Association between comorbidities and survival in patients with metastatic urothelial carcinoma treated with pembrolizumab.

BACKGROUND: This study aims to investigate the relationship between comorbidities and survival in patients with mUC treated with pembrolizumab as a second-line treatment. METHODS: From February 2018 to October 2021, we analyzed the data of 185 consecutive patients with metastatic UC who received pembrolizumab as second-line therapy at The Jikei University Hospital and five affiliated hospitals. We used the Charlson Comorbidity Index (CCI) to assess the comorbidities. The outcomes of interest were progression-free survival (PFS) and overall survival (OS). To compare the survival differences, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and the IPTW-adjusted Cox regression hazards model were used. RESULTS: After IPTW adjustment, patient characteristics were well-balanced between patients with high CCI and those with low CCI. The IPTW-adjusted Kaplan-Meier curves of PFS and OS based on CCI revealed that the patients with high CCI (2 or more) had a shorter PFS (median, 1.6 vs. 2.8 months) and a shorter OS (median, 12.4 vs. 18.8 months) (0-1). Similarly, in the IPTW-adjusted Cox regression hazards model, patients with high CCI had significantly shorter PFS [HR, 1.84 (95% CI 1.26-2.68; p = 0.002)] and OS [HR, 1.98 (95% CI 1.20-3.27; p = 0.008)] than those with lower CCI. CONCLUSIONS: High CCI was associated with a higher risk of disease progression as well as overall mortality in mUC patients treated with second-line pembrolizumab.

Initial management and survival of patients with primary metastatic bladder cancer before the immunotherapy era: a population-based study from Norway.

Before immunotherapy became part of the management of metastatic bladder cancer (mBC), systemic anti-cancer treatment comprised primarily of platinum-based chemotherapy. The objective of this study was to describe the characteristics, the initial management, overall survival (OS) and hospitalisations of patients with mBC before 2018 when immunotherapy for mBC was introduced in Norway.  Material and methods: It is a nationwide population-based study of primary mBC patients (diagnosed 2008-16). Descriptive statistics were applied and stratified for four initial management options (≤150 days after BC diagnosis): chemotherapy, major local treatment (cystectomy/pelvic radiotherapy), multimodal treatment (chemotherapy and local) and no anti-cancer treatment beyond transurethral resection of bladder tumour (untreated). Group differences were evaluated by Chi-square and Kruskal-Wallis test; OS was estimated with Kaplan-Meier. Results: Of the 305 patients included, 76 (25%) patients had chemotherapy, 46 (15%) patients had major local treatment, 21 (7%) patients had multimodal treatment and 162 (53%) patients were untreated.  Median OS ranged from 2.3 months (untreated) to 9.8 months (chemotherapy). Patients who received treatment had a higher rate of hospitalisation, with a median stay of three to four times that of untreated patients. Conclusion: Before immunotherapy, more than 50% of patients with primary mBC did not receive any initial anti-cancer therapy and had a poor survival. Patients treated with chemotherapy had inferior median OS compared to those treated with comparable systemic strategies in contemporary trials. Our results provide a basis for future research on treatment and survival after the introduction of immunotherapy for mBC, aiming to improve the care and outcome of patients with mBC.

Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. METHODS: We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. RESULTS: A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). CONCLUSIONS: Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).

Tendencias de la mortalidad por cáncer de vejiga en España, 1980-2021 / Bladder cancer mortality trends in Spain: 1980-2021

Objetivo Nos proponemos actualizar las tasas de mortalidad por cáncer de vejiga en España de 1980 a 2021, estandarizadas por sexo, grupo de edad y comunidades autónomas (CC. AA.). Materiales y métodos Se utilizaron las bases de datos públicas en línea del Instituto Nacional de Estadística para obtener datos sobre población y mortalidad por cáncer de vejiga. Se calcularon las tasas de mortalidad estandarizadas por edad (TMEE) para todas las edades y las truncadas (<75 y ≥75 años) y se presentaron como tasas por cada 100.000 personas. Se utilizó el modelo de regresión Joinpoint para el cálculo y análisis de las tendencias de las TMEE por cáncer de vejiga. Resultados En la última década, las TMEE por cáncer de vejiga (todas las edades,<75 años y ≥75 años) disminuyeron significativamente en España para ambos sexos. Esta tendencia se observó en 12 CC. AA. para los hombres y en 4 CC. AA. (Andalucía, Canarias, Cataluña y Madrid) para las mujeres, aunque en proporciones diferentes. Para los hombres, la TMEE permaneció estable en Castilla-León y La Rioja (<75 años), Cantabria, Castilla-La Mancha y Valencia (≥75 años) y las 2 regiones castellanas (todas las edades). En el caso de las mujeres, las TMEE también disminuyeron en Valencia (<75 y ≥75), Castilla-León (≥75), Galicia (≥75 y todas las edades) y Navarra (<75 y todas las edades). Conclusión Nuestros resultados revelan variaciones significativas en las tendencias por CC. AA., sexo y grupo de edad, enfatizando la necesidad de un seguimiento continuado e intervenciones específicas para reducir aún más las tasas de mortalidad por cáncer de vejiga en España (AU)

Objective We propose to update bladder cancer mortality rates in Spain from 1980 to 2021, by sex and age-group, by autonomous community (AC). Materials and methods The public online databases of the National Statistical Institute were used to obtain data on population and bladder cancer mortality. Age-standardised mortality rates (ASMRs), all ages and truncated (<75 and ≥75) were estimated and reported as rates per 100,000 persons. Joinpoint regression software was used for estimation and trend analysis of ASMRs bladder cancer. Results In the last decade, the ASMR for bladder cancer (all ages,<75 years and ≥75 years) decreased significantly in Spain for both sexes. This trend was observed in 12 ACs for men and in 4 ACs (Andalusia, Canary Islands, Catalonia and Madrid) for women, although to different degrees. For men, ASMR remained stable in Castilla-León and La Rioja (<75 years), Cantabria, Castilla-La Mancha and Valencia (≥75years) and the 2 Castilian regions (all ages). For women, ASMR also decreased in Valencia (<75 and ≥75), Castilla-León (≥75), Galicia (≥75 and all ages) and Navarre (<75 and all ages). Conclusion Our results reveal significant variations in trends by AC, sex and age group, emphasizing the need for continued follow-up and targeted interventions to further reduce bladder cancer mortality rates in Spain (AU)

Systemic Immune Inflammation Index and T-Staging Predict Prognosis in Patients with Muscle-Invasive Bladder Cancer

Objective: To explore the effect of combining the preoperative systemic immune inflammation index (SII) and T-staging to predict the prognosis of patients with muscle-invasive bladder cancer (MIBC). Methods: The clinical data of 94 MIBC patients who met the inclusion criteria of our hospital from September 01, 2012, to August 31, 2022, were collected. Data included sex, age, smoking history, tumour size, tumour number, pathology, P-grading, T-staging, SII, and overall survival (OS). The optimal cut-off of SII (863.62) was selected by obtaining the receiver operating characteristic (ROC) curve. Then, the samples were divided into the low-SII group (SII <863.62, 51 cases) and the high-SII group (SII ≥863.62, 43 cases). T-staging could be divided into T2 (61 cases) and T3 and higher stages (33 cases) according to the findings on depth of tumour invasion. Furthermore, the role of combined SII and T-staging for prognosis prediction was evaluated by performing Kaplan–Meier survival analysis and Cox proportional hazards modelling in the OS analysis. Results: MIBC patients with higher SII (≥863.62) were associated with shorter OS (p = 0.00005). Patients with more advanced T-stages had shorter OS than those with early T-stages (p = 0.00006). Furthermore, patients who had both higher SII and more advanced T-stages had markedly shorter OS (p = 0.00001). Conclusions: In patients with MIBC, a higher SII and increasing T-stage indicate a worse prognosis and shorter OS. Therefore, the combined SII and T staging approach is a reliable prognostic predictor for patients with MIBC (AU)

El estado inmunológico-inflamatorio-nutricional predice los resultados oncológicos tras la cistectomía radical por carcinoma urotelial de vejiga / Immune-inflammatory-nutritional status predicts oncologic outcomes after radical cystectomy for urothelial carcinoma of bladder

Objetivo Evaluar por primera vez el papel del estado inmunológico-inflamatorio-nutricional (EIIN) en los resultados oncológicos de pacientes sometidos a cistectomía radical abierta (CRA) por carcinoma urotelial (CU). Materiales y métodos Se analizaron retrospectivamente los registros de pacientes consecutivos sometidos a CRA por cáncer de vejiga no metastásico entre los años 2009 y 2020. La quimioterapia neoadyuvante, el tumor no urotelial y la ausencia de seguimiento oncológico fueron criterios de exclusión. Se calcularon los valores del índice de inmunidad-inflamación sistémica (IIS) y del índice pronóstico nutricional (IPN) y se utilizaron los valores de corte óptimos para estos, con el fin de designar cuatro subgrupos: «IIS alto-IPN alto», «IIS bajo-IPN alto», «IIS bajo-IPN bajo» y «IIS alto-IPN bajo». El grupo de EIIN con IIS bajo-IPN alto tuvo la mejor tasa de supervivencia global (SG), mientras que el resto se incluyó en el grupo de EIIN desfavorable. Se elaboraron curvas de supervivencia y se utilizó un modelo de regresión de Cox multivariante para la SG y la supervivencia libre de recidiva (SLR). Resultados Tras aplicar los criterios de exclusión, el tamaño final de la cohorte fue de 173 pacientes. La edad media fue de 64,31±8,35 y la mediana de seguimiento fue de 21 (RIQ: 9-58) meses. Los valores de corte óptimos para IIS y IPN fueron 1.216 y 47, respectivamente. El grupo de EIIN favorable (IIS bajo-IPN alto, n=89) tuvo la mejor tasa de SG (62,9%). El análisis multivariante de regresión de Cox indicó que el EIIN desfavorable (n=84) era un factor independiente de pronóstico para una SG peor (HR: 1,509; IC 95%: 1,104-3,145; p=0,001) y la SLR (HR: 1,285; IC 95%: 1,009-1,636; p=0,042). Conclusión La evaluación preoperatoria del EIIN puede constituir un panel útil para el pronóstico de la SG y la SLR en pacientes sometidos a CRA por CU (AU)

Objective To perform the first investigation of the role of immune-inflammatory-nutritional status (INS) on oncological outcomes in patients undergoing open radical cystectomy (ORC) for urothelial carcinoma (UC). Materials and methods The records of consecutive patients who underwent ORC for non-metastatic bladder cancer between 2009 and 2020 were retrospectively analyzed. Neoadjuvant chemotherapy, non-urothelial tumor biology, and absence of oncological follow-up were exclusion criteria. Systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) values were calculated and optimal cut-off values for these were used to designate four subgroups: «high SII-high PNI», «low SII-high PNI», «low SII-low PNI», and «high SII-low PNI». The low SII-high PNI INS group had best overall survival (OS) rate while the remainder were included in non-favorable INS group. Survival curves were constructed, and a multivariate Cox regression model was used for OS and recurrence-free survival (RFS). Results After exclusions, the final cohort size was 173 patients. The mean age was 64.31±8.35 and median follow-up was 21 (IQR: 9-58) months. Optimal cut-off values for SII and PNI were 1216 and 47, respectively. The favorable INS group (low SII-high PNI, n=89) had the best OS rate (62.9%). Multivariate Cox regression analysis indicated that non-favorable INS (n=84) was a worse independent prognostic factor for OS (HR: 1.509, 95% CI: 1.104-3.145, P=.001) and RFS (HR: 1.285; 95% CI: 1.009-1.636, P=.042). Conclusion Preoperative assessment of INS may be a useful prognostic panel for OS and RFS in patients who had ORC for UC (AU)

A Survival Model for Patients with Upper Tract Urothelial Carcinoma

Objectives: We aimed to establish a survival model for patients with upper tract urothelial carcinoma (UTUC). Methods: A total of 241 patients with UTUC treated from January 2010 to December 2018 were selected. Their general clinical data were collected, and urological indices were measured. They were followed up after discharge, and divided into a death group (n = 51) and a survival group (n = 190) to compare the clinical data. Multivariate logistic regression analysis was performed to analyze the independent risk factors for postoperative death, based on which a nomogram prediction model was established and then validated. Results: The death group had significantly older age, larger tumor diameter, and higher tumor grade, pathological stage and proportion of no adjuvant chemotherapy than those of the control group (p < 0.01). The results of multivariate logistic analysis suggested that high tumor grade, tumor located in the ureter, large tumor diameter, high pathological stage, and lymph node metastasis were independent risk factors for postoperative death. A nomogram prediction model was established based on the prognostic independent risk factors. The area under the curve of receiver operating characteristic curve was 0.828 (95% confidence interval (CI): 0.801–0.845), so the model had good discrimination. The calibration curve showed that the model had high consistency. Conclusions: The established nomogram model can be used to predict the mortality risk of patients with UTUC and postoperative survival, and to develop individualized treatment plans for improving the prognosis and survival (AU)

Impact of a One-Stop Hematuria Clinic on Overall Survival and Bladder Tumor Recurrence.

BACKGROUND AND OBJECTIVE: One-stop clinics have emerged as a tool to optimize the therapeutic management of cancer patients. The main purpose of this study was to assess the role of the one-stop hematuria clinic (OSHC), as compared to a conventional clinic (CC), on the overall and disease-free survival of patients with bladder cancer. METHODS: A five-year follow-up retrospective and single-center study was conducted in patients with primary bladder tumor diagnosed between 2006 and 2015. The primary outcomes were five-year overall survival and one-year relapse rate. RESULTS: A total of 394 patients (160 in OSHC and 234 in CC) were included. No differences were observed in terms of age, sex, smoking habit or risk group between the OSHC and CC groups. The average times from first symptom to diagnosis (24.9 ± 29.1 vs. 100.7 ± 93.6 days) and from first symptom to treatment (70.2 ± 34.0 vs. 155.0 ± 102.9 days) were significantly lower in the OSHC group than in the CC group (p < 0.001 each). There was no significant difference in the five-year survival rate between OSHC and CC (103/160 vs. 150/234, respectively; p = 0.951), although the proportion of relapses during the first year was significantly lower in the OSHC group (35/139, 25.2%) than in the CC one (74/195, 38.0%; p = 0.02). CONCLUSIONS: OSHC significantly reduced the diagnosis and treatment times. The early-relapse rate was significantly lower in the OSHC group, although the five-year survival rate was similar.

Characteristics Contributing to Survival Differences Between Black and White Patients Following Cystectomy.

PURPOSE: Examine patient, tumor, and treatment characteristics effect on the disparity between black and white patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). METHODS: 1,286 black patients in the 2004 to 2016 National Cancer Database fit inclusion criteria. A tapered match was performed from 17,374 white patients sequentially matched to the black cohort on demographics (age, gender, insurance, income, education, county, diagnosis year), presentation (demographic variables, stage, grade, tumor size, Charlson score), and treatment (demographic and presentation variables, lymph node count, hospital volume, neoadjuvant chemotherapy [NAC], treatment delay), creating 3 matched cohorts. Chi-square and Kruskal-Wallis tests were used to compare cohorts. Kaplan-Meier analysis was used to compare 5-year overall survival (OS). RESULTS: 5-year OS rate was 40.4% and 35.6% for unmatched white and black cohorts (P < 0.001), respectively. Following demographics and presentation match, 5-year OS rate for white patients decreased to 39.2% (P = 0.003) and 39.10% (P = 0.019), respectively. After treatment match, 5-year OS rate decreased to 36.7% for white patient (P = 0.32). Following presentation match, 7.2% of black patients vs. 5.8% of white patients had treatment delay, and 10.1% of black patients vs. 11.2% of white patients received NAC. The treatment match resulted in a 0.3% difference between groups for treatment delay and NAC. CONCLUSIONS: Our analysis demonstrates that disparity between black and white patients with muscle-invasive bladder cancer exists in demographic-, presentation-, and treatment-related variables. Treatment variables may be a large contributing factor to survival disparities. Further research is needed to identify social, biological, and organizational inputs that contribute to these disparities.

Using machine learning for mortality prediction and risk stratification in atezolizumab-treated cancer patients: Integrative analysis of eight clinical trials.

BACKGROUND: Few models exist to predict mortality in cancer patients receiving immunotherapy. Our aim was to build a machine learning-based risk stratification model for predicting mortality in atezolizumab-treated cancer patients. METHODS: Data from 2538 patients in eight atezolizumab-treated cancer clinical trials across three cancer types (non-small-cell lung cancer, bladder transitional cell carcinoma, and renal cell carcinoma) were included. The whole cohort was randomly split into development and validation cohorts in a 7:3 ratio. Machine-learning algorithms (extreme gradient boosting, random forest, logistic regression with lasso regularization, support vector machine, and K-nearest neighbor) were applied to develop prediction models. Model performance was mainly assessed by area under the receiver operating characteristic curve (AUC) value, calibration plot, and decision curve analysis. The probability of death risk was then stratified. RESULTS: One thousand and three hundred and seventy-nine (54.33%) patients died. The random forest (RF) model was overall the best in terms of predictive performance, with the AUC of 0.844 (95% confidence interval [CI]: 0.826-0.862) in the development cohort and 0.786 (95% CI: 0.754-0.818) in the validation cohort for predicting mortality. Twelve baseline variables contributing to mortality prediction in the RF model were C-reactive protein, PD-L1 level, cancer type, prior liver metastasis, derived neutrophil-to-lymphocyte ratio, alkaline phosphatase, albumin, hemoglobin, white blood cell count, number of metastatic sites, pulse rate, and Eastern Cooperative Oncology Group (ECOG) performance status. A total of 1782 (70.2%) patients were separated into the high-risk and 756 (29.8%) low-risk groups. Patients in the high-risk group were significantly more likely to die, experience disease progression, discontinue study, and discontinue treatment than patients in the low-risk group (all p values < 0.001). Risk groups were not associated with immune-related adverse events and grades 3-5 treatment-related adverse events (all p values > 0.05). CONCLUSION: RF model has good performance in mortality prediction and risk stratification for cancer patients receiving atezolizumab monotherapy.

Identification of immune-related and autophagy-related genes for the prediction of survival in bladder cancer.

BACKGROUND: Bladder cancer has the characteristics of high morbidity and mortality, and the prevalence of bladder cancer has been increasing in recent years. Immune and autophagy related genes play important roles in cancer, but there are few studies on their effects on the prognosis of bladder cancer patients. METHODS: Using gene expression data from the TCGA-BLCA database, we clustered bladder cancer samples into 6 immune-related and autophagy-related molecular subtypes with different prognostic outcomes based on 2208 immune-related and autophagy-related genes. Six subtypes were divided into two groups which had significantly different prognosis. Differential expression analysis was used to explore genes closely related to the progression of bladder cancer. Then we used Cox stepwise regression to define a combination of gene expression levels and immune infiltration indexes to construct the risk model. Finally, we built a Nomogram which consist of risk score and several other prognosis-related clinical indicators. RESULTS: The risk model suggested that high expression of C5AR2, CSF3R, FBXW10, FCAR, GHR, OLR1, PGLYRP3, RASGRP4, S100A12 was associated with poor prognosis, while high expression level of CD96, IL10, MEFV pointed to a better prognosis. Validation by internal and external dataset suggested that our risk model had a high ability to discriminate between the outcomes of patients with bladder cancer. The immunohistochemical results basically confirmed our results. The C-Index value and Calibration curves verified the robustness of Nomogram. CONCLUSIONS: Our study constructed a model that included a risk score for patients with bladder cancer, which provided a lot of helps to predict the prognosis of patients with bladder cancer.

Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial.

Importance: Robot-assisted radical cystectomy is being performed with increasing frequency, but it is unclear whether total intracorporeal surgery improves recovery compared with open radical cystectomy for bladder cancer. Objectives: To compare recovery and morbidity after robot-assisted radical cystectomy with intracorporeal reconstruction vs open radical cystectomy. Design, Setting, and Participants: Randomized clinical trial of patients with nonmetastatic bladder cancer recruited at 9 sites in the UK, from March 2017-March 2020. Follow-up was conducted at 90 days, 6 months, and 12 months, with final follow-up on September 23, 2021. Interventions: Participants were randomized to receive robot-assisted radical cystectomy with intracorporeal reconstruction (n = 169) or open radical cystectomy (n = 169). Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital within 90 days of surgery. There were 20 secondary outcomes, including complications, quality of life, disability, stamina, activity levels, and survival. Analyses were adjusted for the type of diversion and center. Results: Among 338 randomized participants, 317 underwent radical cystectomy (mean age, 69 years; 67 women [21%]; 107 [34%] received neoadjuvant chemotherapy; 282 [89%] underwent ileal conduit reconstruction); the primary outcome was analyzed in 305 (96%). The median number of days alive and out of the hospital within 90 days of surgery was 82 (IQR, 76-84) for patients undergoing robotic surgery vs 80 (IQR, 72-83) for open surgery (adjusted difference, 2.2 days [95% CI, 0.50-3.85]; P = .01). Thromboembolic complications (1.9% vs 8.3%; difference, -6.5% [95% CI, -11.4% to -1.4%]) and wound complications (5.6% vs 16.0%; difference, -11.7% [95% CI, -18.6% to -4.6%]) were less common with robotic surgery than open surgery. Participants undergoing open surgery reported worse quality of life vs robotic surgery at 5 weeks (difference in mean European Quality of Life 5-Dimension, 5-Level instrument scores, -0.07 [95% CI, -0.11 to -0.03]; P = .003) and greater disability at 5 weeks (difference in World Health Organization Disability Assessment Schedule 2.0 scores, 0.48 [95% CI, 0.15-0.73]; P = .003) and at 12 weeks (difference in WHODAS 2.0 scores, 0.38 [95% CI, 0.09-0.68]; P = .01); the differences were not significant after 12 weeks. There were no statistically significant differences in cancer recurrence (29/161 [18%] vs 25/156 [16%] after robotic and open surgery, respectively) and overall mortality (23/161 [14.3%] vs 23/156 [14.7%]), respectively) at median follow-up of 18.4 months (IQR, 12.8-21.1). Conclusions and Relevance: Among patients with nonmetastatic bladder cancer undergoing radical cystectomy, treatment with robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy resulted in a statistically significant increase in days alive and out of the hospital over 90 days. However, the clinical importance of these findings remains uncertain. Trial Registration: ISRCTN Identifier: ISRCTN13680280; ClinicalTrials.gov Identifier: NCT03049410.

External validation of Pentafecta in patients undergoing laparoscopic radical cystectomy: results from a high-volume center.

BACKGROUND: To investigate whether Pentafecta is suitable for bladder cancer patients receiving laparoscopic radical cystectomy (LRC). METHODS: From November 2013 to December 2020, muscle invasive Bladder Cancer (MIBC) and non-muscle invasive Bladder Cancer (NMIBC) patients who received LRC and urinary diversion were retrospectively analyzed. Pentafecta was defined as meeting five criteria: negative soft margin, ≥ 16 lymph nodes (LNs) removed, major complications free, urinary diversion related sequelae free and clinical recurrence free within 1 year. Analyze the achievement of five criteria and compare the overall survival (OS) of Pentafecta group with non-attainment group. Multivariable Cox's regression was performed to evaluate the impact of Pentafecta on OS. Multivariable logistic regression was performed to explore the effect of surgical experience on Pentafecta attainment. RESULTS: A total of 340 patients were included, negative soft margin, ≥ 16 lymph nodes (LNs) removed, major complications free, urinary diversion related sequelae free and clinical recurrence free within 1 year were observed in 95.3%, 30.3%, 83.8%, 75.0% and 85.6% of patients, respectively. Pentafecta group had a significantly longer OS than the non-attainment group (P = 0.027). The group with 10-15 LNs removed and meeting the other four criteria had a similar OS to group with ≥ 16 LNs removed (Pentafecta group) (5-year OS: 67.3% vs 72.7%, P = 0.861). Pentafecta (HR = 0.33, P = 0.011), positive lymph nodes (HR = 2.08, P = 0.028) and MIBC (HR = 3.70, P < 0.001) were all significant predictors of OS in multivariable Cox's regression. Surgical experience (OR = 1.05, P < 0.001), conduit (OR = 2.09, P = 0.047) and neobladder (OR = 2.47, P = 0.048) were all independent predictors of Pentafecta attainment in multivariable logistic regression. CONCLUSIONS: Pentafecta is suitable for bladder cancer patients receiving LRC and has the potential to be a valuable tool for evaluating the quality of LRC. Based on Pentafecta analysis, removing 10 LNs instead of 16 LNs as the one of the five criteria may be more appropriate for bladder cancer patients.

An Immunosenescence-Related Gene Signature to Evaluate the Prognosis, Immunotherapeutic Response, and Cisplatin Sensitivity of Bladder Cancer.

Immunosenescence refers to the immune system undergoing a series of degenerative changes with advancing age and is tightly associated with the initiation and progression of cancers. However, the immunosenescence-related genes as critical biomarkers for bladder cancer (BLCA) have not been systematically analyzed. We retrieved the immunosenescence-related genes from the public database and verified their association with hallmarks of immunosenescence based on The Cancer Genome Atlas (TCGA) cohort. Through gene pairing, Lasso, and univariate Cox regression, an 8-gene pair model was constructed to evaluate the overall survival of BLCA, which was then validated in the training cohort (P < 0.001, n = 396), two external validation cohorts (P < 0.05, n = 165; P < 0.001, n = 224), and local samples (P < 0.05, n = 10). We also downloaded the clinical information and gene expression matrices of other 32 different cancers from TCGA. The established model showed significant predictive value for the prognosis in 15 cancers (P < 0.05). The risk model could also serve as a promising predictor for immunotherapeutic response, which has been verified by the TIDE algorithm (P < 0.05), IMvigor210 dataset (P < 0.01, n = 298), and other two datasets correlated with immunotherapy (P < 0.05, n = 56; P = 0.17, n = 27). The TCGA dataset, in vitro cell experiments, and pan-cancer analysis displayed that the gene signature was associated with cisplatin sensitivity (P < 0.05). Overall, we proposed a novel immunosenescence-related gene signature to predict prognosis, immunotherapeutic response, and cisplatin sensitivity of BLCA, which were validated in different independent cohorts, local samples, and pan-cancer analyses.

Optimal Timing of Switching from Platinum-based Chemotherapy to Pembrolizumab for Advanced Urothelial Carcinoma Based on Real-world Data: A Multi-institutional Retrospective Study.

BACKGROUND/AIM: The optimal timing of switching from platinum-based chemotherapy to pembrolizumab in patients with advanced urothelial carcinoma (UC) remains unclear. PATIENTS AND METHODS: Thirty-four patients who received pembrolizumab as second-line treatment after first-line platinum-based chemotherapy were retrospectively evaluated. RESULTS: According to overall survival (OS) from pembrolizumab, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (7.0 and 25.5 months, p=0.034), but not between ≤6 and >6 cycles (11.3 and 6.6 months, p=0.658). According to the Cox proportional hazards regression model, the number of chemotherapy cycles was not correlated with better OS in pembrolizumab-treated patients. According to the OS from the first-line treatment, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (17.3 and 37.1 months, p<0.001), but not between ≤6 and >6 cycles (18.6 and 27.3 months, p=0.276). CONCLUSION: The optimal timing of switching from platinum-base chemotherapy to pembrolizumab in advanced UC is around six cycles.

Impact of the Use of Proton Pump Inhibitors on Pembrolizumab Effectiveness for Advanced Urothelial Carcinoma.

BACKGROUND/AIM: This study aimed to clarify the impact of proton pump inhibitors (PPIs) on oncological outcomes in patients who received pembrolizumab for advanced urothelial carcinoma (UC). PATIENTS AND METHODS: Forty advanced UC patients treated with pembrolizumab were retrospectively reviewed and divided into two groups (PPI: 15 patients; without PPI: 25 patients). Tumor response and survival were compared between these groups. The factors associated with survival were also investigated. RESULTS: The objective response rate was significantly lower in the group with PPIs compared with the group without PPIs. Both progression-free survival (PFS) and overall survival (OS) were significantly shorter in the group with PPIs than in the group without PPIs. The use of PPIs was a significant predictor of poor PFS and OS in multivariate analysis. CONCLUSION: The use of PPIs was negatively associated with tumor response and survival in patients with advanced UC treated with pembrolizumab.

Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer: longitudinal expression, transcriptome-level effects and modulation of chemosensitivity.

BACKGROUND: The response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. The proto-oncogene RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response in several solid tumours but has a hitherto unrecognized role in MIBC. METHODS: RBM3 protein expression level in tumour cells was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from a consecutive cohort of 145 patients, 65 of whom were treated with NAC. Kaplan-Meier and Cox regression analyses were applied to estimate the impact of RBM3 expression on time to recurrence (TTR), cancer-specific survival (CSS), and overall survival (OS) in strata according to NAC treatment. The effect of siRNA-mediated silencing of RBM3 on chemosensitivity was examined in RT4 and T24 human bladder carcinoma cells in vitro. Cellular functions of RBM3 were assessed using RNA-sequencing and gene ontology analysis, followed by investigation of cell cycle distribution using flow cytometry. RESULTS: RBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. Patients with high-tumour specific RBM3 expression treated with NAC had a significantly reduced risk of recurrence and a prolonged CSS and OS compared to NAC-untreated patients. In high-grade T24 carcinoma cells, which expressed higher RBM3 mRNA levels compared to RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. Transcriptomic analysis revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Furthermore, siRBM3-transfected T24 cells displayed an accumulation of cells residing in the G1-phase as well as altered levels of recognised regulators of G1-phase progression, including Cyclin D1/CDK4 and CDK2. CONCLUSIONS: The presented data highlight the potential value of RBM3 as a predictive biomarker of chemotherapy response in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.

Prognosis Risk Model Based on Pyroptosis-Related lncRNAs for Bladder Cancer.

OBJECTIVE: Bladder cancer (BC) is the most common malignancy in the urinary system and is prone to recurrence and metastasis. Pyroptosis is a kind of cell necrosis that is triggered by the gasdermin protein family. lncRNAs are noncoding RNAs that are more than 200 nucleotides long. Both pyroptosis and lncRNAs are associated with tumor development and progression. This study is aimed at exploring and establishing a prognostic signature of BC based on pyroptosis-related lncRNAs. METHODS: In this study, The Cancer Genome Atlas (TCGA) database provided us with the RNA sequencing transcriptome data of bladder cancer patients, and we identified differentially expressed pyroptosis-related lncRNAs in bladder cancer. Then, the prognostic significance of these lncRNAs was assessed using univariate Cox regression analysis and LASSO regression analysis. Subsequently, 4 pyroptosis-related lncRNAs, namely, AL121652.1, AL161729.4, AC007128.1, and AC124312.3, were identified by multivariate Cox regression analysis, thus constructing the prognostic risk model. Then, we compared the levels of immune infiltration, differences in cell function, immune checkpoints, and m6A-related gene expression levels between the high- and low-risk groups. RESULT: Patients were divided into low-risk or high-risk groups based on the median risk score. Kaplan-Meier survival analysis indicated that the overall survival of bladder cancer patients in the low-risk group was substantially superior to that in the high-risk group (p < 0.001). The receiver operating characteristic (ROC) curve further confirmed the credibility of our model. Moreover, gene set enrichment analysis (GSEA) indicated that these were different signal pathways significantly enriched between the two groups. Immune infiltration, immune checkpoint, and N6-methyladenosine-related gene analysis also reflected that there were notable differences between the two groups. CONCLUSION: Therefore, this prognostic risk model is based on the level of pyroptotic lncRNAs, which is conducive to individualized assessment of the risk of patients and provides a reference for clinical treatment. This will also help provide insights into the prognosis and treatment of bladder cancer.

Survival in bladder and upper urinary tract cancers in Finland and Sweden through 50 years.

Survival has improved in bladder cancer but few studies have considered extended periods or covered populations for which medical care is essentially free of charge. We analyzed survival in urothelial cancer (UC, of which vast majority are bladder cancers) in Finland and Sweden over a 50-year period (1967-2016) using data from the NORDCAN database. Finland and Sweden are neighboring countries with largely similar health care systems but higher economic resources and health care expenditure in Sweden. We present results on 1- and 5-year relative survival rates, and additionally provide a novel measure, the difference between 1- and 5-year relative survival, indicating how well survival was maintained between these two periods. Over the 50-year period the median diagnostic age has increased by several years and the incidence in the very old patients has increased vastly. Relative 1- year survival rates increased until early 1990s in both countries, and with minor gains later reaching about 90% in men and 85% in women. Although 5-year survival also developed favorably until early 1990s, subsequent gains were small. Over time, age specific differences in male 1-year survival narrowed but remained wide in 5-year survival. For women, age differences were larger than for men. The limitations of the study were lack of information on treatment and stage. In conclusion, challenges are to improve 5-year survival, to reduce the gender gap and to target specific care to the most common patient group, those of 70 years at diagnosis. The most effective methods to achieve survival gains are to target control of tobacco use, emphasis on early diagnosis with prompt action at hematuria, upfront curative treatment and awareness of high relapse requiring regular cystoscopy follow up.