Exploring membranous NECTIN-4 expression patterns and enfortumab vedotin response in prostate cancer.

Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130-150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.

Trophoblast cell surface antigen-2: a promising new biomarker and potential therapeutic target in penile squamous cell carcinoma.

OBJECTIVE: To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC. METHODS: A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. RESULTS: TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC. CONCLUSION: In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC.

Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer.

PURPOSE: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). METHODS: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro. RESULTS: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. CONCLUSION: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.

Bellmunt risk score as a survival predictor in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The prognosis of metastatic castration-resistant prostate cancer (mCRPC) is influenced by numerous individual factors. Despite various proposed prognostic models, the clinical application of these remains limited, probably due to complexity. Our study aimed to evaluate the predictive value of the Bellmunt risk score, which is well-known for urothelial carcinoma and easily assessed, in mCRPC patients. METHODS: The Bellmunt risk score was calculated from three risk factors (Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥1, serum hemoglobin <10 g/dL, presence of liver metastases) in 125 patients who received first-line mCRPC treatment between 2005 and 2023. In addition, a modified score was established (one point each for hemoglobin <10 g/dL and the presence of liver metastases added to the ECOG PS). Associations with overall survival (OS) under first- and second-line therapy were tested using Cox regression analyzes, log-rank tests, concordance index (C-index) and time-dependent receiver operating characteristic. RESULTS: There is a significant correlation between the level of the Bellmunt risk score and shorter OS (hazard ratio: 3.23, 95% confidence interval: 2.06-5.05; log-rank p < 0.001; C-index: 0.724). The semi-quantitative modified risk score showed even better prognostic discrimination (log-rank p < 0.001, C-index: 0.764). The score and its dynamics were also predictive in the second-line setting (log-rank p < 0.001 and = 0.01; C-index: 0.742 and 0.595). CONCLUSIONS: The Bellmunt risk score is easy to assess and provides useful prognostic information in mCRPC, and can support physicians in their treatment decisions.

Elucidating the need for prostate cancer risk calculators in conjunction with mpMRI in initial risk assessment before prostate biopsy at a tertiary prostate cancer center.

OBJECTIVE: Utilizing personalized risk assessment for clinically significant prostate cancer (csPCa) incorporating multiparametric magnetic resonance imaging (mpMRI) reduces biopsies and overdiagnosis. We validated both multi- and univariate risk models in biopsy-naïve men, with and without the inclusion of mpMRI data for csPCa detection. METHODS: N = 565 men underwent mpMRI-targeted prostate biopsy, and the diagnostic performance of risk calculators (RCs), mpMRI alone, and clinical measures were compared using receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA). Subgroups were stratified based on mpMRI findings and quality. RESULTS: csPCa was detected in 56.3%. PI-RADS score achieved the highest area under the curve (AUC) when comparing univariate risk models (AUC 0.82, p < 0.001). Multivariate RCs showed only marginal improvement in csPCa detection compared to PI-RADS score alone, with just one of four RCs showing significant superiority. In mpMRI-negative cases, the non-MRI-based RC performed best (AUC 0.80, p = 0.016), with the potential to spare biopsies for 23%. PSA-density and multivariate RCs demonstrated comparable performance for PI-RADS 3 constellation (AUC 0.65 vs. 0.60-0.65, p > 0.5; saved biopsies 16%). In men with suspicious mpMRI, both mpMRI-based RCs and the PI-RADS score predicted csPCa excellently (AUC 0.82-0.79 vs. 0.80, p > 0.05), highlighting superior performance compared to non-MRI-based models (all p < 0.002). Quality-assured imaging consistently improved csPCa risk stratification across all subgroups. CONCLUSION: In tertiary centers serving a high-risk population, high-quality mpMRI provides a simple yet effective way to assess the risk of csPCa. Using multivariate RCs reduces multiple biopsies, especially in mpMRI-negative and PI-RADS 3 constellation.

Key learnings from concordant systematic biopsies in prostate-specific membrane antigen positron emission tomography/computed tomography-guided prostate biopsies: Enhancing targeting accuracy.

BACKGROUND: Prostate cancer (PCa) diagnosis and staging have evolved with the advent of 68Ga-Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT). This study investigates the role of complementary systematic biopsies (SB) during PSMA-PET/CT-guided targeted prostate biopsies (PET-TB) for PCa detection, grading, and distribution. We address the uncertainty surrounding the necessity of SB in conjunction with PET-TB. METHODS: We analyzed PCa grading and distribution in 30 men who underwent PET-TB and SB because of contraindication to magnetic resonance imaging or high clinical suspicion of PCa. Tumor distribution was assessed in relation to the PET-highlighted lesions. Standardized reporting schemes, encompassing SUVmax, PRIMARY score, and miTNM classification, were evaluated. RESULTS: 80% of patients were diagnosed with PCa, with 70% classified as clinically significant (csPCa). SB detected more csPCa cases than PET-TB, but the differences were not statistically significant. Discordant results were observed in 25% of cases, where SB outperformed PET-TB. Spatial analysis revealed that tumor-bearing cores from SB were often located in close proximity to the PET-highlighted region. Reporting schemes showed potential for csPCa detection with significantly increased SUVmax in csPCA patients. Subsequent follow-up data underscored the importance of SB in precise PCa grading and staging. CONCLUSIONS: While PET-TB can simplify prostate biopsy and reduce invasiveness by core number, SB cannot be omitted yet due to potential PET-TB targeting errors. Factors such as limited spatial resolution and fusion inaccuracies contribute to the need for SB. Standardization in reporting schemes currently cannot compensate for targeting errors highlighting the need for refinement.

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.

Feasibility of Monitoring Response to Metastatic Prostate Cancer Treatment with a Methylation-Based Circulating Tumor DNA Approach.

BACKGROUND: Metastatic prostate cancer (mPCA) poses challenges in treatment response assessment, particularly in cases where prostate-specific antigen (PSA) levels do not reliably indicate a response. Liquid biopsy, focusing on circulating cell-free DNA (ccfDNA) methylation analysis as a proxy for circulating tumor DNA, offers a non-invasive and cost-effective approach. This study explores the potential of two methylation markers, short stature homeobox 2 (SHOX2) and Septin 9 (SEPT9), as on-mPCA-treatment biomarkers. METHODS: Plasma samples were collected from 11 mPCA patients undergoing various treatments. Quantitative assessment of hypermethylated SHOX2 (mSHOX2) and SEPT9 (mSEPT9) levels in ccfDNA was conducted through methylation-specific real-time PCR. Early and overall dynamics of PSA, mSHOX2, and mSEPT9 were analyzed. Statistical evaluation employed Wilcoxon tests. RESULTS: mSHOX2 demonstrated a significant decline post-treatment in patients with a radiographic treatment response as well as in an early treatment setting. mSEPT9 and PSA exhibited non-significant declines. In individual cases, biomarker dynamics revealed unique patterns compared to PSA. DISCUSSION: mSHOX2 and mSEPT9 exhibit dynamics on mPCA treatment. This proof-of-concept study lays the groundwork for further investigation into these markers as valuable additions to treatment response monitoring in mPCA. Further validation in larger cohorts is essential for establishing clinical utility.

Delayed symptomatic renal arteriovenous fistula in a 24 years old male following renal biopsy.

We report a case of a 24-year-old male with a history of kidney biopsy at young age due to chronic renal dysfunction and challenging hypertension, who presented with flank pain and hematuria. Initial imaging suggested renal pelvis enlargement, but MRI revealed a massive renal arteriovenous malformation (AVM). Angiographic embolization was abandoned due to extensive effluent flow, followed by successful surgical resection preserving healthy kidney tissue. This case underscores the importance of considering renal AVMs in the differential diagnosis of young patients with gross hematuria or refractory hypertension to prevent complications and improve patient outcomes.

Ring Finger Protein 34 (RNF34) as a Prognostic Biomarker for Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Ring finger proteins play pivotal roles in diverse cellular processes and are implicated in contribution to cancer. Ring finger protein 34 (RNF34) has antiapoptotic and oncogenic properties. RNF34 is upregulated during carcinogenesis and tumor progression in the colorectal adenoma-carcinoma sequence and was already described to mediate chemoresistance. In clear cell renal cell carcinoma (ccRCC), however, the role and expression patterns of RNF34 are unknown. METHODS: First, we investigated the association of RNF34 mRNA expression with clinicopathological parameters and survival using data obtained from The Cancer Genome Atlas (TCGA) ccRCC cohort (N = 533). To assess RNA34 protein expression, we performed immunohistochemical (IHC) staining of an established ccRCC cohort (University of Bonn) in a tissue microarray (TMA) format. This validation cohort contains 109 primary ccRCC samples. IHC data were associated with clinicopathological parameters and overall survival (Kaplan-Meier analysis). Adjustment for covariables was done using the Cox regression model. RESULTS: RNF34 expression is correlated with adverse clinicopathological parameters. Survival analysis revealed an association between RNF34 expression and shortened survival. Cox regression analysis confirmed RNF34 expression as an independent prognostic parameter. CONCLUSION: Our study provides evidence for RNF34 as a prognostic biomarker in ccRCC and points toward a major role of this protein in renal cell carcinoma carcinogenesis.

Expression of the microtubule-associated protein 2 (MAP2) as a potential independent prognostic marker in prostate cancer.

PURPOSE: Investigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer. MATERIAL AND METHODS: MAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay. RESULTS: MAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001). CONCLUSION: The present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities.

Hypermethylated SHOX2 in circulating cell-free DNA post renal cell carcinoma surgery as TNM-independent biomarker for recurrence risk.

INTRODUCTION: Adjuvant immune checkpoint inhibitor trials in renal cell carcinoma (RCC) call for improved recurrence risk stratification. Due to limitations of circulating tumor DNA (ctDNA) use in RCC, the use of hypermethylated SHOX2 gene (mSHOX2) in circulating cell-free DNA is explored as a surrogate marker for identifying high-risk patients after RCC surgery. METHODS: Liquid biopsies were collected post-surgery from 45 RCC patients (mean duration 4.3 days). Real-time polymerase chain reaction was used to analyze SHOX2 methylation in circulating cell-free DNA. Patients were categorized as mSHOX2 positive or negative by cut-off. Metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using Cox regression and Log-rank analyses (median follow-up time: 60 months). RESULTS: 17 patients were mSHOX2 positive, showing unfavorable OS/CSS (Log-rank P = 0.004 and 0.02) and nearly 6-fold higher recurrence risk (hazard ratio 5.89, 95% CI 1.46-23.8). Multivariable Cox analysis confirmed mSHOX2 as an independent recurrence risk factor, disregarding TNM-based stratification. CONCLUSIONS: mSHOX2 effectively identifies high-risk RCC patients post-surgery, indicating minimal residual disease. This easy to implement biomarker has potential for guiding of adjuvant therapy decisions.

Emotion-centered versus fact-centered medical information to alleviate pain and anxiety in prostate biopsy: A randomized trial.

BACKGROUND: To test the efficacy of emotion-centered (EC) versus fact-centered (FC) written medical information for prostate biopsy to alleviate pain and anxiety in a randomized controlled trial. METHODS: In a single-center, single-blinded study participants were randomized to receive FC or EC (DRKS00022361; 2020). In the EC, the focus was on possible stress reactions and stress-reducing strategies. Participants were asked to complete questionnaires on the day of MRI acquisition (T0) directly before (T1) and after the procedure (T2). The primary outcome measure was the assessment of worst pain in the last 2 h measured by the adapted brief pain inventory. Secondary outcome measures included state anxiety measured by the state-trait anxiety inventory and the subjective evaluation of the impact of the written medical information at T2. For statistical analysis, mixed models were calculated. RESULTS: Of 137 eligible patients, 108 (79%) could be recruited and were randomized. There was a significant effect for time for the outcome variables pain and anxiety. Regarding the comparison for the primary outcome variable worst pain there was a significantly lower increase from T1 to T2 after FC compared to EC (p < 0.004). The course of anxiety displayed no overall group differences. The FC was evaluated as significantly more helpful regarding stress, pain, and anxiety with moderate effect sizes. CONCLUSIONS: FC was favorable with regard to worst experienced pain, assuming that the brief introduction of emotional issues such as stress and coping in written information might be counterproductive particularly in men not used to these subjects.

Deep Learning Super-Resolution Reconstruction for Fast and Motion-Robust T2-weighted Prostate MRI.

Background Deep learning (DL) reconstructions can enhance image quality while decreasing MRI acquisition time. However, DL reconstruction methods combined with compressed sensing for prostate MRI have not been well studied. Purpose To use an industry-developed DL algorithm to reconstruct low-resolution T2-weighted turbo spin-echo (TSE) prostate MRI scans and compare these with standard sequences. Materials and Methods In this prospective study, participants with suspected prostate cancer underwent prostate MRI with a Cartesian standard-resolution T2-weighted TSE sequence (T2C) and non-Cartesian standard-resolution T2-weighted TSE sequence (T2NC) between August and November 2022. Additionally, a low-resolution Cartesian DL-reconstructed T2-weighted TSE sequence (T2DL) with compressed sensing DL denoising and resolution upscaling reconstruction was acquired. Image sharpness was assessed qualitatively by two readers using a five-point Likert scale (from 1 = nondiagnostic to 5 = excellent) and quantitatively by calculating edge rise distance. The Friedman test and one-way analysis of variance with post hoc Bonferroni and Tukey tests, respectively, were used for group comparisons. Prostate Imaging Reporting and Data System (PI-RADS) score agreement between sequences was compared by using Cohen κ. Results This study included 109 male participants (mean age, 68 years ± 8 [SD]). Acquisition time of T2DL was 36% and 29% lower compared with that of T2C and T2NC (mean duration, 164 seconds ± 20 vs 257 seconds ± 32 and 230 seconds ± 28; P < .001 for both). T2DL showed improved image sharpness compared with standard sequences using both qualitative (median score, 5 [IQR, 4-5] vs 4 [IQR, 3-4] for T2C and 4 [IQR, 3-4] for T2NC; P < .001 for both) and quantitative (mean edge rise distance, 0.75 mm ± 0.39 vs 1.15 mm ± 0.68 for T2C and 0.98 mm ± 0.65 for T2NC; P < .001 and P = .01) methods. PI-RADS score agreement between T2NC and T2DL was excellent (κ range, 0.92-0.94 [95% CI: 0.87, 0.98]). Conclusion DL reconstruction of low-resolution T2-weighted TSE sequences enabled accelerated acquisition times and improved image quality compared with standard acquisitions while showing excellent agreement with conventional sequences for PI-RADS ratings. Clinical trial registration no. NCT05820113 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Turkbey in this issue.

[Prostate cancer-multiparametric MRI and alternative approaches in intervention and therapy planning]. / Multiparametrische MRT und alternative Methoden in der Interventions- und Behandlungsplanung beim Prostatakarzinom.

BACKGROUND: In recent years, multiparametric magnetic resonance imaging (mpMRI) of the prostate has gained importance and plays a crucial role in both personalized diagnostics and increasingly in the treatment planning for patients with prostate cancer. OBJECTIVE: The aim of this study is to present established and innovative applications of MRI in the diagnosis and treatment of localized prostate cancer, evaluating their strengths and weaknesses. Furthermore, it will explore alternative approaches and compare them in a comprehensive manner. MATERIALS AND METHODS: A systematic literature review on the application of mpMRI for biopsy and therapy planning was conducted. RESULTS: The integration of modern imaging techniques, especially mpMRI, into the diagnostic algorithm has revolutionized prostate cancer diagnosis. MRI and MRI-guided biopsy detect more significant prostate cancer, with the potential to reduce unnecessary biopsies and the diagnosis of clinically insignificant carcinomas. In addition, MRI provides crucial information for risk stratification and treatment planning in prostate cancer patients, both before radical prostatectomy and during active surveillance. CONCLUSION: Multiparametric MRI offers significant added value for the diagnosis and treatment of localized prostate cancer. The advancement of MRI analysis, such as the implementation of artificial intelligence algorithms, holds the potential for further enhancing imaging diagnostics.

Identification of F-Box/SPRY Domain-Containing Protein 1 (FBXO45) as a Prognostic Biomarker for TMPRSS2-ERG-Positive Primary Prostate Cancers.

BACKGROUND: F-box/SPRY domain-containing protein 1 (FBXO45) plays a crucial role in the regulation of apoptosis via the ubiquitylation and degradation of specific targets. Recent studies indicate the prognostic potential of FBXO45 in several cancers. However, its specific role in prostate carcinoma remains unclear. METHODS: A systematic analysis of FBXO45 mRNA expression in PCA was performed using The Cancer Genome Atlas database and a publicly available Gene Expression Omnibus progression PCA cohort. Subsequently, FBXO45 protein expression was assessed via immunohistochemical analysis of a comprehensive tissue microarray cohort. The expression data were correlated with the clinicopathological parameters and biochemical-free survival. The immunohistochemical analyses were stratified according to the TMPRSS2-ERG rearrangement status. To assess the impact of FBXO45 knockdown on the tumour proliferation capacity of cells and metastatic potential, transfection with antisense-oligonucleotides was conducted within a cell culture model. RESULTS: FBXO45 mRNA expression was associated with adverse clinicopathological parameters in the TCGA cohort and was enhanced throughout progression to distant metastasis. FBXO45 was associated with shortened biochemical-free survival, which was pronounced for the TMPRSS2-ERG-positive tumours. In vitro, FBXO45 knockdown led to a significant reduction in migration capacity in the PC3, DU145 and LNCaP cell cultures. CONCLUSIONS: Comprehensive expression analysis and functional data suggest FBXO45 as a prognostic biomarker in PCA.

[Diagnosis and staging of metastatic hormone-sensitive prostate cancer]. / Diagnostik und Stadieneinteilung beim metastasierten hormonsensitiven Prostatakarzinom.

BACKGROUND: Risk stratification of patients with metastatic hormone-sensitive prostate cancer (mHSPC) has undergone significant changes in recent years in light of new therapies and innovative imaging. OBJECTIVES: Established and innovative methods for detection of metastasis, risk group stratification, and treatment of mHSPC are outlined and compared. MATERIALS AND METHODS: Background knowledge and treatment-relevant guideline recommendations on mHSPC are presented and complemented by recent study results. RESULTS: Integration of modern imaging techniques, especially prostate-specific membrane antigen (PSMA) PET/CT, into the diagnostic algorithm has the potential to significantly improve risk stratification and treatment of mHSPC. By using PSMA PET/CT, metastases are detected early and sensitively. This leads to the definition of new subgroups amenable to modern therapeutic strategies. The prognostic value of using PSMA PET/CT with regard to established risk categories in mHSPC is currently being evaluated. CONCLUSIONS: Modern imaging, especially PSMA PET/CT, has significant added value for the diagnosis and treatment of mHSPC in almost all subgroups. In particular, it helps to select patients who will benefit from intensification or de-escalation of systemic therapy.

Current role of systematic biopsy in diagnosis of clinically significant prostate cancer in primary combined MRI-targeted biopsy: a high-volume single-center study.

PURPOSE: Additive systematic biopsy (SB) contributes to prostate cancer (PCA) detection in MRI-targeted biopsy (TB). However, the reasons for this are not yet clear. We compared the performance of TB, SB and the combined approach (CB) in biopsy-naive men to determine the added value of SB for tumor grading and spatial tumor distribution. METHODS: Two hundred and fifty-nine men with PI-RADS 3-5 graded lesions who underwent CB were enrolled. Data were prospectively collected, and cancer detection rates (CDR) were compared at patient and lesion level. Gleason grade up- and down-grading from biopsy to prostatectomy specimens (n = 56; 21.6%) were determined. Clinically significant cancer (csPCA) was defined as Gleason grade ≥ 2. RESULTS: CDR by CB based on PI-RADS categories 3, 4 and 5 for PCA were 24%, 72% and 98% and 17%, 64% and 96% for csPCA. CB detected more PCA and csPCA than TB (p < 0.001). However, TB showed higher efficiency, defined as CDR per biopsy core, for PCA and csPCA in PI-RADS 4-5 rated patients (p < 0.001). Concordance between biopsy and prostatectomy grading was highest in CB with misdiagnosis of csPCA in 25% of men. TB missed cancer attributed to the index lesion in 10.2% and underestimated csPCA in 7%. In these cases, 76% of csPCA were detected and 85% were upgraded to csPCA by SB in adjacent sectors. CONCLUSION: SB cannot be safely abundant without increased diagnostic uncertainty. When TB missed csPCA, SB detected it close to the MRI-target lesion. Therefore, perifocal biopsies could potentially replace 12-core SB with increased efficiency in taking manageable risks.