Confronting hidden COVID-19 burden: a telemedical solution for elective urological outpatient clinics

Maintaining high-quality care for urological patients is a challenge during and after the Coronavirus disease 2019 (COVID-19) pandemic. We observe an increasing volume of postponed elective visits at our tertiary care hospital, holding the risk for deterioration of non-emergency disease conditions. As it is unclear for how long the pandemic will last, we propose to implement telehealth as a solution to provide regular symptom monitoring compatible with social distancing guidelines during the pandemic and beyond. Telemedical assessment and prioritizing of high-risk patients for individual consults at outpatient services will have to be aligned with available outpatient capacity and local outbreak severity

Identification of the Tumor Infiltrating Lymphocytes (TILs) Landscape in Pure Squamous Cell Carcinoma of the Bladder

Simple Summary Treatment options in squamous cell carcinoma (SCC) of the bladder are limited and prognosis is poor. In this report we investigated the impact of tumor-infiltrating lymphocytes (TILs) in SCC of the bladder in patients undergoing radical cystectomy. We found that subsets of TILs hold predictive value for OS and PFS. We conclude that TILs might stratify patients with bladder SCC for immunotherapy. Background: Tumor infiltrating lymphocytes (TILs) are known as important prognostic biomarkers and build the fundament for immunotherapy. However, the presence of TILs and its impact on outcome in pure squamous cell carcinoma (SCC) of the bladder remains uncertain. Methods: Out of 1600 patients undergoing radical cystectomy, 61 patients revealed pure bladder SCC in the final histopathological specimen. Retrospectively, immunohistochemical staining was performed on a subset of TILs (CD3+, CD4+, CD8+, CD20+). Endpoints were overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). The Kaplan-Meier method was used to evaluate survival outcomes. Results: Strong infiltration of CD3+ was found in 27 (44%);of CD4+ in 28 (46%);of CD8+ in 26 (43%);and of CD20+ in 27 tumors (44%). Improved OS was observed for strong CD3+ (p < 0.001);CD4+ (p = 0.045);CD8+ (p = 0.001);and CD20+ infiltration (p < 0.001). Increased rates of PFS were observed for CD3+ (p = 0.025) and CD20+ TILs (p = 0.002). In multivariate analyses, strong CD3+ (HR: 0.163, CI: 0.044-0.614) and strong CD8+ TILs (HR: 0.265, CI: 0.081-0.864) were revealed as predictors for OS and the strong infiltration of CD20+ cells (HR: 0.095, CI: 0.019-0.464) for PFS. Conclusions: These first results of TILs in bladder SCC revealed predictive values of CD3+, CD8+ and CD20+

The development and characterization of dendritic cell subsets in healthy and atherosclerotic aorta

Arteriosklerose ist eine chronisch inflammatorische Erkrankung der Gefäßwand. Nach aktuellem Wissensstand sind Dendritische Zellen (DCs) maßgeblich an der Entstehung und dem Fortschreiten von Arteriosklerose beteiligt. In der Vergangenheit konnten für DCs unterschiedliche Subsets beschreiben werden, die sowohl proinflammatorische als auch immunregulatorische Funktionen übernehmen können. Die systematische Charakterisierung von DCs in der gesunden Aorta, sowie während der Entstehung von Arteriosklerose ist jedoch noch ausstehend. In der vorliegenden Arbeit wurde zunächst die systematische Einteilung von DCs in vitro mit Hilfe von DCs aus Flt3L-Knochenmarkskulturen durchgeführt. Aufbauend darauf erfolgte die systematische Analyse aortaler DCs durch tierexperimentelle Untersuchungen an gesunden C57BL/6J Mäusen, sowie Apolipoprotein E-defizienten (ApoE-/-) Mäusen und low-density-lipoprotein-receptor-defizienten (Ldlr-/-) Mäusen während der Atherogenese. Mittels immunhistochemischer Untersuchungen von CD11cYFPreporter Mäusen konnten zudem korrelierend DCs in der Gefäßwand der murinen Aorta lokalisiert werden. Zusammenfassend gibt die vorliegende Arbeit erstmalig einen systematischen Überblick über die einzelnen DC-Subsets in der gesunden Aorta und während der Atherogenese. Dies trägt zu einem besseren Verständnis der Rolle der einzelnen DC Subsets während der Entstehung der Arteriosklerose bei und bietet eine mögliche Grundlage für zukünftige Behandlungsstrategien. Die Ergebnisse dieser Arbeit wurden im Februar 2014 als Originalarbeit in geteilter Erstautorenschaft von Martin Busch, Thilo Westhofen und Miriam Koch unter dem Titel Dendritic Cell Subset Distributions in the Aorta in Healthy and Atherosclerotic Mice im Plos One publiziert (1). Die Originalpublikation findet sich im Folgenden unter Absatz 11. Die Ergebnisse dieser Publikation wurden modifiziert unter 6.1-6.5 dargelegt und unter 7.1-7.5 im Kontext der aktuellen Literatur diskutiert. Sofern nicht anders angegeben, wurden alle Experimente von Thilo Westhofen geplant, durchgeführt und ausgewertet.Atherosclerosis is a chronic inflammatory disease of the vessel wall. According to current knowledge, dendritic cells (DCs) are significantly involved in the development and progression of atherosclerosis. In the past, different subsets could be described for DCs, with both proinflammatory and immunoregulatory functions. However, the systematic characterization of DCs in the healthy aorta, as well as during the development of atherosclerosis, is still pending. In the present work, the systematic classification of DCs in vitro was first performed using DCs from Flt3L bone marrow cultures. Based on this, the systematic analysis of aortic DCs was performed by animal studies in healthy C57BL/6J mice, as well as apolipoprotein E-deficient (ApoE-/-) mice and low-density lipoprotein receptor-deficient (Ldlr-/-) mice during atherogenesis. In addition, applying immunohistochemical studies of CD11cYFPreporter mice, correlating DCs were localized in the vessel wall of the murine aorta. In the aorta of healthy C57BL/6 mice and Ldlr-/- mice on a normal diet, CD11c+MHCII+ DCs could be identified and subdivided into 4 distinct subsets CD103-CD11b+F4/80+, CD103-CD11b+F4/80-, CD103-CD11b-F4/80- DCs and CD103+CD11b-F4/80- DCs. After 6 or 12 weeks of proatherogenic high-fat diet, all subsets except the CD103-CD11b-F4/80- DCs showed relevant growth. More detailed characterization of the subsets showed Sirpα expression for the CD103-CD11b+F4/80+subset, the CD103-CD11b+F4/80- subset and partially for the CD103-CD11b-F4/80- subset, but not for CD103+DCs. For all subsets, there were no relevant dynamics during atherogenesis. For CD64, however, no expression in the healthy aorta could be shown for any of the DC subsets. After 12 weeks of proatherogenic high-fat diet, the CD103-CD11b+F4/80- and the CD11b+F4/80+ subset showed a proportional CD64 expression. Conversely, mice with FMS-like tyrosine kinase 3 ligand deficiency (Flt3L-/-) showed loss of CD103-CD11b+F4/80- DCs and CD103+DCs, but not the other subsets. Furthermore, the CD103-CD11b+F4/80- subset and the CD103-CD11b+F4/80+ subset showed an increase in CX3CR1 expression during atherogenesis. In the healthy aorta, no subset showed relevant proportions of CX3CR1-expressing DCs. This suggests an increase of these subsets by possible migrated monocytes. Immunohistochemically, CX3CR1GFPreporter mice were able to locate corresponding CX3CR1+ cells luminal in plaque areas of the aorta. In summary, the present work provides for the first time a systematic overview of the individual DC subsets in the healthy aorta and during atherogenesis. This contributes to a better understanding of the role of the individual DC subsets during the development of atherosclerosis and provides a possible basis for future treatment strategies. The results of this work were published in February 2014 as an original paper with shared first authorship by Martin Busch, Thilo Westhofen and Miriam Koch under the title Dendritic Cell Subset Distributions in the Aorta in Healthy and Atherosclerotic Mice in Plos One (1)

Dendritic Cell Subset Distributions in the Aorta in Healthy and Atherosclerotic Mice

Dendritic cells (DCs) can be sub-divided into various subsets that play specialized roles in priming of adaptive immune responses. Atherosclerosis is regarded as a chronic inflammatory disease of the vessel wall and DCs can be found in non-inflamed and diseased arteries. We here performed a systematic analyses of DCs subsets during atherogenesis. Our data indicate that distinct DC subsets can be localized in the vessel wall. In C57BL/6 and low density lipoprotein receptor-deficient (Ldlr−/−) mice, CD11c+ MHCII+ DCs could be discriminated into CD103− CD11b+F4/80+, CD11b+F4/80− and CD11b−F4/80− DCs and CD103+ CD11b−F4/80− DCs. Except for CD103− CD11b− F4/80− DCs, these subsets expanded in high fat diet-fed Ldlr−/− mice. Signal-regulatory protein (Sirp)-α was detected on aortic macrophages, CD11b+ DCs, and partially on CD103− CD11b− F4/80− but not on CD103+ DCs. Notably, in FMS-like tyrosine kinase 3-ligand-deficient (Flt3l−/−) mice, a specific loss of CD103+ DCs but also CD103− CD11b+ F4/80− DCs was evidenced. Aortic CD103+ and CD11b+ F4/80− CD103− DCs may thus belong to conventional rather than monocyte-derived DCs, given their dependence on Flt3L-signalling. CD64, postulated to distinguish macrophages from DCs, could not be detected on DC subsets under physiological conditions, but appeared in a fraction of CD103− CD11b+ F4/80− and CD11b+ F4/80+ cells in atherosclerotic Ldlr−/− mice. The emergence of CD64 expression in atherosclerosis may indicate that CD11b+ F4/80− DCs similar to CD11b+ F4/80+ DCs are at least in part derived from immigrated monocytes during atherosclerotic lesion formation. Our data advance our knowledge about the presence of distinct DC subsets and their accumulation characteristics in atherosclerosis, and may help to assist in future studies aiming at specific DC-based therapeutic strategies for the treatment of chronic vascular inflammation

Evaluation of Holmium Laser Enucleation of the Prostate Learning Curves with and without a Structured Training Programme

Background/aims!#!To evaluate perioperative parameters, early functional outcomes, and the safety profile of holmium laser enucleation of the prostate learning curves with and without mentoring.!##!Methods!#!The learning curves of 2 surgeons of their first 100 consecutive patients treated with holmium laser enucleation of the prostate were retrospectively analyzed. We analyzed demographic parameters, clinical outcomes, adverse events, and the progress during each learning experience.!##!Results!#!The only statistically significant differences between the two learning curves were found for operation time (138.2 ± 60.7 vs. 98.2 ± 37.7 min; p &amp;lt; 0.001) in favor of the supervised approach, the total weight of resected prostatic tissue (81.5 ± 50.5 vs. 65.0 ± 6.7 g; p &amp;lt; 0.001) with more tissue removal by the surgeon without guidance, and the perioperative hemoglobin drop (1.9 ± 1.4 vs. 1.1 ± 1.0 g/dl; p &amp;lt; 0.001) in favor of the learning curve with a training programme. In multivariate logistic regression, the time factor was independently associated with a higher drop in hemoglobin levels (OR 1.015; 95% CI 1.000-1.023; p = 0.001). The improvements of clinical outcomes as determined by International Prostate Symptom Score, quality of life, peak urinary flow rate and postvoid residual volume were comparable. After the first 50 procedures the mean operation time significantly improved from 147 to 107.5 minutes for the learning curve without supervision (p &amp;lt; 0.001), whereas the surgical time was consistent throughout the 100 cases with a mentoring programme. The overall incidence of treatment-related adverse events was significantly higher without the training programme (16 vs. 5%; p = 0.008).!##!Conclusions!#!Our study clearly showed the benefits of a structured training programme to overcome the steep learning curve

Confronting hidden COVID-19 burden: a telemedical solution for elective urological outpatient clinics

Maintaining high-quality care for urological patients is a challenge during and after the Coronavirus disease 2019 (COVID-19) pandemic. We observe an increasing volume of postponed elective visits at our tertiary care hospital, holding the risk for deterioration of non-emergency disease conditions. As it is unclear for how long the pandemic will last, we propose to implement telehealth as a solution to provide regular symptom monitoring compatible with social distancing guidelines during the pandemic and beyond. Telemedical assessment and prioritizing of high-risk patients for individual consults at outpatient services will have to be aligned with available outpatient capacity and local outbreak severity

The impact of previous inguinal mesh hernioplasty on oncological and patient‐reported outcomes following radical prostatectomy

Background The impact of previous inguinal mesh hernioplasty (MH) with non-resorbable mesh prostheses on surgical performance of radical prostatectomy (RP) has been controversially discussed, with unknown impact of MH on oncologic outcomes and health-related quality of life (HRQOL) following RP. We therefore aimed to assess the influence of previous MH on metastasis-free survival (MFS), biochemical recurrence-free survival (BRFS), and HRQOL following RP. Methods We identified 344 patients with previous MH prior RP within our prospectively assessed institutional database of 6275 patients treated with RP for PC (2008–2019). A 1:3 propensity-score matched analysis of 1345 men (n = 319 previous MH, n = 1026 no previous MH) was conducted. Primary endpoint was MFS and secondary endpoints were BRFS and HRQOL (based on EORTC QLQ-C30). Binary logistic regression, Kaplan–Meier, and Cox regression models tested the effect of previous MH on MFS, BRFS, and HRQOL (p < 0.05). Results Median follow-up was 47 months. Patients with previous MH had significantly lower 5-year MFS (72% vs. 85%, p < 0.001) and 5-year BRFS estimates (43% vs. 57%, p < 0.001). In multivariate analysis, previous MH was confirmed as an independent predictor for impaired MFS (hazard ratio [HR]: 3.772, 95% CI 1.12–12.64, p = 0.031) and BRFS (HR: 1.862, 95% CI: 1.22–2.85, p = 0.004). These results held true if stratified for surgical approach or limited to patients with successful PLND. We found significantly shorter median time to continence recovery for patients without previous MH (p = 0.001) without significant differences in total continence recovery rates, erectile function recovery, and HRQOL. Conclusions Our findings show an impaired oncologic outcome for patients with previous MH following RP with no significant differences regarding continence recovery, erectile function recovery, and general HRQOL

Holmium laser enucleation of the prostate: A truly size‐independent method?

Objectives To evaluate the impact of prostate size on functional outcomes and perioperative morbidity, we analyzed patients undergoing holmium laser enucleation of the prostate (HoLEP) for lower urinary tract symptoms (LUTS). As LUTS secondary to benign prostatic obstruction (BPO) are a chronic progressive disease, prevalence and prostate size increase with age. HoLEP is a size-independent method for surgical treatment of LUTS/BPO and can be offered in medication-refractory patients with durable long-term results and reduced perioperative morbidity. Methods We retrospectively collected data of 852 patients who underwent HoLEP for LUTS secondary to BPO between 2014-2018. Patients were divided into group 1 (≤60 cc), group 2 (>60 < 120 cc), group 3 (≥120 cc). Perioperative parameters, safety and short-term functional outcomes were assessed and analyzed. Results Patients in group 3 were significantly older and showed a significantly higher median prostate-specific antigen level. Perioperative parameters, such as enucleation time and morcellation time significantly differed in favor of smaller prostate sizes, while enucleation and morcellation speed showed favorable results for larger prostate sizes. Larger prostates ≥120 cc showed a significantly higher postoperative drop in hemoglobin. However, patients did not differ in postoperative functional outcomes or Clavien-Dindo grade ≥II complications (4.8% of all patients [41/852]). There was no difference in perioperative complications between all groups (P = 0.760). Conclusion While larger prostates take significantly longer to operate on, postoperative functional outcomes show no difference between all sizes. In conclusion, HoLEP is a size-independent and effective method for surgical treatment of LUTS/BPO in prostates ≥30 cc

The Added Value of Baseline Health-Related Quality of Life in Predicting Survival in High-Risk Prostate Cancer Patients Following Radical Prostatectomy

Objective: Several studies have shown baseline health-related quality of life (HRQOL) to be a valuable prognostic indicator of survival outcomes for various cancer entities in the metastatic setting. To date, there is no evidence regarding the prognostic value of baseline HRQOL for patients undergoing radical prostatectomy (RP) due to localized prostate cancer (PC). / Patients and methods: 1029 patients with high-risk PC according to NCCN risk stratification and prospectively assessed baseline HRQOL prior to RP were identified. Patients were stratified by global health status (GHS) domain of the QLQ-C30 questionnaire. Oncologic endpoints were biochemical recurrence-free survival (BRFS) and metastasis-free survival (MFS). Multivariable Cox regression models were performed to assess prognostic significance of baseline GHS on survival outcomes. Harrell’s discrimination C-index was applied to calculate the predictive accuracy of the model and previous described risk stratification models. Decision curve analysis (DCA) was applied to test the clinical net benefit associated with adding GHS to our multivariable model (p<0.05). / Results: Median follow-up was 43 months. In multivariable analysis, GHS was confirmed as an independent predictor for increased BRFS (HR 0.97, 95%CI 0.96–0.99; p=0.001) and MFS (HR 0.96, 95%CI 0.93–0.99; p=0.013), indicating a relative risk reduction of 2.9% for BRFS and 3.7% for MFS per 1-point increase of baseline GHS. Adding baseline HRQOL to our model and to the CAPRA and NCCN score improved discrimination in predicting BRFS and MFS of the respective models. DCA revealed a net benefit over all threshold probabilities. / Conclusions: Our findings highlight baseline HRQOL to be a valuable and robust prognostic factor for patients with localized high-risk PC prior RP. Baseline HRQOL increased prognostic accuracy of BRFS and MFS

SIRPα expression on aortic DC subsets and macrophages.

<p>Representative histograms of the expression of SIRPα on DC subsets and macrophages in the aorta of <i>Ldlr^−/−</i> mice fed a normal chow or after 12 weeks of high fat diet-feeding. Representative histograms from 6–9 mice per group are shown.</p