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+

Dynamics of urinary and respiratory shedding of Severe acute respiratory syndrome virus 2 (SARS-CoV-2) RNA excludes urine as a relevant source of viral transmission

PURPOSE To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA. METHODS Immunohistochemical staining was performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed. RESULTS High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0-2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3-8 vs median 4, range 1-8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19-48.1 versus median 11.9 × 1000/ml, range 2.9-60.3, p = 0.307), peak CRP (median 20.7~mg/dl, 4.2-40.2 versus median 11.9~mg/dl, range 0.1-51.9, p = 0.316) or peak IL-6 levels (median: 1442~ng/ml, range 26.7-3918 versus median 140~ng/ml, range 3.0-11,041, p = 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze-thaw cycles. CONCLUSIONS SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract

Metabolische, endokrinologische und immunologische Veränderungen beim chronisch-kritisch kranken Patienten mit und ohne Infektion

Der Fortschritt der Intensivmedizin hat in den letzten Jahren zu einer bislang wenig untersuchten Patientengruppe geführt - den chronisch-kritisch kranken Patienten. Diese Patienten zeichnen sich durch eine lange Liegedauer, lange Beatmungsdauer und schwerwiegenden Organdysfunktionen aus. Sie machen rund 20% der Patienten auf Intensivstationen aus, werden in den nächsten Jahren stetig anwachsen und führen zu hohen Kosten sowie zu einem enormen Verbrauch von Ressourcen. Im Rahmen der chronisch-kritischen Erkrankung kann es zu schwerwiegenden endokrinologischen Störungen kommen. Hierzu gehört die stressbedingte Hyperglykämie, die "Critical-illness-related Cortisol insufficiency" und das "Low-T3-Syndrom". Zudem sind chronisch-kritisch kranke Patienten aufgrund der zahlreichen Risikofaktoren weitaus anfälliger für Infektionen. In der Literatur finden sich kaum Studien, welche oben genannte endokrinologischen Störungen parallel untersuchten und deren Interaktionen analysierten. Ziel dieser Arbeit war es daher, den Einfluss einer Infektion auf metabolische, endokrinologische und immunologische Störungen zu untersuchen sowie mögliche Zusammenhänge zwischen diesen zu analysieren. Retrospektiv wurden für diese Arbeit Patienten in die Untersuchung eingeschlossen, welche mindestens sieben Tage auf einer neurochirurgischen Intensivstation behandelt wurden. Neben Alter, Liegedauer, Hauptdiagnose und gegebenenfalls Infektionsursache, wurden Laborparameter wie IL-6, CRP, Procalcitonin, Cortisol, TSH, fT3, fT4, Glukose, Natrium und Kalium sowie die Intensiv-Scores SAPS2 und TISS10 erhoben. Mithilfe von routinemäßig in definierten Intervallen gemessenen Procalcitonin-Werten wurde ermittelt, ob der Patient während der Behandlung frei von Infektionen war. Auf Grund seines hohen negativen prädiktiven Wertes konnte man mit Procalcitonin im Normbereich eine Infektion nahezu ausschließen. Eine Auswertung erfolgte über die Patientengruppen anhand des Infektionsstatus sowie endokrinologischer Störungen und wurde bis einschließlich Tag 35 zu sechs definierten Zeitpunkten durchgeführt. Insgesamt wurden 182 Patienten in die Studie miteingeschlossen, von denen 120 Patienten (65,9%) im Behandlungsverlauf eine Infektion entwickelten und 62 Patienten (34,1%) keine Infektion aufwiesen. Patienten mit einer Infektion zeigten signifikant höhere CRP- und IL-6-Werte. Außerdem führt eine Infektion zu einer deutlichen Supprimierung des freien Triiodthyronins (fT3) bei normalen TSH- und Thyroxin-Werten. Patienten mit einer Infektion entwickelten häufiger ein Low-T3-Syndrom, welches wiederum mit einer erhöhten Mortalität assoziiert war. Das Cortisol war bei Patienten mit Infektion zeitweise ebenfalls signifikant erhöht. Der Glucose-Stoffwechsel wurde durch das Auftreten einer Infektion nicht beeinträchtigt und eine Infektion hatte keinen Einfluss auf die Entwicklung einer stressbedingten Hyperglykämie. Außerdem konnte gezeigt werden, dass die Entwicklung einer "Critical-Illness-related Cortisol insufficiency" weniger häufig mit der Entwicklung eines Low-T3-Syndroms verbunden war. Ansonsten zeigten die endokrinologischen Störungen keine Interaktionen. Diese Arbeit legt dar, dass endokrinologische Störungen häufig bei chronisch-kritisch kranken Patienten vorkommen und durch eine Infektion beeinflusst werden können. Um kausale Zusammenhänge zwischen endokrinologischen Störungen und Infektionen zu verstehen, sollten zu diesem Thema weitergehende Forschung angestrebt werden, verbunden mit dem Ziel eine bessere Behandlung dieser Patientengruppe zu erreichen.The progress in intensive care medicine has led to the evolution of a new patient group - chronic critically ill patients. These patients are characterized by a long duration of hospital stay, long-term mechanical ventilation, and severe organ dysfunctions. They account for around 20 percent of intensive care patients. It is expected that the number of patients will increase causing high costs as well as an enormous consumption of medical resources. Chronic critical illness can cause serious endocrine disturbances such as stress-hyperglycemia, critical-illness-related cortisol insufficiency, and the low-T3-syndrome, which can negatively affect patient outcome. In addition, chronic critically ill patients are more likely to acquire infections due to their exposure to multiple risk factors. In the current literature, there are no studies investigating endocrine disturbances over long-term critical illness as well as development of nosocomial infections. Therefore, the aim of this study is to investigate the effect of an infection on metabolic, endocrine, and immunological disturbances and to show possible interactions. This retrospective study included patients treated in a neurosurgical intensive care unit for a minimum of seven days. Next to patients' age, the duration of stay, the principal diagnosis and if applicable the type of infection was included as well as laboratory parameters such as IL-6, CRP, Procalcitonin, Cortisol, TSH, fT3, fT4, Glucose, Sodium, Potassium and intensive care scores such as SAPS2 and TISS10. In order to determine whether the patient is free from infections, routine procalcitonin determinations were used as biomarkers at defined intervals. Due to a high negative predictive value, a normal value of procalcitonin excludes infection at high probability. Patient groups without and with a probable infection and endocrine disturbances were analyzed and compared within a 35-day period at six given points in time. 182 patients were included into the study in total, of which 120 patients (65.9%) were at risk for infection. 62 patients (34.1%) who did not develop any infection during their treatment. Patients with a probable infection showed significantly higher CRP- and IL-6-values. A probable infection led to a significant suppression of triiodthyronine (fT3) accompanied with normal TSH- and thyroxine-values possibly caused by cytokines. Therefore, patients with a probable infection were prone to develop a low-T3-syndrom, which then was associated with a higher mortality in that group. Serum cortisol was also significantly higher in patients with infection at some measurements. Glucose metabolism was not affected by a probable infection and there was no effect on the development of stress hyperglycemia or critical-illness-related cortisol insufficiency. In addition, this study could show that the development of a critical-illness-related cortisol insufficiency was not associated with a low-T3-syndrome. Other endocrine disturbances did not interact with each other. This study showed that endocrine disturbances are common in chronic critically ill patients and can be complicated by the additional development of an infection. To understand the exact mechanisms and causal relationships between endocrine disturbances and infections, further studies are needed. This may enable a better and more appropriate treatment for the chronic critically ill patients

Asymptomatic bacteriospermia and infertility-what is the connection?

Objective To determine the impact of asymptomatic bacteriospermia on semen quality in subfertile men. Methods We conducted a retrospective, single-centre cohort study in 1300 subfertile men. In those diagnosed with asymptomatic bacteriospermia we performed univariate and multivariate logistic regression models to evaluate the strain-specific association with semen parameters. Results Asymptomatic bacteriospermia was diagnosed in 3.2% of patients. The microbiological semen analysis revealed a poly-microbial result in 60%. The most common bacterial species were coagulase-negative Staphylococci species (71.4%), Streptococcus viridans (50.0%) and Enterococcus faecalis (26.2%). Sexually transmitted pathogens were identified in 11.9% of semen samples. The detection of Streptococcus viridians or Haemophilus parainfluenzae correlated with impaired sperm morphology (p < 0.05). The presence of coagulase-negative Staphylococci species or Enterococcus faecalis was associated with pathological low counts of live spermatozoa (p < 0.05). In multivariate analysis only Enterococcus faecalis showed a significant impact on sperm concentration (OR 4.48;95% CI 1.06-22.10;p = 0.041). Conclusions Asymptomatic bacteriospermia has always been a subject of great controversy. There is still an ongoing debate whether to treat or not to treat. Here, we demonstrate that asymptomatic bacteriospermia is clearly associated with impaired semen quality. Our findings speak in favour of strain-specific interactions with semen parameters. Especially Enterococcus faecalis seriously affects sperm concentration

The Impact of Prostate Volume on the Prostate Imaging and Reporting Data System (PI-RADS) in a Real-World Setting

Multiparametric magnetic resonance imaging (mpMRI) has emerged as a new cornerstone in the diagnostic pathway of prostate cancer. However, mpMRI is not devoid of factors influencing its detection rate of clinically significant prostate cancer (csPCa). Amongst others, prostate volume has been demonstrated to influence the detection rates of csPCa. Particularly, increasing volume has been linked to a reduced cancer detection rate. However, information about the linkage between PI-RADS, prostate volume and detection rate is relatively sparse. Therefore, the current study aims to assess the association between prostate volume, PI-RADS score and detection rate of csP-Ca, representing daily practice and contemporary mpMRI expertise. Thus, 1039 consecutive patients with 1151 PI-RADS targets, who underwent mpMRI-guided prostate biopsy at our tertiary referral center, were included. Prior mpMRI had been assessed by a plethora of 111 radiology offices, including academic centers and private practices. mpMRI was not secondarily reviewed in house before biopsy. mpMRI-targeted biopsy was performed by a small group of a total of ten urologists, who had performed at least 100 previous biopsies. Using ROC analysis, we defined cut-off values of prostate volume for each PI-RADS score, where the detection rate drops significantly. For PI-RADS 4 lesions, we found a volume > 61.5 ccm significantly reduced the cancer detection rate (OR 0.24; 95% CI 0.16–0.38; p 51.5 ccm to significantly reduce the cancer detection rate (OR 0.39; 95% CI 0.25–0.62; p < 0.001). For PI-RADS 3 lesions, none of the evaluated clinical parameters had a significant impact on the detection rate of csPCa. In conclusion, we show that enlarged prostate volume represents a major limitation in the daily practice of mpMRI-targeted biopsy. This study is the first to define exact cut-off values of prostate volume to significantly impair the validity of PI-RADS assessed in a real-world setting. Therefore, the results of mpMRI-targeted biopsy should be interpreted carefully, especially in patients with prostate volumes above our defined thresholds

Listening to Music during Outpatient Cystoscopy Reduces Pain and Anxiety and Increases Satisfaction: Results from a Prospective Randomized Study

BACKGROUND: This study investigates the effect of classical music, music of patients\u27 own choice, or no music on pain reduction during elective cystoscopy. OBJECTIVES: The aim of the study was to describe the effect of listening to classical music, music of patients\u27 own choice, or no music on patient\u27s pain and satisfaction rates when carrying out an elective cystoscopy and the effect on the assessment capability of the performing urologist. DESIGN, SETTING, AND PARTICIPANTS: This randomized trial included 127 patients undergoing elective cystoscopy at the Urological Department of the University Clinic of Munich between June 2019 and March 2020. Outcome Measurements and Statistical Analysis: Patients were assigned randomly to 3 groups: group I: listening to standardized classical music (n = 35), group II: listening to music according to the patients\u27 choice (n = 34), and control group III: no music (n = 44). Prior to cystoscopy, anxiety levels were assessed by the Beck Anxiety Inventory (BAI). The Visual Analog Scale (VAS, range 1-100) was used for a self-assessment of pain, discomfort, and satisfaction. Statistical analysis was done with Spearman\u27s rank correlation and t-tests. RESULTS AND LIMITATIONS: The median age was 63 (range 27-91) years. The duration of cystoscopy was 5.7 (1-30) min. Patients had undergone a median of 2.3 cystoscopies in the past. Between giving informed consent and cystoscopy, patients had to wait for a median of 64 (0-260) min. The median VAS pain score was significantly lower in group I at 1.7 and group II at 2.3 versus 5.2 in the control group III (p \u3c 0.001). The control group III had significantly worse pain and patient satisfaction rates compared with groups I and II. Group I had a significant lower VAS pain score than groups II and III (p \u3c 0.001). Classical music also increased the assessment capability of the preforming urologist. CONCLUSIONS: Listening to music during elective cystoscopy significantly reduces pain and distress and leads to higher patient and surgeon satisfaction. We recommend listening to classical music or music chosen by the patients during outpatient flexible/rigid cystoscopy in daily clinical routine. Patient Summary: In this study, we found that patients who listened to classical music or music of their own choice while undergoing a cystoscopy showed significant reduction of pain and distress

Accuracy and prognostic value of radiological lymph node features in variant histologies of bladder cancer

Purpose To provide first evidence of lymph node (LN) staging using CT scan and its prognostic value in variant histologies of bladder cancer. This knowledge may optimize patient management with variant histologies based on CT morphological findings. Methods Preoperative CT scans of patients with variant histologies who underwent RC between 2004 and 2019 were reanalyzed by two independent radiologists in a blinded review process. Specificity, sensitivity, and accuracy for LN staging as well as LN characteristics were evaluated. Correlation with survival was investigated by Kaplan-Meier method, log-rank test and multivariate analysis. Results 1361 patients with primary tumor of the bladder underwent RC, of which 163 (12%) patients revealed variant histologies. 65 (47.8%) patients have shown an urothelial variant (UV) and 71 (52.2%) a non-urothelial variant (NUV). LN metastases were found in 18 (27.7%) patients with UV and 21 (29.6%) patients with NUV. The accuracy to detect LN metastasis for all variant histologies was 62% with a sensitivity of 46% and a specificity of 70%. Subgroups of UV and NUV revealed an accuracy of 67% and 57%. An increased number of regional LN (HR 2.8;1.34-6.18) and the loss of fatty hilum (HR 0.36, 0.17-0.76) were prognostic parameters. In multivariate analysis, a fatty hilum (HR 0.313, 0.104-0.945) and the presence of lymph node metastases (HR 2.866, 1.140-7.207) were prognostic. Conclusion This first study on CT morphological behavior of variant histologies revealed an accuracy of UV and NUV comparable to UC with low specificity for all variant histologies. CT scan prior RC should be interpreted in regard to histological subtypes

Adverse Pathology after Radical Prostatectomy of Patients Eligible for Active Surveillance—A Summary 7 Years after Introducing mpMRI-Guided Biopsy in a Real-World Setting

Objective: Over the last decade, active surveillance (AS) of low-risk prostate cancer has been increasing. The mpMRI fusion-guided biopsy of the prostate (FBx) is considered to be the gold standard in preoperative risk stratification. However, the role of FBx remains unclear in terms of risk stratification of low-risk prostate cancer outside high-volume centers. The aim of this study was to evaluate adverse pathology after radical prostatectomy (RP) in a real-world setting, focusing on patients diagnosed with Gleason score (GS) 6 prostate cancer (PCa) and eligible for AS by FBx. Subjects and Methods: Between March 2015 and March 2022, 1297 patients underwent FBx at the Department of Urology, Ludwig-Maximilians-University of Munich, Germany. MpMRI for FBx was performed by 111 different radiology centers. FBx was performed by 14 urologists from our department with different levels of experience. In total, 997/1297 (77%) patients were diagnosed with prostate cancer; 492/997 (49%) of these patients decided to undergo RP in our clinic and were retrospectively included. Univariate and multivariable logistic regression analyses were performed to evaluate clinical and histopathological parameters associated with adverse pathology comparing FBx and RP specimens. To compare FBx and systematic randomized biopsies performed in our clinic before introducing FBx (SBx, n = 2309), we performed a propensity score matching on a 1:1 ratio, adjusting for age, number of positive biopsy cores, and initial PSA (iPSA). Results: A total of 492 patients undergoing FBx or SBx was matched. In total, 55% of patients diagnosed with GS 6 by FBx were upgraded to clinically significant PCa (defined as GS ≥ 7a) after RP, compared to 52% of patients diagnosed by SBx (p = 0.76). A time delay between FBx and RP was identified as the only correlate associated with upgrading. A total of 5.9% of all FBx patients and 6.1% of all SBx patients would have been eligible for AS (p > 0.99) but decided to undergo RP. The positive predictive value of AS eligibility (diagnosis of low-risk PCa after biopsy and after RP) was 17% for FBx and 6.7% for SBx (p = 0.39). Conclusions: In this study, we show, in a real-world setting, that introducing FBx did not lead to significant change in ratio of adverse pathology for low-risk PCa patients after RP compared to SBx