Publications by authors named "Tilman Todenhöfer"

136 Publications

Whole blood expression as a prognostic biomarker in metastatic hormone-sensitive and castration-resistant prostate cancer.

Transl Androl Urol 2021 Apr;10(4):1688-1699

Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia.

Background: As potent systemic therapies transition earlier in the prostate cancer disease course, molecular biomarkers are needed to guide optimal treatment selection for metastatic hormone-sensitive prostate cancer (mHSPC). The value of whole blood RNA to detect candidate biomarkers in mHSPC remains largely undefined.

Methods: In this cohort study, we used a previously optimised whole blood reverse transcription polymerase chain reaction assay to assess the prognostic utility [measured by seven-month undetectable prostate-specific antigen (PSA) and time to castration-resistance (TTCR)] of eight prostate cancer-associated gene transcripts in 43 mHSPC patients. Transcripts with statistically significant associations (P<0.05) were further investigated in a metastatic castration-resistant prostate cancer (mCRPC) cohort (n=119) receiving contemporary systemic therapy, exploring associations with PSA >50% response (PSA), progression-free survival (PFS) and overall survival (OS). Clinical outcomes were prospectively collected in a protected digital database. Kaplan-Meier estimates and multivariable Cox proportional-hazards models assessed associations between gene transcripts and clinical outcomes (mHSPC covariates: disease volume, docetaxel use and haemoglobin level; mCRPC covariates: prior exposure to chemotherapy or ARPIs, haemoglobin, performance status and presence of visceral disease). Follow-up was performed monthly during ARPI treatment, three-weekly during taxane chemotherapy, and three-monthly during androgen deprivation therapy (ADT) monotherapy. Serial PSA measurements were performed before each follow-up visit and repeat imaging was at the discretion of the investigator.

Results: Detection of circulating Grainyhead-like 2 () transcript was associated with poor outcomes in mHSPC and mCRPC patients. Detectable expression in mHSPC was associated with a lower rate of seven-month undetectable PSA levels (25% 65%, P=0.059), and independently associated with shorter TTCR (HR 7.3, 95% CI: 1.5-36, P=0.01). In the mCRPC cohort, expression predicted significantly lower PSA response rates (46% 69%, P=0.01), and was independently associated with shorter PFS (HR 3.1, 95% CI: 1.8-5.2, P<0.001) and OS (HR 2.9, 95% CI: 1.6-5.1, P<0.001). Associations were most apparent in patients receiving ARPIs.

Conclusions: Detectable circulating was a negative prognostic biomarker in our mHSPC and mCRPC cohorts. These data support further investigation of as a candidate prognostic biomarker in metastatic prostate cancer, in addition to expanding efforts to better understand a putative role in therapeutic resistance to AR targeted therapies.
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http://dx.doi.org/10.21037/tau-20-1444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100842PMC
April 2021

Receptor Activator of NF Kappa B (RANK) Expression Indicates Favorable Prognosis in Patients with Muscle-invasive Bladder Cancer.

Eur Urol Focus 2021 May 4. Epub 2021 May 4.

Department of Urology, University Hospital, Tübingen, Germany; Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Clinical Trials Unit, Studienpraxis Urologie, Nürtingen, Germany. Electronic address:

Background: Receptor activator of NF kappa B (RANK) and its ligand have an essential role in T-cell regulation and the development of bone metastases. The role of RANK expression in muscle-invasive bladder cancer (MIBC) is unknown.

Objective: To assess the relevance of RANK expression in patients with MIBC.

Design, Setting, And Participants: Expression of RANK was assessed via immunohistochemistry of benign urothelium, MIBC tissue, and lymph node metastases from 153 patients undergoing radical cystectomy. Expression data from The Cancer Genome Atlas (TCGA) cohort were analyzed for potential associations with molecular subtypes and outcome.

Outcome Measurements And Statistical Analysis: RANK expression was correlated with clinical and pathological parameters and to individual data for the clinical course of MIBC.

Results And Limitations: Expression of RANK was significantly higher in both primary tumors (p = 0.02) and lymph node metastases (p = 0.01) compared to normal urothelium. In tumor tissue, RANK expression was significantly lower in patients with locally advanced disease and lymph node involvement compared to those with organ-confined disease (p = 0.0009) and node-negative MIBC (p = 0.0002). In univariable and multivariable analyses, high expression of RANK was associated with a longer time to recurrence (p = 0.0005 and 0.01) and better cancer-specific (p = 0.0004 and 0.007) and overall survival (p = 0.002 and 0.04). High expression of RANK was associated with better outcome for patients with luminal infiltrated tumors in the TCGA cohort.

Conclusions: RANK expression is increased in bladder cancer tissue compared to benign urothelium, with higher expression in organ-defined compared to locally advanced disease. High RANK expression indicates a favorable prognosis in MIBC. The prognostic role differs in tumors of different molecular subtypes.

Patient Summary: Expression of a protein involved in bone turnover regulation (RANK) is higher in bladder cancer tissue than in benign bladder tissue. However, high levels of RANK on tumor cells indicate favorable prognosis for patients with bladder cancer that invades the muscle layer of the bladder.
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http://dx.doi.org/10.1016/j.euf.2021.04.015DOI Listing
May 2021

Utility of pT3 substaging in lymph node-negative urothelial carcinoma of the bladder: do pathologic parameters add to prognostic sub-stratification?

World J Urol 2021 Apr 21. Epub 2021 Apr 21.

Department of Urology, University Hospital, Tübingen, Germany.

Purpose: The value of bladder cancer (BC) substaging into macroscopic (pT3b) and microscopic (pT3a) perivesical fat extension in lymph node (Ln)-negative patients is controversially discussed and limited evidence for prognostic relevance of additional histopathological factors in pT3 BC exists. We evaluated the prognostic value of pT3 substaging and established pathological and clinical parameters with focus on tumor invasive front (TIF) and tumor size.

Methods: Specimens of 52 patients treated with radical cystectomy (RC) for pT3 a/b muscle-invasive BC were reviewed and re-evaluated by a pathologist specialized in uropathology. Clinical variables and standard histopathologic characteristics were assessed including TIF and tumor size. Their value as prognosticators for overall survival (OS) and recurrence-free survival (RFS) was evaluated.

Results: Mean age of patients was 67.55 years. Tumors were staged pT3a in 28 patients (53.8%) and pT3b in 24 (46.8%). Median OS was 34.51 months. Median tumor size was 3.2 cm, median TIF was 11.0 mm. Differences in OS between pT3a and pT3b were not significant (p = 0.45). Carcinoma in situ (CIS) and lymphovascular invasion (LVI) were significantly associated with pT3b tumors. Univariate analysis could not identify pathological prognosticators like TIF or tumor size for OS and RFS (p for all > 0.05).

Conclusion: No significant differences in OS or RFS were observed comparing Ln-negative pT3 BC following radical cystectomy. Additional pathologic variables like TIF could not be identified as prognosticator. Relevance of pT3 BC substaging needs reevaluation in larger prospective cohorts.
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http://dx.doi.org/10.1007/s00345-021-03697-3DOI Listing
April 2021

[Advanced prostate cancer - modern therapies, better prognosis?]

MMW Fortschr Med 2021 04;163(7):41-43

Urologische Klinik und Poliklinik, Klinikum Großhadern d. LMU München, Marchionistr. 15, 81377, München, Deutschland.

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http://dx.doi.org/10.1007/s15006-021-9748-3DOI Listing
April 2021

Retrospective German claims data study on initial treatment of bladder carcinoma (BCa) by transurethral bladder resection (TURB): a comparative analysis of costs using standard white light- (WL-) vs. blue light- (BL-) TURB.

World J Urol 2021 Feb 10. Epub 2021 Feb 10.

Department of Urology, University of Tuebingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany.

Purpose: Photodynamic diagnosis using hexaminolevulinate (HAL)-guided BL-TURB may reduce the recurrence risk in non-muscle invasive BCa compared to standard WL-TURB due to more sensitive tumor detection. The impact of the initial use of WL- vs. BL-TURB on follow-up costs was evaluated in this real-world data analysis.

Methods: Anonymous claims data of German statutory health insurances (GKV) from 2011 to 2016 were analyzed in a primary and adjusted study population. Selection criteria included five quarters before enrolment, one index quarter (InQ) of initial TURB and BCa diagnosis, either within two years for the primary analysis or within four years for the adjusted analysis, and a follow-up period (FU) of either eleven or three quarters, respectively.

Results: In the primary analysis (n = 2331), cystectomy was identified as an important cost driver masking potential differences between cohorts. Therefore, patients undergoing cystectomy (InQ + FU) were excluded from the adjusted study population of n = 4541 patients (WL: 79%; BL: 21%). Mean total costs of BL-TURB were initially comparable to WL-TURB (WL: EUR 4534 vs. BL: EUR 4543) and tended to be lower compared to WL-TURB in the first two quarters of FU. After one year (3rd FU quarter), costs equalized. Considering total FU, mean costs of BL-TURB were significantly lower compared to WL-TURB (WL: EUR 7073 vs BL: EUR 6431; p = 0.045).

Conclusion: This retrospective analysis of healthcare claims data highlights the comparability of costs between BL-TURB and WL-TURB.
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http://dx.doi.org/10.1007/s00345-020-03587-0DOI Listing
February 2021

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer.

Nat Commun 2021 01 8;12(1):184. Epub 2021 Jan 8.

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.

Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.
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http://dx.doi.org/10.1038/s41467-020-20493-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794518PMC
January 2021

[Advanced prostate cancer: sequence of androgen receptor-targeted substances and chemotherapy determines long-term survival].

Urologe A 2021 Feb 21;60(2):212-221. Epub 2020 Dec 21.

Klinik für Urologie, Uroonkologie, robotergestützte und fokale Therapie, Universitätsklinikum Magdeburg, Magdeburg, Deutschland.

The treatment of advanced prostate cancer is changing. New study data and the resulting new therapeutic options have led to increasingly differentiated treatment decisions. Despite the changing therapy landscape, taxane-based chemotherapy-being a life-prolonging treatment-remains an indispensable therapeutic component for chemotherapy-fit patients in the metastatic setting. The current results of the randomized study CARD show that cabazitaxel has a higher oncological effectiveness, including a significant survival benefit and no negative impact on quality of life parameters, compared to a second androgen receptor targeted agent (ARTA) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after treatment with docetaxel and an androgen receptor-targeted agent (ARTA). In mCNPC the combination therapies of ADT (androgen deprivation therapy) plus docetaxel or of ADT plus ARTA have been established. In addition, three ARTAs tested in recent phase III studies in a clinical setting for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) showed that their use significantly prolongs metastasis-free survival and overall survival. The potential early use of ARTAs also has implications for the treatment of mCNPC. The aim of this publication is to provide guidance for clinical routine and to develop criteria for individual therapy decisions with a special focus on the use of chemotherapy.
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http://dx.doi.org/10.1007/s00120-020-01411-6DOI Listing
February 2021

[Molecular subtypes of urothelial carcinoma of the bladder-background and clinical relevance].

Urologe A 2021 Jan;60(1):81-88

Fachgruppe Molekulare Urologie der Arbeitsgruppe urologische Forschung (AuF) der Deutschen Gesellschaft für Urologie, Berlin, Deutschland.

Advanced and metastatic stages of bladder cancer are associated with a poor prognosis. Therapy options are currently limited to systemic therapy with chemo- and immunotherapeutics. In order to improve individual therapy and especially to achieve a more favorable prognosis for these patients, intrinsic molecular subtypes have recently been identified in urothelial carcinoma of the bladder. This review article presents the latest developments, background, and clinical relevance of molecular subtypes in urothelial carcinoma of the bladder. The existing literature and current study data were analyzed to present and evaluate the different molecular classification systems. A focus was placed on the possible therapeutic implications of these molecular subtypes. Although promising progress has been made in the molecular subtyping of urothelial carcinoma, this classification has not yet found its way into clinical application. Multicenter prospective studies with standardized study protocols are still lacking. Previous studies differ in molecular markers, sample collection and preparation procedures, and analytical protocols. Standardization is urgently needed before guidelines can be established and targeted treatment regimens implemented. In principle, the aim should be to develop a stable and as simple as possible methodology, enabling personalized treatment based on molecular subtypes to be broadly applied, and not just in specialized expert centers.
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http://dx.doi.org/10.1007/s00120-020-01396-2DOI Listing
January 2021

[Systemic treatment of advanced prostate cancer].

Urologe A 2020 Dec;59(12):1565-1576

Studienpraxis Nürtingen, Steinengrabenstraße 17, 72622, Nürtingen, Deutschland.

In recent years there have been substantial changes in the therapeutic landscape for systemic treatment of advanced prostate cancer (PCa), which resulted in a multitude of novel treatment options for different stages of the disease. In the current narrative review currently available treatment options for metastatic hormone-sensitive PCa as well as nonmetastatic castration-resistant PCa are presented. In addition, current treatment sequence options and targeted treatment in the stage of metastatic castration-resistant PCa are highlighted.
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http://dx.doi.org/10.1007/s00120-020-01381-9DOI Listing
December 2020

A simple method for detecting oncofetal chondroitin sulfate glycosaminoglycans in bladder cancer urine.

Cell Death Discov 2020 27;6:65. Epub 2020 Jul 27.

Department of Urologic Sciences, University of British Columbia, Vancouver, BC Canada.

Proteoglycans in bladder tumors are modified with a distinct oncofetal chondroitin sulfate (ofCS) glycosaminoglycan that is normally restricted to placental trophoblast cells. This ofCS-modification can be detected in bladder tumors by the malarial VAR2CSA protein, which in malaria pathogenesis mediates adherence of parasite-infected erythrocytes within the placenta. In bladder cancer, proteoglycans are constantly shed into the urine, and therefore have the potential to be used for detection of disease. In this study we investigated whether recombinant VAR2CSA (rVAR2) protein could be used to detect ofCS-modified proteoglycans (ofCSPGs) in the urine of bladder cancer patients as an indication of disease presence. We show that ofCSPGs in bladder cancer urine can be immobilized on cationic nitrocellulose membranes and subsequently probed for ofCS content by rVAR2 protein in a custom-made dot-blot assay. Patients with high-grade bladder tumors displayed a marked increase in urinary ofCSPGs as compared to healthy individuals. Urine ofCSPGs decreased significantly after complete tumor resection compared to matched urine collected preoperatively from patients with bladder cancer. Moreover, ofCSPGs in urine correlated with tumor size of bladder cancer patients. These findings demonstrate that rVAR2 can be utilized in a simple biochemical assay to detect cancer-specific ofCS-modifications in the urine of bladder cancer patients, which may be further developed as a noninvasive approach to detect and monitor the disease.
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http://dx.doi.org/10.1038/s41420-020-00304-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385127PMC
July 2020

Prognostic impact of somatostatin receptor expression in advanced bladder cancer.

Urol Oncol 2020 12 7;38(12):935.e17-935.e28. Epub 2020 Aug 7.

Clinical Trial Unit, Studienpraxis Urologie, Nürtingen, Germany; Medical School, Eberhard-Karls-University Tübingen, Tübingen, Germany. Electronic address:

Introduction And Objectives: Somatostatin receptors (SSTR) recently have been identified as potential targets for treatment of solid tumors. Furthermore, they have been shown to be of high relevance for tumor biology and prognosis in various types of cancer. However, there is a lack of clinical data for SSTR in bladder cancer (BC). Aim of this study was to determine the expression of all relevant somatostatin receptor subtypes in benign urothelium and tumor tissue of patients with muscle invasive BC. Furthermore, their potential role as prognostic factor for cancer-specific survival (CSS) and overall survival (OS) was evaluated.

Methods: The collective included BC and benign urothelium tissue of 103 patients (Median age 69; range 32-84, 79 male, 24 female) who underwent a radical cystectomy. A tissue microarray with subsequent immunohistochemical staining was used to assess membranous expression of SSTR1-5. Results were correlated to clinical and histopathological data as well as CSS and OS.

Results: Expressions of SSTR1-4 were significantly decreased in BC compared to benign urothelium (P < 0.002 each), whereas SSTR5 expression was increased (P = 0.0017). Expression of SSTR1 was associated with organ-confined disease (≤pT2) (P = 0.0477). No correlation between SSTR1-5 expression and N- and M-stage was observed. Univariate analyses showed a significantly longer CSS and OS in patients with high expression of SSTR3 (P = 0.0316 and 0.0044). Multivariate analyses confirmed SSTR3 expression as independent marker of improved CSS and OS (P = 0.0324 and 0.0076).

Conclusions: The majority of somatostatin receptor subtypes exhibit decreased expression in BC compared to benign bladder tissue. Expression of SSTR3 is an indicator for favorable prognosis in patients with muscle-invasive BC. These results support preclinical investigations using somatostatin receptor analogues such as octreotide to influence BC growth.
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http://dx.doi.org/10.1016/j.urolonc.2020.07.005DOI Listing
December 2020

Role of Multiparametric Magnetic Resonance Imaging in Predicting Pathologic Outcomes in Prostate Cancer.

World J Mens Health 2021 Jan 24;39(1):38-47. Epub 2020 Jun 24.

Medical School, Eberhard-Karls-University Tübingen, Tübingen, Germany.

Multiparametric magnetic resonance imaging (mpMRI) and the introduction of standardized protocols for its interpretation have had a significant impact on the field of prostate cancer (PC). Multiple randomized controlled trials have shown that the sensitivity for detection of clinically significant PC is increased when mpMRI results are the basis for indication of a prostate biopsy. The added value with regards to sensitivity has been strongest for patients with persistent suspicion for PC after a prior negative biopsy. Although enhanced sensitivity of mpMRI is convincing, studies that have compared mpMRI with prostatectomy specimens prepared by whole-mount section analysis have shown a significant number of lesions that were not detected by mpMRI. In this context, the importance of an additional systematic biopsy (SB) is still being debated. While SB in combination with targeted biopsies leads to an increased detection rate, most of the tumors detected by SB only are considered clinically insignificant. Currently, multiple risk calculation tools are being developed that include not only clinical parameters but mpMRI results in addition to clinical parameters in order to improve risk stratification for PC, such as the Partin tables. In summary, mpMRI of the prostate has become a standard procedure recommended by multiple important guidelines for the diagnostic work-up of patients with suspicion of PC.
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http://dx.doi.org/10.5534/wjmh.200030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752518PMC
January 2021

Human Prostate Cancer is Characterized by an Increase in Urea Cycle Metabolites.

Cancers (Basel) 2020 07 6;12(7). Epub 2020 Jul 6.

Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Despite it being the most common incident of cancer among men, the pathophysiological mechanisms contributing to prostate cancer (PCa) are still poorly understood. Altered mitochondrial metabolism is postulated to play a role in the development of PCa. To determine the key metabolites (which included mitochondrial oncometabolites), benign prostatic and cancer tissues of patients with PCa were analyzed using capillary electrophoresis and liquid chromatography coupled with mass spectrometry. Gene expression was studied using real-time PCR. In PCa tissues, we found reduced levels of early tricarboxylic acid cycle metabolites, whereas the contents of urea cycle metabolites including aspartate, argininosuccinate, arginine, proline, and the oncometabolite fumarate were higher than that in benign controls. Fumarate content correlated positively with the gene expression of oncogenic HIF1α and NFκB pathways, which were significantly higher in the PCa samples than in the benign controls. Furthermore, data from the TCGA database demonstrated that prostate cancer patients with activated NFκB pathway had a lower survival rate. In summary, our data showed that fumarate content was positively associated with carcinogenic genes.
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http://dx.doi.org/10.3390/cancers12071814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408908PMC
July 2020

Impact of Histopathological Prostate Inflammation on Urine-Based Prostate Cancer Prediction Using the Prostate Cancer Gene 3 Score.

Urol Int 2020 8;104(5-6):483-488. Epub 2020 May 8.

Department of Urology, Eberhard Karls University of Tübingen, Tübingen, Germany.

Introduction: The Prostate Cancer gene 3 (PCA3) urine test has gained importance in the diagnostic workup of prostate cancer (PC). Limited evidence suggests that PCA3 is not altered in the presence of inflammation.

Objective: To assess the impact of histological inflammation on PCA3.

Methods: PCA3 was evaluated in patients prior to prostate biopsy (n = 193) and to radical prostatectomy (n = 197). In patients without PC, inflammation was assessed and quantified by individual scores integrating grade and extent. Uni- and multivariate analyses were performed to assess the impact of inflammation grade on PCA3.

Results: The PCA3 scores prior to prostatectomy were lower (median 45) than those before positive biopsy (57; p = 0.008). Of 101 negative biopsies, 78% showed inflammation. The median PCA3 scores in the groups with no inflammation and with maximum grade 1 (n = 22), 2 (n = 38), and 3 (n = 19) inflammation were 45, 38, 27, and 25 (p = 0.016). The multivariate models revealed a decrease in PCA3 proportional to the grade and extent of inflammation (p < 0.04 each).

Conclusions: The present data imply that the PCA3 score decreases in the presence of inflammation, which is relevant, for instance, to testing after a recently performed biopsy. In general, inflammation should be regarded as a factor putatively influencing PCA3 and other available and upcoming PC tests.
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http://dx.doi.org/10.1159/000506885DOI Listing
March 2021

Editorial Comment.

J Urol 2020 07 28;204(1):77. Epub 2020 Apr 28.

Studienpraxis Urology, Clinical Trial Unit, Nuertingen, Germany.

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http://dx.doi.org/10.1097/JU.0000000000000803.01DOI Listing
July 2020

[Chemotherapy provides improved outcomes compared to novel hormonal therapy : Optimal treatment sequence after failure of abiraterone or enzalutamide].

Urologe A 2020 Apr 4. Epub 2020 Apr 4.

Studienpraxis Urology, Clinical Trial Unit, Steinengrabenstr. 17, 72622, Nuertingen, Deutschland.

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http://dx.doi.org/10.1007/s00120-020-01177-xDOI Listing
April 2020

Toward noninvasive follow-up of low-risk bladder cancer - Rationale and concept of the UroFollow trial.

Urol Oncol 2020 12 18;38(12):886-895. Epub 2020 Mar 18.

Urologie 24, Nürnberg, Germany; Department of Urology, Friedrich-Alexander University, Erlangen, Germany. Electronic address:

Background: Follow-up recommendations for patients with nonmuscle invasive bladder cancer (NMIBC) are largely based upon expert opinion. A growing body of evidence suggests that current follow-up strategies for bladder cancer patients with low and intermediate risk represent overdiagnosis and may lead to overtreatment. The goal of this study is to explore the options of a noninvasive follow-up in patients with pTa G1-2/low-grade NMIBC.

Methods: The risks and options for a urine marker-guided, noninvasive follow-up of patients with pTa G1-2/low-grade NMIBC were defined and the study design for a prospective randomized trial (UroFollow) was developed based upon the current literature.

Results: The investigators postulated that follow-up of patients with pTa G1-2/low-grade NMIBC requires a high sensitivity of urinary tumor markers. However, data from prospective studies with prediagnostic urine samples are scarce, even for approved markers, and cross-sectional studies with symptomatic patients overestimate the sensitivity. So far, cell-based markers (e.g., uCyt+ and UroVysion) in urine appeared to have higher sensitivities and specificities in low-grade NMIBC than urine cytology and markers analyzing soluble tumor-associated antigens. Marker panels are more sensitive than single-marker approaches at the expense of a lower specificity. Given a prospective randomized comparison with a marker sensitivity of 80% compared to usual care with cystoscopy, the sample size calculation yielded that 62 to 185 patients under study per arm are needed depending on different recurrence rates.

Conclusions: Based upon these findings the UroFollow trial has been designed as a prospective randomized study comparing a noninvasive marker-based (UroVysion, NMP22, urine cytology, and ultrasound) follow-up with the current standard of care over a period of 3 years.
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http://dx.doi.org/10.1016/j.urolonc.2020.01.006DOI Listing
December 2020

Age-Adapted Prostate Cancer Gene 3 Score Interpretation - Suggestions for Clinical Use.

Clin Lab 2020 Mar;66(3)

Background: The prostate cancer antigen 3 (PCA3) gene urine assay is established for biopsy decision in case of prostate cancer (PC) suspicion. Recent findings pointed to an age dependence of PCA3, with putative impact on test interpretation. However, to date no experience has been reported with regard to the extent age might modify the score in certain age ranges. Therefore, the aim of the present study was to re-evaluate the age dependency and, moreover, give suggestions for interpretation of the PCA3 score in dependence of patient's age in daily routine.

Methods: The study comprised 684 patients before prostate biopsy or prostatectomy. Post-massage voided urine samples were assessed by PCA3 measurement. PCA3 scores were correlated to patient's age. The collective was divided into four subcollectives by quartiles of age distribution. For every subcollective the cutoff value at specificity of ≥ 60 was determined. Results were classified by age-class specific cutoff values and test qualities were compared at different cutoffs.

Results: In the collective, 59.1% of patients had a positive biopsy. PCA3 correlated to patient's age in univariate and multivariate analysis (p < 0.001 each). The division into age subcollectives revealed groups < 60, 60 - 65, 66 - 69 and > 69 years. Median PCA3 values of patients without/with PC were 17/32, 27/42, 34/55 and 52/68 in the four age classes. Cutoff values for which specificity was determined with ≥ 60 were 23, 39, 42, and 65. Constant cutoff values showed lower sensitivities in younger and lower specificities in older patients. Only the age adjusted values revealed an improved performance with PPV 68.7, accuracy 59.5 and sensitivity 57.7 at specificity of 62.1% in the whole cohort.

Conclusions: The study confirms that the PCA3 score increases with age. The recommended cutoff score of 35 is suitable especially for patients aged in their sixties. Lower reference values between 20 and 30 have to be taken into account in patients aged < 60 years and higher values around 40 to 50 may point to suspicion for PC in patients > 69 years. These results may further improve the diagnostic performance of the PCA3 test and keep the PCA3 test as a significant test in PC diagnostics along with new upcoming urine markers.
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http://dx.doi.org/10.7754/Clin.Lab.2019.190714DOI Listing
March 2020

Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer.

Dis Markers 2019 11;2019:1296865. Epub 2019 Dec 11.

Department of Urology, Eberhard Karls University of Tübingen, Tübingen, Germany.

The aim of this study was to evaluate the expression of mammalian target of rapamycin (mTOR), phosphorylated-mTOR (p-mTOR), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in prostate cancer (PCa) in order to assess intratumoral heterogeneity and correlation with clinicopathological parameters. Tissue samples from 115 patients undergoing radical prostatectomy were included in a tissue microarray comprising (A) tissue from the tumor center, (B) malignant border of the tumor, (C) tumor-adjacent benign tissue, and (D) tumor-distant benign prostatic tissue. Immune reactive scores 0-12 were correlated with clinical data in reference to localization. A meta-analysis of studies investigating the association between biochemical recurrence (BCR) and parameters of the mTOR pathway was conducted. Regardless of the location within the tumor, cancer tissue showed higher expression of mTOR, p-mTOR, and 4EB-P1 compared to benign tissue ( < 0.01). Significant differences in expression between tissue samples from groups C and D were observed for mTOR and p-mTOR. When considering expression according to the pathological stage, we observed lower p-mTOR expression in pT3 vs. pT2 (7.9 and 6.3; = 0.01). After a median follow-up of 74.5 months (IQR 65.0-84.0), 27 patients (23.47%) developed BCR. Weak staining of mTOR was associated with shorter time to BCR (HR: 2.0; = 0.049) after correcting for PSA and T stage. However, a significant association of mTOR expression with BCR was found for specimens from the malignant border of the tumor (B) but not the tumor center (A) ( = 0.0034 log rank). In a meta-analysis, we found that the expressions of mTOR ((RR) = 0.70; 95% CI 0.43-1.12; = 0.13) and 4E-BP1 ((RR) = 0.86; = 0.53) were not statistically associated with BCR, while strong staining of p-mTOR was associated with a lower risk of BCR ((RR) = 0.57; = 0.002). All 3 markers showed stronger expression in PCa and exhibited local gradients in relation to the border of tumor and healthy tissue. Our results suggest an important role of intratumor heterogeneity for the use of mTOR parameters as biomarkers in PCa.
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http://dx.doi.org/10.1155/2019/1296865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927025PMC
May 2020

Re: Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer.

Eur Urol 2020 04 23;77(4):559-560. Epub 2019 Dec 23.

Department of Urology, Albert-Ludwigs University, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2019.12.012DOI Listing
April 2020

Amplification of 7p12 Is Associated with Pathologic Nonresponse to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer.

Am J Pathol 2020 02 13;190(2):442-452. Epub 2019 Dec 13.

Department of Internal Medicine V, Medical University Innsbruck, Innsbruck, Austria; Tyrolean Cancer Research Institute, Innsbruck, Austria.

Pathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P < 0.001), with a median time to recurrence of 41.2 versus 5.5 months in nonresponders. DNA damage repair alterations were noticed in 38.1% (n = 8), confirming a positive correlation with high tumor mutational burden (P = 0.007). Chromosomal 7p12 amplification, including the genes HUS1, EGFR, ABCA13, and IKZF1, predicted nonresponse in patients with a sensitivity, a negative predictive value, and a specificity of 71.4%, 87.5%, and 100%, respectively. Total count of CD3 T cells/mm tumor was a significant predictor of NAC response. In conclusion, 7p12 amplification may predict nonresponse to NAC and worse survival in MIBC. Multicenter, prospective trials with sufficient statistical power may further fortify these findings.
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http://dx.doi.org/10.1016/j.ajpath.2019.10.018DOI Listing
February 2020

Pathophysiology of Tumor Cell Release into the Circulation and Characterization of CTC.

Recent Results Cancer Res 2020 ;215:3-24

Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The traditional model of metastatic progression postulates that the ability to form distant metastases is driven by random mutations in cells of the primary tumor.
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http://dx.doi.org/10.1007/978-3-030-26439-0_1DOI Listing
October 2019

Editorial Comment.

J Urol 2020 01 3;203(1):81. Epub 2019 Oct 3.

Clinical Trial Unit, Studienpraxis Urology, Nuertingen.

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http://dx.doi.org/10.1097/01.JU.0000602792.03998.76DOI Listing
January 2020

Molecular subtypes and response to immunotherapy in bladder cancer patients.

Transl Androl Urol 2019 Jul;8(Suppl 3):S293-S295

Department of Urology, University of Bern, Inselspital Bern, Bern, Switzerland.

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http://dx.doi.org/10.21037/tau.2019.06.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642947PMC
July 2019

Prognostic Utility of a Whole-blood Androgen Receptor-based Gene Signature in Metastatic Castration-resistant Prostate Cancer.

Eur Urol Focus 2021 Jan 15;7(1):63-70. Epub 2019 May 15.

Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address:

Background: The treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly in recent years. Identifying predictive and/or prognostic biomarkers in the context of this rapidly expanding therapeutic armamentarium remains a pressing and unmet clinical need.

Objective: To develop a prognostic whole-blood gene signature for mCRPC patients.

Design, Setting, And Participants: As part of an ongoing prospective, multicentre biomarker research study (Australian Prostate Biomarker Alliance), we enrolled 115 mCRPC patients commencing chemotherapy (n = 34) or androgen receptor (AR) pathway inhibitors therapy (n = 81) and obtained pretreatment whole-blood samples in PAXgene RNA tubes. Gene expression was assessed using reverse transcription-polymerase chain reaction.

Outcome Measurements And Statistical Analysis: Gene transcripts correlating with overall survival (OS) at p < 0.10 in univariate Cox regression models were incorporated into a multigene signature. Kaplan-Meier survival estimates and multivariate analyses were used to assess association with clinical outcomes. Prognostic strength of the signature was estimated using a concordance probability estimate (CPE).

Results And Limitations: Based on univariate analysis for OS, the following genes were incorporated into a multigene signature: AR splice variant 7 (AR-V7), and three androgen-regulated genes: GRHL2, HOXB13, and FOXA1. The number of positive transcripts clearly stratified survival outcomes (median OS: not reached vs 24.8 mo vs 16.2 mo for 0, 1, and ≥2 transcripts, respectively; p = 0.0052). Notably, this multigene signature retained prognostic significance on multivariable analysis (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; p = 0.019). Moreover, CPE for this model was 0.78, indicating strong discriminative capacity. Limitations include short follow-up time.

Conclusions: Our data demonstrate the prognostic utility of a novel whole-blood AR-based signature in mCRPC patients commencing contemporary systemic therapies. Our pragmatic assay requires minimal processing, can be performed in most hospital laboratories, and could represent a key prognostic tool for risk stratification in mCRPC.

Patient Summary: We found that expression of certain genes associated with the androgen receptor could help determine how long men with advanced prostate cancer survive after starting modern drug therapies.
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http://dx.doi.org/10.1016/j.euf.2019.04.020DOI Listing
January 2021

Bone Health Issues in Patients with Prostate Cancer: An Evidence-Based Review.

World J Mens Health 2020 Apr 2;38(2):151-163. Epub 2019 May 2.

Department of Urology, Eberhard Karls University, Tuebingen, Germany.

Bone health in prostate cancer patients represents a prerequisite for acceptable quality of life and optimal outcome of this disease. The major threat for bone health in prostate cancer displays cancer treatment induced bone loss as well as the development of bone metastases. In recent years, several new pharmaceuticals targeting bone metabolism such as denosumab or androgen pathway targeting drugs (abiraterone acetate and enzalutamide) have been approved for the treatment of progressive disease aiming to interrupt the vicious circle of bone metastasis and aberrant bone resorption. This development raised the awareness of the pivotal role of bone health in prostate cancer and introduced (symptomatic) skeletal related events as an important end point in recent clinical trials. Bone targeted drugs have become standard of care in patients with metastatic castration resistant prostate cancer, their role in metastatic hormone sensitive prostate cancer has been discussed controversely. In oligometastatic prostate cancer patients several promising approaches in metastasis directed therapy, including conventional surgery, stereotactic ablative radiation and image-guided single-fraction robotic stereotactic radiosurgery (CyberKnife®) were launched but are not in routine clinical use until now caused by sparse clinical evidence.
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http://dx.doi.org/10.5534/wjmh.190044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076314PMC
April 2020

Sex-Specific Associations of Testosterone With Metabolic Traits.

Front Endocrinol (Lausanne) 2019 13;10:90. Epub 2019 Mar 13.

Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany.

Testosterone levels are differentially linked with diabetes risk in men and women: lower testosterone levels in men and higher testosterone levels in women are associated with type 2 diabetes, though, the mechanisms are not fully clear. We addressed sex-specific links between testosterone and major pathogenetic mechanisms of diabetes. We analyzed data of 623 subjects (202 male, 345 female without, and 76 female with oral contraceptive therapy [OCT]) for whom insulin sensitivity and insulin secretion were assessed by oral glucose tolerance test. Body fat percentage was assessed by bioelectrical impedance. Testosterone was measured by enzyme-linked immunoassay; free testosterone and Framingham risk score were calculated. There were significant interactions between testosterone and sex for all tested metabolic traits. Increasing testosterone was associated with less body fat, elevated insulin sensitivity, and reduced glycemia, independent of adiposity in men. In women without OCT, testosterone correlated with more body fat, insulin resistance, and higher glucose concentrations. Testosterone was not associated with insulin secretion in either sex, but with lower Framingham risk score in men and higher Framingham risk score in women. Similar to diabetes risk, insulin resistance has different association directions with testosterone levels in males and females. Insulin resistance could therefore constitute the best biological candidate linking testosterone levels and diabetes prevalence. The question of antiandrogen therapy being able to improve metabolism, glucose tolerance and cardiovascular risk in women was not clarified in our study but should be reviewed with higher numbers in a carefully matched study to reduce the influence of confounding variables.
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http://dx.doi.org/10.3389/fendo.2019.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425082PMC
March 2019

Determination of Free-PSA (fPSA) and fPSA/PSA-Ratio Using A Point-of-Care Device.

Clin Lab 2019 Jan;65(1)

Background: Prostate specific antigen (PSA) and free PSA (fPSA) are important tools for diagnosing prostate cancer (PC). Efforts are continuously undertaken to provide more patient-centered healthcare. The application of point-of-care (POC) systems for laboratory analyses represents a step in this direction. Previous investigations on total PSA measurements using a POC system (concile® Ω100 POC reader) showed good concordance with standard laboratory measurements. For the same POC reader a novel system for fPSA was developed. In the current study, we prospectively evaluated the quality of the POC system for fPSA.

Methods: Sixty-four patients undergoing PSA measurements in our outpatient clinic between 06/2015 and 09/2015 were enrolled in the study. We measured total PSA (tPSA) and fPSA with a POC reader system (concile® Ω100) and a standard laboratory system (Siemens Immulite 2000®) and compared the respective results using linear regression analyses for PSA, fPSA, and fPSA/tPSA ratio (%fPSA).

Results: The coefficients of determination (r²) for fPSA and %fPSA were 0.85 (p < 0.001) and 0.82 (p < 0.001) in the subgroup with total PSA between 4 and 10 ng/mL. In the subgroup with tPSA ≤ 4 ng/mL, r² for fPSA concile® was 0.55 (p < 0.001) and 0.10 (p = 0.088) for %fPSA. In the subgroup of tPSA > 10 ng/mL the r² for fPSA and %fPSA was 0.50 (p = 0.022) and 0.50 (p = 0.022), respectively.

Conclusions: The POC fPSA values correlated well with the laboratory analyses, specifically in the clinically relevant diagnostic range of tPSA 4 - 10 ng/mL. These results complement the tPSA data obtained previously and indicate the reliability of the fPSA method and the resulting %fPSA score.
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http://dx.doi.org/10.7754/Clin.Lab.2018.180710DOI Listing
January 2019

[High-throughput molecular analysis of urothelial carcinoma: potential clinical applications].

Aktuelle Urol 2019 Feb 7;50(1):84-93. Epub 2019 Feb 7.

Department of Urology, University Hospital Bern, Switzerland.

The application of next-generation high-throughput techniques for the identification of molecular alterations in tumour tissue has greatly improved our knowledge of the biology of urothelial carcinoma. Gene expression analysis performed as part of the Cancer Genome Atlas project (TCGA) enabled the identification of molecular subtypes with distinct biologic features. The knowledge gained through these analyses could lead to a significant change in the clinical management of patients with urothelial carcinoma through targeted applications. Initial studies indicate that the determination of molecular subtypes could inform the decision on whether or not to use neoadjuvant chemotherapy. Moreover, drugs with effects limited to patients with specific genetic alterations are currently under investigation in clinical trials. The identification of specific mutations in circulating tumour DNA (ctDNA) using liquid biopsies enables the characterisation of metastatic tumours without a tissue biopsy. Moreover, circulating tumour DNA could be used in the aftercare of patients with urothelial carcinoma.
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http://dx.doi.org/10.1055/a-0755-7284DOI Listing
February 2019