and omitting standard systematic biopsies. PATIENT SUMMARY: In this report, we looked at the performance of microultrasound in the setting of diagnosing prostate cancer. We found that microultrasound is a good addition to magnetic resonance imaging (MRI) of the prostate and presents an alternative for men who may not undergo MRI.

[Current practice patterns of perioperative cystectomy management in Germany: a questionnaire survey]. / Sicher zwischen Leitlinie und Leitplanke: Umfrage zur Praxis des perioperativen Managements der radikalen Zystektomie in Deutschland.

OBJECTIVE: Radical cystectomy (RCX) is the standard treatment for muscle-invasive and treatment-refractory non-invasive bladder cancer, but that is associated with high morbidity. We now survey current practice patterns on perioperative management among German urological departments of all sizes METHODS: Members of the German Association of Urology and the German Society of Residents in Urology (GeSRU) were contacted by email and asked to answer a 24-item online questionnaire covering clinically relevant aspects of current guidelines and controversies. RESULTS: Responses were obtained from at least 19 % of all German urological centers. About 60 % performed preoperative staging using CT urography and chest CT. The most common perioperative antibiotic prophylaxis was a third generation cephalosporin combined with metronidazole (46 %), administered for a median of 5 days. Stentograms for ileal conduit and neobladder are routinely performed in 38 % and 55 % of patients, respectively. Ureteral stents were usually removed 11 - 12 days after the procedure (ileal conduit and neobladder). Based on the surrogate parameters of preoperative bowel preparation, postoperative start of oral nutrition and use of nasogastric tube, fast-track concepts such as ERAS were not generally established (< 50 %). Robot-assisted cystectomy appears to be performed in 15 % of German urological centers and was associated with the number of performed cystectomies (p < 0.001). CONCLUSIONS: Most aspects of perioperative management in cystectomy patients - staging diagnostics, use of antibiotics, stent removal - are performed in accordance with current guidelines. Other clinical questions such as stent imaging before removal and fast track concepts are handled heterogeneously. Guideline-adherence was not associated with hospital size or number of procedures performed.

Comparison of micro-ultrasound and multiparametric magnetic resonance imaging for prostate cancer: A multicenter, prospective analysis.

INTRODUCTION: High-resolution micro-ultrasound has the capability of imaging prostate cancer based on detecting alterations in ductal anatomy, analogous to multiparametric magnetic resonance imaging (mpMRI). This technology has the potential advantages of relatively low cost, simplicity, and accessibility compared to mpMRI. This multicenter, prospective registry aims to compare the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of mpMRI with high-resolution micro-ultrasound imaging for the detection of clinically significant prostate cancer. METHODS: We included 1040 subjects at 11 sites in seven countries who had prior mpMRI and underwent ExactVu micro-ultrasound-guided biopsy. Biopsies were taken from both mpMRI targets (Prostate Imaging-Reporting and Data System [PI-RADS] >3 and micro-ultrasound targets (Prostate Risk Identification using Micro-ultrasound [PRIMUS] >3). Systematic biopsies (up to 14 cores) were also performed. Various strategies were used for mpMRI target sampling, including cognitive fusion with micro-ultrasound, separate software-fusion systems, and software-fusion using the micro-ultrasound FusionVu system. Clinically significant cancer was those with Gleason grade group ≥2. RESULTS: Overall, 39.5% were positive for clinically significant prostate cancer. Micro-ultrasound and mpMRI sensitivity was 94% vs. 90%, respectively (p=0.03), and NPV was 85% vs. 77%, respectively. Specificities of micro-ultrasound and MRI were both 22%, with similar PPV (44% vs. 43%). This represents the initial experience with the technology at most of the participating sites and, therefore, incorporates a learning curve. Number of cores, diagnostic strategy, blinding to MRI results, and experience varied between sites. CONCLUSIONS: In this initial multicenter registry, micro-ultrasound had comparable or higher sensitivity for clinically significant prostate cancer compared to mpMRI, with similar specificity. Micro-ultrasound is a low-cost, single-session option for prostate screening and targeted biopsy. Further larger-scale studies are required for validation of these findings.

Outcome of Photoselective Vaporization of the Prostate with the GreenLight-XPS 180 Watt System Compared to Transurethral Resection of the Prostate.

The aim of this paper was to compare the perioperative and postoperative results of photoselective vaporization of the prostate with the GreenLight-XPS 180 Watt System (PVP) and transurethral resection of the prostate (TURP). This retrospective study included 140 men who underwent PVP and 114 men who underwent TURP for symptomatic benign prostate enlargement (BPE) between June 2010 and February 2015. The primary outcome measures were the patient reported outcome, operative results, International Prostate Symptom Score-Quality of Life (IPSS-QoL), complication rates, catheterization time, and length of hospital stay. The median follow-up times were 27 months (range 14-44) for the PVP group and 36 months (range 25-47) for the TURP group. The patient characteristics were well balanced in both groups with a median age of 71 years (PVP group) vs. 70 years (TURP group) and a comparable prostate volume (median 50 mL in the PVP group vs. 45 mL in the TURP group). The IPSS-QoL was significantly higher in the PVP group than in the TURP group (median 22 + 4; range 16-27 + 3-5 vs. median 19 + 3; range 15-23 + 3-4; p = 0.02). Men undergoing PVP were more likely to be on anticoagulants (PVP group n = 23; 16% vs. TURP group n = 2; 2%, p < 0.001). The median operation time (OT; min) for both procedures was comparable with 68 min (PVP group; range 53-91) vs. 67 min (TURP group; range 46-85). The rate of severe intraoperative bleeding was significantly lower in the PVP group than in the TURP group (n = 7; 5% vs. n = 16; 14%; p = 0.01). The postoperative catheterization time and length of hospital stay was significantly lower in the PVP group (median 1-2 days; range 1-4) vs. the TURP group (median 2-4 days; range 2-5; both p < 0.001). Complication rates (Clavien-Dindo classification ≥III) based on the follow-up data showed no statistically significant difference between the PVP group and the TURP group (n = 6; 4% vs. n = 6; 5%; p = 0.28). The IPSS on follow-up showed an equivalent reduction in symptoms for both treatment modalities (IPSS-QoL of 5 + 1; range 2-11 + 0-2 for both). There were no differences concerning urge (PVP group n = 3; 2% vs. TURP group n = 3; 3%; p = 0.90) and men were similarly satisfied with the postoperative outcome (PVP group 92% vs. TURP group 87%; p = 0.43). The PVP group was associated with a shorter hospitalization time and showed a reduced risk of bleeding, despite patients remaining on anticoagulants, without increasing the overall operative time. There was no difference in the patient reported outcome for both procedures.

Urinary expression of genes involved in DNA methylation and histone modification for diagnosis of bladder cancer in patients with asymptomatic microscopic haematuria.

The aim of the present study was to identify and test a urine marker panel of genes involved in DNA methylation and histone modification for the detection of urothelial carcinoma of the bladder (UCB). RNA samples obtained from the voided urine of 227 patients with asymptomatic microscopic haematuria (AMH) were analysed. Gene array analysis was performed on 18 randomly selected cDNA samples, which revealed that histone deacetylase 9 (HDAC9), HDAC3, tRNA (cytosine-5-)-methyltransferase1 and DNA methyltransferase 1 were differentially expressed between patients with UCB and control subjects. Subsequently, reverse transcription-quantitative polymerase chain reaction analysis was employed to test the performance of the identified four-gene panel on the remaining 209 cDNA samples. In this targeted discovery cohort, all four genes were significantly associated with UCB on univariable analyses [each odds ratio (OR) >2, P<0.05], but only HDAC3 was significant following multivariable analysis (OR=2.8, P=0.011). The addition of HDAC3 to a base risk factor model improved its accuracy by 1.4%. These data suggest that urinary HDAC3 is associated with the presence of UCB in patients with AMH; however, HDAC3 improved the accuracy of the established risk factors only to a marginal extent.