Lower baseline testosterone level is related to earlier development of castration resistance in metastatic prostate cancer: a multi-center cohort study.

Purpose: In the era of concurrent combination therapy in metastatic hormone sensitive prostate cancer, the impact of the testosterone level before initiating androgen deprivation therapy on treatment outcome is still uncertain. We aimed to investigate its effect on time-to-castration-resistance in a metastatic hormone sensitive prostate cancer cohort. Methods: This is a multi-center retrospective study of 5 databases from China, Japan, Austria and Spain including 258 metastatic hormone sensitive prostate cancer patients with androgen deprivation therapy initiated between 2002 and 2021. Baseline testosterone was divided into high and low groups using 12 nmol/L as cutoff level. Primary outcome was time-to-castration-resistance. Secondary outcomes were survival functions. Kaplan-Meier method was employed to evaluate the correlation between baseline testosterone and time-to-castration-resistance. Subgroup analysis was performed to elucidate the effect of upfront combination-therapy and metastatic volume. Results: Median age was 72 years. Median follow-up time was 31 months. Median pre-treatment prostate-specific-antigen level was 161 ng/mL. Majority of case were graded as International-Society-of-Urological-Pathology grade 5 (63.6%). 57.8% patients had high volume disease and 69.0% received upfront combination treatment. 44.6% of the cohort developed castration-resistance. The low testosterone group demonstrated shorter mean-time-to-castration-resistance (19.0 vs 22.4 months, p=0.031). The variance was more significant in patients without combination therapy (13.2 vs 26.3 months, p=0.015). Cancer-specific and overall survival were inferior in the low baseline testosterone level group without receiving combination therapy (p=0.001). Conclusions: Lower pre-treatment testosterone level is correlated to shorter time-to-castration resistance and worse survival in metastatic prostate cancer patients without upfront combination therapy. Those with low baseline testosterone should be encouraged to adopt combination therapy to delay progression.

Real-World Evidence of Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer: An Austrian Multicenter Study.

INTRODUCTION: Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC). PATIENTS AND METHODS: We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI). RESULTS: Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients. CONCLUSIONS: Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study.

BACKGROUND: The European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. OBJECTIVE: To assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. RESULTS AND LIMITATIONS: A prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). CONCLUSIONS: 177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. PATIENT SUMMARY: 177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

Real-world comparison of Docetaxel versus new hormonal agents in combination with androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer descrying PSA Nadir ≤ 0.05 ng/ml as marker for treatment response.

PROPOSE: Using Docetaxel chemotherapy or new hormonal agents (NHT) to intensify upfront systemic therapy resulted in improved survival rates compared to androgen deprivation monotherapy (ADT). Hence, combination therapies have become the new standard of care (SOC) in metastatic hormone-sensitive prostate cancer (mHSPC). However, head-to-head trails comparing different therapies as well as treatment-guiding biomarkers are still lacking. Thus, the aim of the present study was to compare clinical outcomes of Docetaxel versus NHT therapy in the real-world setting as well as to elaborate biomarkers predicting clinical outcome. METHODS: We retrospectively assessed overall-survival (OS), progression-free survival 1 and 2 (PFS1/2) and time to progression (TTP) in 42 patients treated by either ADT + NHT or ADT + Docetaxel. In addition, we investigated clinical prognostic biomarkers. RESULTS: Our survival analysis revealed 3-year OS of 89.4% in the NHT group compared to 82.4% in the Docetaxel group. 3-year PFS1 was 59.6% in the NHT group compared to 32.2% in the Docetaxel group and the TTP was 53.8% vs 32.2% (pOS = 0.189; pPFS1 = 0.082; pTTP = 0.055). In addition, castration-resistance occurred more often in the Docetaxel group (78.6% vs 25%, p = 0.004). Interestingly, a PSA-Nadir ≤ 0.05 ng/ml during therapy was associated with increased survival rates (p < 0.001) while PSA levels at primary diagnosis had no influence on therapy outcome. Furthermore, a thyroid-stimulating hormone (TSH) increase during therapy was associated with improved clinical outcome (p = 0.06). CONCLUSION: We observed a trend towards a higher benefit of NHT as first-line treatment compared to Docetaxel in men with mHSPC. Of note, a PSA-Nadir ≤ 0.05 ng/ml or a TSH-increase during therapy were predictors for therapy response.

Xpert® bladder cancer detection as a diagnostic tool in upper urinary tract urothelial carcinoma: preliminary results.

Objectives: Upper urinary tract urothelial carcinoma (UTUC) represents about 5-10% of all urothelial malignancies with an increasing incidence. The standard diagnostic tools for the detection of UTUC are cytology, computed tomography (CT) urography, and ureterorenoscopy (URS). No biomarker to be included in the daily clinical practice has yet been identified. The aim of our study was to evaluate the potential role of Xpert® Bladder-Cancer (BC)-Detection in the diagnosis of UTUC. Methods: Eighty-two patients underwent 111 URS with Xpert® BC-Detection, cytology, or Urovysion® analysis of UT for suspicion of UTUC. Twenty-four cases were excluded from the analysis due to a non-diagnostic Xpert® BC-Detection, cytology, or Urovysion®. Samples were analyzed with upper tract (UT) urinary cytology, with Xpert® BC-Detection on UT urines, and with Urovysion® Fluorescence in situ hybridization (FISH) test. After urine collection, the patients underwent retrograde pyelography and/or URS, and if positive a UT biopsy. The Xpert® BC-Detection was reported by the software as negative or positive [cut-off total Linear Discriminant Analysis (LDA) = 0.45]. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of cytology, Xpert® BC-Detection and Urovysion-FISH were calculated using URS and/or histology results as reference. Results: In all, 27 (31%) of 87 URS resulted positive, with 20 low-grade (LG) and 7 high-grade (HG) tumors. Overall sensitivity was 51.9% for cytology, 100% for Xpert® BC-Detection, and 92.6% for Urovysion. The sensitivity of cytology increased from 26% in LG to 100% in HG tumors. For Xpert® BC-Detection, sensitivity was 100% both in LG and in HG, and for Urovysion-FISH, it increased from 90% in LG to 100% in HG tumors. PPV was 82.4% for cytology, 35% for Xpert® BC-Detection, and 73.5% for Urovysion. NPV was 81.4% for cytology, 100% for Xpert® BC-Detection, and 96.2% for Urovysion. Conclusion: The excellent NPV of Xpert® BC-Detection allows to avoid unnecessary endoscopic exploration of the UT, reducing invasiveness and URS complications in the follow-up of UTUC.

PROPOSe: A Real-life Prospective Study of Proclarix, a Novel Blood-based Test to Support Challenging Biopsy Decision-making in Prostate Cancer.

BACKGROUND: Prostate-specific antigen (PSA)-based detection of prostate cancer (PCa) often leads to negative biopsy results or detection of clinically insignificant PCa, more frequently in the PSA range of 2-10 ng/ml, in men with increased prostate volume and normal digital rectal examination (DRE). OBJECTIVE: This study evaluated the accuracy of Proclarix, a novel blood-based diagnostic test, to help in biopsy decision-making in this challenging patient population. DESIGN, SETTING, AND PARTICIPANTS: Ten clinical sites prospectively enrolled 457 men presenting for prostate biopsy with PSA between 2 and 10 ng/ml, normal DRE, and prostate volume ≥35 cm3. Transrectal ultrasound-guided and multiparametric magnetic resonance imaging (mpMRI)-guided biopsy techniques were allowed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Serum samples were tested blindly at the end of the study. Diagnostic performance of Proclarix risk score was established in correlation to systematic biopsy outcome and its performance compared with %free PSA (%fPSA) and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator (RC) as well as Proclarix density compared with PSA density in men undergoing mpMRI. RESULTS AND LIMITATIONS: The sensitivity of Proclarix risk score for clinically significant PCa (csPCa) defined as grade group (GG) ≥2 was 91% (n = 362), with higher specificity than both %fPSA (22% vs 14%; difference = 8% [95% confidence interval {CI}, 2.6-14%], p = 0.005) and RC (22% vs 15%; difference = 7% [95% CI, 0.7-12%], p = 0.028). In the subset of men undergoing mpMRI-fusion biopsy (n = 121), the specificity of Proclarix risk score was significantly higher than PSA density (26% vs 8%; difference = 18% [95% CI, 7-28%], p < 0.001), and at equal sensitivity of 97%, Proclarix density had an even higher specificity of 33% [95% CI, 23-43%]. CONCLUSIONS: In a routine use setting, Proclarix accurately discriminated csPCa from no or insignificant PCa in the most challenging patients. Proclarix represents a valuable rule-out test in the diagnostic algorithm for PCa, alone or in combination with mpMRI. PATIENT SUMMARY: Proclarix is a novel blood-based test with the potential to accurately rule out clinically significant prostate cancer, and therefore to reduce the number of unneeded biopsies.

Long-Term Treatment with Simvastatin Leads to Reduced Migration Capacity of Prostate Cancer Cells.

Statins have been shown to improve survival of metastatic prostate cancer (mPCa). Nevertheless, their therapeutic use is still under debate. In the present study, we investigated the short-term effects of three different statins (simvastatin, atorvastatin and rosuvastatin) in various PCa cell lines mimicking androgen-sensitive and -insensitive PCa. Moreover, we generated three new PCa cell lines (LNCaPsim, ABLsim, PC-3sim) that were cultured with simvastatin over several months. Our data showed that the three statins expressed highly diverse short-term effects, with the strongest growth-inhibitory effect from simvastatin in PC-3 cells and almost no effect from rosuvastatin in any of the cell lines. Long-term treatment with simvastatin resulted in a loss of response to statins in all three cell lines, which was associated with an upregulation of cholesterol and fatty acid pathways as revealed through RNA sequencing. Despite that, long-term treated cells exhibited diminished spheroid growth and significantly reduced migration capacity per se and to differentiated osteoclasts. These findings were strengthened by reduced expression of genes annotated to cell adhesion and migration after long-term simvastatin treatment. Notably, mPCa patients taking statins were found to have lower numbers of circulating tumor cells in their blood with reduced levels of PSA and alkaline phosphatase. Our data suggest that long-term usage of simvastatin hampers the metastatic potential of PCa cells and may therefore be a potential therapeutic drug for mPCa.

A real-world comparison of docetaxel versus abiraterone acetate for metastatic hormone-sensitive prostate cancer.

BACKGROUND: Docetaxel (D) or secondary hormonal therapy (SHT) each combined with androgen deprivation therapy (ADT) represent possible treatment options in males with metastasized hormone-sensitive prostate cancer (mHSPC). Real-world data comparing different protocols are lacking yet. Thus, our objective was to compare the efficacy and safety of abiraterone acetate (AA)+ADT versus D+ADT in mHSPC. METHODS: In a retrospective multicenter analysis including males with mHSPC treated with either of the aforementioned protocols, overall survival (OS), progression-free survival 1 (PFS1), and progression-free survival 2 (PFS2) were assessed for both cohorts. Median time to event was tested by Kaplan-Meier method and log-rank test. The Cox-proportional hazards model was used for univariate and multivariate regression analyses. RESULTS: Overall, 196 patients were included. The AA+ADT cohort had a longer PFS1 in the log-rank testing (23 vs. 13 mos., p < 0.001), a longer PFS2 (48 vs. 33 mos., p = 0.006), and longer OS (80 vs. 61 mos., p = 0.040). In the multivariate analyses AA+ADT outperformed D+ADT in terms of PFS1 (HR = 0.34, 95% CI = 0.183-0.623; p = 0.001) and PFS2 (HR = 0.33 95% CI = 0.128-0.827; p = 0.018), respectively, while OS and toxicity rate were similar between both groups. CONCLUSIONS: AA+ADT is mainly associated with a similar efficacy and overall toxicity rate as D+ADT. Further prospective research is required for validation of the clinical value of the observed benefit of AA+ADT for progression-free end-points.

Validation of Cell-Free RNA and Circulating Tumor Cells for Molecular Marker Analysis in Metastatic Prostate Cancer.

Since tissue material is often lacking in metastatic prostate cancer (mPCa), there is increasing interest in using liquid biopsies for treatment decision and monitoring therapy responses. The purpose of this study was to validate the usefulness of circulating tumor cells (CTCs) and plasma-derived cell-free (cf) RNA as starting material for gene expression analysis through qPCR. CTCs were identified upon prostate-specific membrane antigen and/or cytokeratin positivity after enrichment with ScreenCell (Westford, Massachusetts, USA) filters or the microfluidic ParsortixTM (Guildford, Surrey, United Kingdom) system. Overall, 50% (28/56) of the patients had ≥5 CTCs/7.5 mL of blood. However, CTC count did not correlate with Gleason score, serum PSA, or gene expression. Notably, we observed high expression of CD45 in CTC samples after enrichment, which could be successfully eliminated through picking of single cells. Gene expression in picked CTCs was, however, rather low. In cfRNA from plasma, on the other hand, gene expression levels were higher compared to those found in CTCs. Moreover, we found that PSA was significantly increased in plasma-derived cfRNA of mPCa patients compared to healthy controls. High PSA expression was also associated with poor overall survival, indicating that using cfRNA from plasma could be used as a valuable tool for molecular expression analysis.

A presumed extragonadal germ cell tumor that turned out to be a gastric cancer-a case report.

A solely retroperitoneal mass in males in combination with elevated serum Alpha-Fetoprotein (AFP) and beta-human choriogonadotropin (ß-HCG) levels is highly indicative of a metastatic testicular cancer. Although testicular cancers are rare, they represent the most common diagnosed cancer in males between 14 and 40 years. However, in cases without evidence of a primary testicular tumor, the rare diagnosis of a retroperitoneal extragonadal germ cell tumor (EGCT) must be assumed. Here, we describe the first published case of a 66-year-old man presenting with this typical clinical picture and the diagnosis of an AFP and ß-HCG producing advanced gastric cancer with retroperitoneal lymph node metastases mimicking a primary retroperitoneal EGCT. The final diagnosis was only made by gastroscopy performed after a CT-guided retroperitoneal lymph node biopsy revealed an adenocarcinoma, suggesting an upper gastrointestinal tract primary origin. However, a specific initial anamnesis and also in the primary staging, including a full-body CT-scan there was no hint for another primary tumor. Only the slightly unusual extension of the retroperitoneal mass up to the ligamentum hepatoduodenale and the pylorus, as well as the atypical age made us question our initial diagnosis. This extraordinary case is of special clinical interest to all practising physicians and once again highlights the importance of keeping rare differential diagnosis such as AFP-producing gastrointestinal tumors in mind.

Recent Insights on Genetic Testing in Primary Prostate Cancer.

Prostate cancer (PCa) is one of the most common cancers in developed countries. The results of large trials indicate that the proportion of PCa attributable to hereditary factors is as high as 15%, highlighting the importance of genetic testing. Despite improved understanding of the prevalence of pathogenic variants among men with PCa, it remains unclear which men will most benefit from genetic testing. In this review, we summarize recent evidence on genetic testing in primary PCa and its impact on routine clinical practice. We outline current guideline recommendations on genetic testing, most importantly, for mutations in BRCA1/2, MMR, CHEK2, PALB2, and HOXB13 genes, as well as various single nucleotide polymorphisms associated with an increased risk of developing PCa. The implementation of genetic testing in clinical practice, especially in young patients with aggressive tumors or those with positive family history, represents a new challenge for the coming years and will identify men with pathogenic variants who may benefit from early screening/intervention and specific therapeutic options.

Diagnostic value of Xpert® Bladder Cancer Monitor in the follow-up of patients affected by non-muscle invasive bladder cancer: an update.

AIMS: Xpert® Bladder Cancer Monitor is a urinary marker based on the evaluation of five target mRNAs overexpressed in patients with bladder cancer (BC). The aim of our study is to update our results regarding the diagnostic accuracy of the Xpert® Bladder Cancer Monitor test in the follow-up of patients with non-muscle invasive bladder cancer (NMIBC). METHODS: We conducted a prospective study on 1015 samples of 416 patients (mean age 72.2 ± 10.3 years) under follow-up for NMIBC. Patients underwent voided urinary cytology, the Xpert® Bladder Cancer Monitor test and cystoscopy and, if positive, a transurethral resection of the bladder. Xpert® Bladder Cancer Monitor was reported as negative or positive: cut-off total Linear Discriminant Analysis (LDA) = 0.5. RESULTS: We identified 168 recurrent tumours: 126 (75%) were low-grade (LG) and 42 (25%) high-grade (HG). Overall sensitivity was 17.9% for cytology, 52.4% for Xpert® Bladder Cancer Monitor and 54.2% for the two tests combined. The sensitivity of cytology increased from 6.3% in LG to 52.4% in HG tumours whereas Xpert® Bladder Cancer Monitor showed a sensitivity ranging from 42.9% in LG to 80.9% in HG tumours. Combined cytology and Xpert® Bladder Cancer Monitor yielded an overall sensitivity of 45.2% for LG and 80.9% for HG tumours. Overall specificity was 98.5% for cytology and 78.4% for Xpert® Bladder Cancer Monitor and 78.2% for the two tests combined. The area under the curve (AUC) for Xpert® Bladder Cancer Monitor was 0.71; stratifying the patients according to the European Association of Urology risk groups, the AUC was 0.69, 0.67 and 0.85 for low, intermediate and high risk, respectively (p = 0.0003). CONCLUSION: Our data confirm a significantly higher sensitivity of Xpert® Bladder Cancer Monitor than for cytology in a larger patient cohort. The test performed very well in terms of specificity but could not reach the high value of cytology. Along with voided urinary cytology the test could allow to reduce cystoscopies in follow-up patients, reducing discomfort to the patients and costs.

[Penile metastasis of a carcinoma of the salivary glands at the tongue base: a case report]. / Penismetastase eines Speicheldrüsenkarzinoms der Zungenbasis: Ein Fallbeispiel.

We report the case of a 64-year-old man, initially diagnosed with a polymorphous adenocarcinoma of the small salivary glands at the tongue base, with occurrence of a penile metastasis ten years after diagnosis. To our knowledge, only two such cases have been described in the literature to date.

Organ-Sparing Surgery in Testicular Tumor: Is This the Right Approach for Lesions ≤ 20 mm?

Background: This study was conducted in order to analyze factors predicting malignancy in patients undergoing organ-sparing surgery (OSS) for small testicular lesions. Methods: Patients with small (£20 mm) marker-negative clinical stage I testicular tumors were managed by OSS with tumor enucleation and frozen section examination (FSE) for the past 15 years at our institution. Benign and malignant cases were compared, focusing on preoperative and postoperative lesion sizes. Results: Eighty-nine patients were enrolled in this retrospective study. Ten (11.2%) of them were treated for synchronous bilateral tumors. Sixty-seven (67.7%) of ninety-nine lesions were benign, confirming a high concordance rate (98%) between FSE and final histology. Patients with benign tumors were significantly older than patients with malignant tumors (p = 0.026), and benign tumors were detected more frequently during urologic work-up of hormone disorders (p = 0.001). Preoperative tumor size was a strong predictor of malignancy (area under the curve (AUC) = 0.726; p < 0.001). According to the Youden index, the best cutoff to predict tumor dignity was 13.5 mm, resulting in a sensitivity and specificity of 53% and 85%, respectively. No cases of local recurrence or distant metastasis were confirmed after a median follow-up of 42 months. Conclusion: Our findings are consistent with previous reports, supporting an OSS approach in small testicular tumors whenever possible. Most tumors ≤ 20 mm were benign, and in the case of malignancy, OSS with FSE and consecutive orchiectomy is oncologically safe due to the high concordance rate of FSE and final histology, thus preventing a two-stage procedure.

Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer.

The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration resistance as well as in the resistance to 2nd generation antiandrogens like enzalutamide. In our study, we examined the potential of natural AKR1C3 inhibitors in various prostate cancer cell lines and a three-dimensional co-culture spheroid model consisting of cancer cells and cancer-associated fibroblasts (CAFs) mimicking enzalutamide resistant prostate cancer. One of our compounds, named MF-15, expressed strong antineoplastic effects especially in cell culture models with significant enzalutamide resistance. Furthermore, MF-15 exhibited a strong effect on androgen receptor (AR) signaling, including significant inhibition of AR activity, downregulation of androgen-regulated genes, lower prostate specific antigen (PSA) production, and decreased AR and AKR1C3 expression, indicating a bi-functional effect. Even more important, we demonstrated a persisting inhibition of AR activity in the presence of AR-V7 and further showed that MF-15 non-competitively binds within the DNA binding domain of the AR. The data suggest MF-15 as useful drug to overcome enzalutamide resistance.

Emerging promising biomarkers for treatment decision in metastatic castration-resistant prostate cancer.

Prostate cancer is one of the most common causes of death in males. Even if treatment is often of curative intent in early stages of the disease, up to 50% of patients relapse after primary therapy. Moreover, 10% to 15% of patients present in a primary metastatic stage of disease. In the past years the treatment landscape of metastatic castration-resistant prostate cancer expanded due to the development of second-generation antiandrogens (abiraterone acetate, enzalutamide), chemotherapeutic agents and radium-223. With the availability of several therapeutic lines, we are now confronted with the problem of choosing the most suitable therapy in each state of disease. As often observed in clinical routine, prostate specific antigen is not sufficient for early prediction of a therapy response. Furthermore, biomarkers for prediction of the optimal first-line therapy are badly needed in order to avoid primary resistance. Therefore, the present short review article gives an overview of currently available clinical and preclinical biomarkers for treatment response to metastatic castration-resistant prostate cancer therapeutic agents with the aim of providing support for a personalized decision-making process in everyday use.

Incidental Testicular Pathologies in Patients With Idiopathic Hydrocele Testis: Is Preoperative Scrotal Ultrasound Justified?

BACKGROUND/AIM: Hydrocele testis is a common disease with a prevalence of 1% in adults. Although it can be diagnosed by physical examination, scrotal ultrasound represents a standard diagnostic tool, to exclude underlying pathologies among them testicular or scrotal malignancies. PATIENTS AND METHODS: We conducted a retrospective analysis of 156 patients aged between 20 and 60 years who underwent surgical hydrocelectomy between 2003 and 2018. Pre-surgical ultrasound, histological results, complications and patients' characteristics were analysed. RESULTS: Malignancies were found in 0% of patients in the pre-surgical ultrasound. Interestingly, we found a higher incidence of hydrocele testis in patients with increasing age and 27% presented with symptoms other than painless enlargement of the scrotum. Among them recurrent pain was the most common. Surgical complications occurred in only 3.2%. CONCLUSION: Testicular cancer is an important differential diagnosis of hydrocele testis. However, in our study no case of incidental testicular cancer or scrotal malignancy was found in the pre-surgical ultrasound.

Comparison of 2 new real-time polymerase chain reaction-based urinary markers in the follow-up of patients with non-muscle-invasive bladder cancer.

BACKGROUND: The objective of the current study was to compare the diagnostic accuracy of 2 new real-time polymerase chain reaction-based urinary markers with each other and with urinary cytology, cystoscopy, and/or histology in patients being followed for non-muscle-invasive bladder cancer. METHODS: A total of 487 patients were enrolled in the study. Patients were evaluated using voided urine cytology, the Xpert Bladder Cancer Monitor, the Bladder EpiCheck test, and white light cystoscopy. RESULTS: The overall sensitivity was 27.17% for cytology, 64.13% for the Bladder EpiCheck test, and 66.3% for the Xpert Bladder Cancer Monitor. The overall specificity was 98.82% for cytology, 82.06% for the Bladder EpiCheck test, and 76.47% for the Xpert Bladder Cancer Monitor. The negative predictive value was very similar for the 3 tests at 83.56% for cytology, 89.42% for the Bladder EpiCheck test, and 89.35% for the Xpert Bladder Cancer Monitor. When combined, the Bladder EpiCheck test and Xpert Bladder Cancer Monitor detected overall 79.35% of the tumors: 70.37% in low-grade and 92.11% in high-grade tumors. CONCLUSIONS: The Xpert Bladder Cancer Monitor and Bladder EpiCheck test were found to perform very well in terms of sensitivity. Together, the 2 tests detected approximately 92.11% of high-grade tumors. Their specificity was high but could not reach the excellent value of cytology. The negative predictive value was the same for both tests and was higher than that for cytology, especially when the tests were used together (92.24%). These 2 new tests hold promise as urinary biomarkers. They may be used in combination to maximize sensitivity in a less invasive way, thereby reducing invasiveness in the follow-up of patients with non-muscle-invasive bladder cancer and decreasing discomfort for the patients as well as complications and costs.

Efficacy and Safety of Two Fosfomycin Regimens as Antimicrobial Prophylaxis for Transrectal Prostate Biopsy: A Randomised Study.

PURPOSE: Prostate biopsy is the gold standard for prostate cancer diagnosis; unfortunately, this procedure is not free from complications. Recent studies have shown an increase in antibiotic resistance. The aim of our prospective randomized study was to evaluate the efficacy and safety of a prostate biopsy prophylaxis protocol using 2 vs. 3 fosfomycin doses. METHODS: Two hundred and ninety-seven patients undergoing transrectal systematic ultrasound (US)-guided (n = 277) or transrectal fusion prostate biopsy (n = 20) were prospectively evaluated and randomized by date of birth, to receive 2 (even years, group A) versus 3 doses of fosfomycin (odd years, group B), and prospectively evaluated. RESULTS: Two hundred and ninety-seven patients were randomized to group A (n = 162) or group B (n = 135). The 2 groups were comparable with respect to age, comorbidity, PSA value, prostate volume, operative time and urine culture results. Out of 297 patients, 44 (14.8%) developed complications after the procedure; 2.7% (8/297) of patients developed fever >38° requiring hospitalization (6 [3.7%] in group A and 2 [1.5%] in group B, p = 0.29). Patients who underwent fusion biopsy were more frequently readmitted in comparison with patients undergoing US-guided prostate biopsy (p = 0.000). CONCLUSION: The low fever and prostatitis rate suggest that fosfomycin prophylaxis is safe and efficient. There is no significant difference in clinical outcome between the 2 dosage regimens.

Diagnostic predictive value of the Bladder EpiCheck test in the follow-up of patients with non-muscle-invasive bladder cancer.

BACKGROUND: The objective of this study was to evaluate the diagnostic accuracy of the Bladder EpiCheck test in the follow-up of patients with non-muscle-invasive bladder cancer (NMIBC) and to compare it with the accuracy of urinary cytology, cystoscopy, and/or histology. METHODS: In total, 243 patients were enrolled in the current study. Patients were evaluated by voided urine cytology, by the Bladder EpiCheck test, and by white-light cystoscopy. RESULTS: Overall sensitivity was 33.3% for cytology, 62.3% for Bladder EpiCheck, and 66.7% for the 2 tests combined. The sensitivity of cytology increased from 7.7% in low-grade (LG) tumors to 66.6% in high-grade (HG) tumors; whereas, for the Bladder EpiCheck test, the sensitivity was 46.1% in LG tumors and 83.3% in HG tumors. Combined cytology and Bladder EpiCheck testing yielded an overall sensitivity of 56.4% for LG tumors and 90% for HG tumors. Overall specificity was 98.6% for cytology, 86.3% for Bladder EpiCheck, and 85.6% for the 2 tests combined. The positive predictive value was 92% for cytology and 68.2% for Bladder EpiCheck. For the 2 tests combined, it was 68.6%. The negative predictive value was similar for the 2 tests: 75.8% for cytology, 82.9% for Bladder EpiCheck, and 84.5% for the 2 tests combined. CONCLUSIONS: The sensitivity of the Bladder EpiCheck test was significantly higher than that of cytology. The test performed very well in terms of specificity but could not reach the high value of cytology. The positive predictive value was higher for Bladder EpiCheck, whereas the negative predictive value was approximately the same for both tests.