A high-fidelity prototype of a sterile information system for the perioperative area: OR-Pad.

PURPOSE: Supporting the surgeon during surgery is one of the main goals of intelligent ORs. The OR-Pad project aims to optimize the information flow within the perioperative area. A shared information space should enable appropriate preparation and provision of relevant information at any time before, during, and after surgery. METHODS: Based on previous work on an interaction concept and system architecture for the sterile OR-Pad system, we designed a user interface for mobile and intraoperative (stationary) use, focusing on the most important functionalities like clear information provision to reduce information overload. The concepts were transferred into a high-fidelity prototype for demonstration purposes. The prototype was evaluated from different perspectives, including a usability study. RESULTS: The prototype's central element is a timeline displaying all available case information chronologically, like radiological images, labor findings, or notes. This information space can be adapted for individual purposes (e.g., highlighting a tumor, filtering for own material). With the mobile and intraoperative mode of the system, relevant information can be added, preselected, viewed, and extended during the perioperative process. Overall, the evaluation showed good results and confirmed the vision of the information system. CONCLUSION: The high-fidelity prototype of the information system OR-Pad focuses on supporting the surgeon via a timeline making all available case information accessible before, during, and after surgery. The information space can be personalized to enable targeted support. Further development is reasonable to optimize the approach and address missing or insufficient aspects, like the holding arm and sterility concept or new desired features.

[Organoids for the advancement of intraoperative diagnostic procedures]. / Organoide zur Weiterentwicklung der intraoperativen Diagnostik.

In the context of cancer surgery, there is always a trade-off between oncological safety and preservation of function. This is especially true in pelvic surgery due to the close relationship to the pelvic floor muscles, blood supply and nerves. Currently, risk models, preoperative imaging, the surgeon's assessment, and the intraoperative frozen section serve as the basis for decision-making. New imaging techniques and standardization in frozen section have significantly improved this in recent years. However, limitations remain due to time delays as well as more difficult correct anatomical assignment in the follow-up. Alternative intraoperative techniques may overcome this limitation in the future. Patient-derived organoids have emerged as an important new research vehicle in recent years. They are based on tumor stem cells that, under special culture conditions, form three-dimensional replicas of the original tissue. This makes them ideally suited for testing individual system therapies but also as a validation technique for new intraoperative diagnostic procedures. The Research Training Group 2543/I, which is funded by the German Research Foundation, is researching the potential of new diagnostic methods in an interdisciplinary team regarding validation in addition to intraoperative frozen sections.

[BCG-induced (bacillus Calmette-Guérin) abdominal granulomatosis after occult bladder perforation]. / Intraabdominelle BCG-Granulomatose (Bacillus Calmette-Guérin) nach okkulter Blasenperforation.

We present the case of a 57-year-old man who developed an intraperitoneal bladder fistula with BCG-induced (bacillus Calmette-Guérin) abdominal granulomatosis after transurethral resection of a papillary non-muscle invasive bladder cancer and subsequent BCG-instillation therapy. The bladder fistula was eliminated surgically. The detection of Mycobacterium tuberculosis in the operative sample drawings as well as the histological detection of BCG-granuloma led to specific treatment and a report to the responsible health department.

The HELENA study: Hexvix®-TURB vs. white-light TURB followed by intravesical adjuvant chemotherapy-a prospective randomized controlled open-label multicenter non-inferiority study.

PURPOSE: Photodynamic diagnosis and white-light TURB with adjuvant intravesical chemotherapy (ICT) is widely used in treatment of bladder cancer. This non-inferiority trial is designed to demonstrate non-inferiority regarding recurrence-free survival (RFS) of Hexvix® TURB followed by immediate instillation compared to white-light TURB with immediate instillation followed by maintenance ICT. METHODS: Between 07/2010 and 12/2016, 129 patients with EORTC intermediate risk non-muscle invasive bladder cancer treated with TURB were included in this multicentre phase III study. Patients were randomized and received either white-light TURB with immediate ICT followed by maintenance ICT (n = 62, 20 mg Mitomycin weekly for 6 weeks as induction phase, afterwards 20 mg/month for 6 months) or Hexvix® TURB with immediate ICT only (n = 67, 40 mg Mitomycin). Primary study endpoint was RFS after 12 months. Hexvix® TURB was counted as non-inferior to white light alone if the upper limit of the one-sided 95% confidence interval of hazard ratio was lower than 1.676. Due to the non-inferiority design, the per-protocol population was used as the primary analysis population (n = 113) RESULTS: Median follow-up was 1.81 years. Hexvix® group showed more events (recurrence or death) than white-light group (19 vs. 10) resulting in a HR of 1.29 (upper limit of one-sided 95%-CI = 2.45; pnon-inferiority = 0.249). The ITT population yielded similar results (HR = 1.67); 3.18], pnon-inferiority = 0.493). There was no significant difference in overall survival between both groups (p = 0.257). CONCLUSION: Non-inferiority of Hexvix® TURB relative to white-light TURB with maintenance Mitomycin instillation in intermediate risk urothelial carcinoma of the bladder was not proven. Hence a higher effect of maintenance ICT is to assume compared to a Hexvix®-improved TURB only, confirming its important role in patient treatment.

Expression patterns of the immune checkpoint ligand CD276 in urothelial carcinoma.

BACKGROUND: CD276 is an immune checkpoint molecule. Elevated CD276 expression by urothelial carcinoma is associated with poor prognosis, but little is known about its expression across different tumor stages. We therefore investigated CD276 expression in bladder cancer (BC) cells and in tissue samples of BC stages from pT2 to pT4. METHODS: CD276 expression was explored in 4 urothelial cancer cell lines and 4 primary normal urothelial cell populations by quantitative RT-PCR, Western blot and flow cytometry. CD276 was investigated in bladder tumors from 98 patients by immunohistochemistry using a score (0-300) incorporating both, staining intensity and area of CD276 staining. Normal appearing urothelium in the bladder of the same patients served as controls. RESULTS: The urothelial carcinoma cell lines expressed significantly higher levels of CD276 on transcript (p < 0.006), total protein levels (p < 0.005), and on the cell surface (p < 0.02) when compared to normal urothelial cells. In pT2-T4 tumor tissue samples, CD276 was overexpressed (median score 185) when compared to corresponding healthy tissues from the same patients (median score 50; p < 0.001). No significant differences in CD276 expression were recorded in late, locally advanced ≥ pT3a tumors (median score 185) versus organ-confined < pT3a tumors (median score 190), but it was significantly lower in the normal urothelial tissue associated with ≥ pT3a tumors (median score 40) versus < pT3a tumors (median score 80; p < 0.05). CONCLUSION: CD276 expression is significantly elevated in urothelial carcinoma cells in all stages but varies between individuals considerably. Reduced CD276 expression in normal urothelial cells may imply that these cells would be protected from CD276-mediated immuno therapies.

[COVID-19 in european urology : Which lessons have we learned?] / COVID-19 in der europäischen Urologie : Was haben wir bisher gelernt?

The coronavirus has challenged all medical systems worldwide. Herein both waves of COVID-19 (coronavirus disease 2019) in spring and autumn 2020 differ principally. Whereas Europe was hit by the first wave more or less unprepared, which was aggravated by the high virulence of COVID-19, the second wave is characterized by a much higher contagiosity of the virus with very high incidences. On the other hand the virus has attenuated, which is reflected by the significantly lower incidence-related mortality rate. However, the overall increasing number of infected patients represents again a great challenge for the medical management of the disease. France and Spain are doing better in comparison to Germany and Italy this time. The absolute number of deaths per week is higher than during the peak of the first wave. However, urologists in these countries have also experienced greater restrictions in their activities in the second shutdown than in Germany, where there is only a reduction of beds to between 75 and 90%. Mostly all levels are operated. Of importance for Germany, however, is the plateau on a high level for several weeks probably due to the reduced efficacy of a light lock-down. This finally resulted in a total lock-down in mid-December 2020. Subsequently in Germany some hospitals are also reaching their limits with similar consequences for the departments of urology facing a 50% reduction of beds and operating only level III and IV indications. Nevertheless, the management of urologic patients during the COVID-19 pandemic is carried out in Europa on a high standard. Therefor the risk of secondary harm to our patients is expected to be rather minimal in the long run.

Correction to: The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

In multivariate analysis, GS of the regular prostatectomy specimen was the only statistically significant parameter for pT2R1 prostate cancer.

68Ga-PSMA-PET/CT-directed IGRT/SBRT for oligometastases of recurrent prostate cancer after initial surgery.

Background: We evaluated efficacy and toxicity of 68Ga-PSMA-Positron Emission Tomography/Computed Tomography (PET/CT)-directed stereotactic body radiotherapy and image-guided radiotherapy (SBRT/IGRT) for oligometastases of prostate cancer recurrences after previous surgery.Methods: Nineteen patients were analyzed within a prospective PET-registry study (064/2013BO1) and retrospectively analyzed (807/2017BO2) fulfilling the following inclusion criteria: biochemical recurrence after radical prostatectomy, ≤five 68Ga-PSMA-PET/CT positive lesions. Biochemical control was evaluated with EORTC (European Organization for Research and Treatment of Cancer)- and Phenix-definitions. Toxicity was scored according to CTCAE-criteria v. 4.03.Results: A total of 38 oligometastases (19 patients, 2 with re-treatment) were treated with SBRT/IGRT from October 2014 to July 2017. 68Ga-PSMA-PET/CT-positive lesions were detected on average 39 months (5-139) after prostatectomy (pT2b-3b pN0-1 cM0). Mean PSA (Prostate-specific antigen)-level at time of imaging reached 2.2 ng/mL (range 0.2-10.1). PET/CT-positive lesions were treated with different fractionation schedules reaching biological equivalent doses (BED) of 116.7-230.0 Gy. Concomitant androgen deprivation therapy (ADT) was given in seven patients. After a median follow-up of 17 months (4-42) all patients were alive. Estimated 1-year PSA- control (n = 19) reached 80.8% (Phenix) and 67.5% (EORTC). A PSA-decline (≥50%) was detected in 16/19 patients after radiotherapy. Higher graded G3+-acute toxicity did not occur. Temporary late G3-proctitis was detected in one patient.Conclusions: Reaching of nadir ≤0.1 or 0.2 ng/mL was associated by improved DMFS (distant metastases free survival) and could serve as a surrogate endpoint for RT of oligometastases after initial prostatectomy. Short term effects of 68Ga-PSMA-PET/CT-based ablative radiotherapy for oligometastases demonstrated an acceptable toxicity profile and favorable biochemical response.

[Influence of immunomodulators on urological imaging]. / Einfluss von Immunmodulatoren auf die urologische Bildgebung.

BACKGROUND: Immune checkpoint inhibitors (ICI) have led to great advances in the therapy of metastatic renal cell and urothelial carcinoma. Currently ICI are approved for the first-line therapy of cisplatin-unfit patients (Atezolizumab, Pembrolizumab) and second-line therapy in patients with metastasized urothelial cancer (Atezolizumab, Nivolumab, Pembrolizumab). For the therapy of metastasized RCC, Nivolumab is approved as a second-line therapy and in combination with the CTLA­4 antibody Ipilimumab as a first-line therapy. OBJECTIVES: What does the optimized radiological follow-up and therapy response assessment for ICI, which differ in their pathways from common chemotherapeutics and anti-angiogenetic drugs, look like? What strategies are needed to meet the upcoming challenges concerning interpretation of the acquired images? METHODS: A systematic literature search was carried out for urothelial and renal cell carcinoma. RESULTS: Immune-related response criteria have been introduced to better characterize the imaging changes occurring under ICI, as monitoring response to immunotherapy still relies on RECIST. CONCLUSIONS: To properly identify and predict response after treatment with ICI, additional studies with long-term follow-ups are needed. Because of the growing use of ICI, radiologists and urologist should be familiar with common imaging findings (such as pseudo progress) under immunotherapy to correctly interpret these findings in daily routine.

[Surgical reconstruction of the ureter]. / Rekonstruktionsmöglichkeiten des Harnleiters.

Defects in ureteral continuity and function can originate from various etiologies such as stricture, radiotherapy, tuberculosis, tumor, trauma or perforation due to iatrogenic injury. The surgical options for the management of ureteral defects are complex and depend on the location of the defect. The aim of the surgical management of ureteral stricture is the reconstruction of an anti-refluxive and nonobstructive flow of urine to preserve kidney function. There are numerous possibilities for the reconstruction of ureteral defects ranging from ureteroneocystostomy with or without psoas-hitch- or Boari-flap to ileal ureteral replacement. Nearly all these techniques can either be done in open surgery or in a laparoscopically or robotic-assisted manner. The technique of robotic-assisted reconstruction of ureteral defects is challenging but offers a great opportunity. The aim of this article is to provide an overview of current surgical procedures in ureteric reconstruction.

[Active surveillance in prostate cancer]. / Active Surveillance beim Prostatakarzinom.

Prostate cancer remains among the most commonly diagnosed malignancies worldwide in men. In patients with low-risk prostate cancer, the risk of metastasis and mortality is very low; therefore, a tumor surveillance strategy can be used. In patients undergoing active surveillance, curative active therapy is postponed without compromising opportunities for cure until there is evidence of progression or the patient desires active therapy. The aim of active surveillance in prostate cancer patients is to minimize treatment-related toxicity without impairing patient survival. To maintain patients under active surveillance, the following criteria should be met: prostate-specific antigen (PSA) ≤10 ng/ml, Gleason score ≤6, cT1 or cT2a, ≤2 biopsy cores with <50% cancer involvement of every positive core. Follow-up in active surveillance patients is based on repeat biopsy, serial PSA measurements, and digital rectal examination.

[Cost-effectiveness analysis of blue light cystoscopy with hexylaminolevulinate in transurethral resection of the bladder]. / Kosten-Effektivitäts-Analyse zur Verwendung der Blaulichtzystoskopie mit Hexylaminolevulinat bei der transurethralen Resektion der Harnblase.

BACKGROUND: Photodynamic diagnosis using the optical imaging agent hexaminolevulinate (HAL, Hexvix®, Ipsen Pharma GmbH, Ettlingen, Germany) as an adjunct to white light cystoscopy (WLC) during the initial transurethral resection of bladder tumours (TURB) improves the detection rate of bladder cancer and leads to fewer recurrences. OBJECTIVES: A cost-effectiveness analysis was carried out in order to calculate the consequences for the German healthcare system. METHODS: We combined a short-term decision tree and a Markov model to evaluate outcomes over a long period of time. The alternatives investigated were HAL-assisted blue light cystoscopy (BLC) as adjunct to WLC (HAL + BLC/WLC) compared with WLC alone in patients undergoing TURB. RESULTS: HAL + BLC/WLC compared to WLC alone was associated with 0.07 incremental quality-adjusted life years (QALYs) and cost savings of 537 € per patient. CONCLUSION: HAL + BLC/WLC compared with WLC alone resulted in both cost savings and improved patient outcome rendering it the "dominant" strategy.

[Mode of action, new targets and potential biomarkers in modern immunotherapy]. / Wirkmechanismen, neue Angriffspunkte und potentielle Biomarker bei moderner Immuntherapie.

Immune checkpoint inhibitors (ICI) have significantly improved the systemic therapy of metastatic disease in genitourinary malignancies. With the European Medicines Agency (EMA) approval of the antibodies nivolumab and pembrolizumab directed against programmed cell death 1 (PD-1) as well as the PD-L1 antibody atezolizumab, three agents are available for the treatment of metastatic urothelial carcinoma and renal cell carcinoma. This article describes the underlying mode of action of PD-1/PD-L1 blockade and other ICIs to activate the immune system for effective tumor rejection. Future therapeutic strategies are focusing on the combination of ICI with targeted therapies to enhance the immune defense, especially in the local tumor microenvironment. A further clinical need exists for the establishment of biomarkers to predict a therapy response under ICI, in particular for the role of the PD-L1 status. Biomarkers for predicting primary or acquired therapy resistance are also of clinical importance to enable good patient selection for ICI therapy.

[Current and established diagnostic modalities for bladder cancer]. / Aktuelle und etablierte Diagnoseverfahren beim Harnblasenkarzinom.

INTRODUCTION: In this paper, current guidelines regarding diagnostic and staging modalities of urothelial cancer of the bladder are summarized and an overview of endoscopic, imaging, and molecular methods currently being tested are outlined. METHODS: Relevant passages from current guidelines and recent literature as well as to a certain extent our own research are examined. RESULTS: Over the last decade, imaging mainly in the form of photodynamic diagnosis (PDD) has undergone further development and found its way into several guidelines. PDD-based transurethral resection of the bladder (TURB) proved to have a long-term effect regarding recurrence rate, progression and reduction of cystectomy in some patients. More light-filtering techniques and improvements in the screen resolution are currently being clinically tested. Molecular substaging using combinations of immunohistochemical biomarkers has the potential to change the clinical management of advanced urothelial cancer. CONCLUSION: New visualization techniques are likely to improve recurrence intervals and prognosis of bladder cancer. Molecular substaging will revolutionize prognostic assessment and therapeutic strategies of urothelial cancer.

No influence of smoking status on the performance of urine markers for the detection of bladder cancer.

PURPOSE: The performance of urinary markers for detecting bladder cancer (BC) is influenced by various factors. The aim of the present study was to evaluate the influence of smoking habits on the performance of four commonly used urine markers. METHODS: Urine samples of 723 patients with suspected BC were analysed using urine cytology, fluorescence in situ hybridization (FISH), immunocytology (uCyt+ test), and quantitative nuclear matrix protein 22 (NMP22) immunoassay. The smoking habits of all patients were recorded and a cystoscopy performed within 2 weeks after urinary marker testing. Rates of false negative and false positive results were compared between non-smokers, former smokers, and current smokers by contingency analyses. RESULTS: We included 723 patients in this study, 431 (59.6%) of which were non-smokers, 215 former smokers (29.7%), and 77 (10.7%) current smokers. 148 patients (20.5%) had a tumour at the time of urinary marker testing. Respective rates of false positive test results among non-smokers, former smokers, and current smokers were: 16.3, 19.1, and 11.5% (p = 0.81) for urine cytology; 36.8, 42.0, and 32.7% for the uCyt+ test (p = 0.88); 18.0, 19.1, and 13.5% for FISH (p = 0.66); and 69.5, 71.6, and 71.2% for NMP22 (p = 0.67). Respective rates of false negatives among non-smokers, former smokers, and current smokers were: 31.4, 15.1, and 28.0% for cytology (p = 0.34); 21.4, 22.6, and 16.0% for uCyt+ test (p = 0.67); 24.3, 13.2, and 28.0% for FISH (p = 0.88); and 10.0, 18.9, and 8.0% for NMP22 (p = 0.80). CONCLUSIONS: Our results strongly suggest that smoking habits do not affect performance characteristics of urinary markers in the diagnostics of BC.

Rare and changeable as a chameleon: paraneoplastic syndromes in renal cell carcinoma.

INTRODUCTION: Paraneoplastic syndromes (PNS) in renal cell carcinoma (RCC) are important to be recognized by the treating physician, because they may lead to diagnosis of underlying malignant disease. On the other hand, PNS may dominate the clinical picture and can hide the true disorder like a chameleon. When realized, a PNS can be used as a 'neoplastic tumour marker', especially in case of recurrence. Their occurrence can even be linked to prognosis of disease. METHODS: A PubMed search combining the MeSH terms renal cell carcinoma and paraneoplastic syndrome was executed in April 2015. All hits concerning these MeSH terms have been taken into account when writing this review. RESULTS: There is a big gap between reporting and incidence of paraneoplastic syndromes in renal cell carcinoma. Most of the articles in Medline are case reports and reviews of research done in the 1950s-1990s. One problem is that a clear definition of a paraneoplastic syndrome is still lacking. The most important PNS in RCC are hypercalcemia. It is important that PNS are not only arising in advanced stages of renal cell carcinoma; in contrast, a PNS can often be the first symptom of RCC. CONCLUSION: Paraneoplastic syndromes are often unrecognized but are important biomarkers in RCC. Further research into the underlying pathomechanisms of PNS may improve our understanding of the RCC tumour biology and is urgently needed.

[Current guideline-oriented follow-up of small renal masses : Applied risk scores and future outlook]. / Aktuelle leitliniengerechte Nachsorge kleiner Nierentumoren : Angewandte Risikoscores und Zukunftsausblick.

After surgical resection of renal cell carcinoma by laparoscopic or open partial or complete nephrectomy, medical aftercare based on the current guidelines should be provided. This seems desirable, especially because one third of patients after initial curative tumor resection develop recurrence over time. In this article, the current recommendations for follow-up will be systematically presented based on the accepted German S3 guideline and the European Association of Urology (EAU) guideline. Another point of this article will be the presentation of the currently applied risk scores to predict prognosis with a focus on molecular markers. The goal is to improve the prediction of survival and to facilitate risk-adjusted aftercare.

[TKI 2.0 - changes in the medical treatment of renal cell carcinoma]. / TKI 2.0 ­ Wandel in der medikamentösen Therapie des Nierenzellkarzinoms.

Only for renal cell carcinoma (RCC) in a local stage curative treatment option by surgical resection exists. For metastatic disease the 5­year survival rate decreases radically. A factor that contributes to this is the low sensibility to radiation and chemotherapeutics. Since the approval of the tyrosine kinase inhibitors in 2006 effective drugs for the treatment of mRCC is available. The specific inhibition of the vascular-endothelial-growth (VEGF)-receptor and the "mammalian Target of Rapamycin" (mTOR) leads to a prolongation of the progression-free survival as well as the overall survival rate. For a long time, the current target therapy with TKI appeared to be exhausted, but since recently research has gone a step further. Thus, Cabozantinib and Lenvatinib in the combination with Everolimus have been approved for second-line therapy in mRCC. For the first time a clinical study demonstrated positive results for an adjuvant treatment with sunitinib in patients with a high-risk RCC. Furthermore, in april 2016 the immune checkpoint inhibitor Nivolumab was approved for second-line therapy in mRCC in Germany. The following report examines briefly the current therapeutic recommendations, new findings and drug approvals and ongoing clinical trials.