Improvements in urinary symptoms, health-related quality of life, and psychosocial distress in the early recovery period after radical cystectomy and urinary diversion in 842 German bladder cancer patients: data from uro-oncological rehabilitation.

PURPOSE: This study aims to investigate urinary symptoms (continence and stoma care), health-related quality of life (HRQoL) and psychosocial distress (PD) in the early postoperative period after radical cystectomy (RC) and urinary diversion for ileal conduit (IC) and ileal neobladder (INB) to obtain a better basis for patient counseling. METHODS: Data for 842 bladder cancer patients, who underwent 3 weeks of inpatient rehabilitation (IR) after RC and urinary diversion (447 IC, 395 INB) between April 2018 and December 2019 were prospectively collected. HRQoL, PD, and urinary symptoms were evaluated by validated questionnaires at the beginning (T1) and the end of IR (T2). In addition, continence status and micturition volume were objectively evaluated in INB patients by 24-h pad test and uroflowmetry, respectively. RESULTS: Global HRQoL was severely impaired at T1, without significant difference between the two types of urinary diversion. All functioning and symptom scales of HRQoL improved significantly from T1 to T2. In INB patients, all continence parameters improved significantly during IR, while patients with an IC reported fewer problems concerning urostomy management. The proportion of patients suffering from high PD decreased significantly from 50.7 to 34.9%. Age ≤ 59 years was the only independent predictor of high PD. Female patients and patients ≤ 59 years were more likely to use individual psycho-oncological counseling. CONCLUSION: HRQoL, PD and urinary symptoms improved significantly in the early recovery period after RC. Patients with urinary continence reported higher HRQoL and less PD. Psychosocial support should be offered especially to younger patients.

Simulation of the effects of molecular urine markers in follow-up of patients with high-risk non-muscle invasive bladder cancer.

A plethora of urine markers for the management of patients with bladder cancer has been developed and studied in the past. However, the clinical impact of urine testing on patient management remains obscure. The goal of this manuscript is to identify scenarios for the potential use of molecular urine markers in the follow-up of patients with high-risk non-muscle-invasive BC (NMIBC) and estimate potential risks and benefits. Information on the course of disease of patients with high-risk NMIBC and performance data of a point-of-care test (UBC rapid™), an MCM-5 directed ELISA (ADXBLADDER™), and 2 additional novel assays targeting alterations of mRNA expression and DNA methylation (Xpert bladder cancer monitor™, Epicheck™) were retrieved from high-quality trials and/or meta-analyses. In addition, the sensitivity of white light cystoscopy (WLC) and the impact of a urine marker result on the performance of WLC were estimated based on fluorescence cystoscopy data and information from the CeFub trial. This information was applied to different scenarios in patient follow-up and sensitivity, estimated number of cystoscopies, and the numbers needed to diagnose were calculated. The sensitivity of guideline-based regular follow-up (SOC) at 1 year was calculated at 96%. For different marker-supported strategies sensitivities ranging from 77% to 97.9% were estimated. Calculations suggest that several strategies are effective for the SOC. While for the SOC 24.6 WLCs were required to diagnose 1 tumor recurrence (NND), this NND dropped below 5 in some marker-supported strategies. Based on the results of this simulation, a marker-supported follow-up of patients with HR NMIBC is safe and offers the option to significantly reduce the number of WLCs. Further research focusing on prospective randomized trials is needed to finally find a way to implement urine markers into clinical decision-making.

Use of Multiple Machine Learning Approaches for Selecting Urothelial Cancer-Specific DNA Methylation Biomarkers in Urine.

Diagnosing urothelial cancer (UCa) via invasive cystoscopy is painful, specifically in men, and can cause infection and bleeding. Because the UCa risk is higher for male patients, urinary non-invasive UCa biomarkers are highly desired to stratify men for invasive cystoscopy. We previously identified multiple DNA methylation sites in urine samples that detect UCa with a high sensitivity and specificity in men. Here, we identified the most relevant markers by employing multiple statistical approaches and machine learning (random forest, boosted trees, LASSO) using a dataset of 251 male UCa patients and 111 controls. Three CpG sites located in ALOX5, TRPS1 and an intergenic region on chromosome 16 have been concordantly selected by all approaches, and their combination in a single decision matrix for clinical use was tested based on their respective thresholds of the individual CpGs. The combination of ALOX5 and TRPS1 yielded the best overall sensitivity (61%) at a pre-set specificity of 95%. This combination exceeded both the diagnostic performance of the most sensitive bioinformatic approach and that of the best single CpG. In summary, we showed that overlap analysis of multiple statistical approaches identifies the most reliable biomarkers for UCa in a male collective. The results may assist in stratifying men for cystoscopy.

An empirical survey on the adaption of neoadjuvant chemotherapy in bladder cancer.

OBJECTIVE: To determine the adaption of neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) in Germany, Austria and Switzerland and especially underlying reasons for potential low adherence to guidelines. METHODS: We conducted a non-validated survey amongst 336 urologic departments in Germany, Austria and Switzerland. RedCap questionnaires were electronically distributed and included 23 items concerning the general NAC administration standards and guideline compliance in patient counselling regarding actual treatment. RESULTS: Return rate of the questionnaire was 19.1% (63/336). Although 45 departments (71.4%) claim to perform NAC as standard-of-care, only 49% of eligible patients actually receive NAC. An advanced disease stage (≥cT3) and a high tumor-volume were mentioned to support application of NAC, whereas 35% of responders worry a deterioration of patients' preoperative status due to NAC. Furthermore, 26.7% of respondents are concerned about the low extent of survival benefit. CONCLUSION: Application of NAC in eligible MIBC-patients in Germany, Austria and Switzerland remains low. Although the majority of urologic departments discusses NAC and acknowledges the need for intensified treatment in advanced disease stages, not all eligible patients will actually receive NAC before radical cystectomy.

A prospective evaluation of quality of life, psychosocial distress, and functional outcomes two years after radical cystectomy and urinary diversion in 842 German bladder cancer patients.

PURPOSE: This study aims to evaluate survival, health-related quality of life (HRQoL), psychosocial distress, and functional outcomes after radical cystectomy (RC) and urinary diversion for ileal neobladder (INB) or ileal conduit (IC) in a contemporary German cohort of bladder cancer patients. METHODS: Patients undergoing inpatient rehabilitation after RC between April 2018 and December 2019 in one high-volume rehabilitation center were surveyed regarding HRQoL, psychosocial distress, and functional outcomes until two years after RC. RESULTS: Eight-hundred forty-two patients (683 male, 159 female; 395 INB, 447 IC) were included. Patients with an IC suffered more often from locally advanced disease (≥ pT3; 41.4% vs. 24.1%, p < 0.001) and lymph node metastases (19.9% vs. 11.8%, p = 0.002), resulting in worse probability of survival (p < 0.001). Global HRQoL improved steadily during follow-up, but significant differences in subscales persisted between cohorts. Multivariable regression analysis identified IC, male sex, and patient age ≤ 59 years as independent predictors for persistent high psychosocial distress. Almost 42% of female patients reported severe urinary incontinence two years after RC. Most men reported severely diminished erectile function, even after nerve-sparing surgery. CONCLUSION: Global HRQoL two years after RC is comparable to the general German population. Female patients should be informed about worse continence rates. Conversely, men should be educated about erectile dysfunction. Aftercare should include psycho-oncologic counseling, especially for patients at risk. IMPLICATIONS FOR CANCER SURVIVORS: Patients should be counseled on long-term functional outcomes and persistent psychosocial distress after RC. Closer cooperation between urologists and psycho-oncologists is needed.

Endoscopic trans-anal tube placement is a safe and helpful tool for colonic decompression: final results of a standardized single-centre retrospective assessment of 125 patients.

OBJECTIVES: Endoscopic trans-anal colonic decompression (ECD) may be requested in the case of massive colon distension, but evidence regarding success and safety issues remains scarce. The aim of this analysis is to examine the technical success, complications and clinical outcome in a large series of patients undergoing an ECD in various clinical scenarios. A standardized evaluation system was used to identify the pre-interventional risk parameters that might be helpful to guide clinical decision making. METHODS: In this single-centre retrospective study, the modified Clavien-Dindo classification (CDC) was applied to assess technical success, complications and clinical outcome of 125 consecutive patients who underwent ECD between 2007 and 2020. PRIMARY ENDPOINT: post interventional 90-day mortality. Secondary endpoints: periprocedural complications (CDC event IV-V) and technical success rate. All Martin criteria for standardized reporting of complications were met. Uni- and multivariable analyses for prediction of complications were carried out. RESULTS: The overall technical success rate was 90%. The periprocedural complication rate was low with 3%. Overall 90-day mortality was 31%. Univariable analyses showed a significant correlation between 90-day mortality and ASA≥4 (p<0.001, odds ratio [OR] 15.33), general anaesthesia (p=0.05, OR 21.42) and elevated serological infection parameters (p 0.028, OR 1.004). The pre-interventional multivariable model identified ASA ≥4 (p <0.001; OR 10.94) as the only independent risk factor. CONCLUSIONS: ECD is a safe, easily available, technical feasible, inexpensive and successful tool for colonic decompression in various colonic obstruction scenarios, even in critically ill patients. ASA Score ≥IV can be helpful to identify patients at risk for complications/mortality after ECD.

PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma.

PD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status (mPD-L1) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.

Influence of the Anesthetic Technique on Circulating Extracellular Vesicles in Bladder Cancer Patients Undergoing Radical Cystectomy: A Prospective, Randomized Trial.

Anesthetics have been shown to alter tumor progression and seem to influence surgical cancer outcome. Circulating extracellular vesicles as mediators of intercellular communication are involved in cancer progression and may be influenced by anesthetics. In this prospective, randomized study, effects of anesthetics on extracellular vesicles and associated micro-RNAs in bladder cancer patients undergoing radical cystectomy were tested. Extracellular vesicles from 51 patients at four perioperative time points receiving Propofol or Sevoflurane were extracted with polymer-based methods and quantified with a nanoparticle-tracking analysis. Vesicle-associated micro-RNAs were analyzed with a real-time polymerase chain reaction using array cards and single assays for tumor-associated miR-21-5p, miR-15a-5p, miR-17-5p and miR-451a. Plasma extracellular vesicle concentration (suture: fold change (fc) in Propofol at 4.1 ± 3.9 vs. Sevoflurane at 0.8 ± 0.5; p = 0.003) and associated miRNAs increased significantly (+30% post induction, +9% 30 Min surgery) in the Propofol group. Tumor-associated miRNAs increased during surgery in both groups (fc in miR-21-5p: 24.3 ± 10.2, p = 0.029; fc in miR-15a-5p: 9.7 ± 3.8, p = 0.027; fc in miR-17-5p: 5.4 ± 1.7, p = 0.014), whereas antitumor miR-451a increased in the Propofol group only (fc: 2.5 ± 0.6 vs. 1.0 ± 0.2; p = 0.022). Anesthetics influence extracellular vesicles and associated micro-RNAs of bladder cancer patients during surgery. Increased expression of antitumor micro-RNA may be an explanatory approach for decreased tumor cell viability after Propofol.

Prospective evaluation of return to work, health-related quality of life and psychosocial distress after radical cystectomy: 1-year follow-up in 230 employed German bladder cancer patients.

PURPOSE: To evaluate return to work (RTW), health-related quality of life (HRQoL) and psychosocial distress (PD) after radical cystectomy (RC) and creation of an ileal conduit (IC) or an orthotopic ileal neobladder (NB) for bladder cancer. METHODS: The study relied on prospectively collected data for 842 patients, who underwent 3 weeks of inpatient rehabilitation (IR) after surgery between April 2018 and December 2019. HRQoL (EORTC QLQ-C30) and PD (Questionnaire on Stress in Cancer Patients [QSC-R10]) were evaluated at the beginning (T1) and end (T2) of IR as well as both 6 (T3) and 12 months after surgery (T4). Regression analyses were performed to identify predictors of HRQoL and RTW, respectively. RESULTS: Two hundred thirty patients (IC n = 51, NB n = 179) were employed before surgery (27.3%). HRQoL improved steadily, while high PD was present in 51.0% of patients at T4. RTW rate was 86.8 and 80.6% at T3 and T4, respectively. Linear regression analysis identified RTW as the only predictor for better HRQoL at T4 (OR [odds ratio] 12.823, 95% CI [confidence interval] 2.927-22.720, p = 0.012). Multivariate regression analysis identified age ≤ 59 years (OR 7.842; 95% CI 2.495-24.645; p < 0.001) as an independent positive predictor and lymph node metastasis (OR 0.220; 95% CI 0.054-0.893; p = 0.034) as an independent negative predictor of RTW at T4. CONCLUSION: Global HRQoL improved steadily during the follow-up and RTW rates are high. However, patients often reported high PD, reflecting a need for additional psychosocial support within aftercare.

Xpert bladder cancer monitor to predict the need for a second TURB (MoniTURB trial).

To determine whether Xpert bladder cancer monitor, a noninvasive PCR-based biomarker test, can predict the need for 2nd transurethral resection of the bladder (TURB) better than clinical assessment. Patients scheduled for TURB were prospectively screened. After initial TURB, patients were assigned to 2nd TURB or follow-up cystoscopy at 3 months (FU) by clinicians' discretion. Central urine cytology and Xpert monitor tests were performed prior to the 1st TURB and 2nd TURB or FU, respectively. Statistical analysis to compare clinical assessment and Xpert monitor comprised sensitivity (SENS), specificity (SPEC), NPV and PPV. Of 756 screened patients, 171 were included (114 with 2nd TURB, 57 with FU). Residual tumors were detected in 34 patients who underwent 2nd TURB, and recurrent tumors were detected in 2 patients with FU. SENS and SPEC of Xpert monitor were 83.3% and 53.0%, respectively, PPV was 32.6% and NPV was 92.1%. Clinical risk assessment outperformed Xpert monitor. In patients with pTa disease at initial TURB, Xpert monitor revealed a NPV of 96%. Xpert monitor was not superior than clinical assessment in predicting the need for 2nd TURB. It might be an option to omit 2nd TURB for selected patients with pTa disease.

Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort.

Background: Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. Objective: To analyze the efficacy and safety of EV in a cohort of real-world patients. Design setting and participants: Retrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysis: Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitations: The median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. Conclusions: Administration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summary: Enfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.

Prospective evaluation of functional outcomes in 395 patients with an ileal neobladder 1 year after radical cystectomy.

PURPOSE: This study aims to report on functional outcomes in a large cohort of patients who underwent inpatient rehabilitation (IR) in a highly specialized, high-volume German urologic rehabilitation center after radical cystectomy (RC) and creation of an ileal neobladder (INB). METHODS: Data for 842 patients, who underwent three weeks of IR after RC and urinary diversion between April 2018 and December 2019 were prospectively collected. INB patients were surveyed on continence and sexual function. Data were collected at 4 weeks (T1), 6 months (T2), and 12 months (T3) after RC. Multivariate logistic regressions were performed to identify predictors of better functional outcomes. RESULTS: INB was chosen as urinary diversion in 395 patients (357 male, 38 female). Social continence (maximum of one safety pad/24 h) was reported by 78.3% of men and 64.0% of women at T3. Severe incontinence was reported by 27.3% of men and 44.0% of women. Male sex was identified as an independent predictor for the use of no pads at T3 (OR 4.110; 95% CI 1.153-14.655; p = 0.029). Nerve-sparing surgery was identified as an independent predictor both for the use of only a safety pad (OR 1.918; 95% CI 1.031-3.569; p = 0.040) and good erectile function at T3 (OR 4.377; 95% CI 1.582-12.110; p = 0.004). CONCLUSION: Urologists should aspire for nerve-sparing surgery. When advising patients before RC, functional outcomes (continence, sexual function) should be given special attention. Women should be counseled on potentially prolonged urinary incontinence.

Functional outcome after radical prostatectomy in 1313 patients: A single-center study.

OBJECTIVES: To assess the impact of urinary continence and erectile function on the quality of life in men undergoing radical prostatectomy (RP) for prostate cancer (PC), we analyzed the preoperative and 1-year postoperative outcomes of five functional domains and their influencing factors. PATIENTS AND METHODS: In this prospective study, all patients undergoing open or robot-assisted RP between Febuary 2017 and March 2020 in a single academic center were included. Patient-reported outcomes were assessed pre- and 12 months postoperatively using the Expanded Prostate Index Composite (EPIC-26) survey, evaluating continence, irritative/obstructive micturition, gastrointestinal symptoms, sexuality, and overall vitality. We examined the impact of RP on sexual function and urinary continence using multivariable logistic regression models, accounting for patient and tumor characteristics. RESULTS: Overall, 1313 consecutive patients gave consent for study participation and completed both surveys. The median age was 66 years (IQR: 60-70). The majority of patients (n = 601, 46%) had an intermediate risk PC. Robotic RP was performed in 71.6% and nerve-sparing technique in 81% of the cases. The median pre- versus postoperative scores were the following: urinary continence 100 (IQR: 91.8-100) versus 85.5 (64.8-100), irritative micturition 87.5 (IQR: 75-100) versus 93.8 (IQR: 87.5-100), gastrointestinal symptoms the same with 100 (IQR: 95.8-100), vitality 95 (IQR: 80-100) versus 90 (IQR: 75-100), and erectile function 65.3 (IQR: 38.8-87.5) versus 22.2 (IQR: 12.5-48.7), respectively. Age (p < 0.001), risk classification (p = 0.002), and nerve-sparing surgery (p = 0.016) were associated with good sexual function (EPIC-26 score ≥60), while only age (p = 0.001) was statistically significantly associated with good urinary continence (EPIC-26 score ≥80). CONCLUSION: Non-modifiable factors such as age and PC risk classification impact urinary continence and sexual function after RP. Nevertheless, urologic surgeons should further focus on improving nerve-sparing techniques, the only modifiable variable, to reduce the surgery's negative impact on urinary continence and sexual function.

Psychosocial distress and quality of life in patients after radical cystectomy - one year follow-up in 842 German patients.

PURPOSE: This study aims to report on psychosocial distress and QoL in bladder cancer patients after radical cystectomy (RC) and urinary diversion to obtain a better basis for patient counseling and postoperative care. METHODS: The study relied on prospectively collected data for 842 patients, who underwent three weeks of inpatient rehabilitation after RC and creation of an ileal conduit (IC) or ileal neobladder (INB). Data on QoL and psychosocial distress were collected by validated questionnaires. Multivariate logistic regression was performed to identify predictors for high psychosocial distress. RESULTS: Four-hundred and forty-seven patients (326 male, 121 female) received an IC, while 395 patients (357 male, 38 female) received an INB. Health-related QoL improved steadily in the whole cohort during follow-up. Patients with an INB reported better physical function but suffered more from diarrhea and financial worries. Patients with an IC reported reduced satisfaction with their body image, increased worries about the future, and suffered more from constipation. Psychosocial distress increased significantly during follow-up. One year after surgery, 43.1% of patients suffered from high psychosocial distress. Multivariate regression analysis identified age ≤ 59 years (OR 1.731; CI 1.056-2.838; p = 0.030) and lymph node metastases (OR 2.073; CI 1.133-3.793; p = 0.018) as independent predictors for high psychosocial distress. CONCLUSION: QoL improves significantly in all patients one year after RC. However, psychosocial distress remains high in a substantial number of patients. IMPLICATIONS FOR CANCER SURVIVORS: To prevent chronic psychological disorders, easily accessible opportunities for psycho-oncological counseling are needed for patients following RC.

Return to work improves quality of life and reduces psychosocial distress after radical cystectomy: data from a contemporary series of 230 German patients.

PURPOSE: This study aims to evaluate health-related quality of life (HRQoL), psychosocial distress, and return to work (RTW) 2 years after radical cystectomy (RC) and inpatient rehabilitation (IR). MATERIAL AND METHODS: The study relied on prospectively collected data for 842 patients, who underwent 3 weeks of IR after RC and creation of an ileal conduit (IC) or ileal neobladder (INB). Validated questionnaires surveyed patients on HRQoL and psychosocial distress (EORTC QLQ-C30, QSC-R10). Furthermore, employment status was evaluated. Regression was performed to identify predictors for HRQol, psychosocial distress, and RTW. RESULTS: Two-hundred and thirty patients were employed pre-surgery (77.8% INB, 22.2% IC). Patients with an IC suffered significantly more often from locally advanced disease (≥ pT3: 43.1% vs 22.9%; p = 0.004). Two years after surgery, 16.1% of patients had died (median days of survival 302 (IQR 204-482). Global HRQoL improved steadily, while high psychosocial distress was present in 46.5% of patients 2 years after surgery. Employment was reported by 68.2% of patients, of which 90.3% worked full-time. Retirement was reported by 18.5%. Multivariate logistic regression analysis identified age ≤ 59 years as the only positive predictor for RTW 2 years after surgery (OR 7.730; 95% CI 3.369-17.736; p < 0.001). Gender, surgical technique, tumor stage, and socioeconomic status did not influence RTW in this model. In multivariate linear regression analysis, RTW was identified as an independent predictor of better global HRQoL (p = 0.018) and lower psychosocial distress (p < 0.001), whereas younger patient age was identified as an independent predictor for higher psychosocial distress (p = 0.002). CONCLUSION: Global HRQoL and RTW are high among patients two years after RC. However, role and emotional, cognitive, and social functioning were significantly impaired, while high psychosocial distress persists in a material number of patients. IMPLICATIONS FOR CANCER SURVIVORS: Our study highlights how a successful RTW decreases psychosocial distress and increases QoL in patients after RC for urothelial cancer. Nonetheless, additional efforts by employers and healthcare providers are needed in aftercare after creation of an INB or IC.

Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution.

Urothelial cancer (UC) care is moving toward precision oncology. For tumor biology-driven treatment of metastatic UC (mUC), molecular subtypes play a crucial role. However, it is not known whether subtypes change during metastatic evolution. To address this, we analyzed a UC progression cohort (N = 154 patients) with 138 matched primary tumors (PRIM) and synchronous or metachronous distant metastasis (MET) by immunohistochemistry, and mRNA sequencing in a subgroup of 20 matched pairs. Protein-based tumor cell subtypes and histomorphology remained stable during metastatic progression (concordance: 94%, 95% confidence interval [CI] 88-97%). In comparison, transcriptome-based molecular consensus subtypes exhibited higher heterogeneity between PRIM and MET (concordance: 45%, 95% CI 23-69%), with switches particularly occurring between luminal and stroma-rich tumors. Of note, all tumors classified as stroma rich showed luminal tumor cell differentiation. By an in-depth analysis, we found a negative correlation of luminal gene and protein expression with increasing desmoplastic stroma content, suggesting that luminal tumor cell differentiation of "stroma-rich tumors" is superimposed by gene expression signals stemming from the stromal compartment. Immunohistochemistry allows tumor cell subtyping into luminal, basal, or neuroendocrine classes that remain stable during metastatic progression. These findings expand our biological understanding of UC MET and have implications for future subtype-stratified clinical trials in patients with mUC. PATIENT SUMMARY: Urothelial carcinomas (UCs) occur in different appearances, the so-called molecular subtypes. These molecular subtypes will gain importance for the therapy of metastatic UCs in the future. We could demonstrate that the subtype remains stable during metastasis, which is highly relevant for future studies.

Avoiding Prostate Biopsies in Patients at Low Risk for Prostate Cancer: A Prospective Evaluation of a PSA-Density-Based Safety Net.

INTRODUCTION AND OBJECTIVES: Decision-making to perform prostate biopsy should include individual risk assessment. Patients classified as low risk by the Rotterdam Prostate Cancer Risk Calculator are advised to forego biopsy (PBx). There is concern about missing clinically significant prostate cancer (csPCa). A clear pathway for follow-up is needed. MATERIAL AND METHODS: Data for 111 consecutive patients were collected. Patients were encouraged to adhere to a PSA-density-based safety net after PBx was omitted. Cut off values indicating a re-evaluation were PSA density >0.15 ng/mL/ccm in PBx-naïve patients and >0.2 ng/mL/ccm in men with past-PBx. Primary endpoint was whether men had their PSA taken regularly. Secondary endpoint was whether a new multiparametric MRI was performed when PSA-density increased. Tertiary endpoint was whether biopsy was performed when risk stratification revealed an increased risk. RESULTS: Median follow-up was 12 months (IQR 9-15 months). The primary endpoint was reached by 97.2% (n = 106). The secondary endpoint was reached by 30% (n = 3). The tertiary endpoint was reached by 50% (n = 2). Histopathologic analyses revealed csPCa in none of these cases. Risk stratification did not change (p = 0.187) with the majority of patients (89.2%, n = 99). CONCLUSION: The concern of missing csPCa when omitting PBx in the risk-stratified pathway may be negated. Changes in risk stratification during follow-up should lead to subsequent PBx. We suggest implementing a safety net based on PSA density and digital rectal examination (DRE).

Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. METHODS: TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. FINDINGS: Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. INTERPRETATION: Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. FUNDING: Bristol Myers Squibb.