BACKGROUND: Radical cystectomy (RC) is the standard treatment for muscle invasive bladder cancer, but approximately half of all patients will ultimately succumb to disease progression despite apparent cure with extirpative surgery. Elderly patients are at especially high risk of advanced disease and may benefit from perioperative systemic therapy.
OBJECTIVE: To assess the real-world benefit of adjuvant chemotherapy (AC) in patients ≥75 years old.
METHODS: We retrospectively reviewed patients who underwent RC for non-metastatic urothelial carcinoma of the bladder (UCB) from 12 participating international medical institutions. Kaplan-Meier survival curves and Cox regression models were used to assess the association between age groups, administration of AC and oncological outcome parameters such as recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS).
RESULTS: 4,335 patients were included in the analyses, of which 820 (18.9%) were ≥75 years old. These elderly patients had a higher rate of adverse pathologic features. In an univariable subgroup analysis in patients ≥75 years with lymph node metastasis, 5-year OS was significantly higher in patients who had received AC (41% vs. 30.9%, p = 0.02). In a multivariable Cox model that was adjusted for several established outcome predictors, there was a significant favorable association between the administration of AC in elderly patients and OS, but no RFS or CSS.
CONCLUSIONS: In this large observational study, the administration of AC was associated with improved OS, but not RFS or CSS, in elderly patients treated with RC for UCB. This is of clinical importance, as elderly patients are more likely to have adverse pathologic features and experience worse survival outcomes. Treatment of UCB should include both a multidisciplinary approach and a geriatric evaluation to identify patients who are most likely to tolerate and benefit from AC.

BACKGROUND: This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab.
METHODS: This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model.
RESULTS: During the median follow-up period of 7.3 months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2 g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42 mg/L was a significant prognostic factor for OS (p = 0.001).
CONCLUSIONS: The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.

Background: Mutations of fibroblast growth factor receptor 3 (FGFR3) are associated with urothelial carcinoma (UC) oncogenesis and are considered an important therapeutic target. Therefore, we evaluated the FGFR3 mutation rate and its clinical significance in urothelial carcinoma (UC) using next-generation sequencing. Methods: A total of 123 patients with UC who were treated at Chonnam National University Hospital (Gwang-ju, Korea) from January 2018 to December 2020 were enrolled. We performed NGS using the Oncomine panel with tumor specimens and blood samples corresponding to each specimen. We analyzed the FGFR3 mutation results according to the type of UC and the effects on early recurrence and progression. Results: The mean age of the patients was 71.39 ± 9.33 years, and 103 patients (83.7%) were male. Overall, the FGFR3 mutation rate was 30.1% (37 patients). The FGFR3 mutation rate was the highest in the non-muscle-invasive bladder cancer (NMIBC) group (45.1%), followed by the muscle-invasive bladder cancer (22.7%) and upper tract UC (UTUC) (14.3%) groups. Patients with FGFR3 mutations had a significantly lower disease stage (p = 0.019) but a high-risk of NMIBC (p < 0.001). Conclusions: Our results revealed that FGFR3 mutations were more prevalent in patients with NMIBC and lower stage UC and associated with a high-risk of NMIBC. Large multicenter studies are needed to clarify the clinical significance of FGFR3 mutations in UC.

BACKGROUND: Clients want to know the ultimate cause of death in their pet after cancer treatment. The cause of euthanasia and investigation of urinary obstruction in treated dogs with urothelial carcinoma (UC) has not been specifically reported in veterinary literature.
OBJECTIVE: Our hypothesis was that the majority of treated dogs with UC are euthanized secondary to primary tumor factors, such as urinary obstruction.
METHODS: Fifty-nine client-owned dogs diagnosed with UC.
METHODS: Retrospective observational study on clinical signs and disease at euthanasia of dogs with UC treated by radiation therapy or chemotherapy or both.
RESULTS: The median overall survival time (OST) of all dogs was 339 days (range, 17-1996; 95% confidence interval [CI], 185-392; interquartile range [IQR], 112-505). Of dogs deemed to have been euthanized because of UC (50/59, 85%), the primary cause was considered to be local progression in 31/50 (62%), most often because of perceived complete or partial urinary obstruction (24/31, 77%). No variables were found to be predictive of urinary obstruction. The overall documented metastatic rate was 56%. In dogs euthanized because of UC, metastasis was deemed to be the cause in 19/50 (38%) dogs.
CONCLUSIONS: Regardless of the type of treatment, UC in dogs has a poor prognosis and there is a continuing need to improve treatments that focus on local control of the primary tumor, given its high contribution to the decision for euthanasia. Proactive management to avoid the high frequency of urinary obstruction may be worthy of future investigation.

UNASSIGNED: Bladder carcinoma ranks tenth among all cancers worldwide predominantly affecting elderly males. Common risk factors being cigarette smoke and aniline dyes. Immunohistochemical markers play a pivotal role for its diagnosis and prognosis.
UNASSIGNED: To analyze the immunohistochemical expression of p53, CD10, Ki-67 in bladder cancers correlating with demographic features, pathological grade, and stage and to establish as prognostic biomarkers.
UNASSIGNED: Surgical samples of total of 70 cases of bladder tumor were collected, processed, stained in routine hematoxylin and eosin followed by immunohistochemistry of p53, CD10, and Ki67 markers performed on randomly selected 30 cases only.
UNASSIGNED: Out of 70 cases 69 cases (98.6%) were carcinomas; urothelial carcinoma being 71.4% (n = 50) with male: female ratio = 7.7:1 and mean age = 61.81 ± 12.83 years. Out of 30 cases, p53 was positive in 50% of cases, 30% - negative and 20% - equivocal. p53 positive expression pattern was more in high grade (HG) than low grade (LG). Significant difference was observed in the mean p53 scoring (%) and different stages (P = 0.043). CD10 expression was negative in 56.6%, (1+) in 16.6%, and (2+) in 26.6% of cases and significant difference in CD 10 expression was observed between the high and LG (P = 0.001). Ki-67 labeling index was appreciably higher in HG than the LG tumor (32.49% ± 24.35%; 6.86% ± 8.1%). Majority of Ki-67 expression was observed in stage pT2, followed by the pT1 stage.
UNASSIGNED: Cocktail of p53, CD10, and Ki67 is useful as potential prognostic markers in bladder cancers.

Although upper tract urothelial carcinoma (UTUC) is more common in the elderly, outcomes of neoadjuvant chemotherapy (NAC) in this population have never been explored. The objective of the study was to assess the impact of NAC on pathologic response and oncological outcomes stratified by age.
This multicenter study included 164 patients treated with NAC and radical nephroureterectomy (RNU) for clinically non-metastatic, high-risk UTUC. The cohort was stratified into two groups according to median age. Patients received either cisplatin-based or non-cisplatin-based chemotherapies. Pathologic responses were defined as pathologic objective response (pOR; ≤ ypT1N0) and pathologic complete response (pCR; ypT0N0). Univariable and multivariable logistic and Cox regression analyses were performed to identify predictors for pathologic response and survival outcomes.
The cohorts\' median age was 68 years with the elderly group (> 68 years) comprising 74 patients. Neoadjuvant chemotherapy included methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) in 66 (40%), gemcitabine cisplatin (GC) in 66 (40%) and non-cisplatin chemotherapy in 32 patients (20%). Younger patients received more often MVAC (50% vs. 28%) while elderly received more GC (34% vs. 47%) or non-cisplatin chemotherapy (16% vs. 24%) (P = .02). Overall, pOR and pCR were similar across age groups (52% vs. 47%; P = .5 and 10% vs. 8%; P = .7). While GC and non-cisplatin chemotherapy showed a lower pCR of 5% and 3%, respectively, MVAC revealed a pCR of 17% (P = .03) and was independently associated with a higher pCR (OR 4.31; P = .03). Kaplan-Meier analysis showed no difference in recurrence-free and cancer-specific survival, whereas a lower rate was seen in overall survival for the elderly.
Elderly patients with high-risk UTUC eligible for cisplatin-based NAC prior to RNU may benefit from this multimodal therapy equally as their younger counterparts. Cisplatin-ineligible patients undergoing non-cisplatin-based NAC appeared to have lower response rates and should be considered for immediate RNU.

Urothelial Carcinoma (UC) is the most common tumour of the canine urinary bladder. Recently, BRAF mutation testing emerged as a diagnostic option, but its prognostic significance is unknown. This study investigates the relationship between BRAF (variant V595E) mutation status and overall survival in UC-bearing dogs. Seventy-nine patients histologically diagnosed with UC of the bladder and/or urethra between 2006 and 2019 were included in this retrospective single-center-study. Treatment consisted of meloxicam (n=39, group 1 \"Melox\"), mitoxantrone and meloxicam (+/- followed by metronomic chlorambucil) (n=23, group 2 \"Chemo\") or partial cystectomy followed by meloxicam +/- mitoxantrone (n=17, group 3 \"Sx\"). Survival was significantly influenced by treatment (p=0.0002) and tumour location (p<0.001) in both uni- and multivariable analyses. BRAF mutation was identified in 51 tumours (=64.6%) and had no statistically significant influence on overall survival: MST for BRAF-negative patients 359 vs. 214 days for BRAF-positive dogs (p=0.055). However, in BRAF-positive dogs, survival depended significantly on type of treatment in univariable analysis: MSTs for groups 1-3 were 151 days, 244 days, and 853 days, respectively (p=0.006); In BRAF-positive group 2 (\"Chemo\")-patients, adjuvant metronomic chlorambucil after mitoxantrone more than doubled MST compared to patients receiving mitoxantrone alone (588 days vs. 216 days; p=0.030). In contrast, MSTs were not significantly different in BRAF-negative patients among the 3 treatment groups (p=0.069). Multivariate analysis of these data was not possible due to group size limitations. This study identified tumour location and treatment type, but not BRAF mutation status, as independent prognostic factors for overall survival. This article is protected by copyright. All rights reserved.

OBJECTIVE: To evaluate the long-term oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU) and the impact of diagnostic ureteroscopy (URS) on survival outcomes.
METHODS: A retrospective analysis of all consecutive patients undergoing RNU for suspected UTUC at a UK tertiary referral centre from a prospectively maintained database was conducted. The primary outcome measures were 5- and 10-year cancer-specific survival (CSS). The secondary outcomes were: overall survival (OS), recurrence-free survival (RFS), impact of prior diagnostic URS on OS, CSS and intravesical RFS (intravesical-RFS), and predictors of intravesical recurrence. Statistical analysis was performed in R using the \'survminer\' and \'survival\' packages. The Kaplan-Meier method was used to calculate survival functions and these were expressed in graphical form. Uni-/multivariate survival analyses were performed using the Cox proportional hazard regression model. Statistical significance in this study was set at P < 0.05.
RESULTS: A total of 422 patients underwent RNU with confirmed UTUC. The median (interquartile range) follow-up of patients with confirmed UTUC was 9.2 (5.6-12.7) years. The 5- and 10-year CSS rates were 70.5% (95% confidence interval [CI] 65.9-74.9) and 67.1% (95% CI 62.4-71.6), respectively. OS (HR 1.04 [95% CI 0.78-1.38]; P = 0.46) and CSS (HR 0.96 [95% CI 0.68-1.34]; P = 0.81) were similar in the diagnostic URS and the direct RNU cohorts. intravesical RFS was superior for the direct RNU cohort (HR 1.94 [95% CI 1.19-3.17]; P = 0.008). In multivariate analysis, prior URS, T2 stage, proximal ureter tumour and bladder cancer history were predictors of metachronous bladder recurrence.
CONCLUSIONS: This single-centre retrospective cohort study reports the long-term oncological outcomes of RNU with a median follow-up of 9.2 years, serving as a reference standard in counselling patients undergoing RNU. Stage and grade of the RNU specimen were the only two studied factors that appeared to adversely impact long-term CSS and OS. Our results suggest that the risk of intravesical recurrence is increased nearly twofold in patients who have undergone diagnostic URS prior to RNU. Prior URS, however, does not appear to adversely impact long-term CSS and OS. The authors suggest that a risk-stratified approach be adopted, wherein diagnostic URS is offered only in equivocal cases.

BACKGROUND: While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors.
METHODS: Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study\'s primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples.
CONCLUSIONS: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials.
BACKGROUND: Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018.

BACKGROUND: The European Association of Urology risk stratification dichotomizes patients with upper tract urothelial carcinoma (UTUC) into two risk categories.
OBJECTIVE: To evaluate the predictive value of a new classification to better risk stratify patients eligible for kidney-sparing surgery (KSS).
METHODS: This was a retrospective study including 1214 patients from 21 centers who underwent ureterorenoscopy (URS) with biopsy followed by radical nephroureterectomy (RNU) for nonmetastatic UTUC between 2000 and 2017.
UNASSIGNED: A multivariate logistic regression analysis identified predictors of muscle invasion (≥pT2) at RNU. The Youden index was used to identify cutoff points.
CONCLUSIONS: A total of 811 patients (67%) were male and the median age was 71 yr (interquartile range 63-77). The presence of non-organ-confined disease on preoperative imaging (p < 0.0001), sessile tumor (p < 0.0001), hydronephrosis (p = 0.0003), high-grade cytology (p = 0.0043), or biopsy (p = 0.0174) and higher age at diagnosis (p = 0.029) were independently associated with ≥pT2 at RNU. Tumor size was significantly associated with ≥pT2 disease only in univariate analysis with a cutoff of 2 cm. Tumor size and all significant categorical variables defined the high-risk category. Tumor multifocality and a history of radical cystectomy help to dichotomize between low-risk and intermediate-risk categories. The odds ratio for muscle invasion were 5.5 (95% confidence interval [CI] 1.3-24.0; p = 0.023) for intermediate risk versus low risk, and 12.7 (95% CI 3.0-54.5; p = 0.0006) for high risk versus low risk. Limitations include the retrospective design and selection bias (all patients underwent RNU).
CONCLUSIONS: Patients with low-risk UTUC represent ideal candidates for KSS, while some patients with intermediate-risk UTUC may also be considered. This classification needs further prospective validation and may help stratification in clinical trial design.
UNASSIGNED: We investigated factors predicting stage 2 or greater cancer of the upper urinary tract at the time of surgery for ureter and kidney removal and designed a new risk stratification. Patients with low or intermediate risk may be eligible for kidney-sparing surgery with close follow-up. Our classification scheme needs further validation based on cancer outcomes.