[68 Ga]Ga-FAPI-46 PET/CT for locoregional lymph node staging in urothelial carcinoma of the bladder prior to cystectomy: initial experiences from a pilot analysis.

INTRODUCTION: [68 Ga]Ga-FAPI-46 PET/CT is a novel hybrid imaging method that previously showed additional diagnostic value in the assessment of distant urothelial carcinoma lesions. We hypothesized that patients with bladder cancer benefit from [68 Ga]Ga-FAPI-46 PET/CT prior to radical cystectomy for locoregional lymph node staging. MATERIALS AND METHODS: Eighteen patients underwent [68 Ga]Ga-FAPI-46 PET/CT for evaluation of lymph node (LN) status in predefined LN regions. Two hundred twenty-nine intraoperatively removed LN served as histopathological reference standard. RESULTS: Urothelial carcinoma (UC) spread was found in ten LN in seven different regions (14.3%). Hereby, [68 Ga]Ga-FAPI-46 PET/CT was positive in four out of seven regions (57.1%) and showed significantly increased FAPI uptake compared to non-pathological regions. In the remaining three out of seven (42.9%) regions, [68 Ga]Ga-FAPI-46 PET/CT was rated negative since no pathological increased FAPI uptake was detected or the proximity of the urinary tract prevented a differentiation from physiological uptake. CT was inconspicuous in these three regions. In total, two FAP-positive LN regions were found without histopathological counterpart. Overall, sensitivity, specificity, positive predictive value, and negative predictive value were 57.1%, 95.2%, 66.7%, and 93.0% for PET imaging. CONCLUSION: In summary, this innovative [68 Ga]Ga-FAPI-46 PET/CT method showed high specificity and negative predictive value in patients with bladder UC with a future potential to optimize therapy planning.

Hypothalamic Thyroid Hormone Receptor α1 Signaling Controls Body Temperature.

Background: The importance of thyroid hormones (THs) for peripheral body temperature regulation has been long recognized, as medical conditions such as hyper- and hypothyroidism lead to alterations in body temperature and energy metabolism. In the past decade, the brain actions of THs and their respective nuclear receptors, thyroid hormone receptor α1 (TRα1) and thyroid hormone receptor beta (TRß), coordinating body temperature regulation have moved into focus. However, the exact roles of the individual TR isoforms and their precise neuroanatomical substrates remain poorly understood. Methods: Here we used mice expressing a mutant TRα1 (TRα1+m) as well as TRß knockouts to study body temperature regulation using radiotelemetry in conscious and freely moving animals at different ambient temperatures, including their response to oral 3,3',5-triiodothyronine (T3) treatment. Subsequently, we tested the effects of a dominant-negative TRα1 on body temperature after adeno-associated virus (AAV)-mediated expression in the hypothalamus, a region known to be involved in thermoregulation. Results: While TRß seems to play a negligible role in body temperature regulation, TRα1+m mice had lower body temperature, which was surprisingly not entirely normalized at 30°C, where defects in facultative thermogenesis or tail heat loss are eliminated as confounding factors. Only oral T3 treatment fully normalized the body temperature profile of TRα1+m mice, suggesting that the mutant TRα1 confers an altered central temperature set point in these mice. When we tested this hypothesis more directly by expressing the dominant-negative TRα1 selectively in the hypothalamus via AAV transfection, we observed a similarly reduced body temperature at room temperature and 30°C. Conclusion: Our data suggest that TRα1 signaling in the hypothalamus is important for maintaining body temperature. However, further studies are needed to dissect the precise neuroanatomical substrates and the downstream pathways mediating this effect.

The Characterization of Non-oncologic Chronic Drug Therapy in Bladder Cancer Patients and the Impact on Recurrence-Free and Cancer-Specific Survival: A Prospective Study.

We aimed to characterize non-oncologic chronic drug therapy of bladder cancer (BC) patients and evaluate a possible impact on recurrence-free (RFS) and cancer-specific survival (CSS). Patients with a first diagnosis (FD) of BC or radical cystectomy (RC) were included in a prospective, monocentric, observational study. Drugs and medical data was assessed at start and three-monthly for 24 months. Drugs were classified by anatomical-therapeutic-chemical code (ATC). Endpoints for outcome analysis were RFS and CSS in univariate (Kaplan-Meier curves and log-rank test, Cox regression for Hazard Ratio (HR)) and multivariate (Cox regression models) analyses. Of 113 patients, 52 had FD and 78 RC. Median age was 74 and 72 years, 83% and 82% were male. Drugs of 114 ATC classes were taken by 48 (92%) FD patients (median number 4.5/IQR 2-7.5) and 73 (94%) of RC patients (median 5/IQR 2-9). In univariate analysis (log-rank test (p)/Cox regression (HR, 95% CI, p)), polypharmacy (p = 0.036/HR = 2.83, 95% CI = 1.02-7.90, p = 0.047), calcium channel blockers (p = 0.046/HR = 2.47, 95% CI = 0.97-6.27, p = 0.057) and proton pump inhibitors (p = 0.015/HR = 3.16, 95% CI = 1.18-8.41, p = 0.022) had a significant negative impact on RFS in RC patients, statins (p = 0.025/HR = 0.14, 95% CI = 0.02-1.06, p = 0.057) a positive effect on RFS in FD patients, angiotensin-converting enzyme inhibitors (p = 0.008/HR = 10.74, 95% CI = 1.20-96.17, p = 0.034) and magnesium (p = 0.042/HR = 5.28, 95% CI = 0.88-31.59, p = 0.067) a negative impact on CSS in FD patients. In multivariate analysis, the only significant drug effects were the negative impact of angiotensin-converting enzyme inhibitors (HR = 15.20, 95% CI = 1.30-177.67, p = 0.030) and magnesium (HR = 22.87, 95% CI = 1.57-333.81), p = 0.022) on CSS in FD patients, and the positive impact of statins (HR = 0.12, 95% CI = 0.01-0.97, p = 0.047) on RFS in FD patients. Impact of non-oncologic drugs on RFS and CSS was small in this prospective study. Thus, appropriate treatment of comorbidities is encouraged.

Resistance to thyroid hormone induced tachycardia in RTHα syndrome.

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.

Outcomes and Prognostic Factors of Patients with Urothelial Carcinoma Undergoing Radical Cystectomy and pT0 in the Final Histology Without Neoadjuvant Chemotherapy.

Purpose: Absence of tumor in the final histopathology after radical cystectomy (RC) is a rare but potentially favorable outcome. Therefore, we aimed to analyze outcomes and prognostic factors of patients with urothelial carcinoma (UC) undergoing RC and T0 in the final histology without neoadjuvant chemotherapy at a high-volume academic center. Patients and Methods: We retrospectively analyzed patients undergoing RC for pure UC between 2004 and 2020. Cancer-specific survival (CSS) and overall survival (OS) were calculated using Kaplan-Meier analysis and group comparison by Log rank test. Potential prognostic factors were analyzed using univariate Cox regression models. Results: A total of 1051 patients with UC underwent RC. 72 patients (6.7%) showed pT0 in the final histology. Across all T-stages, 5-year CSS was significantly different with 88% for pT0, 80% for pTa/pTis, 78% for pT1, 76% for pT2, 51% for pT3 and 27% for pT4 in our cohort (p=0.001). Neither instillation therapy (HR 0.31, 95% CI 0.07-1.43), number of TURB prior RC (HR 1.47, 95% CI 0.25-6.18), use of photodynamic diagnostics (PDD) (HR 0.64, 95% CI 0.14-3.02), performing a second resection (HR 0.87, 95% CI 0.27-2.86), muscle-invasive disease prior RC at any TURB (HR 0.7, 95% CI 0.2-2.39) or muscle-invasive disease in the TURB prior RC (HR 1.0, 0.31-3.29) were associated with CSS in univariate analysis. Conclusion: pT0 reveals a survival benefit in patients undergoing RC for UC and therefore presents a distinctive tumor entity. As clinical and cystoscopic characteristics do not improve patient stratification, further research is warranted to define risk groups in this specific tumor entity.

Long-term Health-related Quality of Life (HRQOL) After Radical Cystectomy and Urinary Diversion - A Propensity Score-matched Analysis.

INTRODUCTION: Radical cystectomy (RC) and urinary diversion by ileal conduit (IC) or ileal orthotopic neobladder (ONB) is the standard-of-care for surgical treatment of muscle-invasive bladder cancer. Yet, it is unclear how urinary diversion affects the patient's health-related quality of life (HRQOL) in the longer-term. METHODS: HRQOL was assessed preoperatively, 3mo postoperatively and then annually until a maximum follow-up of 48 months using the validated EORTC QLQ-C30- as well as the bladder cancer-specific FACT-BL- and QLQ-BLM30-questionnaires. A propensity-score matching for the variables "age," "ASA-classification," "cardiovascular co-morbidity," "sex" as well as "tumor stage," and "preoperative physical functioning score" was performed. Hypothetical predictors for decreased general HRQOL were analyzed using multivariable logistic regression models. RESULTS: After propensity-score matching, 246 patients were analyzed. HRQOL assessment revealed significant differences regarding preoperative QLQ-C30 symptoms which diminished during the postoperative time course. Similarly, we did not find significant differences based on bladder cancer-specific FACT-BL and QLQ-BLM HRQOL assessment including body image (48 months: 29.6.4 [IC] vs. 40.7 [ONB]; P = .733). Regarding general HRQOL, we found increased global health status scores for ONB throughout the whole observational period without reaching statistical significance (48 months: 55.0 [IC] vs. 70.1 [ONB]; P = .079). In multivariate analysis, cardiovascular comorbidity was an independent predictor of impaired HRQOL 24 months (HR 2.20; CI95% 1.02-5.72, P = .044) and 36 months (HR 6.84; CI95% 1.61-29.14, P = .009) postoperatively. CONCLUSION: We did not observe significant differences in bladder-specific as well as generic HRQOL in the longer-term and consequently, the type of urinary diversion was not an independent predictor of good general HRQOL in a follow-up period of 4 years.

Feasibility of [68Ga]Ga-FAPI-46 PET/CT for detection of nodal and hematogenous spread in high-grade urothelial carcinoma.

BACKGROUND: [68Ga]Ga-FAPI-46 is a novel positron emission tomography (PET) ligand that targets fibroblast activation protein (FAP) expression as FAP inhibitor (FAPI) and could already show promising results in several tumor entities. It could be demonstrated that an increased FAP expression correlates with tumor aggressivity in urothelial carcinoma (UC). Given the limited value of [18F]FDG in UC, [68Ga]Ga-FAPI-46 could add diagnostic information in staging and response assessment in UC. We present the first data of [68Ga]Ga-FAPI-46 PET imaging in a pilot cohort of UC patients evaluating uptake characteristics in metastases and primary tumors. METHODS: Fifteen patients with UC prior to or after local treatment underwent [68Ga]Ga-FAPI-46 PET/CT imaging for detection of metastatic spread. We compared the biodistribution in non-affected organs and tumor uptake of UC lesions by standard uptake value measurements (SUVmean and SUVmax). Additionally, metastatic sites on PET were compared to its morphological correlate on contrast-enhanced computed tomography (CT). RESULTS: Overall, 64 tumor sites were detected on PET and/or CT. The highest uptake intensity was noted at the primary site (SUVmax 20.8 (range, 8.1-27.8)) followed by lymph node metastases (SUVmax 10.6 (range, 4.7-29.1)). In 4/15 (26.7%) patients there were [68Ga]Ga-FAPI-46-positive lesions that were missed on standard routine CT imaging. On the other hand, 2/15 patients had suspicious prominent bipulmonary nodules as well as pelvic lymph nodes previously rated as suspicious for metastatic spread on CT, but without increased FAPI expression; here histopathology excluded malignancy. CONCLUSION: [68Ga]Ga-FAPI-46 PET shows distinctly elevated uptake in UC lesions. Therefore, the tracer has potential as a promising new biomarker in metastatic UC patients, as [68Ga]Ga-FAPI-46 PET might improve detection of metastatic sites compared to CT alone. These findings highly emphasize larger studies investigating FAPI imaging in UC patients.

Clinical Implication of Borderline CT-Morphological Metastatic Spread in Bladder Cancer: What You See Is Not Always What You Got.

INTRODUCTION: Palliative radical cystectomy (pRC) may be offered to selected bladder cancer (BC) patients with grievous local symptoms. However, there is only scarce information on perioperative complications and prognosis, especially in the case of metastatic spread. We intended to analyze morbidity and oncological outcome in this patient subgroup. MATERIALS: Patients undergoing pRC because of BC with radiologic evidence of metastases were included in this retrospective study. Perioperative adverse events (AEs) were graded by the Clavien-Dindo Classification system. All patients underwent CT-based surveillance, and questionnaires were sent for survival follow-up in predefined intervals. Oncological outcome and predictive markers were assessed in univariate and multivariate analyses, using log-rank tests and Cox-regression analyses. RESULTS: Between 2004 and 2016, 77 patients were identified. Median age at surgery was 70 years (IQR 66-77) and the median follow-up time was 12 months (IQR 4-44). Preoperative staging revealed pulmonary, hepatic, bone, peritoneal, and various other metastasis in 46/77 (60%), 14/77 (18%), 11/77 (14%), 5/77 (7%), and 11/77 (14%) cases, respectively. Most frequently observed symptoms at the time of pRC were severe gross hematuria (n = 41) and intense pain (n = 11). Most AEs were of minor grade (83%). The median length of stay was 20 days. Median CSS was 13 months with a 5-year CSS of 34%. Intriguingly and unsuspectedly, preoperatively suspicious lung lesions were confirmed during surveillance only in 33%, respectively. In multivariate analysis, intraoperative blood transfusions (HR = 2.25, 95% CI: 1.09-4.63, p = 0.028) were significantly associated with decreased CSS. The best outcome was observed in patients with only subpleural metastases (CSS 80 months, p = 0.039) and normal CRP- and Hb values. CONCLUSION: pRC can be performed with acceptable perioperative morbidity and mortality. Pulmonary lesions seem to have a risk of false-positive results and should be biopsied in all uncertain cases. Localization of lung metastases together with preoperative CRP- and Hb levels seem to play a prognostic role.

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Retrospective evaluation of the impact of non-oncologic chronic drug therapy on the survival in patients with bladder cancer.

Background Chronic drug therapy may impact recurrence and survival of patients with bladder cancer and thus be of concern regarding drug choice and treatment decisions. Currently, data are conflicting for some drug classes and missing for others. Objective To analyze the impact of common non-oncologic chronic drug intake on survival in patients with bladder cancer and radical cystectomy. Setting. Patients with bladder cancer and radical cystectomy (2004-2018) at the University Hospital Munich. Method Data from an established internal database with patients with bladder cancer and radical cystectomy were included in a retrospective study. Drug therapy at the time of radical cystectomy and survival data were assessed and follow-up performed 3 months after radical cystectomy and yearly until death or present. Impact on survival was analyzed for antihypertensive, antidiabetic, anti-gout, antithrombotic drugs and statins, using the Kaplan-Meier method, log-rank test and Cox-regression models. Main outcome measure Recurrence free survival, cancer specific survival and overall survival for users versus non-users of predefined drug classes. Results Medication and survival data were available in 972 patients. Median follow-up time was 22 months (IQR 7-61). In the univariate analysis, a significant negative impact among users on recurrence free survival (n = 93; p = 0.038), cancer specific survival (n = 116; p < 0.001) and overall survival (n = 116; p < 0.001) was found for calcium-channel blockers, whereas angiotensin-receptor-blockers negatively influenced overall survival (n = 96; p = 0.020), but not recurrence free survival (n = 73; p = 0.696) and cancer specific survival (n = 96; p = 0.406). No effect of angiotensin-receptor-blockers and calcium-channel blockers was seen in the multivariate analysis. None of the other studied drugs had an impact on survival. Conclusion There was no impact on bladder cancer recurrence and survival for any of the analyzed drugs. Considering our results and the controverse findings in the literature, there is currently no evidence to withhold indicated drugs or choose specific drug classes among the evaluated non-oncologic chronic drug therapies. Thus, prospective studies are required for further insight. Trail registration This is part of the trial DRKS00017080, registered 11.10.2019.

Value of Geriatric Assessment in Patients With Genitourinary Carcinoma.

Objectives: This work aims to evaluatecomprehensive geriatric assessment (CGA) tools to better guide patients with urogenital carcinomas perioperatively and, consequently, to intensify or reduce hospital resource use. Methods: After informed consent, 111patients were included, all aged more than 65 years, with oncological surgery (with proof of a malignancy), a Mini Mental State Examination (MMSE) score of at least 23 points, and a prospective life expectancy of more than 2 months. Patients were divided into 2 groups: prostate cancer (n = 88) and distal urinary tract cancer (n = 29). Further CGA tools were Instrumental Activities of Daily Living (iADL), Activities of Daily Living (ADL), and the Charlson Comorbidity Index (CCI). The relationships between CGA and complications, hospital duration, death rate, and baseline characteristics were analyzed. Results: In comparison with the patients with prostate cancer, those with kidney/distal urinary tract cancer had higher CCI scores (median, 3 vs 2; P <.001), MMSE scores (29 vs 28; P = .031), complication rates (55.2% vs 22.0%; P = .001), and hospital duration (16 vs 10 days; P <.001), as well as more deaths in the group (8 vs 0). Comorbidities (6 vs 2; P <.001), Physical Status Classification System (ASA state [3 vs 2; P <.001]), and median age (74 vs 71 years; P =.008) were all higher in the kidney/distal urinary tract group, and they had fewer problems with postoperative ADL items, which were significantly lower than those of the prostate group (P = .043). Intra- and intergroup comparisons of preoperative and 1-year ADL/iADL values did not differ significantly. Conclusion: These study results underscore the importance of CGA in patients with genitourinary carcinoma; most patients have high regenerative potential. Patients with kidney/distal urinary tract cancers are older, have more comorbidities, and have more postoperative impairments than patients with prostate cancer.

Colloidal Lignin Particles and Epoxies for Bio-Based, Durable, and Multiresistant Nanostructured Coatings.

There is a need for safe and sustainable alternatives in the coating industry. Bio-based coatings are interesting in this perspective. Although various oils and waxes have been used as traditional wood coatings, they often lack sufficient durability. Lignin is an abundant natural polyphenol that can be used to cure epoxies, but its poor water solubility has impeded the use of unmodified lignin in coatings in the past. To address this issue, water-dispersible colloidal lignin particles (CLPs) and an epoxy compound, glycerol diglycidyl ether (GDE), were used to prepare multiprotective bio-based surface coatings. With the GDE/CLP ratios of 0.65 and 0.52 g/g, the cured CLP-GDE films became highly resistant to abrasion and heat. When applied as a coating on wooden substrates, the particulate morphology enabled effective protection against water, stains, and sunlight with very thin layers (less than half the weight of commercial coatings) while retaining the wood's breathability excellently. Optimal hydrophobicity was reached with a coat weight of 6.9 g(CLP)/m2, resulting in water contact angle values of up to 120°. Due to their spherical shape and chemical structure, the CLPs acted as both a hardener and a particulate component in the coating, which removed the need for an underlying binding polymer matrix. Light interferometry measurements showed that while commercial polymeric film-forming coatings smoothened the substrate noticeably, the particulate morphology retained the substrate's roughness in lightweight coatings, allowing for a high water contact angle. This work presents new strategies for lignin applications in durable particulate coatings and their advantages compared to both currently used synthetic and bio-based coatings.

Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer.

Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen-activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer-specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer-specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.

Radical cystectomy for locally advanced urothelial carcinoma of the urinary bladder: Health-related quality of life, oncological outcomes and predictors for survival.

PURPOSE: While survival outcomes of locally advanced bladder cancer patients undergoing radical cystectomy are known to be poor, less is known regarding patient-reported outcomes and predictive features for survival in this patient subgroup. METHODS: One hundred and eighteen consecutive patients with pT4a cM0 urothelial carcinoma of the bladder were included. Based on pathological review, patients were stratified into 3 subgroups based on existence of additional lesions and invasion depth of the respective lesions. Cancer-specific survival and overall survival (OS) was determined using Kaplan-Meier-analyses and multivariate Cox regression models (P <0.05). Health-related quality of life was assessed using the validated EORTC-QLQ-C30 questionnaire pre- and postoperatively. RESULTS: Seventy-two (61.0%) patients were ineligible for neoadjuvant chemotherapy. Median follow-up based on censored patients was 12 months. Twelve month OS rate was 56.1%, 24 months OS rate was 21.1%. A total of 44.4% of the patients stated good general health-related quality of life. In multivariate analysis, we found significantly adverse OS outcomes for female patients (hazard ratio 2.35, 95% confidence interval 1.09-5.08, P = 0.030). Patients with at least 1 additional locally advanced tumor had significantly worse OS outcomes compared to patients who had no additional lesions in multivariate Cox regression analysis (hazard Ratio 3.37, 95% confidence interval 1.29-8.78, P = 0.013). CONCLUSION: Existence of multiple locally advanced lesions and female gender is an independent predictor of worse survival outcomes in patients with pT4a urothelial carcinoma undergoing radical cystectomy.

Prognostic value of pretreatment inflammatory markers in variant histologies of the bladder: is inflammation linked to survival after radical cystectomy?

PURPOSE: To investigate differences in standard preoperative inflammatory markers in patients with urothelial carcinoma (UC) and variant histologies undergoing radical cystectomy (RC) and determine its impact on survival. METHODS: Patients undergoing RC at an academic high-volume center were retrospectively analyzed. Preoperatively taken CRP, leukocytes, hemoglobin (Hb), and thrombocytes were analyzed as routine inflammatory biomarkers. Log-rank tests and Kruskal-Wallis analysis were used to calculate for differences in survival and in blood levels of biomarkers. RESULTS: 886 patients with complete follow-up and UC or variant histology underwent RC at our institution between 2004 and 2019. Although variant histology presents with significantly higher t stage than UC, cancer-specific survival (CSS) of UC (1-year-CSS: 93%) is not significantly different to variant histology of UC with squamous differentiation (UCSD, 1-year-CSS: 81%), squamous cell carcinoma (SCC, 1-year-CSS: 82%), and adenocarcinoma (AC, 1-year-CSS: 81%). In UC, alterations in all biomarkers except leukocytes beyond routine cut-off values were associated with poor survival (p < 0.01), whereas Hb beyond cut-off values are associated with poor prognosis in SCC (p < 0.05). CRP levels are significantly elevated in UCSD and SCC at time of surgery compared to UC (p < 0.05). CONCLUSION: Inflammatory biomarkers reveal distinctive patterns across UC and variant histologies of bladder cancer. As inflammation might play an important role in cancer progression, further research is warranted to understand those molecular mechanisms and their potential therapeutic impact in variant histology of bladder cancer.

Transurethral en bloc submucosal hydrodissection vs conventional resection for resection of non-muscle-invasive bladder cancer (HYBRIDBLUE): a randomised, multicentre trial.

OBJECTIVE: To determine whether transurethral en bloc submucosal hydrodissection of bladder tumours (TUEB) improves the quality of the resection compared to conventional transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A randomised, multicentre trial (HYBRIDBLUE) was conducted with a superiority design. Six German academic centres participated between September 2012 and August 2015. Based on literature analysis, a sample size for accurate histopathological assessment concerning muscle invasion was assumed to be feasible in 50% (P0 = 0.5) of TURBT and 80% of TUEB cases. After pre-screening of a total of 305 patients, participants were allocated to two study arms: Group I: hexaminolevulinate (HAL)-guided TUEB; Group II: conventional HAL-guided TURBT. The primary endpoint was the proportion of specimens that could be reliably evaluated pathologically concerning muscle invasiveness. Secondary endpoints included rates of histopathological completeness of the resection, muscularis propria content, recurrence, and complication rates. RESULTS: A total of 115 patients (TUEB 56; TURBT 59) were eligible for final analysis. Adequate histopathological assessment, which included muscularis propria content and tumour margins (R0 vs R1), was present in 48/56 (86%) TUEB patients compared to 37/59 (63%; P = 0.006) in the TURBT group. R0 was confirmed in 30/56 TUEB patients (57%) and five of 59 TURBT patients (9%; P < 0.001). No complications of Grade ≥III were observed in both arms. At 3 and 12 months, three and 19 patients recurred in the TUEB group vs seven and 11 patients in the TURBT group, respectively (P = 0.33 and P = 0.08). CONCLUSIONS: In this randomised study, TUEB was shown to be clinically safe regarding perioperative endpoints. An adequate histopathological assessment concerning muscle invasion was significantly better assessable in the TUEB arm compared to standard TURBT. This finding indicates the clinical potential for reducing the rate of early re-resections. Yet, a larger study with recurrence-free survival as the primary endpoint is needed to assess the oncological efficacy between both techniques.

Bladder Cancer Stage Development, 2004-2014 in Europe Compared With the United States: Analysis of European Population-based Cancer Registries, the United States SEER Database, and a Large Tertiary Institutional Cohort.

BACKGROUND: The purpose of this study was to analyze trends of bladder cancer (BC) stages and incidence in Europe and the United States (US). MATERIALS AND METHODS: Tumor stages after radical cystectomy were assessed in a monocentric cohort from 2006 to 2016. BC incidence was assessed between 2004 and 2014 based on the German Center for Cancer Registry Data dataset at the Robert Koch Institute (n = 111,002), the Netherland Cancer Registry (n = 64,226), cancer registration statistics of England (n = 179,883), and the pooled data from the Scandinavian cancer registries, NORDCAN (n = 77,585) and the SEER (Surveillance, Epidemiology, and End Results) database (n = 184,519) for the complete populations and gender-specific subgroups. The average annual percent changes (AAPC) were used for statistical evaluation. RESULTS: Non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC) did not change in the institutional cohort at the point of radical cystectomy. The incidence of total BC (AAPC, -0.3), NMIBC (AAPC, -0.1), and non-metastasized MIBC (AAPC, 0.1) did not change in Germany during the time period under survey. BC total incidence in the Netherlands did not change significantly. In England and the Nordic countries, the incidence of total BC increased (AAPC, 0.8 and 0.5, respectively). In contrast, both the incidence of total BC (AAPC, -1.4), NMIBC (AAPC, -1.6), and non-metastasized MIBC (AAPC, -1.6) significantly decreased in the US. CONCLUSIONS: Between 2004 and 2014 the incidence of BC was significantly sinking in the US, was stable in Germany and the Netherlands, and increased in England and the Nordic countries. Predominantly, differences in the smoking prevalence within the last decades but also gender-specific factors might be responsible for this discrepancy.

Midterm Health-related Quality of Life After Radical Cystectomy: A Propensity Score-matched Analysis.

BACKGROUND: Radical cystectomy (RC) and urinary diversion affect various dimensions of patents' health-related quality of life (HRQOL). Knowledge regarding patient-reported HRQOL following RC is mainly based on retrospective findings of cross-sectional studies. OBJECTIVE: To provide data from a large prospective propensity score-matched cohort with a systematic follow-up of up to 2 yr. DESIGN, SETTING, AND PARTICIPANTS: A total of 134 consecutive patients who underwent RC and ileal conduit (IC) or orthotopic ileal neobladder (ONB) urinary diversion in a tertiary care centre were prospectively enrolled, and a propensity score matching analysis based on American Society of Anesthesiologists score, age, and tumour stage was performed. Exclusion criteria encompassed age <30 yr and RC due to benign diseases. HRQOL was addressed with the validated European Organization for Research and TREATMENT: of Cancer QLQ-C30 questionnaire. HRQOL was assessed preoperatively, and at 3, 12, and 24 mo postoperatively. Of the nondeceased patients, 85.1% (IC) and 78.2% (ONB) completed the study. INTERVENTION: RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was good general HRQOL based on previously published cut-off values. Secondary endpoints encompassed the respective HRQOL domains. Univariate and multivariate analyses were performed using binary logistic regression models. RESULTS AND LIMITATIONS: In the longitudinal analysis of RC patients, functioning and symptoms scores show a similar natural HRQOL course for IC and ONB patients. After 24 mo, general HRQOL was significantly higher in the ONB subcohort (60.5 vs 73.6, p=0.013). Good general HRQOL was reached by 32.4 (IC) versus 61.1% (ONB; p=0.019). In the multivariable analysis, ONB was not an independent predictor of good HRQOL (odds ratio 2.211, 95% confidence interval 0.684-7.150, p=0.185). Limitations include the nonbladder specificity of the QLQ-C30 questionnaire and the small sample size. CONCLUSIONS: The current study provides prospective data from a unique propensity score-matched contemporary patient cohort. We display the natural history of general HRQOL and its subdomains without observing significantly higher midterm postoperative HRQOL in patients undergoing continent urinary diversion in the multivariable analysis. PATIENT SUMMARY: We analyse the health-related quality of life (HRQOL) of European patients who underwent radical cystectomy due to bladder cancer and found that HRQOL was slightly better for orthotopic ileal neobladder than for ileal conduit urinary diversion after 24 mo.

Preoperative Thrombocytosis in Patients Undergoing Radical Cystectomy for Urothelial Cancer of the Bladder: An Independent Prognostic Parameter for an Impaired Oncological Outcome.

BACKGROUND: Preoperative thrombocytosis (PTC) is frequently observed in various solid malignancies and often associated with an unfavourable oncological outcome. OBJECTIVES: The aim of this study was to investigate the influence of PTC in patients undergoing radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder on the oncological prognosis and additionally on perioperative blood transfusions (PBT). METHOD: A retrospective analysis of 866 patients undergoing RC in a tertiary care centre was performed. PTC was defined as a platelet count >400 G/L. A chi-square test and Mann-Whitney test were used to investigate the association of PTC with categorical clinicopathological variables. A logrank test and multivariable Cox regression analyses were used to assess the association of PTC with cancer-specific survival. RESULTS: PTC was detected in 8% (n = 67) of the patients and was significantly associated with muscle invasion (p = 0.004), advanced tumour stages (p = 0.003) and nodal metastases (p < 0.001) and with a higher rate of PBT (p< 0.001). In the multivariate analysis, PTC was significantly related to poor oncological survival (hazard ratio 2.23, 95% CI 1.51-3.30, p < 0.001). CONCLUSION: PTC is significantly associated with an impaired oncological outcome in patients undergoing RC for UC. PTC therefore represents an independent and easy to determine prognostic parameter for patients' oncological outcome. Intriguingly, PTC is significantly associated with an increased rate of PBT.

Long-Term Follow-Up and Oncological Outcome of Patients Undergoing Radical Cystectomy for Bladder Cancer following an Enhanced Recovery after Surgery (ERAS) Protocol: Results of a Large Randomized, Prospective, Single-Center Study.

INTRODUCTION: Enhanced recovery after surgery (ERAS) concepts are implemented in various surgical disciplines. For patients undergoing radical cystectomy, prospective data are still rare. In the year 2014, our group could prove significant benefits of ERAS for these patients in a prospective randomized study compared to a conservative regimen. OBJECTIVE: To evaluate long-term follow-up results of ERAS concepts in patients undergoing radical cystectomy for bladder cancer. METHODS: Of the 101 patients who had initially prospectively been randomized to ERAS or a conservative regimen, 35 patients could be included in the study. Median follow-up time was 83 months. Primary end point assessed quality of life. Secondary end points were cancer-specific survival and overall survival. RESULTS: Five to seven years after the initial inclusion to the study, no significant difference regarding quality of life parameters was detected (p values range between 0.112 and 0.970). Continence status in patients with neobladder showed no significant differences between ERAS and conservative regimens (p = 0.785). Cancer-specific survival in the ERAS group did not differ significantly from that in the conservative group (49 vs. 58%, p = 0.725). CONCLUSIONS: While ERAS represents an excellent way to improve postoperative reconvalescence and quality of life in the short-term follow-up, our data do not support the idea that there is also a long-term effect in terms of quality of life issues.