Long-Term Follow-Up of Peritoneal Interposition Flap in Symptomatic Lymphocele Reduction following Robot-Assisted Radical Prostatectomy: Insights from the PIANOFORTE Trial.

The available randomised controlled trials (RCTs) assessing the influence of peritoneal interposition flaps (PIF) on the reduction of symptomatic lymphoceles (sLCs) post robot-assisted radical prostatectomy (RARP) do not constitute a sufficient follow-up (FU) to assess the long-term effects. The PIANOFORTE trial was the first of these RCTs, showing no sLC reduction at the 3-month FU. Therefore, all 232 patients from the PIANOFORTE trial were invited for long-term FU. One hundred seventy-six patients (76%) presented themselves for FU and constituted the study group (SG). The median FU duration was 43 months. No significant differences in group allocation or LC endpoints at 90 days were observed between SG patients and patients not presenting themselves for the FU. During the FU period, four patients (2.3%) in the SG developed sLCs, and six patients (3.4%) developed asymptomatic lymphoceles (aLCs), which persisted in five patients (2.9%). There were no significant differences between PIF and non-PIF regarding sLC/aLC formation or persistence, newly developed complications, stress urinary incontinence or biochemical/clinical tumour recurrence. Therefore, this long-term FU confirms the primary outcomes of the PIANOFORTE trial that, while PIF does not impact complications or functionality, it does not reduce sLC/aLC rates. Furthermore, it shows the potential occurrence of LC after the third postoperative month.

Ureteroplasty with buccal mucosa graft without omental wrap: an effective method to treat ureteral strictures.

PURPOSE: Successful treatment options for ureteral strictures are limited. Surgical options such as ileal interposition and kidney autotransplantation are difficult and associated with morbidity and complications. Techniques such as Boari flap and psoas hitch are limited to distal strictures. Only limited case studies on the success of open buccal mucosa graft (BMG) ureteroplasty exist to this date. The purpose of this study was to evaluate the success of open BMG ureteroplasty without omental wrap. METHODS: In this single-center retrospective study between July 2020 and January 2023, we included 14 consecutive patients with ureteric strictures who were treated with open BMG ureteroplasty without omental wrap. The primary outcome was the success of open BMG ureteroplasty. Further endpoints were complications and hospital readmission. Outcome variables were assessed by clinical examination, kidney sonography, and patient anamnesis. RESULTS: Out of 14 patients, 13 were stricture and ectasia-free without a double-J stent at a median follow-up of 15 months (success rate 93%). No complications were observed at the donor site, and the complication rate overall was low with 3 out of 14 patients (21%) having mild-to-medium complications. CONCLUSIONS: Open BMG ureteroplasty without omental wrap is a successful and feasible technique for ureteric stricture repair.

A novel grading approach predicts worse outcomes in stage pT1 non-muscle-invasive bladder cancer.

OBJECTIVE: To develop a prognostically relevant scoring system for stage pT1 non-muscle-invasive bladder cancer (NMIBC) incorporating tumour budding, growth pattern and invasion pattern because the World Health Organisation grading system shows limited prognostic value in such patients. PATIENTS AND METHODS: The tissue specimens and clinical data of 113 patients with stage pT1 NMIBC who underwent transurethral resection of bladder tumour were retrospectively investigated. Tumour budding, and growth and invasion patterns were evaluated and categorised into two grade groups (GGs). GGs and other clinical and histopathological variables were investigated regarding recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) using univariable and multivariable Cox regression analyses. RESULTS: The integration of two tumour budding groups, two growth patterns, and two invasion patterns yielded an unfavourable GG (n = 28; 24.7%) that had a high impact on oncological outcomes. The unfavourable GG was identified as an independent RFS and OS predictor (P = 0.004 and P = 0.046, respectively) and linked to worse PFS (P = 0.001) and CSS (P = 0.001), irrespective of the European Association of Urology risk group. The unfavourable GG was associated with higher rates of BCG-unresponsive tumours (P = 0.006). Study limitations include the retrospective, single-centre design, diverse therapies and small cohort. CONCLUSIONS: We present a morphology-based grading system for stage pT1 NMIBC that correlates with disease aggressiveness and oncological patient outcomes. It therefore identifies a highest risk group of stage pT1 NMIBC patients, who should be followed up more intensively or receive immediate radical cystectomy. The grading incorporates objective variables assessable on haematoxylin and eosin slides and immunohistochemistry, enabling an easy-to-use low-cost approach that is applicable in daily routine. Further studies are needed to validate and confirm these results.

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

Risk factors for bladder neck contracture after transurethral resection of the prostate.

INTRODUCTION: Transurethral resection of the prostate (TURP) is the most frequently used treatment of benign prostate hyperplasia with a prostate volume of <80 mL. A long-term complication is bladder neck contracture (BNC). The aim of the present study was to identify the risk factors for BNC formation after TURP. METHODS: We conducted a retrospective analysis of all TURP primary procedures which were performed at one academic institution between 2013 and 2018. All patients were analyzed and compared with regard to postoperative formation of a BNC requiring further therapy. Uni- and multivariable logistic regression analyses (MVAs) were performed to identify possible risk factors for BNC development. RESULTS: We included 1368 patients in this analysis. Out of these, 88 patients (6.4%) developed BNC requiring further surgical therapy. The following factors showed a statistically significant association with BNC development: smaller preoperative prostate volume (p = 0.001), lower resected prostate weight (p = 0.004), lower preoperative levels of prostate-specific antigen (PSA, p < 0.001), shorter duration of the surgery (p = 0.027), secondary transurethral intervention (due to urinary retention or gross hematuria) during inpatient stay (p = 0.018), positive (≥100 CFU/mL) preoperative urine culture (p = 0.010), and urethral stricture (US) formation requiring direct visual internal urethrotomy (DVIU) postoperatively after TURP (p < 0.001), in particular membranous (p = 0.046) and bulbar (p < 0.001) strictures. Preoperative antibiotic treatment showed a protective effect (p = 0.042). Histopathological findings of prostate cancer (PCA) in the resected prostate tissue were more frequent among patients who did not develop BNC (p = 0.049). On MVA, smaller preoperative prostate volume (p = 0.046), positive preoperative urine culture (p = 0.021), and US requiring DVIU after TURP (p < 0.001) were identified as independent predictors for BNC development. CONCLUSION: BNC is a relevant long-term complication after TURP. In particular, patients with a smaller prostate should be thoroughly informed about this complication.

Body Composition of Patients Undergoing Radical Cystectomy for Bladder Cancer: Sarcopenia, Low Psoas Muscle Index, and Myosteatosis Are Independent Risk Factors for Mortality.

BACKGROUND: We assessed a wide array of body composition parameters to identify those most relevant as prognostic tools for patients undergoing radical cystectomy (RC) due to bladder cancer (BC). METHODS: In this retrospective, single-center study, preoperative computed tomography (CT) scans of 657 patients were measured at the level of the 3rd lumbar vertebra (L3) to determine common body composition indices including sarcopenia, myosteatosis, psoas muscle index (PMI), subcutaneous and visceral fat index (SFI and VFI), visceral-to-subcutaneous fat ratio (VSR), and visceral obesity. Predictors of overall survival (OS) and cancer-specific survival (CSS) were identified in univariate and multivariate survival analysis. RESULTS: Sarcopenia and a low PMI were independently associated with shorter OS (Sarcopenia: HR 1.30; 95% CI 1.02-1.66; p = 0.04 and a low PMI: HR 1.32; 95% CI 1.02-1.70; p = 0.03) and CSS (Sarcopenia: HR 1.64; 95% CI 1.19-2.25; p < 0.01 and a low PMI: HR 1.41; 95% CI 1.02-1.96; p = 0.04). Myosteatosis, measured as decreasing average Hounsfield units of skeletal muscle, was an independent risk factor for OS (HR 0.98; 95% CI 0.97-1.00; p = 0.01) and CSS (HR 0.98; 95% CI 0.96-1.00; p < 0.05). The assessed adipose tissue indices were not significant predictors for OS and CSS. CONCLUSIONS: Sarcopenia, a low PMI, and myosteatosis are independent predictors for OS and CSS in patients undergoing radical cystectomy for bladder cancer.

Prognostic impact of variant histologies in urothelial bladder cancer treated with radical cystectomy.

OBJECTIVES: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). MATERIALS AND METHODS: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox' regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as 'organ-confined' (≤pT2N0), 'locally advanced' (pT3-4N0) and 'node-positive' (pTanyN1-3). RESULTS: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. CONCLUSIONS: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management.

[Adrenal tumors: diagnostics, perioperative management and surgical treatment]. / Nebennierentumoren: Diagnostik, perioperatives Management und operative Therapie.

Space-occupying lesions of the adrenal glands are one of the most frequent tumors; however, only a fraction of approximately 20% need further diagnostics and treatment. The diagnostic standard is native computed tomography (CT). For larger tumors and those that cannot be clearly classified as benign, the supplementary radiological modalities magnetic resonance imaging (MRI), contrast CT and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) should be used. Adrenal gland neoplasms can be hormone-active or hormone-inactive. The most important hormone-active adrenal gland neoplasms are those with autonomous cortisol secretion and autonomous aldosterone secretion as well as pheochromocytomas. Several laboratory tests are available each for the respective hormone activity. The indications for surgery are dependent on the dignity, size and hormone activity. Minimally invasive surgical techniques have become more important due to advantages such as lower blood loss; nevertheless, open surgery is still indispensable for large suspected tumors. Care must be taken preoperatively and postoperatively, particularly in cases of hormone-active tumors.

Short-Term and Long-Term Morbidity after Radical Cystectomy in Patients with NMIBC and Comparison with MIBC: Identifying Risk Factors for Severe Short-Term Complications.

INTRODUCTION: RC represents a viable treatment option for certain NMIBC patients. However, studies investigating morbidity in the context of RC for NMIBC are scarce. The goal of the current study was to assess and compare morbidity after RC performed in patients with NMIBC and patients with MIBC and to identify risk factors for severe short-term complications. METHODS: Medical records of 521 patients who underwent RC for bladder cancer were retrospectively reviewed. Patients were divided into patients with NMIBC and patients with MIBC. The groups were compared and risk factors for severe complications were identified. RESULTS: RC for NMIBC was performed in 123 patients (23.6%). Histological upstaging was seen in 47 NMIBC patients (38.2%) and in 231 MIBC patients (58%, p < 0.001). OS was 29.8% and CSS was 15.5%. Both endpoints were higher for RC for MIBC (p < 0.001). More complications affecting the urinary diversion were seen with RC for NMIBC (p = 0.033) and more continent urinary diversions (p = 0.040) were performed in those patients. Obesity (p = 0.008), a higher ASA score (p = 0.004), and preoperative medical drug anticoagulation (p = 0.025) were risk factors for severe short-term morbidity after both, RC for NMIBC and for MIBC. CONCLUSION: Patients who underwent RC for NMIBC are exposed to a comparably high perioperative risk than patients with MIBC. RC seems to be a viable treatment option for certain NMIBC patients with a significant histological upstaging in both groups. In patients with obesity, a high ASA score, and with medical drug anticoagulation, the indication for surgery should be confirmed especially strict and possible treatment alternatives should be considered particularly thorough.

Body Composition as a Comorbidity-Independent Predictor of Survival following Nephroureterectomy for Urothelial Cancer of the Upper Urinary Tract.

Radical nephroureterectomy (NUE) is the gold standard treatment for high-risk urothelial cancer of the upper urinary tract (UTUC). Besides sarcopenia and frailty, fat distribution is moving increasingly into focus. Components of body composition were assessed in patients undergoing NUE due to UTUC. The study cohort included 142 patients. By using CT-based measurements, the skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) were measured at the height of the third lumbar vertebra. Overall survival (OS) and cancer-specific survival (CSS) were estimated using univariable und multivariable Cox regression models. The prevalence of sarcopenia in the study population (n = 142) was 37%. OS and CSS were significantly reduced in sarcopenic patients. In the multivariable cox regression analysis, including age, ACE-27, T-stage, R-stage, LVI and necrosis, sarcopenia remained a significant risk factor of OS (HR, 1.77; 95% CI 1.02-3.07; p = 0.042) and CSS (HR, 2.17; 95% CI 1.18-3.99; p = 0.012). High visceral adipose tissue seems to be protective, although not statistically significant. Sarcopenia is a comorbidity-independent risk factor in patients who underwent NUE due to UTUC. Visceral fat represents a potentially protective factor. These results suggest that specific factors of body composition can be used for better risk stratification.

Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.

Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8+ TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our analyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcriptional regulators, and deregulated genes involved in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.

The Search for the Optimal cut-off Value of p53-Immunohistochemistry to Predict Prognosis of Invasive Bladder Cancer: A Multi-Center, Multi-Laboratory Analysis.

Introduction: Mutations in the TP53 gene are indicative of worse outcome in bladder cancer and are usually assessed by immunohistochemistry. To define p53-overexpression, a threshold of >10% is most commonly used (cut-off1). Recently, a novel cut-off (aberrant = 0% or ≥50%) (cut-off2) showed better correlation to clinical outcome. In this study, we evaluate the association between p53-immunohistochemistry cut-offs, clinico-pathological variables and disease-specific survival (DSS). Methods: Seven-hundred-fifty chemotherapy-naïve patients who underwent radical cystectomy were included (92% muscle-invasive bladder cancer. In addition to cut-off1 and cut-off2, a third cut-off (cut-off3) was determined based on the highest Youden-index value. Cut-off values were associated with clinico-pathological variables and FGFR3 mutation status. The Kaplan-Meier method was used to estimate DSS. Results: Aberrant p53-expression was found in 489 (65%) (cut-off1) and 466 (62%) (cut-off2) tumors. Cut-off3 was determined at 25% and aberrant p53-expression in 410 cases (55%) (cutoff3). p53-expression levels were significantly associated with higher pT-stage (cut-off1/2/3: P = 0.047, P = 0.006 and P = 0.0002, respectively), higher grade (all, P < 0.0001), and FGFR3 wild-type (cut-off1: P = 0.02, cut-offs2&3: P = 0.001). Median follow-up was 5.3 years (interquartile range, 4.0-6.0 years). p53-expression was not associated with DSS for any of the three cut-offs (cut-off1/2/3: P-log-rank = 0.566, 0.77 and 0.50, respectively). If we only considered locally advanced bladder cancer, results on DSS remained non-significant. Conclusion: This multi-center, multi-laboratory study showed that, regardless of the cut-off used, p53-immunohistochemistry did not enable selection of patients with worse outcome. Our results suggest that p53-immunohistochemistry alone is not suitable to guide clinical decision making after radical cystectomy.

[Disseminated tumour cells in bladder cancer]. / Disseminierte Tumorzellen beim Harnblasenkarzinom.

Molecular analysis of disseminated tumour cells (DTC) may aid in predicting the course of the disease and response to therapies in individual patients. It has been shown in bladder cancer and many other cancer types that the presence of disseminated tumour cells or occult micrometastases in bone marrow or lymph nodes is associated with shorter survival. This type of analysis is particularly important for patients who have been declared disease-free after postsurgery histopathological and clinical imaging analysis. However, comprehensive molecular analysis of disseminated tumour cells is challenging due to the low amount of material and great heterogeneity of the disease. Therefore, currently the routine molecular analysis of these cells is hardly possible in daily clinical practice. Nevertheless, we see daily advances in clinical utility of analysis of cellular or cell-free liquid biopsy analytes taken before, during or after surgery. These advances will enable an integration of translational research workflows into clinical decision-making.

Prognostic and Predictive Value of Fibroblast Growth Factor Receptor Alterations in High-grade Non-muscle-invasive Bladder Cancer Treated with and Without Bacillus Calmette-Guérin Immunotherapy.

BACKGROUND: Limited data are available on the prognostic and predictive value of fibroblast growth factor receptor alterations (FGFRa) relative to clinical outcomes in patients with non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To determine whether FGFRa may be clinically useful in stratifying for treatment response in a real-world cohort of patients with pT1 NMIBC treated and untreated with bacillus Calmette-Guérin (BCG) instillation therapy. DESIGN, SETTING, AND PARTICIPANTS: A pooled dataset of matched clinical and genomic data (1992-2015) for pT1 NMIBC patients was assessed by the Bladder Cancer Research Initiative for Drug Targets in Germany consortium. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Key efficacy outcomes were recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS), which were estimated by Kaplan-Meier analysis, with hazard ratios calculated using a multivariate Cox proportional-hazard model. RESULTS AND LIMITATIONS: In this retrospective study of 263 patients with high-grade NMIBC, at a median follow-up of 63 mo, 32% showed recurrence and 15% progressed to muscle-invasive bladder cancer. FGFRa were found in 43% of patients, including 39% mutations and 5.7% fusions. FGFRa were associated with lower rates of concomitant carcinoma in situ. Among patients with or without FGFRa, there was no significant difference in PFS, RFS, and DSS in those who were BCG treated or BCG naive, or in the overall population. Limitations include the retrospective design from a single-center setting. CONCLUSIONS: In patients with high-risk NMIBC, FGFRa were frequently observed. Patients with FGFRa who often exhibit recurrence/relapse after BCG treatment have a high unmet need. PATIENT SUMMARY: Our retrospective study suggests that fibroblast growth factor receptor alterations (FGFRa) occur frequently in non-muscle-invasive bladder cancer (NMIBC). Outcomes were similar with or without FGFRa in patients with NMIBC, both overall and for standard bacillus Calmette-Guérin (BCG) treatment.

Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients.

OBJECTIVES: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort. PATIENTS AND METHODS: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS). RESULTS: pT-stage was

Kynurenine induces T cell fat catabolism and has limited suppressive effects in vivo.

BACKGROUND: L-kynurenine is a tryptophan-derived immunosuppressive metabolite and precursor to neurotoxic anthranilate and quinolinate. We evaluated the stereoisomer D-kynurenine as an immunosuppressive therapeutic which is hypothesized to produce less neurotoxic metabolites than L-kynurenine. METHODS: L-/D-kynurenine effects on human and murine T cell function were examined in vitro and in vivo (homeostatic proliferation, colitis, cardiac transplant). Kynurenine effects on T cell metabolism were interrogated using [13C] glucose, glutamine and palmitate tracing. Kynurenine was measured in tissues from human and murine tumours and kynurenine-fed mice. FINDINGS: We observed that 1 mM D-kynurenine inhibits T cell proliferation through apoptosis similar to L-kynurenine. Mechanistically, [13C]-tracing revealed that co-stimulated CD4+ T cells exposed to L-/D-kynurenine undergo increased ß-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 µM, which is close to human kidney (6 µM) and head and neck cancer (14 µM) but well below the 1 mM required for apoptosis. D-kynurenine protected Rag1-/- mice from autoimmune colitis in an aryl-hydrocarbon receptor dependent manner but did not attenuate more stringent immunological challenges such as antigen mismatched cardiac allograft rejection. INTERPRETATION: Our dietary kynurenine model achieved tissue concentrations at or above human cancer kynurenine and exhibited only limited immunosuppression. Sub-suppressive kynurenine concentrations in human cancers may limit the responsiveness to indoleamine 2,3-dioxygenase inhibition evaluated in clinical trials. FUNDING: The study was supported by the NIH, the Else Kröner-Fresenius-Foundation, Laffey McHugh foundation, and American Society of Nephrology.

Dose estimates of occupational radiation exposure during radioguided surgery of Tc-99m-PSMA-labeled lymph nodes in recurrent prostate cancer.

AIM: [99mTc]Tc-PSMA-based radioguided surgery (TPRS) represents a curative approach for localized relapse of prostate cancer. For its simplified regulatory permission, the radiation protection authorities require a 99mTc- activity below the exemption limit of 10 MBq at the time of surgery. Our aim was to determine the optimal amount of radioactivity (OAR) to comply with that limit and to estimate the maximum number of TPRS procedures per year and surgeon without triggering the full monitoring obligations. METHODS: In this retrospective study, a dose rate meter was calibrated using measurements on phantoms and from recently injected (1 min p. i.) patients to determine the activity in the patient from measured dose rates. The effective half-life of 99mTc-PSMA-I&S in patients was determined from repeated dose rate measurements to estimate dose parameters of relevance for radiation protection. External exposures of the surgeons were measured with personal dosimeters calibrated in Hp(10). The surgeon's finger dose Hp(0.07) is estimated from radioactivity measured in resected lymph nodes. Potenzial incorporations were estimated for an activity of 10 MBq. RESULTS: From the first 6 subsequent patients, an effective half-life of 4.15 h was observed. Assuming an operation time 24 h p. i., the OAR was 550 MBq. Operations lasting in average 2 h in a distance of 0.25 m to the patient imply a body dose for surgeons of 4.16 µSv per procedure. Based on these estimates, the surgeon's Hp(10) is less than 1 mSv per year with up to 241 operations per year. Hp(0.07) and potential incorporation of activity do not lead to further limitations. SUMMARY: All radiation protection regulations are met with adherence to OAR recommended here without triggering the full monitoring obligations from radiation protection regulations.

Risk factors associated with positive surgical margins' location at radical cystectomy and their impact on bladder cancer survival.

PURPOSE: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). METHODS: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan-Meier method was used to estimate DSS stratified by margins' status and location. Log-rank statistics and Cox' regression models were used to determine significance. RESULTS: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). CONCLUSIONS: PSMs' location represents distinct risk factors' patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.

Randomized Crossover-Controlled Evaluation of Simultaneous Bilateral Transcutaneous Electrostimulation of the Posterior Tibial Nerve During Urodynamic Studies in Patients With Lower Urinary Tract Symptoms.

PURPOSE: Transcutaneous tibial nerve stimulation (TTNS) has proven to be a valuable treatment option for various lower urinary tract conditions, such as overactive bladder syndrome and neurogenic detrusor overactivity. The aim of this study was to investigate acute changes in urodynamic parameters due to bilateral TTNS. METHODS: Fifty-one patients (18-87 years; 61% female) with various lower urinary tract symptoms were enrolled in this study. They were single-blinded and randomly assigned to receive simultaneous bilateral TTNS either during their first urodynamic examination, followed by a second round using a placebo stimulation technique, or vice versa. RESULTS: For subjects without signs of anatomical pathologies, the filling volume at the first desire to void (FDV) increased significantly by 54 mL (interquartile range [IQR], 26-81 mL; P<0.01) under the influence of TTNS compared to placebo. The maximum cystometric capacity increased by 41 mL (IQR, 10-65 mL; P=0.02). The median micturition volume of patients with pathological postvoid residual volumes (>100 mL) increased by 76 mL compared to patients without urinary retention (IQR, 6-166 mL; P=0.03). CONCLUSION: Compared to placebo, simultaneous bilateral TTNS showed significant improvements in bladder functioning, such as delayed FDV, increased maximum cystometric capacity, and reduced urinary retention. Patients with signs of anatomical pathologies did not seem to benefit from TTNS. Further studies need to be conducted to compare the effectiveness of bilateral versus unilateral TTNS.

The comprehensive complication index is associated with a significant increase in complication severity between 30 and 90 days after radical cystectomy for bladder cancer.

OBJECTIVE: To assess the true cumulative morbidity after RC by implementing the Comprehensive Complication Index (CCI) over a 90-day period, since recent evidence suggests underreporting of the cumulative morbidity after radical cystectomy (RC) with inconsistent complication rates when reported with conventional reporting systems. PATIENTS AND METHODS: Medical records of 433 patients with bladder cancer who underwent RC were retrospectively reviewed over a 90-day period. Clinical variables were assessed and complications were graded by the Clavien-Dindo Classification (CDC). The resulting 30- and 90-day CCI-scores were calculated and compared for each patient. Multivariable regression models for developing at least one severe (≥CDC IIIb) complication were designed. RESULTS: Overall, 848 complications were recorded in 371 patients (85.7%). Severe complications occurred in 130 patients (30%) and the cumulative morbidity corresponded to the level of a severe complication in 159 patients (36.7%), meaning an upgrade in 6.7% of patients compared to the CDC. The 90-day CCI (24.2 (median, IQR 20.9-39.7)) was higher than the 30-day CCI (22.6 (median, IQR 8.7-39.7)), (p < 0.001). Comorbidity indices (ASA, ACE 27), BMI, and incontinent urinary diversions were independent risk factors for suffering a severe complication within 90 days post-surgery. CONCLUSION: The cumulative morbidity (CCI) after RC seems to be higher than previously reported with CDC, especially over a 90-day period. The CCI is an appropriate assessment-tool with an upgrade in morbidity in a significant proportion of patients when compared to the CDC. BMI, several comorbidity indices, and incontinent urinary diversions are independent risk factors for suffering a severe complication after RC.