PD-L1 as a Urine Biomarker in Renal Cell Carcinoma-A Case Series and Proof-of-Concept Study.

BACKGROUND: Renal cell carcinoma (RCC) is among the most lethal urologic malignancies once metastatic. Current treatment approaches for metastatic RCC (mRCC) involve immune checkpoint inhibitors (ICIs) that target the PD-L1/PD-1 axis. High PD-L1 expression in tumor tissue has been identified as a negative prognostic factor in RCC. However, the role of PD-L1 as a liquid biomarker has not yet been fully explored. Herein, we analyze urine levels of PD-L1 in mRCC patients before and after either ICI therapy or surgical intervention, as well as in a series of patients with treatment-naïve RCC. PATIENTS AND METHODS: The mid-stream urine of patients with mRCC (n = 4) or treatment-naïve RCC, i.e., prior to surgery from two centers (cohort I, n = 49: cohort II, n = 29) was analyzed for PD-L1 by ELISA. The results from cohort I were compared to a control group consisting of patients treated for non-malignant urologic diseases (n = 31). In the mRCC group, urine PD-L1 levels were measured before and after tumor nephrectomy (n = 1) or before and after ICI therapy (n = 3). Exosomal PD-L1 in the urine was analyzed in selected patients by immunoblotting. RESULTS: A strong decrease in urine PD-L1 levels was found after tumor nephrectomy or following systemic treatment with ICIs. In patients with treatment-naïve RCC (cohort I), urine PD-L1 levels were significantly elevated in the RCC group in comparison to the control group (median 59 pg/mL vs. 25.7 pg/mL, p = 0.011). PD-L1 urine levels were found to be elevated, in particular, in low-grade RCCs in cohorts I and II. Exosomal PD-L1 was detected in the urine of a subset of patients. CONCLUSION: In this proof-of-concept study, we show that PD-L1 can be detected in the urine of RCC patients. Urine PD-L1 levels were found to correlate with the treatment response in mRCC patients and were significantly elevated in treatment-naïve RCC patients.

Development and outcomes of surgical and urological kidney transplantation programs in Germany: a total population analysis from 2006 to 2021.

PURPOSE: Kidney transplantation (KT) is the most frequently performed organ transplantation. In Germany, KT is performed in urology and surgery departments with unknown consequences of this parallel structure. The aim of the study was to compare the development and outcome of KT in urology and surgery departments. METHODS: On an institutional level, we analyzed the annual caseload from 2006 to 2021 with the reimbursement. INFO tool based on hospitals' quality reports (Reimbursement Institute, Hürth, Germany). For outcome comparison we extracted raw data from the transplantation centers' quality reports (Deutsche Stiftung Organtransplantation, DSO). RESULTS: A total of 23,599 cases (17,781 deceased donor and 5,818 living donor KTs) were included. The total number of KTs decreased from 1851 in 2006 to 1701 in 2021 (- 8%; p = 0.12). The total number of urological KTs decreased from 592 cases in 2006 to 395 cases in 2021 (- 33.3%; p = 0.01). Further analysis revealed no significant differences between intra- and postoperative complications and graft quality at one year for deceased donor KTs (DDKT) although differences in immediate renal function and graft quality at discharge could be observed. There were no significant differences in immediate renal function and graft quality at discharge for living donor KTs (LDKT) between the specialties. CONCLUSION: KTs performed in urology departments declined between 2006 and 2021. Nevertheless, intra- and postoperative complications as well as long-term function did not differ between surgical and urological KT programs. Hence, an interdisciplinary approach, especially considering the upcoming challenges in KT as, e.g., robot-assisted surgery seems reasonable.

Trends in the use of testicular prostheses in Germany: a total population analysis from 2006-2021.

INTRODUCTION: Testicular tumors are the most common malignancies in young adults and their incidence is growing. The implantation of a testicular prosthesis, for example, during orchiectomy is a standard procedure but its frequency in Germany is unknown. This study aims to analyze trends of testicular prosthesis implantation in recent years in Germany. MATERIAL AND METHODS: The nationwide German hospital billing database and the German hospital quality reports from 2006 to 2021 were studied. RESULTS: A total of 12,753 surgical procedures with implantation of testicular prosthesis and 1,244 procedures with testicular prosthesis explantation were included. Testicular prosthesis implantation increased in total from 699 cases in 2006 to 870 cases in 2020 (+11.4 cases/year; p < 0.001). The share of implantation of testicular prosthesis due to testicular tumor decreased from 72.6% in 2006 to 67.5% in 2020 (p < 0.001). The share of implantation due to gender affirming surgery increased from 6.8% in 2006 to 23.3% in 2020 (p < 0.001). The share of implantation due to testicular atrophy decreased from 11.4% in 2006 to 3.4% in 2020 (p < 0.001). Simultaneous implantation of testicular prosthesis during orchiectomy for testicular cancer increased from 7.8% in 2006 to 11.4% in 2020 (p < 0.001). In 2006, 146 hospitals (85%) performed < 5 testicular prosthesis implantation, while 20 hospitals (12%) performed 5-15 implantation procedures and 6 hospitals (3%) performed > 15 testicular implantation surgeries. In 2021, 115 hospitals (72%) performed < 5 testicular prosthesis implantation, while 39 hospitals (25%) performed 5-15 implantation procedures and 5 hospitals (3%) performed > 15 testicular implantation surgeries. CONCLUSION: This study shows that implantation of testicular prostheses is steadily increasing. Explantation rates are low. Besides testicular cancer transgender surgeries were the main driver for increasing case numbers in recent years.

Enhancing Human Papillomavirus Vaccination Rates through Better Knowledge? Insights from a Survey among German Medical Students.

INTRODUCTION: Vaccination against human papillomavirus (HPV) significantly reduces the risk for malignant diseases like cervix, anal, or penile cancer. However, although vaccination rates are rising, they are still too low mirroring a lack of disease awareness in the community. This study aims to evaluate knowledge about HPV vaccination as well as the vaccination rate among German medical students. MATERIAL AND METHODS: Medical students were surveyed during a German medical students' sports event. The self-designed survey on HPV vaccination consisted of 24 items. The data collection was anonymous. RESULTS: Among 974 participating medical students 64.9% (632) were women, 335 (34.4%) were male and 7 (0.7%) were nonbinary. Mean age was 23.1 ± 2.7 (± standard deviation; range 18-35) years. Respondents had studied mean 6.6 ± 3.3 (1-16) semesters and 39.4% (383) had completed medical education in urology. 613 (64%) respondents reported that HPV had been discussed during their studies. 7.6% (74) had never heard of HPV. In a multivariate model female gender, the knowledge about HPV, and having worked on the topic were significantly associated with being HPV-vaccinated. Older students were vaccinated less likely. CONCLUSIONS: Better knowledge and having worked on the topic of HPV were associated with a higher vaccination rate. However, even in this highly selected group the knowledge about HPV vaccination was low. Consequently, more information and awareness campaigns on HPV vaccination are needed in Germany to increase vaccination rates.

Trends in kidney transplantation and living donor nephrectomy in Germany: a total population analysis from 2006 to 2021.

PURPOSE: To analyze recent trends of surgical access routes, length of hospital stay (LOS), and mortality in kidney transplantation (KT) and living donor nephrectomy (LDN) in Germany. MATERIALS AND METHODS: We studied the nationwide German hospital billing database and the German hospital quality reports from 2006 to 2021. RESULTS: There were a total of 35.898 KTs. In total, 9044 (25%) were living donor transplantations, while 26.854 (75%) were transplantations after donation after brain death (DBD). The share of open LDN decreased from 82% in 2006 to 22% in 2020 (- 4%/year; p < 0.001). The share of laparoscopic LDN increased from 18% in 2006 to 70% in 2020 (+ 3%/year; p < 0.001). The share of robotic LDN increased from 0% in 2006 to 8% in 2020 (+ 0.6%/year; p < 0.001). Robotic-assisted KT increased from 5 cases in 2016 to 13 procedures in 2019 (p = 0.2). LOS was shorter after living donor KT, i.e., 18 ± 12.1 days versus 21 ± 19.6 days for DBD renal transplantation (p < 0.001). Moreover, LOS differed for open versus laparoscopic versus robotic LDN (9 ± 3.1 vs. 8 ± 2.9 vs. 6 ± 2.6; p = 0.031). The overall in-hospital mortality was 0.16% (n = 5) after LDN, 0.47% (n = 42) after living donor KT and 1.8% (n = 475) after DBD KT. CONCLUSIONS: There is an increasing trend toward minimal-invasive LDN in recent years. Overall, in-hospital mortality was low after KT. However, 5 deceased healthy donors after LKD caution that the risks of this procedure should also be taken very seriously.

Hydronephrotic pelvic kidney mimicking urinary retention in an 18-year-old male.

We present a case of a hydronephrotic pelvic kidney in an 18-year-old male reporting about inability to void. Ultrasound showed a hypoechogenic mass mimicking a full urinary bladder. Anticipating urinary retention, a foley was inserted but no urin could be aspirated. Imaging showed a hydronephrotic pelvic kidney with no relevant function obstructing the urinary bladder and the contralateral ureter. Nephrectomy was performed and postoperative course was uneventful. A hydronephrotic pelvic kidney is a rare but important differential diagnosis in young men reporting lower abdominal pain and inability to void.

Better Knowledge about Testicular Cancer Might Improve the Rate of Testicular (Self-)Examination: A Survey among 1,025 Medical Students in Germany.

INTRODUCTION: Testicular cancer (TC) is the most common malignancy among young men. Public awareness of the disease and testicular (self-)examination (TSE) is low. This study aims to evaluate the awareness of German medical students on TC. METHODS: A 25-item questionnaire on TC was handed out during a medical student's football tournament in Germany. Data collection was anonymous. RESULTS: Questionnaires were answered by 573 (56%) female and 452 (44%) male medical students. Most students had gaps in their knowledge about TC: 483 (48%) students knew, the most common age at which TC occurs, and 413 (41%) knew its cure rate. Having dealt with TC during their studies was significantly associated with a better knowledge about TC (p = 0.001). These students also had a higher rate of TSE among male students (66% vs. 52%, p = 0.002). This also applies to examining the partner's testicles by female students (25% vs. 13%, p < 0.001). CONCLUSION: Even in a positively selected collective like medical students, the knowledge about TC is low. Better knowledge might improve the chance of detecting the disease early. Therefore, our joint project of urologists, patients, and supporters called Prevention and Advocacy of Testicular Education e.V. (PATE) works on rising public TC awareness in Germany.

[Impact of the COVID-19 pandemic on urology residency training programs in Germany]. / Auswirkungen der COVID-19 Pandemie auf die urologische Weiterbildung in Deutschland.

BACKGROUND: Several international medical societies reported a negative impact on urology residency training programs due to the COVID-19 pandemic. OBJECTIVES: The aim of this study was to investigate the impact of the pandemic on urological residency in Germany. MATERIALS AND METHODS: From the 20th of May 2020 until the 20th of June 2020, a Germany-wide online survey on the continuing residency training was distributed via the members of the working group, social media (Facebook, Twitter, Instagram) and the German Society of Residents in Urology (GeSRU e.V.) newsletter. The survey covered 3 topics: 1) basic characteristics of the participants, 2) general and 3) subjective influence of the COVID-19 pandemic on clinics and further residency training. RESULTS: A total of 50 residents took part in the survey; 54% were women. The median age was 31 years. Most of the participants were in their 2nd (22%) and 5th (26%) year of training and worked in a university hospital (44%) or in a clinic of maximum care (30%). 38% of the respondents stated that they only served urological emergencies during the COVID-19 pandemic. For 28% this meant a very large delay (80-100%) in the specialisation, while 28% stated only a minor impact. 66% documented training impairments caused by fewer operations, low patient numbers in the outpatient department (50%), congress (50%) and workshop (44%) cancellations. 46% of residents reported direct contact with COVID-19 patients while 10% were deployed on interdisciplinary IMC units. Numerous physical distancing and hygiene measures have been implemented by the clinics. CONCLUSION: On average, around 50% of the urology residents indicated significant restrictions in training due to the COVID-19 pandemic in Germany. The delay in training cannot currently be measured in units of time, but it can be assumed that training for residents during the pandemic is likely to be of a lower quality compared to previous generations.

Interleukin-2 and Interferon-α for Advanced Renal Cell Carcinoma: Patient Outcomes, Sexual Dimorphism of Responses, and Multimodal Treatment Approaches over a 30-Year Period.

INTRODUCTION: Cytokine-based immunotherapy (IT) has been the mainstay of systemic treatment of advanced renal cell carcinoma (RCC) from the late 1980s until 2007. With the introduction of immune checkpoint inhibitors, a renaissance of immune oncological approaches is rapidly unfolding. MATERIALS AND METHODS: In the present study, we revisited survival outcomes, sexual dimorphism of treatment responses, and the relevance of multimodal treatment approaches over a 30-year period in 156 patients with advanced RCC treated with subcutaneous (s.c.) interleukin-2 (IL-2) and interferon-α (IFN-α) between 1990 and 2009. RESULTS: The median progression-free survival following the first IT was 5.8 months with a wide range from 0 to 197 months. The median overall survival (OS) was 25.8 months and the median cancer-specific survival after tumor nephrectomy was 24.6 months. A group of 29 patients (18.6%) and 11 patients (7.1%) survived longer than 5 and 10 years after surgery, respectively. A difference in the 5-year OS rate between male and female patients was detected (men, 21.6%; women, 11.1%). However, no sex-specific survival advantage was observed after 10 years. CONCLUSIONS: We provide evidence that IT with s.c. IL-2 and IFN-α played a vital role in long-term survivors either by inducing lasting complete remissions or as part of multimodal approaches that allowed patients to survive until novel therapies became available. The implications for current immune oncological treatment approaches are being discussed.

Impact of Surgeon's Experience in Rigid versus Elastic MRI/TRUS-Fusion Biopsy to Detect Significant Prostate Cancer Using Targeted and Systematic Cores.

Multiparametric magnetic resonance imaging (mpMRI) and MRI/ultrasound fusion-targeted prostate biopsy (FB) have excellent sensitivity in detecting significant prostate cancer (sPC). FB platforms can be distinguished by rigid (RTB) or elastic image registration (ETB). We compared RTB and ETB by analyzing sPC detection rates of both RTB and ETB at different stages of the surgeons' learning curve. Patients undergoing RTB between 2015-2017 (n = 502) were compared to patients undergoing ETB from 2017-2019 (n = 437). SPC detection rates were compared by Chi-square-test on patient-basis. Combination of transperineal systematic biopsy and each TB served as reference and sub-analyses were performed for different grades of surgeon's experience. In the RTB subgroup, 233 men (46%) had sPC, compared to 201 (46%) in the ETB subgroup. RTB alone detected 94% of men with sPC and ETB 87% (p = 0.02). However, for at least intermediate-experienced surgeons (>100 FB), no differences occurred between RTB and ETB. In the total cohort, at least intermediate-experienced surgeons detected significantly more sPC (10%, p = 0.008) than novices. Thus, targeted transperineal MRI/TRUS-FB with a RTB registration system showed a similar sPC detection rate to ETB in experienced surgeons but a superior sPC detection rate to ETB in the total cohort. Low-experienced surgeons seem to benefit from RTB.

A Platform and Multisided Market for Translational, Software-Defined Medical Procedures in the Operating Room (OP 4.1): Proof-of-Concept Study.

BACKGROUND: Although digital and data-based technologies are widespread in various industries in the context of Industry 4.0, the use of smart connected devices in health care is still in its infancy. Innovative solutions for the medical environment are affected by difficult access to medical device data and high barriers to market entry because of proprietary systems. OBJECTIVE: In the proof-of-concept project OP 4.1, we show the business viability of connecting and augmenting medical devices and data through software add-ons by giving companies a technical and commercial platform for the development, implementation, distribution, and billing of innovative software solutions. METHODS: The creation of a central platform prototype requires the collaboration of several independent market contenders, including medical users, software developers, medical device manufacturers, and platform providers. A dedicated consortium of clinical and scientific partners as well as industry partners was set up. RESULTS: We demonstrate the successful development of the prototype of a user-centric, open, and extensible platform for the intelligent support of processes starting with the operating room. By connecting heterogeneous data sources and medical devices from different manufacturers and making them accessible for software developers and medical users, the cloud-based platform OP 4.1 enables the augmentation of medical devices and procedures through software-based solutions. The platform also allows for the demand-oriented billing of apps and medical devices, thus permitting software-based solutions to fast-track their economic development and become commercially successful. CONCLUSIONS: The technology and business platform OP 4.1 creates a multisided market for the successful development, implementation, distribution, and billing of new software solutions in the operating room and in the health care sector in general. Consequently, software-based medical innovation can be translated into clinical routine quickly, efficiently, and cost-effectively, optimizing the treatment of patients through smartly assisted procedures.

Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer.

BACKGROUND: Mutations in DNA damage repair genes, in particular genes involved in homology-directed repair, define a subgroup of men with prostate cancer with a more unfavorable prognosis but a therapeutic vulnerability to PARP inhibition. In current practice, mutational testing of prostate cancer patients is commonly done late i.e., when the tumor is castration resistant. In addition, most sequencing panels do not include TP53, one of the most crucial tumor suppressor genes in human cancer. In this proof-of-concept study, we sought to extend the clinical use of these molecular markers by exploring the early prognostic impact of mutations in TP53 and DNA damage repair genes in men with primary, nonmetastatic prostate cancer undergoing radical prostatectomy (RPX). METHODS: Tumor specimens from a cohort of 68 RPX patients with intermediate (n = 11, 16.2%) or high-risk (n = 57, 83.8%) disease were analyzed by targeted next generation sequencing using a 37 DNA damage repair and checkpoint gene panel including TP53. Sequencing results were correlated to clinicopathologic variables as well as PSA persistence or time to PSA failure. In addition, the distribution of TP53 and DNA damage repair gene mutations was analyzed in three large publicly available datasets (TCGA, MSKCC and SU2C). RESULTS: Of 68 primary prostate cancers analyzed, 23 (33.8%) were found to harbor a mutation in either TP53 (n = 12, 17.6%) or a DNA damage repair gene (n = 11, 16.2%). The vast majority of these mutations (22 of 23, 95.7%) were detected in primary tumors from patients with high-risk features. These mutations were mutually exclusive in our cohort and additional data mining suggests an enrichment of DNA damage repair gene mutations in TP53 wild-type tumors. Mutations in either TP53 or a DNA damage repair gene were associated with a significantly worse prognosis after RPX. Importantly, the presence of TP53/DNA damage repair gene mutations was an independent risk factor for PSA failure or PSA persistence in multivariate Cox regression models. CONCLUSION: TP53 or DNA damage repair gene mutations are frequently detected in primary prostate cancer with high-risk features and define a subgroup of patients with an increased risk for PSA failure or persistence after RPX. The significant adverse impact of these alterations on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.

Detection of PD-L1 in the urine of patients with urothelial carcinoma of the bladder.

There are currently five programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors approved for the treatment of locally advanced or metastatic urothelial carcinoma (UC) of the bladder. For platinum-ineligible patients, testing of tumor specimens for PD-L1 expression is required. However, scoring of PD-L1 immunohistochemistry is complex due to different antibodies used, the requirement to score expression in different cellular compartments and intratumoral heterogeneity. It can also be difficult to obtain and test longitudinal tumor samples, which would be desirable to monitor treatment responses and tumor evolution under treatment-induced selective pressure. In the present proof-of concept study, we provide evidence that PD-L1 can be detected in the urine of patients with non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Urine PD-L1 levels were significantly higher in NMIBC and MIBC patients when compared to patients with various non-malignant urological diseases. Further prospective and independent studies are required to assess the value of PD-L1 in the urine as a novel biomarker with potential for the early detection, prediction and therapeutic monitoring of patients with UC of the bladder.

Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery.

BACKGROUND: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missing. PATIENTS AND METHODS: In vitro drug screening of tumor-derived short-term cultures obtained from seven patients with clear cell RCC was performed. For one patient, a patient-derived xenograft (PDX) mouse model was established for in vivo validation experiments. Drug effects were further investigated in established RCC cell lines. RESULTS: The proteasome inhibitor carfilzomib was among the top hits identified in three of four patients in which an in vitro drug screening could be performed successfully. Carfilzomib also showed significant acute and long-term cytotoxicity in established RCC cell lines. The in vivo antitumoral activity of carfilzomib was confirmed in a same-patient PDX model. The cytotoxicity of carfilzomib was found to correlate with the level of accumulation of ubiquitinated proteins. CONCLUSIONS: In this proof-of-concept study, we show that patient-individualized in vitro drug screening and preclinical validation is feasible. However, the fact that carfilzomib failed to deliver a clinical benefit in RCC patients in a recent phase II trial unrelated to the present study underscores the complexities and limitations of this strategy.

Evolution of Salvage Radical Prostatectomy from Open to Robotic and Further to Retzius Sparing Surgery.

Salvage radical prostatectomy (sRP) has evolved from open to minimally invasive approaches. sRP can be offered to patients with local recurrence to improve biochemical recurrence (BCR)-free and overall survival. We evaluate oncological outcome and continence after retropubic (RRP), conventional (cRARP), and Retzius-sparing robotic (rsRARP) surgery. MATERIALS/METHODS: A total of 53 patients undergoing sRP between 2010 and 2020 were included. Follow-up included oncological outcome and continence. RESULTS: sRP was done as RRP (n = 25), cRARP (n = 7), or rsRARP (n = 21). Median blood loss was 900 mL, 500 mL, and 300 mL for RRP, cRARP, and rsRARP, respectively. At 12 months, 5 (20%), 0, and 4 (19%) patients were continent, 9 (36%), 3 (43%), and 7 (33%) had grade 1 incontinence, 5 (20%), 2 (29%), and 3 (14%) had grade 2 incontinence, and 3 (12%), 2 (29%), and 4 (19%) had grade 3 incontinence for RRP, cRARP, or rsRARP, respectively. During a mean follow-up of 52.6 months, 16 (64%), 4 (57%), and 3 (14%) developed BCR in the RRP-, cRARP-, and rsRARP-group, respectively. CONCLUSIONS: Over the years, sRP has shifted from open to laparoscopic/robotic surgery. RARP shows good oncological and functional outcome. rsRARP ensures direct vision on the rectum during preparation and can therefore increase safety and surgeon's confidence, especially in the salvage setting.

Recovery of pad-free continence in elderly men does not differ from younger men undergoing robot-assisted radical prostatectomy for aggressive prostate cancer.

PURPOSE: To analyze urinary continence outcome following robot-assisted radical prostatectomy (RARP) for aggressive prostate cancer in men aged ≥ 70 and < 70 years. METHODS: Retrospective analyses of prospectively collected long-term data from a monocentric cohort of 350 men with D'Amico high-risk prostate cancer undergone robot-assisted radical prostatectomy at a single institution between 2005 and 2016. The association between time since operation and zero-pad urinary continence recovery was comparatively analyzed by separate pre-operative and post-operative Cox proportional-hazard regression models. RESULTS: Median age in the age group ≥ 70 years was 73 years compared with 62 years in the < 70 year age group. Distribution of men receiving adjuvant and salvage radiotherapy/hormonal therapy was similar in both age groups. Urinary continence recovery rate at 12, 24, and 36 months after surgery of men aged ≥ 70 years was 66, 79 and 83%, respectively, and statistically similar to that of men < 70 years: 71, 81, and 85% (log-rank test p = 0.24). Multivariable analyses demonstrated no significant difference in return to continence between the two age groups (p = 0.28 and p = 0.17). In addition, clinical stage and type of nerve sparing (unilateral, bilateral or non-nerve sparing) were found to be independently predictive of pad-free continence recovery. CONCLUSIONS: Regardless of age, return to continence in men with aggressive prostate cancer undergoing RARP continues to improve way beyond the first 12 months after surgery. Considering the dire effects of post-operative radiotherapy on continence in this aggressive cancer cohort, advanced age alone should not discourage recommending multimodal therapy involving RARP.