Do we need MRI in all biopsy naïve patients? A multicenter cohort analysis.

PURPOSE: The combined approach (CB) of magnetic resonance imaging (MRI)-guided biopsy (TB) and systematic biopsy (SB) is strongly recommended based on numerous studies in biopsy naïve men with suspicion of clinically significant prostate cancer (csPCA). However, the unbalanced accessibility of MRI, challenges related to reimbursement and the scarcity of specialized medical practitioners continue to impede a widespread implementation. Therefore, our objective was to determine a subset of men that could undergo SB without an increased risk of underdiagnosis at reduced expenses. METHODS: A multicenter analysis of 2714 men with confirmed PCA and suspicious MRI who underwent CB were enrolled. Cancer detection rates were compared between the different biopsy routes SB, TB and CB using McNemar paired test. Additionally, Gleason grade up- and down-grading was determined. RESULTS: CB detected more csPCA than TB and SB (p < 0.001), irrespective of MRI findings or biopsy route (transperineal vs. transrectal). Thereby, single biopsy approaches misgraded > 50% of csPCA. TB showed higher diagnostic efficiency, defined as csPCA detection per biopsy core than CB and SB (p < 0.001). For patients with abnormal DRE and PSA levels > 12.5 ng/ml, PSAD > 0.35 ng/ml/cm3, or > 75 years, SB and CB showed similar csPCA detection rates. CONCLUSION: Conducting CB provides the highest level of diagnostic certainty and minimizes the risk of underdiagnosis in almost all biopsy-naive men. However, in patients with suspicious DRE and high PSA levels, PSAD, or advanced age solely using SB leads to similar csPCA detection rates. Thus, a reduced biopsy protocol may be considered for these men in case resources are limited.

[Precision oncology options in urological cancers]. / Zielgerichtete Therapieoptionen in der Uroonkologie.

Advancements in the molecular genetic understanding of urological tumors have enabled the identification of numerous new therapeutic targets. Based on routinely applicable tumor sequencing, individual treatment decisions have been introduced in the context of precision oncology. This work provides an overview of the latest targeted tumor therapies in the treatment of prostate cancer, urothelial carcinoma, and renal cell carcinoma. Current studies on the administration of FGFR-inhibitors ("fibroblast growth factor receptor") in metastatic urothelial carcinoma show a high tumor response in patients with selected FGFR alterations. PARP-inhibitors ("Poly-[ADP-Ribose-]Polymerase") are routinely used in the treatment of metastatic prostate cancer. Patients with a BRCA mutation ("BReast CAncer gene") show high radiological response rates. Moreover, we discuss the latest results of the combination of PARP inhibitors with novel androgen receptor pathway inhibitors. In metastatic prostate cancer, there are numerous ongoing studies evaluating the promising drug targets PI3K/AKT/mTOR ("Phosphatidylinositol-3-Kinase")/AKT/mTOR ("mammalian target of rapamycine") and VEGF signaling pathways ("vascular endothelial growth factor"). A HIF-2a inhibitor ("hypoxia inducible factor") offers a promising new therapeutic option for metastatic renal cell carcinoma. Overall, molecular diagnostics to determine the right therapy for the right patient subgroup at the right time is important for uro-oncological precision medicine.

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.

Prediction of Significant Prostate Cancer in Equivocal Magnetic Resonance Imaging Lesions: A High-volume International Multicenter Study.

BACKGROUND: Decision of performing prostate biopsy in men with Prostate Imaging Reporting and Data System (PI-RADS) 3 findings in prostate magnetic resonance imaging (MRI) is challenging as they have a low but still relevant risk of harboring significant prostate cancer (sPC). OBJECTIVE: To identify clinical predictors of sPC in men with PI-RADS 3 lesions in prostate MRI and to analyze the hypothetical effect of incorporating prostate-specific antigen density (PSAD) into biopsy decision. DESIGN, SETTING, AND PARTICIPANTS: We analyzed a retrospective multinational cohort from ten academic centers comprising 1476 men who underwent a combined prostate biopsy (MRI targeted plus systematic biopsy) between February 2012 and April 2021 due to a PI-RADS 3 lesion in prostate MRI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the detection of sPC (ISUP ≥2) in a combined biopsy. Predictors were identified by a regression analysis. Descriptive statistics were applied to evaluate the hypothetical effect of involving PSAD into biopsy decision. RESULTS AND LIMITATIONS: Of all patients, 273/1476 (18.5%) were diagnosed with sPC. MRI-targeted biopsy diagnosed fewer sPC cases than combined strategy: 183/1476 (12.4%) versus 273/1476 (18.5%), p < 0.01. Age (odds ratio [OR] 1.10 [95% confidence interval {CI}: 1.05-1.15], p < 0.001), prior negative biopsy (OR 0.46 [0.24-0.89], p = 0.022), and PSAD (p < 0.001) were found to be independent predictors of sPC. Applying a PSAD cutoff of 0.15, 817/1398 (58.4%) biopsies would have been avoided at the cost of missing sPC in 91 (6.5%) men. Limitations were the retrospective design, heterogeneity of the study cohort due to the long inclusion period, and no central revision of MRI. CONCLUSIONS: Age, previous biopsy status, and PSAD were found to be independent predictors of sPC in men with equivocal prostate MRI. Implementation of PSAD into biopsy decision can avoid unnecessary biopsies. Clinical parameters such as PSAD need validation in a prospective setting. PATIENT SUMMARY: In this study, we looked for clinical predictors of significant prostate cancer in men with Prostate Imaging Reporting and Data System 3 lesions in prostate magnetic resonance imaging. We identified age, previous biopsy status, and especially prostate-specific antigen density as independent predictors.

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.

[Molecular diagnostics and molecular tumor board in uro-oncology : Precision medicine using the example of metastatic castration-resistant prostate cancer]. / Molekulare Diagnostik und molekulares Tumorboard in der Uroonkologie : Präzisionsmedizin am Beispiel des metastasierten kastrationsresistenten Prostatakarzinoms.

Novel approaches to molecular tumor profiling evaluate DNA, RNA and protein alterations to create a detailed molecular map that enables precise and personalized treatment decisions. As the field of molecular profiling is constantly evolving, the training and networking of doctors is of decisive importance. Through the establishment of precision medicine with precision oncological consultations supported by interdisciplinary molecular tumor boards, many patients with difficult to treat tumor diseases can be advised and treated. Many pathophysiological relationships in progressive tumors can be elucidated resulting in new therapeutic options for the profiled patients; however, understanding the complex mutational profiles remains a very demanding task that requires a suitably trained and committed team that should be in close contact with the scientific advancements in precision oncology.

Active surveillance inclusion criteria under scrutiny in magnetic resonance imaging-guided prostate biopsy: a multicenter cohort study.

BACKGROUND: Although multiparametric magnetic resonance imaging (mpMRI) is recommended for primary risk stratification and follow-up in Active Surveillance (AS), it is not part of common AS inclusion criteria. The objective was to compare AS eligibility by systematic biopsy (SB) and combined MRI-targeted (MRI-TB) and SB within real-world data using current AS guidelines. METHODS: A retrospective multicenter study was conducted by a German prostate cancer (PCa) working group representing six tertiary referral centers and one outpatient practice. Men with PCa and at least one MRI-visible lesion according to Prostate Imaging Reporting and Data System (PI-RADS) v2 were included. Twenty different AS inclusion criteria of international guidelines were applied to calculate AS eligibility using either a SB or a combined MRI-TB and SB. Reasons for AS exclusion were assessed. RESULTS: Of 1941 patients with PCa, per guideline, 583-1112 patients with PCa in both MRI-TB and SB were available for analysis. Using SB, a median of 22.1% (range 6.4-72.4%) were eligible for AS. Using the combined approach, a median of 15% (range 1.7-68.3%) were eligible for AS. Addition of MRI-TB led to a 32.1% reduction of suitable patients. Besides Gleason Score upgrading, the maximum number of positive cores were the most frequent exclusion criterion. Variability in MRI and biopsy protocols potentially limit the results. CONCLUSIONS: Only a moderate number of patients with PCa can be monitored by AS to defer active treatment using current guidelines for inclusion in a real-world setting. By an additional MRI-TB, this number is markedly reduced. These results underline the need for a contemporary adjustment of AS inclusion criteria.

Potential Candidates for Focal Therapy in Prostate Cancer in the Era of Magnetic Resonance Imaging-targeted Biopsy: A Large Multicenter Cohort Study.

BACKGROUND: Focal therapy (FT) with its favorable side-effect profile represents an option between active surveillance and traditional whole-gland treatment in localized prostate cancer (PCa). Consensus statements recommend eligibility criteria based on magnetic resonance imaging (MRI)-targeted and systematic combination biopsy. OBJECTIVE: To estimate the future potential of FT by analyzing the number of men eligible for FT among all men with biopsy-proven PCa and to judge the potential of different energy sources. DESIGN, SETTING, AND PARTICIPANTS: Consensus criteria on FT were analyzed. Patients with biopsy-proven PCa from six tertiary referral hospitals and one outpatient practice in Germany had received a software-based combination biopsy. Men with Prostate Imaging Reporting and Data System (PI-RADS) ≥3 lesions based on PI-RADS v2 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were analyzed for potential treatment by FT and hemiablation. MRI lesions were mapped according to prostatic zones. RESULTS AND LIMITATIONS: In total, 2371 patients were analyzed. According to consensus criteria (biopsy-proven unifocal lesion of International Society of Urological Pathology [ISUP] grade group ≤2, prostate-specific antigen [PSA] ≤15ng/mL, and life expectancy >10yr), 303 patients (12.8%; ISUP 1: n=148 [6.2%]; ISUP 2: n=155 [6.5%]) were potential candidates for FT. A maximum PSA level of <10ng/mL would exclude further 60 (2.5%) of these men. The eligibility for hemiablation is slightly higher (16.2%). Unifocal lesions (n=288) were equally distributed within the prostate (anteriorly [31%], apically [29%], and dorsally [36%]). CONCLUSIONS: With adherence to consensus statements, only a minority of PCa patients present as potential candidates for FT. Distribution of tumor localization suggests the need for different energy modalities to warrant an optimal FT treatment. PATIENT SUMMARY: We analyzed how many men who receive a magnetic resonance imaging-targeted and systematic prostate biopsy are candidates for the experimental focal therapy of the prostate. When following expert recommendations, only a small number of men are potential candidates for this alternative treatment.

Mesenchymal stem cells from reaming material possess high osteogenic potential and react sensitively to bone morphogenetic protein 7.

BACKGROUND: Femoral material harvested using the Reamer-Irrigator-Aspirator (RIA) system is an alternative source for autogenous bone material in the treatment of non-unions, especially in combination with bone morphogenetic proteins (BMP). So far, there is no in vivo evidence of BMP-7 interacting with mesenchymal stem cells (MSCs) from RIA material (RIA-MSCs) and iliac crest autogenous bone (BMSCs). The aim of this study was to compare their osteogenic potential when stimulated with BMP-7 in vivo. METHODS: RIA-MSC and BMSC from 11 donors were isolated and the character of MSCs was investigated in vitro. Constructs consisting of MSC, ß-tricalcium phosphate and 2 concentrations of BMP-7 (0.1 µg/mL and 1 µg/mL) were implanted in mice for 8 weeks. Bone formation in the constructs was analyzed quantitatively and qualitatively. RESULTS: All cell populations used were determined to be MSCs. The qualitative in vivo analysis showed formation of bone tissue. With regard to quantity, bone formation was significantly higher in RIA constructs without or with stimulation with 0.1 µg/mL BMP-7, compared with BMSC constructs. We found no significant differences between constructs stimulated with 1 µg/mL BMP-7. In the RIA group, we observed a significant increase in bone formation after stimulation with 0.1 µg/mL BMP-7. No significant change could be found using a higher concentration. In the BMSC group, we detected a significant increase when using 0.1 µg/mL and 1 µg/mL BMP-7. CONCLUSIONS: RIA material is a source of MSCs with high osteogenic potential. Our results showed that stimulation by BMP-7 leads to an increased osteogenic potential of MSCs. In this respect, RIA-MSCs reacted more sensitively than BMSCs.