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Histologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for their biological differences. Here we show using single cell analysis that HVs harbor a tumor cell state characterized by expression of MUC16 (CA125), MUC4 , and KRT24 . This cell state is enriched in metastases, predicted to be highly resistant to chemotherapy, and linked with poor survival. We also find enriched expression of TM4SF1 , a transmembrane protein, in HV tumor cells. Chimeric antigen receptor (CAR) T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in a TM4SF1 expression-dependent manner, highlighting its potential as a therapeutic target. Single cell analysis of histologic variant bladder tumors detects a shared CA125+ tumor cell state associated with aggressive clinical features and reveals enriched expression of TM4SF1, a membrane protein that can be targeted with CAR T cells.

With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4 , and that the PPARγ agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients. Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

Background Financial toxicity of bladder cancer care may influence how patients utilize healthcare resources, from emergency department (ED) encounters to office visits. We aim to examine whether greater household net worth (HHNW) confers differential access to healthcare resources after radical cystectomy (RC). Methods This population‐based cohort study examined the association between HHNW and healthcare utilization costs in the 90 days post‐RC in commercially insured patients with bladder cancer. Costs accrued from the index hospitalization to 90 days after including health plan costs (HPC) and out‐of‐pocket costs (OPC). Multivariable logistic regression models were generated by encounter (acute inpatient, ED, outpatient, and office visit). Results A total of 141,903 patients were identified with HHNW categories near evenly distributed. Acute inpatient encounters incurred the greatest HPC and OPC. Office visits conferred the lowest HPC while ED visits had the lowest OPC. Black patients harbored increased odds of an acute inpatient encounter (OR 1.22, 95% CI 1.16–1.29) and ED encounter (OR 1.20, 95% CI 1.14–1.27) while Asian (OR 0.76, 95% CI 0.69–0.85) and Hispanic (OR 0.74, 95% CI 0.69–0.78, p < 0.001) patients had lower odds of an outpatient encounter, compared to White counterpart. Increasing HHNW was associated with decreasing odds of acute inpatient or ED encounters and greater odds of office visits. Conclusions Lower HHNW conferred greater risk of costly inpatient encounters while greater HHNW had greater odds of less costly office visits, illustrating how financial flexibility fosters differences in healthcare utilization and lower costs. HHNW may serve as a proxy for financial flexibility and risk of financial hardship than income alone. Our study of 141,903 patients, representing the largest cohort of commercially insured patients to examine the association between household net worth (HHNW) and healthcare utilization costs after RC to date, showed that lower HHNW conferred greater risk of acute inpatient encounters (and higher costs) while greater HHNW had greater odds of office visits (and lower costs). Greater financial flexibility fosters differences in healthcare utilization (and lower costs). HHNW may provide a more comprehensive measure of financial flexibility than income alone and serve as a proxy for healthcare access.

Patients with muscle-invasive bladder cancer (MIBC) have poorer prognoses if cancer has metastasized to the lymph nodes. Genomic markers of lymph node involvement (LNI) would be useful for treatment planning, especially if measured at the biopsy stage, but large-scale studies of tumor tissue at any stage are needed to discover robust markers of LNI. We performed a genome-wide query of copy number alterations (CNA) in 237 MIBC surgical tumor specimens from patients in The Cancer Genome Atlas who had radical cystectomy and lymphadenectomy without neoadjuvant treatment. Pathology reports were independently reviewed to confirm LNI, and copy number data was analyzed to confirm gene-level gains and losses while adjusting for tumor purity and ploidy. Using logistic regression and elastic net models, we identified the CNA most significantly associated with LNI. Multivariable logistic regression was used to describe these CNA associations while adjusting for clinical variables. Kaplan-Meier and Cox regression were used to describe their association with overall survival. Gains in 26 genes were identified as having strong associations with LNI. After adjusting for age, gender, race, pathological tumor stage, histology, and number of nodes examined, gains in 22 genes on chr3p25 or chr11p11 remained significantly associated with LNI (p<0.01) and improved model discrimination over clinical variables alone (p = 0.04). They were also associated with shorter overall survival (adjusted p = 0.02). These results suggest that a simple genomic test for gains in chr3p25 and chr11p11 could inform adjuvant treatment or clinical trial decisions if validated in external cohorts. Additional studies will also be needed to determine if these CNA are detectible in biopsy tissue and can inform clinical decisions at the preoperative stage.

BackgroundImmune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI.MethodsWe undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors.ResultsWe identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03).ConclusionsThe presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

Background Elucidation of epigenetic alterations in bladder cancer will lead to further understanding of the biology of the disease and hopefully improved therapies. Our aim was to perform an integrative epigenetic analysis of invasive urothelial carcinoma of the bladder to identify the epigenetic abnormalities involved in the development and progression of this cancer. Methods Pre-processed methylation data and RNA-seq data were downloaded from The Cancer Genome Atlas (TCGA) and processed using the R package TCGA-Assembler. An R package MethylMix was used to perform an analysis incorporating both methylation and gene expression data on all samples, as well as a subset analysis comparing patients surviving less than 2 years and patients surviving more than 2 years. Genes associated with poor prognosis were individually queried. Pathway analysis was performed on statistically significant genes identified by MethylMix criteria using ConsensusPathDB. Validation was performed using flow cytometry on bladder cancer cell lines. Results A total of 408 patients met all inclusion criteria. There were a total of 240 genes differentially methylated by MethylMix criteria. Review of individual genes specific to poor-prognosis patients revealed the majority to be candidate tumor suppressors in other cancer types. Pathway analysis showed increase in methylation of genes involved in antioxidant pathways including glutathione and NRF2. Genes involved in estrogen metabolism were also hypermethylated while genes involved in the EGFR pathway were found to be hypomethylated. EGFR expression was confirmed to be elevated in six bladder cancer cell lines. Conclusions In patients with invasive urothelial carcinoma, we found differential methylation in patients with better and worse prognosis after cystectomy. Differentially methylated genes are involved in many relevant oncologic pathways, including EGFR and antioxidant pathways, that may be a target for therapy or chemoprevention.

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a tendency for recurrence and capacity for progression. Intravesical instillation therapy has been employed in various clinical settings, which are summarized within this review. Several chemotherapeutic agents have shown clinical efficacy in reducing recurrence rates in the post-transurethral resection of bladder tumor (TURBT) setting, including mitomycin C (MMC), doxorubicin, and epirubicin. Mounting evidence also supports the use of intravesical MMC following nephroureterectomy to reduce later urothelial bladder recurrence. In the adjuvant setting, bacillus Calmette-Guérin (BCG) immunotherapy is an established first-line agent in the management of carcinoma in situ (CIS) and high-grade non muscle invasive urothelial carcinoma (UC). Among high and intermediate-risk patients (based on tumor grade, size, and focality) improvements in disease-free intervals have been seen with adjunctive administration of MMC prior to scheduled BCG dosing. Following failure of first-line intravesical therapy, gemcitabine and valrubicin have demonstrated modest activity, though valrubicin remains the only agent currently Food and Drug Administration (FDA)-approved for the treatment of BCG-refractory CIS. Techniques to optimize intravesical chemotherapy delivery have also been explored including pharmacokinetic methods such as urinary alkalization and voluntary dehydration. Chemohyperthermia and electromotive instillation have been associated with improved freedom from recurrence intervals but may be associated with increased urinary toxicity. Improvements in therapeutic selection may be heralded by novel opportunities for genomic profiling and refinements in clinical risk stratification.

Background Testicular sex cord stromal tumors (SCSTs) are managed similarly to germ cell tumors (GCTs); however, few studies have directly compared outcomes between these tumor types. Using the National Cancer Database (NCDB), we sought to compare overall and stage-specific all-cause mortality (ACM) between SCSTs versus GCTs. Methods NCDB was queried for patients diagnosed with SCSTs and GCTs between 2004 and 2013. Descriptive statistics were used to compare sociodemographic and clinical characteristics between groups. Univariable and multivariable Cox proportional hazards regression analyses were used to assess associations with ACM. Results We identified 42,192 patients diagnosed with testicular cancer between 2004 and 2013, with 280 having SCSTs and 41,912 patients having GCTs. Median age for SCSTs and GCTs was 45 (interquartile range [IQR] 34–59) and 34 (IQR 27–43), respectively ( p  < 0.001). Median follow-up was 39 and 52 months, respectively. Overall, patients with SCSTs had greater risk of ACM compared to those with GCTs (HR 1.69, 95% CI 1.14–2.50). Private insurance, greater education, and fewer comorbidities were associated with reduced risk of ACM ( p  < 0.05 for all). Among those with stage I disease, tumor type was not associated with ACM on multivariable analysis. Among those with stage II/III disease, patients with SCSTs had increased risk of ACM compared to patients with GCTs (HR 3.29, 95% CI 1.89–5.72). Conclusions Patients with advanced SCSTs had worse survival outcomes compared to those with advanced GCTs. These data suggest a need for further investigation to ascertain effective management recommendations for SCSTs.

Background Black individuals with muscle‐invasive bladder cancer (MIBC) experienced 21% lower odds of guideline‐based treatment (GBT) and differences in treatment explain 35% of observed Black‐White differences in survival. Yet little is known of how interactions between race/ethnicity and receipt of GBT drive within‐ and between‐race survival differences. Methods Black, White, and Latino individuals diagnosed with nonmetastatic, locally advanced MIBC from 2004 to 2013 within the National Cancer Database were included. Guideline‐based treatment was defined as the receipt including one or more of the following treatment modalities: radical cystectomy (RC), neoadjuvant chemotherapy with RC, RC with adjuvant chemotherapy, and/or chemoradiation based on American Urological Association guidelines. Cox proportional hazards model of mortality estimated effects of GBT status, race/ethnicity, and the GBT‐by‐race/ethnicity interaction, adjusting for covariates. Results Of the 54 910 MIBC individuals with 125 821 person‐years of posttreatment observation (max = 11 years), 6.9% were Black, and 3.0% were Latino. Overall, 51.4%, 45.3%, and 48.5% of White, Black, and Latino individuals received GBT. Latino individuals had lower hazard of death compared to Black (HR 0.81, 95% CI 0.75‐0.87) and White individuals (HR 0.92, 95% 0.86‐0.98). With GBT, Latino and White individuals had similar outcomes (HR = 1.00, 95% 0.91‐1.10) and both fared better than Black individuals (HR = 0.88, 95% 0.79‐0.99 and HR = 0.88, 95% 0.83‐0.94, respectively). Without GBT, Latino individuals fared better than White (HR = 0.85, 95% 0.77‐0.93) and Black individuals (HR = 0.74, 95% 0.67‐0.82) while White individuals fared better than Black individuals (HR = 0.87, 95% 0.83‐0.92). Black individuals with GBT fared worse than Latinos without GBT (HR = 1.02, 95% 0.92‐1.14), although not statistically significant. Conclusion Low GBT levels demonstrated an “under‐allocation” of GBT to those who needed it most—Black individuals. Interventions to improve GBT allocation may mitigate race‐based survival differences observed in MIBC. Receipt of guideline‐based treatment nearly eliminated survival disparities between Latino and white individuals with bladder cancer but the benefit was not the same for black individuals, highlighting several potential targets for intervention.

Table 4 was missing the following - CI = Confidence interval, GCTs = Germ cell tumors, HR = Hazard ratio, SCSTs = Sex cord stromal tumors, *p < 0.05, **p < 0.01, ***p < 0.001 [IMAGE OMITTED: SEE PDF] [RAW_REF_TEXT] Correction [/RAW_REF_TEXT] [RAW_REF_TEXT] Open Access [/RAW_REF_TEXT] [RAW_REF_TEXT] Published:17 July 2020 [/RAW_REF_TEXT] Correction to: A comparison of stage-specific all-cause mortality between testicular sex cordstromal tumors and germ cell tumors: results from the National Cancer Database [RAW_REF_TEXT] Kyle B. Zuniga 1,2,3 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Samuel L. Washington III1 , [/RAW_REF_TEXT] [RAW_REF_TEXT] Sima P. Porten1 & [/RAW_REF_TEXT] [RAW_REF_TEXT] Maxwell V. Meng1 [/RAW_REF_TEXT] BMC Urology volume 20, Article number: 103 (2020) Cite this article [RAW_REF_TEXT] 4 Accesses [/RAW_REF_TEXT] [RAW_REF_TEXT] 1 Altmetric [/RAW_REF_TEXT] [RAW_REF_TEXT] Metrics details [/RAW_REF_TEXT] [RAW_REF_TEXT] The original article was published in BMC Urology 2020 20:40 [/RAW_REF_TEXT] Correction to: BMC Urol (2020) 20:40 https://doi.org/10.1186/s12894-020-00609-2 It was highlighted that the original article [1] contained the below errors in Tables 2, 3 and 4 and in the legends of Tables 3 and 4. Table 4 was missing the following - CI = Confidence interval, GCTs = Germ cell tumors, HR = Hazard ratio, SCSTs = Sex cord stromal tumors, *p < 0.05, **p < 0.01, ***p < 0.001 [/RAW_REF_TEXT] Table 2 Stage-specific comparison of the sociodemographic and clinical characteristics of patients with SCSTs versus GCTs Full size table Table 3 Univariable and multivariable Cox proportional hazards regression analysis on the association between sociodemographic and clinical characteristics and mortality of the overall cohort Full size table Table 4 Multivariable Cox proportional hazards regression analysis on the association between sociodemographic and clinical characteristics and mortality by stage Full size table Correction Open Access Published:17 July 2020 [/RAW_REF_TEXT] Correction to: A comparison of stage-specific all-cause mortality between testicular sex cordstromal tumors and germ cell tumors: results from the National Cancer Database [RAW_REF_TEXT] Kyle B. Zuniga 1,2,3 , Samuel L. Washington III1 , Sima P. Porten1 & Maxwell V. Meng1 [/RAW_REF_TEXT] BMC Urology volume 20, Article number: 103 (2020) Cite this article [RAW_REF_TEXT] 4 Accesses 1 Altmetric Metrics details The original article was published in BMC Urology 2020 20:40 [/RAW_REF_TEXT] Correction to: BMC Urol (2020) 20:40 https://doi.org/10.1186/s12894-020-00609-2 It was highlighted that the original article [1] contained the below errors in Tables 2, 3 and 4 and in the legends of Tables 3 and 4.