Publications by authors named "Isabel Heidegger"

100 Publications

Focal Therapy for Prostate Cancer: Complications and Their Treatment.

Front Surg 2021 12;8:696242. Epub 2021 Jul 12.

Department of Urology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Focal therapy is a modern alternative to selectively treat a specific part of the prostate harboring clinically significant disease while preserving the rest of the gland. The aim of this therapeutic approach is to retain the oncological benefit of active treatment and to minimize the side-effects of common radical treatments. The oncological effectiveness of focal therapy is yet to be proven in long-term robust trials. In contrast, the toxicity profile is well-established in randomized controlled trials and multiple robust prospective cohort studies. This narrative review summarizes the relevant evidence on complications and their management after focal therapy. When compared to whole gland treatments, focal therapy provides a substantial benefit in terms of adverse events reduction and preservation of genito-urinary function. The most common complications occur in the peri-operative period. Urinary tract infection and acute urinary retention can occur in up to 17% of patients, while dysuria and haematuria are more common. Urinary incontinence following focal therapy is very rare (0-5%), and the vast majority of patients recover in few weeks. Erectile dysfunction can occur after focal therapy in 0-46%: the baseline function and the ablation template are the most important factors predicting post-operative erectile dysfunction. Focal therapy in the salvage setting after external beam radiotherapy has a significantly higher rate of complications. Up to one man in 10 will present a severe complication.
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http://dx.doi.org/10.3389/fsurg.2021.696242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311122PMC
July 2021

Radiation Therapy After Radical Prostatectomy: What Has Changed Over Time?

Front Surg 2021 9;8:691473. Epub 2021 Jul 9.

Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.

The role and timing of radiotherapy (RT) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) remains controversial. While recent trials support the oncological safety of early salvage RT (SRT) compared to adjuvant RT (ART) in selected patients, previous randomized studies demonstrated that ART might improve recurrence-free survival in patients at high risk for local recurrence based on adverse pathology. Although ART might improve survival, this approach is characterized by a risk of overtreatment in up to 40% of cases. SRT is defined as the administration of RT to the prostatic bed and to the surrounding tissues in the patient with PSA recurrence after surgery but no evidence of distant metastatic disease. The delivery of salvage therapies exclusively in men who experience biochemical recurrence (BCR) has the potential advantage of reducing the risk of side effects without theoretically compromising outcomes. However, how to select patients at risk of progression who are more likely to benefit from a more aggressive treatment after RP, the exact timing of RT after RP, and the use of hormone therapy and its duration at the time of RT are still open issues. Moreover, what the role of novel imaging techniques and genomic classifiers are in identifying the most optimal post-operative management of PCa patients treated with RP is yet to be clarified. This narrative review summarizes most relevant published data to guide a multidisciplinary team in selecting appropriate candidates for post-prostatectomy radiation therapy.
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http://dx.doi.org/10.3389/fsurg.2021.691473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298897PMC
July 2021

Intermediate-risk Prostate Cancer-A Sheep in Wolf's Clothing?

Eur Urol Oncol 2021 Jul 22. Epub 2021 Jul 22.

Sorbonne Université, Urology Department, Hôpital Pitié-Salpêtrière, Paris, France.

This case-based discussion describes a 65-year-old man newly diagnosed with International Society of Urological Pathology (ISUP) grade 2 prostate cancer (PCa). According to the European Association of Urology classification system, the patient harbors an intermediate-risk cancer. In step-by step discussion, we elaborate guideline-based treatment modalities for intermediate-risk PCa focused on debating active surveillance versus active treatment. Thereby, we discuss the importance of patient characteristics, including age, hereditary factors, life expectancy and comorbidity status, findings of multiparametric magnetic resonance imaging, as well as prostate-specific antigen (PSA) density and PSA kinetics, in predicting the clinical course of the disease. In addition, we focus on cribriform pathology as a predictor of adverse outcomes and critically discuss its relevance in patient management. Lastly, we outline genomic stratification in ISUP 2 cancer as a future tool to predict PCa aggressiveness. PATIENT SUMMARY: Based on current guidelines, patients with intermediate-risk prostate cancer are treated actively or can alternatively undergo an active surveillance approach when favorable risk factors are present. One major issue is to discriminate between patients who benefit from an active therapy approach and those who benefit from a deferred treatment. Therefore, reliable biomarkers and early predictors of disease progression are needed urgently.
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http://dx.doi.org/10.1016/j.euo.2021.07.004DOI Listing
July 2021

Radical Prostatectomy: Sequelae in the Course of Time.

Front Surg 2021 28;8:684088. Epub 2021 May 28.

Division of Oncology/Unit of Urology, Urological Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy.

Radical prostatectomy (RP) is a frequent treatment for men suffering from localized prostate cancer (PCa). Whilst offering a high chance for cure, it does not come without a significant impact on health-related quality of life. Herein we review the common adverse effects RP may have over the course of time. A collaborative narrative review was performed with the identification of the principal studies on the topic. The search was executed by a relevant term search on PubMed from 2010 to February 2021. Rates of major complications in patients undergoing RP are generally low. The main adverse effects are erectile dysfunction varying from 11 to 87% and urinary incontinence varying from 0 to 87% with a peak in functional decline shortly after surgery, and dependent on definitions. Different less frequent side effects also need to be taken into account. The highest rate of recovery is seen within the first year after RP, but even long-term improvements are possible. Nevertheless, for some men these adverse effects are long lasting and different, less frequent side effects also need to be taken into account. Despite many technical advances over the last two decades no surgical approach can be clearly favored when looking at long-term outcome, as surgical volume and experience as well as individual patient characteristics are still the most influential variables. The frequency of erectile function and urinary continence side effects after RP, and the trajectory of recovery, need to be taken into account when counseling patients about their treatment options for prostate cancer.
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http://dx.doi.org/10.3389/fsurg.2021.684088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193923PMC
May 2021

Recent Insights on Genetic Testing in Primary Prostate Cancer.

Mol Diagn Ther 2021 Jul 12;25(4):425-438. Epub 2021 Jun 12.

Department of Urology, Medical University Innsbruck, Anichstreet 35, 6020, Innsbruck, Austria.

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.
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http://dx.doi.org/10.1007/s40291-021-00529-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249272PMC
July 2021

Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer.

Oncogene 2021 Apr 1;40(17):3087-3100. Epub 2021 Apr 1.

Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

Despite increasing options for treatment of castration-resistant prostate cancer, development of drug resistance is inevitable. The glucocorticoid receptor (GR) is a prime suspect for acquired therapy resistance, as prostate cancer (PCa) cells are able to increase GR signaling during anti-androgen therapy and thereby circumvent androgen receptor (AR)-blockade and cell death. As standard AR-directed therapies fail to block the GR and GR inhibitors might result in intolerable side effects, the identification of GR signature genes, which are better suited for a targeted approach, is of clinical importance. Therefore, the specific epithelial and stromal GR signature was determined in cancer-associated fibroblasts as well as in abiraterone and enzalutamide-resistant cells after glucocorticoid (GC) treatment. Microarray and ChIP analysis identified MAO-A as a directly up-regulated mutual epithelial and stromal GR target, which is induced after GC treatment and during PCa progression. Elevated MAO-A levels were confirmed in in vitro cell models, in primary tissue cultures after GC treatment, and in patients after neoadjuvant chemotherapy with GCs. MAO-A expression correlates with GR/AR activity as well as with a reduced progression-free survival. Pharmacological MAO-A inhibition combined with 2 generation AR signaling inhibitors or chemotherapeutics results in impaired growth of androgen-dependent, androgen-independent, and long-term anti-androgen-treated cells. In summary, these findings demonstrate that targeting MAO-A represents an innovative therapeutic strategy to synergistically block GR and AR dependent PCa cell growth and thereby overcome therapy resistance.
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http://dx.doi.org/10.1038/s41388-021-01754-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084733PMC
April 2021

Data Sharing Under the General Data Protection Regulation: Time to Harmonize Law and Research Ethics?

Hypertension 2021 Apr 15;77(4):1029-1035. Epub 2021 Feb 15.

Urologie 24, Nuremberg, and Department of Urology, Friedrich-Alexander University of Erlangen, Germany (B.J.S-D).

The General Data Protection Regulation (GDPR) became binding law in the European Union Member States in 2018, as a step toward harmonizing personal data protection legislation in the European Union. The Regulation governs almost all types of personal data processing, hence, also, those pertaining to biomedical research. The purpose of this article is to highlight the main practical issues related to data and biological sample sharing that biomedical researchers face regularly, and to specify how these are addressed in the context of GDPR, after consulting with ethics/legal experts. We identify areas in which clarifications of the GDPR are needed, particularly those related to consent requirements by study participants. Amendments should target the following: (1) restricting exceptions based on national laws and increasing harmonization, (2) confirming the concept of broad consent, and (3) defining a roadmap for secondary use of data. These changes will be achieved by acknowledged learned societies in the field taking the lead in preparing a document giving guidance for the optimal interpretation of the GDPR, which will be finalized following a period of commenting by a broad multistakeholder audience. In parallel, promoting engagement and education of the public in the relevant issues (such as different consent types or residual risk for re-identification), on both local/national and international levels, is considered critical for advancement. We hope that this article will open this broad discussion involving all major stakeholders, toward optimizing the GDPR and allowing a harmonized transnational research approach.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968961PMC
April 2021

Atezolizumab for PD-L1-Selected Patients with NSCLC.

N Engl J Med 2021 02;384(6):584

Medical University of Innsbruck, Innsbruck, Austria

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http://dx.doi.org/10.1056/NEJMc2032432DOI Listing
February 2021

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

Eur Urol Oncol 2021 Jan 6. Epub 2021 Jan 6.

Johanniter Krankenhaus Bonn, Department of Urology, Bonn, Germany.

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 cm. 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.
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http://dx.doi.org/10.1016/j.euo.2020.12.003DOI Listing
January 2021

A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy?

Eur Urol Oncol 2020 Nov 23. Epub 2020 Nov 23.

Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.

Context: The role of immune checkpoint inhibition (ICI) in the treatment of prostate cancer (PC) still remains elusive. It has been proposed that combination of ICI with other molecules increases the efficacy of immunotherapy in PC.

Objective: To systematically review the literature to assess the potential role of ICI in combination with additional therapies for the management of metastatic castration-resistant PC (mCRPC).

Evidence Acquisition: A systematic review using Medline and scientific meeting records was carried out in September 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. Ongoing trials of immunotherapy with standard mCRPC therapeutics were identified via a systematic search on ClinicalTrials.gov.

Evidence Synthesis: A total of five full-text papers, ten congress abstracts, and 15 trials on ClinicalTrials.gov were identified. Preclinical evidence suggests that combinational approaches might be considered to enhance the efficacy of ICI in PC patients. This led to the design of more than 50 immunotherapy-based clinical trials. The majority of the studies focus on ICI combinations with vaccines, androgen deprivation therapy, chemotherapy, PARP inhibition, radiotherapy, and prostate-specific membrane antigen-guided radioligand therapy. Preliminary analyses reported promising findings for the use of ICI in combination with other anticancer therapies. However, no phase 3 trial has yet reported final results, so no level 1 evidence with long-term outcomes currently supports the combination of ICI with mCRPC therapies.

Conclusions: Preclinical and clinical trials have demonstrated that combining immunotherapy with standard mCRPC treatment options has the potential to provide a synergistic effect. Nonetheless, a better understanding of the mechanism and of the optimal treatment approach is still needed.

Patient Summary: We reviewed the literature on immunotherapy in combination with standard treatments for patients with metastatic castration-resistant prostate cancer (mCRPC). Current evidence supports the hypothesis that immunotherapeutic drugs might be effective in mCRPC if combined with other treatment options. However, results of ongoing trials are still awaited before this novel treatment approach can be implemented in the daily practice.
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http://dx.doi.org/10.1016/j.euo.2020.10.010DOI Listing
November 2020

Recent Scientific Developments in Metastatic Prostate Cancer.

Authors:
Isabel Heidegger

Cancers (Basel) 2020 Nov 6;12(11). Epub 2020 Nov 6.

Department of Urology, Medical University Innsbruck, 6020 Innsbruck, Austria.

In recent years, the treatment landscape of advanced prostate cancer has radically changed [...].
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http://dx.doi.org/10.3390/cancers12113280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694445PMC
November 2020

Contemporary role of palliative cystoprostatectomy or pelvic exenteration in advanced symptomatic prostate cancer.

World J Urol 2020 Nov 1. Epub 2020 Nov 1.

Department of Urology, Ludwig-Maximilians University of Munich, Munich, Germany.

Objective: To access the feasibility of palliative cystoprostatectomy/pelvic exenteration in patients with bladder/rectal invasion due to prostate cancer (PC).

Patients And Methods: Twenty-five men with cT4 PC were retrospectively identified in the institutional databases of six tertiary referral centers in the last decade. Local invasion was documented by CT or MRI scans and was confirmed by urethrocystoscopy. Oncological therapies, local symptoms, previous local treatments, time from diagnosis to intervention and type of surgical procedure were recorded. Patients were divided into groups: ADT group (12 pts) and 13 pts without any history of previous local/systemic treatments for PCa (nonADT groups). Perioperative complications were classified using the Clavien-Dindo system. Overall survival (OS) was defined as the time from surgery to death from any cause. A Cox regression analysis, stratified for ISUP score and previous hormonal treatment (ADT) was also performed for survival analysis.

Results: Ileal conduit was the main urinary diversion in both cohorts. For the entire cohort, complication rate was 44%. No significant differences regarding perioperative complications and complication severity between both subgroups were observed (p = 0.2). Median follow-up was 15 months (range 3-41) for the entire cohort with a median survival of 15 months (95% CI 10.1-19.9). In Cox regression analysis stratified for ISUP score, no statistically significant differences in OS in patients with and without previous ADT before cystectomy or exenteration were observed (HR 3.26, 95% CI 0.62-17.23, p = 0.164).

Conclusion: Palliative cystoprostatectomy and pelvic exenteration represent viable treatment options associated with acceptable morbidity and good short-term survival outcome.
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http://dx.doi.org/10.1007/s00345-020-03493-5DOI Listing
November 2020

Initial Experience with Radical Prostatectomy Following Holmium Laser Enucleation of the Prostate.

Eur Urol Focus 2020 Sep 19. Epub 2020 Sep 19.

Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.

Background: Although an increasing number of prostate cancer (PCa) patients received holmium laser enucleation of the prostate (HoLEP) previously for benign prostatic obstruction (BPO), there is still no evidence regarding the outcomes of radical prostatectomy (RP) in this setting.

Objective: To assess functional and oncological results of RP in PCa patients who received HoLEP for BPO previously in a contemporary multi-institutional cohort.

Design, Setting, And Participants: A total of 95 patients who underwent RP between 2011 and 2019 and had a history of HoLEP were identified in two institutions. Functional as well as oncological follow-up was prospectively assessed and retrospectively analyzed.

Intervention: RP following HoLEP compared with RP without previous transurethral surgery.

Outcome Measurements And Statistical Analysis: Patients with complete follow-up data were matched with individuals with no history of BPO surgery using propensity score matching. Complications were assessed using the Clavien-Dindo scale.

Results And Limitations: The median follow-up was 50.5 mo. We found no significant impact of previous HoLEP on positive surgical margin rate (14.0% [HoLEP] vs 18.8% [no HoLEP], p =  0.06) and biochemical recurrence-free survival (hazard ratio 0.74, 95% confidence interval [CI] 0.32-1.70, p =  0.4). Patients with a history of HoLEP had increased 1-yr urinary incontinence rates after RP. After adjusting for confounders, no significant impact of previous HoLEP was found (odds ratio [OR] 0.87, 95% CI 0.74-1.01; p = 0.07). Previous HoLEP did not hamper 1-yr erectile function recovery (OR 1.22, 95% CI 1.05-1.43; p =  0.01). Limitations include retrospective design and small sample size.

Conclusions: RP after previous HoLEP is surgically feasible, with low complication rates and no negative impact on biochemical recurrence-free survival. However, in a multivariable analysis, we observed significantly worse 1-yr continence rates in patients after previous HoLEP.

Patient Summary: In the current study, we assessed the oncological and functional outcomes of radical prostatectomy in patients who underwent holmium laser enucleation of the prostate (HoLEP) previously due to prostatic bladder outlet obstruction. A history of HoLEP did not hamper oncological results, 1-yr continence, and erectile function recovery.
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http://dx.doi.org/10.1016/j.euf.2020.09.003DOI Listing
September 2020

Management of Patients with Node-positive Prostate Cancer at Radical Prostatectomy and Pelvic Lymph Node Dissection: A Systematic Review.

Eur Urol Oncol 2020 10 12;3(5):565-581. Epub 2020 Sep 12.

Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.

Context: Optimal management of prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy and pelvic lymph node dissection still remains unclear.

Objective: To assess the effectiveness of postoperative treatment strategies for pathologically node-positive PCa patients. The secondary aim was to identify the most relevant prognostic factors to guide the management of pN1 patients.

Evidence Acquisition: A systematic review was performed in January 2020 using Medline, Embase, and other databases. A total of 5063 articles were screened, and 26 studies including 12 537 men were selected for data synthesis and included in the current review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations.

Evidence Synthesis: Ten-year biochemical recurrence (BCR)-free, clinical recurrence-free, cancer-specific (CSS), and overall (OS) survival rates ranged from 28% to 56%, 70% to 92%, 72% to 98%, and 60% to 87.6%, respectively. A total of seven, five, and six studies assessed the oncological outcomes of observation, adjuvant radiotherapy (aRT), or adjuvant androgen deprivation therapy (ADT), respectively. Initial observation followed by salvage therapies at the time of recurrence represents a safe option in selected patients with a low disease burden. The use of aRT with or without ADT might improve survival in men with locally advanced disease and a higher number of positive nodes. Risk stratification according to pathological Gleason score, number of positive nodes, pathological stage, and surgical margins status is the key to risk stratification and selection of the optimal postoperative therapy. Limitations of this systematic review are the retrospective design of the studies included and the lack of data on adverse events.

Conclusions: While the majority of men with pN1 disease would experience BCR after surgery, long-term disease-free survival has been reported in selected patients. Management options to improve oncological outcomes include observation versus adjuvant therapies such as aRT and/or ADT. Disease characteristics should be used to select the optimal postoperative management for pN1 PCa patients.

Patient Summary: Finding node-positive prostate cancer after a radical prostatectomy often leads to high postoperative prostate-specific antigen levels and is overall a poor prognostic factor. However, this does not necessarily translate into poor survival for all men. Management can be tailored to the severity of disease and options include observation, androgen deprivation therapy, and/or radiotherapy.
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http://dx.doi.org/10.1016/j.euo.2020.08.005DOI Listing
October 2020

Olaparib for Metastatic Castration-Resistant Prostate Cancer.

N Engl J Med 2020 08;383(9):890-891

Medical University of Innsbruck, Innsbruck, Austria

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http://dx.doi.org/10.1056/NEJMc2023199DOI Listing
August 2020

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.

Cancers (Basel) 2020 Jul 28;12(8). Epub 2020 Jul 28.

Department of Urology, Medical University Innsbruck, 6020 Innsbruck, Austria.

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.
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http://dx.doi.org/10.3390/cancers12082092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465893PMC
July 2020

Treatment of Metastasized Prostate Cancer Beyond Progression After Upfront Docetaxel-A Real-world Data Assessment.

Eur Urol Focus 2020 Jul 8. Epub 2020 Jul 8.

Department of Urology and Pediatric Urology, University Medicine Mainz, Mainz, Germany.

Background: Besides second-generation hormone therapy (sHT), upfront docetaxel along with androgen deprivation therapy is the current standard of care for metastasized hormone-sensitive prostate cancer (mHSPC). Evidence on second-line therapy upon progression on chemohormonal treatment outside clinical trials is scarce.

Objective: To comparatively assess the efficacy of subsequent therapy after upfront docetaxel in mHSPC in a real-world setting.

Design, Setting, And Participants: This is a retrospective multicenter analysis. Males with mHSPC on androgen-deprivation therapy progressed to castration-resistant prostate cancer (CRPC) after upfront docetaxel.

Outcome Measurements And Statistical Analysis: Overall survival (OS), progression-free survival 2 (PFS2), and time to progression 2 (TTP2) were assessed. Chi-square test and Mann-Whitney U test were used for univariate comparison between the sHT and non-sHT (other therapies) cohorts. Median time to event was tested by Kaplan-Meier method and log-rank test. Univariate and multivariate analysis regression was performed with the Cox proportional-hazard model.

Results And Limitations: Sixty-five patients were included in the final analysis. Median TTP2 was 20 mo, median PFS2 was 29 mo, and median OS was not reached; sHT was an independent predictor of favorable PFS2 as compared with non-sHT. Time to CRPC was also confirmed to be the strongest predictor for novel endpoints PFS2 and TTP2. Time to CRPC >18 mo conferred advantage to sHT over non-sHT in relation to PFS2 and OS. Second-line therapies were well tolerated. The analysis is prone to inherent flaws and biases due to its retrospective nature.

Conclusions: In real-world patients progressing after upfront docetaxel, sHT is independently associated with favorable PFS2 favoring drug class switch. Longer time to CRPC predicts strongly for superior PFS2 and TTP2. Further prospective research is warranted in order to guide treatment sequencing and improve outcomes and quality of life of males with metastasized prostate cancer.

Patient Summary: We analyzed the efficacy of second-line therapy after docetaxel in hormone-dependent metastatic prostate cancer. Novel hormone therapy appears to be a preferable option for deferring progression optimally. Larger patient databases are eagerly awaited.
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http://dx.doi.org/10.1016/j.euf.2020.06.018DOI Listing
July 2020

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

Urol Oncol 2020 11 24;38(11):801-815. Epub 2020 Jun 24.

Department of Urology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

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.
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http://dx.doi.org/10.1016/j.urolonc.2020.05.025DOI Listing
November 2020

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

Anticancer Res 2020 May;40(5):2861-2864

Department of Urology, Medical University Innsbruck, Innsbruck, Austria

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.
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http://dx.doi.org/10.21873/anticanres.14261DOI Listing
May 2020

External Validation of the 2019 Briganti Nomogram for the Identification of Prostate Cancer Patients Who Should Be Considered for an Extended Pelvic Lymph Node Dissection.

Eur Urol 2020 08 5;78(2):138-142. Epub 2020 Apr 5.

Department of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.

The 2019 Briganti nomogram was developed to calculate the risk of lymph node invasion (LNI) and identify prostate cancer (PCa) patients diagnosed with magnetic resonance imaging (MRI)-targeted biopsy who should be considered for an extended pelvic lymph node dissection (ePLND). Since its implementation is still limited by lack of a formal external validation, we aimed to validate this tool in a large contemporary cohort. We identified 487 patients diagnosed using MRI-targeted with concomitant systematic biopsy who underwent radical prostatectomy (RP) and an anatomically defined ePLND at six centers. The external validity of the 2019 Briganti nomogram for estimating LNI risk was assessed via calibration, discrimination, and decision curve analyses (DCAs). A total of 38 (8%) patients had LNI at final pathology. The median number of nodes removed was 18 (interquartile range 14-24). On external validation, the 2019 Briganti nomogram had an area under the receiver operating characteristic curve (AUC) of 79%. Although there was some miscalibration, this was at predicted probabilities >35% and therefore outside the clinically relevant range. DCA demonstrated that the 2019 Briganti nomogram improved clinical risk prediction against LNI threshold probabilities of ≤30%. For a 7% cutoff, 273 (56%) ePLNDs would be spared and only 2.6% LNIs would be missed. The 2019 Briganti nomogram was characterized by higher AUC compared to the 2012 and 2017 Briganti nomograms and the Memorial Sloan Kettering Cancer Center risk calculator (79% vs 75% vs 65% vs 74%) and demonstrated the highest net benefit on DCA. This first multi-institutional validation of the 2019 Briganti nomogram in predicting LNI in PCa patients diagnosed with MRI-targeted biopsy confirms the highest AUC, better calibration and the highest net benefit compared with available tools and should be adopted to identify candidates for ePLND among men diagnosed with MRI-targeted biopsy. PATIENT SUMMARY: We performed the first multi-institutional validation of the first nomogram predicting lymph node invasion specifically developed using data from prostate cancer patients diagnosed with magnetic resonance imaging (MRI)-targeted biopsy. This nomogram exhibited excellent characteristics on external validation compared with available tools and should be adopted to identify candidates for extended pelvic lymph node dissection among men diagnosed with MRI-targeted biopsy.
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http://dx.doi.org/10.1016/j.eururo.2020.03.023DOI Listing
August 2020

Health-related Quality of Life in Patients with Advanced Prostate Cancer: A Systematic Review.

Eur Urol Focus 2020 Feb 20. Epub 2020 Feb 20.

Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, University Hospital-Hamburg Eppendorf, Hamburg, Germany.

Context: The assessment of "soft" endpoints such as health-related quality of life (HRQOL) is increasingly relevant when evaluating the optimal treatment sequence of novel therapeutic options in patients with advanced prostate cancer (PCa).

Objective: To systematically review contemporary data regarding HRQOL outcomes in patients with advanced PCa.

Evidence Acquisition: A systematic review of the literature published between January 2011 and March 2019 was performed using the PubMed/Medline Database. In total, 873 articles were screened, and 14 articles including 12 661 patients were selected for synthesis and included in the current analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and European Association of Urology recommendations.

Evidence Synthesis: Regarding HRQOL assessment, the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire was used in 11 of 14 studies, the European Quality of Life 5-Dimensions (EQ-5D) questionnaire in six of 14 studies, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) in two of 14, and its prostate-specific amendment QLQ-PR25 was used in one of 14 studies. Three studies included patients with metastatic castration-sensitive prostate PCa, and found beneficial HRQOL effects for abiraterone acetate and docetaxel compared with standard androgen deprivation therapy. Two studies included patients with nonmetastatic castration-resistant PCa, and positive HRQOL effects for enzalutamide and apalutamide were observed. Nine studies focused on patients with metastatic castration-resistant PCa. Hereby, beneficial HRQOL outcomes were described for enzalutamide, abiraterone acetate, and radium-223. Evidence synthesis was mostly based on studies with a low risk of bias based on standardized risk of bias assessment. Limitations include hampered comparability between different validated questionnaires, lack of baseline values, and unclear impact of supportive care on HRQOL outcomes.

Conclusions: There is strong evidence from several phase III trials supporting a beneficial effect of current systemic treatment options on HRQOL outcomes in patients with advanced PCa compared with standard androgen deprivation therapy.

Patient Summary: In this systematic review, we provide an overview of contemporary data from large clinical trials on the effect of current treatment strategies on patients' health-related quality of life (HRQOL). We summarize the assessment tools that have been used to measure HRQOL and show that there are robust data for positive HRQOL effects of numerous agents in different clinical stages of advanced prostate cancer.
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http://dx.doi.org/10.1016/j.euf.2020.01.017DOI Listing
February 2020

The Impact of Cand1 in Prostate Cancer.

Cancers (Basel) 2020 Feb 12;12(2). Epub 2020 Feb 12.

Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Evidence has accumulated asserting the importance of cullin-RING (really interesting new gene) ubiquitin ligases (CRLs) and their regulator Cullin-associated neural-precursor-cell-expressed developmentally down-regulated 8 (NEDD8) dissociated protein 1 (Cand1) in various cancer entities. However, the role of Cand1 in prostate cancer (PCa) has not been intensively investigated so far. Thus, in the present study, we aimed to assess the relevance of Cand1 in the clinical and preclinical setting. Immunohistochemical analyses of radical prostatectomy specimens of PCa patients showed that Cand1 protein levels are elevated in PCa compared to benign areas. In addition, high Cand1 levels were associated with higher Gleason Scores, as well as higher tumor recurrence and decreased overall survival. In line with clinical findings, experiments in different PCa cell lines revealed that knockdown of Cand1 reduced cell viability and proliferation and increased apoptosis, therefore underlining its role in tumor progression. We also found that the cyclin-dependent kinase inhibitor p21 is significantly upregulated upon downregulation of Cand1. Using bioinformatic tools, we detected genes encoding for proteins linked to mRNA turnover, protein polyubiquitination, and proteasomal degradation to be significantly upregulated in Cand1 tumors. Next generation sequencing of PCa cell lines resistant to the anti-androgen enzalutamide revealed that is mutated in enzalutamide-resistant cells, however, with little functional and clinically relevant impact in the process of resistance development. To summarize the present study, we found that high Cand1 levels correlate with PCa aggressiveness.
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http://dx.doi.org/10.3390/cancers12020428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072594PMC
February 2020

Treatment of non-metastatic castration resistant prostate cancer in 2020: What is the best?

Urol Oncol 2020 04 15;38(4):129-136. Epub 2020 Jan 15.

Department of Urology, Technical University of Munich, Munich, Germany.

Lately the development of 3 novel second-generation androgen receptor antagonists (enzalutamide, apalutamide, and darolutamide) chanced the treatment landscape of nonmetastatic castration-resistant prostate cancer. After proofing their clinical efficacy in large phase III registration trials with good compatibilities and tolerable side effects currently all 3 substances are Food and Drug Administration-approved in nonmetastatic castration-resistant prostate cancer. The present short review article provides an overview about these new treatment options and discusses their use in daily routine focusing on patient selection as well as on the impact of novel sensitive imaging modalities like prostate-specific membrane antigen-positron-emission tomography for detection of this stage of disease.
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http://dx.doi.org/10.1016/j.urolonc.2019.11.007DOI Listing
April 2020

Hereditary prostate cancer - Primetime for genetic testing?

Cancer Treat Rev 2019 Dec 11;81:101927. Epub 2019 Nov 11.

Department of Urology, La Croix du Sud Hospital, Toulouse, France; Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France.

Prostate cancer (PCa) remains the most common cancer in men. The proportion of all PCa attributable to high-risk hereditary factors has been estimated to 5-15%. Recent landmark discoveries in PCa genetics led to the identification of germline mutations/alterations (eg. BRCA1, BRCA2, ATM or HOXB13), single nucleotide polymorphisms or copy number variations associated with PCa incidence and progression. However, offering germline testing to men with an assumed hereditary component is currently controversial. In the present review article, we provide an overview about the epidemiology and the genetic basis of PCa predisposition and critically discuss the significance and consequence in the clinical routine. In addition, we give an overview about genetic tests and report latest findings from ongoing clinical studies. Lastly, we discuss the impact of genetic testing in personalized therapy in advanced stages of the disease.
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http://dx.doi.org/10.1016/j.ctrv.2019.101927DOI Listing
December 2019

Drug-Drug Interactions in Prostate Cancer Treatment.

Clin Genitourin Cancer 2020 04 27;18(2):e71-e82. Epub 2019 May 27.

Department of Urology, Medical University Innsbruck, Innsbruck, Austria. Electronic address:

Polypharmacy is associated with an increased risk of drug-drug interactions (DDIs), which can cause serious and debilitating drug-induced adverse events. With a steadily aging population and associated increasing multimorbidity and polypharmacy, the potential for DDIs becomes considerably important. Prostate cancer (PCa) is the most common cancer in men and occurs mostly in elderly men in the Western world. Therefore, the aim of this review is to give an overview of DDIs in PCa therapy to better understand pharmacodynamic and pharm kinetic side effects as well as their interactions with other medications. Last, we explore potential future strategies, which might help to optimize treatment and reduce adverse events patients with polypharmacy and PCa.
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http://dx.doi.org/10.1016/j.clgc.2019.05.016DOI Listing
April 2020

Targeting the Tumor Microenvironment in Renal Cell Cancer Biology and Therapy.

Front Oncol 2019 14;9:490. Epub 2019 Jun 14.

Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

Renal cell cancer (RCC) is a highly vascularized and immunogenic tumor type. The inhibition of vessel formation by anti-angiogenic therapies, as well as the stimulation of the immune system by immunotherapy has revolutionized the therapeutic landscape of RCC in recent years. Nevertheless, both therapies are associated with therapy resistance due to a highly dynamic, adaptive and heterogeneous tumor microenvironment (TME). The aim of this short review article is to provide an overview of the components of the RCC TME as well as to discuss their contribution to disease progression. In addition, we report on preclinical and clinical findings and how the different TME components can be modulated to impede treatment progression as well as to overcome therapy resistance to anti-angiogenic or immunomodulating therapy concepts. Furthermore, we discuss the predictive and prognostic role of the TME in RCC therapy. We also report on the concept of combinational targeting of anti-angiogenic therapies and immune checkpoint inhibitor therapy, also including the latest results of clinical studies discussed at recent oncological meetings. Finally, promising new therapeutic targets within the TME are mentioned.
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http://dx.doi.org/10.3389/fonc.2019.00490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587703PMC
June 2019

Organ-sparing surgery of penile cancer: higher rate of local recurrence yet no impact on overall survival.

World J Urol 2020 Feb 6;38(2):417-424. Epub 2019 May 6.

Department of Urology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

Purpose: To report on the oncological outcome of organ-sparing surgery (OSS) compared to (total or partial) penectomy regarding recurrence patterns and survival in squamous cell carcinoma (SCC) of the penis.

Methods: This was a retrospective study of all patients with penile SCC and eligible follow-up data of at least 2 years at our institution. Patients with tumors staged ≥ pT1G2 underwent invasive lymph node (LN) staging by dynamic sentinel-node biopsy or modified inguinal lymphadenectomy. Radical inguinal lymphadenectomy was performed when LNs were palpable at diagnosis and in those with a positive LN status after invasive nodal staging. Follow-up visits were assessed, and local, regional and distant recurrences were defined and analyzed.

Results: 55 patients were identified with a mean follow-up of 63.7 months. Surgical management was OSS in 26 patients (47.2%) and partial or total penectomy in 29 cases (52.8%). Histopathological staging was: pTis (12.7%), pTa (16.3%), pT1a (18.2%), pT1b (5.5%), pT2 (29.1%) and pT3 (18.2%), respectively. Patients in the penectomy group were significantly older (mean 68 vs. 62 years; p = 0.026) with a higher rate of advanced tumor stage (≥ pT2: 44.8% vs. 11.5%; p = 0.002). The local recurrence rate was 42.3% (n = 11) following OSS compared to 10.3% (n = 3) after penectomy (p = 0.007). Kaplan-Meier curves showed no significant differences between the two groups regarding metastasis-free and overall survival.

Conclusions: OSS is associated with a higher local recurrence rate compared to penectomy, yet it has no negative impact on overall and metastasis-free survival.
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http://dx.doi.org/10.1007/s00345-019-02793-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994547PMC
February 2020

Aggressive variants of prostate cancer - Are we ready to apply specific treatment right now?

Cancer Treat Rev 2019 May 11;75:20-26. Epub 2019 Mar 11.

Department of Urology, Fundeni Clinical Institute, University of Medicine and Pharmacy, Carol Davila Bucharest, Bucharest, Romania.

Recently, adoption of novel drugs for systemic treatment of metastatic prostate cancer has led to a striking improvement of response rate and survival in both hormone-sensitive and castration-resistant disease. In most cases, prostate cancer essentially depends on androgen receptor signaling axis, even in castration-resistant setting, and hence may be targeted by second generation hormonal therapy. However, a subset of patients bears androgen-independent cancer biology with a short-term response to hormonal treatment, early and extensive visceral metastases, low PSA levels and poor outcomes. Identification and specific management of these rapidly fatal malignancies is of an unmet medical need since their classification and utilized therapeutic regimens vary significantly. Unfortunately, molecular pathways have not been sufficiently elucidated yet in order to provide an effective targeted treatment with a prolonged response. Lack of diagnostic and predictive biomarkers for these cancers makes successful counteractions against them even more sophisticated. In this comprehensive review, we aimed at summarizing the current body of literature reporting on causal molecular machinery as well as diagnostic and therapeutic concepts of aggressive prostate tumors and draw clinically relevant conclusions for the up-to-date sensible disease management.
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http://dx.doi.org/10.1016/j.ctrv.2019.03.001DOI Listing
May 2019

Therapeutic rationale of targeting BCG and immune checkpoints in non-muscle-invasive bladder cancer: Is this the Future?

Urol Oncol 2019 06 28;37(6):343-345. Epub 2019 Feb 28.

Medical University Innsbruck, Department of Urology, Innsbruck, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.urolonc.2019.02.001DOI Listing
June 2019
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