Clinical and pathological nodal staging score for urothelial carcinoma of the bladder: an external validation.

PURPOSE: Radical cystectomy (RC) and pelvic lymph node dissection (LND) are standard treatments for muscle-invasive urothelial carcinoma of the bladder. Lymph node staging is a prerequisite for clinical decision-making regarding adjuvant chemotherapy and follow-up regimens. Recently, the clinical and pathological nodal staging scores (cNSS and pNSS) were developed. Prior to RC, cNSS determines the minimum number of lymph nodes required to be dissected; pNSS quantifies the accuracy of negative nodal staging based on pT stage and dissected LNs. cNSS and pNSS have not been externally validated, and their relevance for prediction of cancer-specific mortality (CSM) has not been assessed. METHODS: In this retrospective study of 2,483 RC patients from eight German centers, we externally validated cNSS and pNSS and determined their prediction of CSM. All patients underwent RC and LND. Median follow-up was 44 months. cNSS and pNSS sensitivities were evaluated using the original beta-binominal models. Adjusted proportional hazards models were calculated for pN0 patients to assess the predictive value of cNSS and pNSS for CSM. RESULTS: cNSS and pNSS both pass external validation. Adjusted for other clinical parameters, cNSS can predict outcome after RC. pNSS has no independent impact on prediction of CSM. The retrospective design is the major limitation of the study. CONCLUSIONS: In the present external validation, we confirm the validity of both cNSS and pNSS. cNSS is an independent predictor of CSM, thus rendering it useful as a tool for planning the extent of LND.

Intraoperative technologies to assess margin status during radical prostatectomy - a narrative review.

Positive surgical margin (PSM) is a frequent concern for surgeons performing radical prostatectomy for prostate cancer (PCa). PSM are recognized as risk factors for earlier biochemical recurrence and expose patients to adjuvant or salvage treatments such as external radiotherapy and hormonotherapy. Several strategies have been established to reduce PSM rate, while still allowing safe nerve-sparing surgery. Precise preoperative staging by multiparametric magnetic resonance imaging (mpMRI) and fusion biopsy is recommended to identify suspicious areas of extracapsular extension (ECE) that warrant special attention during dissection. However, even with optimal imaging, ECE can be missed, some cancers are not well defined or visible, and capsular incision during surgery remains an issue. Hence, intraoperative frozen section techniques, such as the neurovascular structure-adjacent frozen section examination (NeuroSAFE) have been developed and lately widely disseminated. The NeuroSAFE technique reduces PSM rate while allowing higher rate of nerve-sparing surgery. However, its use is limited to high volume or expert center because of its high barrier-to-entry in terms of logistics, human resources and expertise, as well as cost. Also, NeuroSAFE is a time-consuming process, even in expert hands. To address these issues, several technologies have been developed for an ex vivo and in vivo use. Ex vivo technology such as fluorescent confocal microscopy and intraoperative PET-CT require the extraction of the specimen for preparation, and digital images acquisition. In vivo technology, such as augmented reality based on mpMRI images and PSMA-fluorescent guided surgery have the advantage to provide an intracorporeal analysis of the completeness of the resection. The current manuscript provides a narrative review of established techniques, and details several new and promising techniques for intraoperative PSM assessment.

Interventional therapies for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH).

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). After failure of medical treatment, surgical managements has to be considered. Surgical management of lower urinary tract symptoms attributed to BPH has progressed over time as urologic surgeons search for more innovative and less invasive forms of treatment. Transurethral resection of the prostate (TURP) has long been the "gold standard" to which all other forms of treatment are compared. There are several different methods of surgical treatment of BPH, including whole gland enucleation, laser vaporization, and induction of necrosis with delayed reabsorption as well as hybrid techniques. As with any form of surgical intervention, long-term results define success. Long-term follow-up consists of examining overall efficacy with attention to associated adverse events. TURP has the luxury of the longest follow-up, while less invasive forms of treatment starting to acquire long-term data. There are several surgical options for BPH; newer methods do show promise, while the "gold standard" continues to demonstrate excellent surgical results.

The current role of precision surgery in oligometastatic prostate cancer.

Oligometastatic prostate cancer (omPCa) is a novel intermediate disease state characterized by a limited volume of metastatic cells and specific locations. Accurate staging is paramount to unmask oligometastatic disease, as provided by prostate-specific membrane antigen-positron emission tomography. Driven by the results of prospective trials employing conventional and/or modern staging modalities, the treatment landscape of omPCa has rapidly evolved over the last years. Several treatment-related questions comprising the concept of precision strikes are under development. For example, beyond systemic therapy, cohort studies have found that cytoreductive radical prostatectomy (CRP) can confer a survival benefit in select patients with omPCa. More importantly, CRP has been consistently shown to improve long-term local symptoms when the tumor progresses across disease states due to resistance to systemic therapies. Metastasis-directed treatments have also emerged as a promising treatment option due to the visibility of oligometastatic disease and new technologies as well as treatment strategies to target the novel PCa colonies. Whether metastases are present at primary cancer diagnosis or detected upon biochemical recurrence after treatment with curative intent, targeted yet decisive elimination of disseminated tumor cell hotspots is thought to improve survival outcomes. One such strategy is salvage lymph node dissection in oligorecurrent PCa which can alter the natural history of progressive PCa. In this review, we will highlight how refinements in modern staging modalities change the classification and treatment of (oligo-)metastatic PCa. Further, we will also discuss the current role and future directions of precision surgery in omPCa.

[Quality criteria in urology : How to obtain comparable results?] / Qualitätskriterien in der Urologie : Wie kann eine Vergleichbarkeit der Ergebnisse geschaffen werden?

The standardization of procedural flow and medical documentation increasingly allows further possibilities. The best-known example of process standardization is the centralized treatment of complex clinical pictures, while patient-reported outcome measurements (PROMs) enable standardized documentation. Using the example of prostate cancer, existing literature on the topic of quality optimization in medicine is discussed. The following key points are addressed: (1) Increasing use of standardized PROMs for outcome documentation. (2) The transfer of complex clinical pictures to dedicated specialized centers has been shown to increase the quality of patient care as long as standardized PROMs are used. (3) Healthcare policymakers benefit from the use of PROMs and increasingly pursue a "value-based healthcare" approach.

Minimizing complications during retropubic radical prostatectomy - Is ureteral stenting necessary?

OBJECTIVES AND AIMS: To avoid damage to the ureters during bladder neck preparation in radical prostatectomy for prostate cancer, it may be helpful to insert ureteral stents temporarily or to intravenously administer indigo carmine dye for enhanced visualisation of ureteric orifices. We evaluated our bladder neck preserving technique at radical prostatectomy with regard to ureteric injuries. PATIENTS AND METHODS: We analysed 369 consecutive radical prostatectomies operated in our clinic in a bladder neck preserving technique. The following parameters were assessed in this retrospective study: number of prophylactic ureteric stent insertions, application of indigo carmine dye, observed injuries of the ureters by the surgeon, postoperative increase of serum creatinine and postoperative status of kidney ultrasound. RESULTS: In 7/369 prostatectomies (1.90%) a ureteric stent insertion was performed, indigo carmine was not applied to any patient at all, yet no intraoperative injury of a ureter was observed by a surgeon. No revision was necessary due to a ureteral injury within the observation period of one year after surgery. In 17 patients with preoperative normal creatinine value a pathological value was observed on the first postoperative day (mean 1.4 mg/dl). In these patients no consecutive postrenal acute renal failure was observed, no hydronephrosis was monitored by ultrasound and no further intervention was necessary. CONCLUSIONS: Bladder neck preserving operation technique does not implicate the need of prophylactic ureteric stent insertions and has no higher incidence of ureteric injuries.

Comparison of guideline recommendations with daily practice in patients with renal cell carcinoma.

OBJECTIVES AND AIMS: To compare guideline recommendations with daily practice patterns in a German patient cohort with renal cell carcinoma. PATIENTS AND METHODS: 81 patients with T1 oder T2 renal cell carcinoma (RCC) were included in this prospective single-center study. All patients were operated in a single institution either by open radical nephrectomy (ORN) or nephron sparing surgery (NSS). Patients and doctors were evaluated using a written questionnaire with a follow-up of 12 months. Follow-up intervals, follow-up modalities (e. g. imaging modalities, laboratory controls of blood and urine) and the call on psycho-oncological support were evaluated. RESULTS: The majority of patients (72%) were followed up by their urologists. Follow-up examinations included abdominal ultrasound, urine and blood diagnostics, conventional chest x-rays, computed tomography (CT) of abdomen, chest or head or abdominal Magnetic Resonance Imaging (MRI). There were no significant differences between patients operated by ORN or NSS. In total, 12.5% of patients were asking for psycho-oncological support. CONCLUSIONS: In general, patients were followed up according to existing guideline recommendations. Only a small proportion of patients asked for psycho-oncological treatment.

Adherence to Guideline Recommendations for Perioperative Chemotherapy in Patients with pN2-3 M0 Squamous Cell Carcinoma of the Penis: Temporal Trends and Survival Outcomes.

AIMS: To analyse contemporary perioperative chemotherapy (CHT) guideline adherence rates for pN2-3 M0 squamous cell carcinoma of the penis, as well as CHT association with cancer-specific (CSM) and other-cause mortality (OCM). MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results databases, 311 pN2-3 M0 squamous cell carcinoma of the penis patients treated with inguinal lymph node dissection were identified. Univariable and multivariable logistic regression analyses focused on CHT rates, whereas cumulative incidence plots and multivariable competing risks regression analyses tested for CSM and OCM rates. RESULTS: CHT was administered to 140 (45%) patients and rates increased from 37.5 to 62.2% (2004-2015; P = 0.02). Specifically, annual CHT rates increased over time in patients younger or equal to 65 years and in patients older than 65 years (44.4-84.6% versus 28.6-50%, respectively), but this trend was not statistically significant (P = 0.1 and P = 0.2, respectively). The median follow-up was 13 months for both CHT (interquartile range 8.0-32.2) and no-CHT subgroups (interquartile range 5.0-40.0). In multivariable logistic regression analyses, more contemporary year of diagnosis interval (odds ratio 2.08, P < 0.01) and age older than 75 years (odds ratio 0.14, P < 0.001) were independent predictors of CHT use. In multivariable competing risks regression analyses, CHT use did not affect CSM (hazard ratio 1.02; P = 0.7) or OCM (hazard ratio 1.56; P = 0.8). CONCLUSIONS: CHT adherence rates sharply increased in the most recent years. Despite this increase over time, the lack of efficacy regarding CSM benefit is disappointing.

[Influence of modern diagnostic methods on the treatment of nonmetastatic castration-resistant prostate cancer]. / Einfluss moderner Diagnostikverfahren auf die Therapie des nichtmetastasierten kastrationsresistenten Prostatakarzinoms.

Until 2018, patients with nonmetastatic castration-resistant prostate cancer (nmCRPC/M0CRPC) did not have a generally acknowledged standard of care therapy. As a result, these patients were often managed in a nonstandardized individual fashion and comparative analyses were lacking. In the current narrative review, we give an overview on the respective entities of nmCRPC and summarize novel treatment options that arose from the publication of the results of the SPARTAN and PROSPER trials and their subanalyses. We critically address the role that novel imaging modalities, namely 68Ga-PSMA-PET/CT (68Ga prostate-specific membrane antigen positron emission tomography/computed tomography) will play in the diagnosis of nmCRPC and raise the question whether incidence rates of true nmCRPC will significantly decline in the nearer future.

[Current controversies in the treatment of localized prostate cancer]. / Aktuelle Kontroversen in der Therapie des lokal begrenzten Prostatakarzinoms.

In the prostate-specific antigen (PSA) era, most prostate cancers (PCa) are diagnosed in a localized stage and a plethora of therapeutic options are warranted in different clinical settings and disease stages of localized PCa. In the current narrative review, we give an overview of the current controversies in the therapeutic landscape of localized PCa and focus on organ-sparing approaches, percutaneous radiotherapy, brachytherapy as well as retropubic and robot-assisted prostatectomy by summarizing studies that have been published within the last two years.

Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control Study.

BACKGROUND: Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes. OBJECTIVE: To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT). DESIGN, SETTING, AND PARTICIPANTS: PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis. INTERVENTION: The SOC cohort (n=1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort (n=263) received either salvage lymph node dissection (n=166) or stereotactic body radiotherapy (n=97) at PSA progression to a positron emission tomography-detected nodal recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS AND LIMITATIONS: At a median follow-up of 70 (interquartile range: 48-98) mo, MDT was associated with an improved CSS on univariate (p=0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17-0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3-99.6) and 95.7% (95% CI: 93.2-97.3) for MDT and SOC, respectively (p=0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort. CONCLUSIONS: MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis-generating and inform future randomized trials in this setting. PATIENT SUMMARY: Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes.

[Organ-sparing surgery for penile cancer]. / Organerhaltende Chirurgie des Peniskarzinoms.

In patients with penile cancer health-related quality of life is closely related to organ-sparing surgery. To achieve an ideally suited treatment modality for this rare but aggressive tumor entity different operating techniques like micrographic surgery, laser treatment, and glansectomy were developed. These should offer optimal oncological treatment while preserving sexual function. This article gives an overview of indications and limits of organ-sparing treatment in penile cancer.

[Diagnosis of urothelial carcinoma]. / Diagnostik des Harnblasenkarzinoms.

Bladder cancer represents the fifth most common malignancy in the US. In Germany we face 25,000 new incidences of urothelial cancers every year. At present a variety of different techniques is available for the diagnosis of bladder cancer. On the one hand techniques are needed that show the possible presence of a tumour and on the other hand procedures that can confirm a lesion to be a tumour, like in most cases histology does. The following article gives an overview of the currently used standards in the diagnosis of urothelial cancer. Also new techniques for diagnosis and surveillance of urothelial cancer are discussed. The combination of white light endoscopy and urine cytology is currently considered the gold standard for diagnosis. Transurethral biopsies or TUR-BT subsequently follow in the case of positive findings. To optimize the sensitivity and lower the recurrence rate as well as the residual tumour rate, fluorescence endoscopy can be used as an additional approach. Also urine-based markers play an important role in the diagnosis and surveillance of urothelial carcinomas, but cannot yet be recommended as a single procedure in the routine diagnosis of bladder tumour.

CEA-related cell adhesion molecule-1 is involved in angiogenic switch in prostate cancer.

We demonstrate here that epithelial carcinoembryonic antigen (CEA)-related cell adhesion molecule-1 (CEACAM1) downregulation in prostate intraepithelial neoplasia (PIN) is inversely correlated with its upregulation in adjacent blood vessels. CEACAM1 silencing in prostate cancer cell line DU-145 via small interfering ribonucleic acid (siRNA) increased but its overexpression suppressed the expression of angiogenic/lymphangiogenic factors such as vascular endothelial growth factor (VEGF)-A, -C and -D, and angiogenic inhibitor collagen 18/endostatin. Furthermore, CEACAM1 overexpression in DU-145 cells increased but CEACAM1 silencing reduced angiopoietin-1 expression. Inverse relation was found for angiopoietin-2. Supernatant of CEACAM1-overexpressing DU-145 suppressed but that of CEACAM1-silenced increased the VEGF-induced endothelial tubes. Electron microscopically the majority of PIN-associated blood vessels was structurally destabilized exhibiting endothelial fenestration, trans- and inter-endothelial gaps. In some PIN areas, invasion of single tumor cells into the destabilized blood vessels was observed. These data show that disappearance of epithelial CEACAM1 in PIN is accompanied by its upregulation in adjacent vasculature which apparently correlates with vascular destabilization and increased vascularization of prostate cancer. Strategies to either conserve the epithelial CEACAM1 or to target endothelial CEACAM1 might be useful for an anti-angiogenic therapy of prostate cancer.

[Molecular imaging of tumor blood vessels]. / Molekulare Bildgebung der Tumorgefässe.

In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of the anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of vascular remodeling. Tumor imaging by X-ray, CT, MRI and ultrasound has to be improved by coupling with molecular markers targeting the tumor vessels. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not result in a reduction of tumor diameter. But remodeling of the tumor vessels under anti-angiogenic therapy obviously occurs at an early stage and seems to be a convincing parameter for tumor imaging. Despite the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodeling of the microtumor vessels. Thus, new imaging approaches are needed to overcome this issue.

[One molecule, two faces. Epithelial loss of cell adhesion molecule CEACAM1 activates angiogenesis in bladder and prostate cancer]. / Ein Molekül, zwei Gesichter. Epithelialer Verlust des Zelladhäsionsmoleküls CEACAM1 aktiviert Angiogenese beim Harnblasen- und Prostatakarzinom.

BACKGROUND: Angiogenesis is a prerequisite for tumor growth and metastasis in which CEACAM1 plays an essential role. PATIENTS AND METHODS: The role of CEACAM1 in vascularization and invasion of prostate and bladder cancer was studied. RESULTS: Our analyses demonstrate an epithelial downregulation of CEACAM1 in superficial bladder tumors and in PIN of the prostate. Concurrently, CEACAM1 is upregulated in endothelial cells of tumor blood vessels. CEACAM1 knockdown in tumor cell lines of the prostate and urinary bladder via siRNA results in an increase of tumor vascularization while CEACAM1 overexpression in these cells suppresses it. CONCLUSIONS: CEACAM1-induced signaling mechanisms play a role in induction of angiogenesis in superficial tumors of the prostate and bladder. Strategies to either conserve the epithelial CEACAM1 or to target endothelial CEACAM1 might be useful for an antiangiogenic therapy of bladder and prostate cancer.

[PDE5 inhibitors. A new option in the treatment of ureteral colic?]. / PDE-5-Inhibitoren. Ein neuer Therapieansatz in der Behandlung der Harnleiterkolik?

BACKGROUND: PDE5 inhibitors represent the gold standard in the medical therapy of erectile dysfunction (ED). Promising results have been published regarding further urological indications such as treatment of ureteral colic. The aim of the present study was to evaluate the functional effects of the PDE5 inhibitors sildenafil (SIL), vardenafil (VAR), and tadalafil (TAD) on tissue tension and cyclic nucleotide levels of human ureteral smooth muscle segments in vitro. METHODS: Relaxant responses of human ureteral smooth muscle were investigated in vitro using the organ bath technique. Cyclic nucleotides cAMP and cGMP were determined by specific radioimmunoassays. RESULTS: Relaxing effects of ureteral muscle tension were observed in the rank order VAR>SIL>TAD. While only VAR significantly elevated cGMP levels 3.3-fold over control, no increase for cAMP levels was observed. CONCLUSIONS: Our data provide evidence that cGMP is involved in the control of the normal function of the smooth musculature of the human ureter. Our findings suggest the potential of using selective inhibitors of PDE isoenzymes in the treatment of ureteral colic.

[Fluorescence cystoscopy at bladder cancer: present trials]. / Die Fluoreszenzzystoskopie beim Harnblasenkarzinom : Aktueller Stellenwert.

Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm. Although many aspects of the management of not-muscle-infiltrating bladder cancer are now well established, significant challenges remain, which influence patient outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity and increase quality of life and survival. Fluorescence cystoscopy, often referred to as "photodynamic diagnosis" (PDD) with intravesical application of photosensitizing agents has been developed in order to enhance the early detection of bladder cancer. Since March 2005 the hexyl-ALA ester (Hexvix) has been approved for the diagnosis of bladder cancer in 27 EU/EEA countries through the European Mutual Recognition Procedure. There is growing evidence that PDD enhances the detection of bladder cancer, particularly of high-grade flat lesions. Furthermore, transurethral resection of bladder tumor under fluorescence guidance has been shown to reduce the risk of recurrent tumors. Nevertheless, a resulting relatively decreased number of recurrences have still to be verified in prospective randomized trials.

[Imaging procedures to diagnose prostate cancer]. / Bildgebende Verfahren bei der Diagnose des Prostatakarzinoms.

Prostate cancer is one of the most frequent malignant diseases in men. Despite constant progress achieved in imaging procedures, prostate biopsy is the gold standard for diagnosing prostate cancer. For the assessment of lymph node status, only staging lymphadenectomy provides valid information. The aim of this work is to analyze the imaging procedures available in Germany and their value in primary and lymph node staging as well as biochemical recurrence.

[Radical prostatectomy in locally advanced prostate cancer]. / Radikale Prostatektomie beim klinisch lokal fortgeschrittenen Prostatakarzinom.

BACKGROUND: Due to an inverse stage migration, the proportion of patients with more aggressive and locally advanced prostate cancer (PCa) has increased over the last few years. The natural history in these patients shows a higher risk of local complications and worse oncologic outcome. OBJECTIVES: To analyze the impact of radical prostatectomy (RP) in patients with locally advanced PCa. MATERIALS AND METHODS: A review of the literature was performed using PubMed and MEDLINE databases focusing on articles addressing locally advanced PCa. RESULTS: Current guidelines recommend local therapy in patients with locally advanced PCa among other treatment options. Thereby no strong evidence favoring radiotherapy or RP is present. Compared to patients without local treatment, RP may improve oncologic outcome and decrease the risk of local complications. Due to more difficult surgery and an increased need of multimodal therapy, higher perioperative morbidity and worse functional outcomes compared to patients with localized PCa are reported. No reliable prospective data indicating a widespread use of neoadjuvant treatment exists. Indication for further adjuvant or salvage therapies depends on pathologic results and postoperative course. CONCLUSIONS: RP is one of the treatment options with good long-term results which can be offered to patients with locally advanced PCa. Nevertheless, patients need to be counselled especially about the worse postoperative functional outcome compared to patients with localized PCa.