Tumor heterogeneity is common in cancer, however recent studies have applied single gene expression signatures to classify bladder cancers into distinct subtypes. Such stratification assumes that a predominant transcriptomic signature is sufficient to predict progression kinetics, patient survival and treatment response. We hypothesize that such static classification ignores intra-tumoral heterogeneity and the potential for cellular plasticity occurring during disease development. We have conducted single cell transcriptome analyses of mouse and human model systems of bladder cancer and show that tumor cells with multiple lineage subtypes not only cluster closely together at the transcriptional level but can maintain concomitant gene expression of at least one mRNA subtype. Functional studies reveal that tumor initiation and cellular plasticity can initiate from multiple lineage subtypes. Collectively, these data suggest that lineage plasticity may contribute to innate tumor heterogeneity, which in turn carry clinical implications regarding the classification and treatment of bladder cancer.

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IMPORTANCEOpioid prescriptions for treatment of pain in emergency departments (EDs) are associated with long-term opioid use. The temporal pattern of opioid prescribing in the context of the opioid epidemic remains unknown. OBJECTIVE To examine the temporal pattern of opioid prescribing within an ED for varying pain conditions between 2009 and 2018. DESIGN, SETTING, AND PARTICIPANTS A population-based, cross-sectional study was conducted at the ED of an urban academic medical center. All patients treated within that ED between January 1, 2009, and December 31, 2018, were included. MAIN OUTCOMES AND MEASURESThe proportion of patients prescribed an opioid for treatment of pain in the ED temporally by condition, condition type, patient demographics, and physician prescriber.

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Objectives To evaluate whether pathological downstaging (pDS) was more informative in predicting overall survival (OS) than pathological complete response (pCR) in patients treated with neoadjuvant chemotherapy (NAC) for upper tract urothelial carcinoma (UTUC). Patients and Methods The National Cancer Database was queried for patients with high‐grade cN0M0 disease who had received NAC. pDS was defined as a decrease of at least one stage from cT to pT stage along with pN0, including pCR. A multivariable Cox model predicting OS was generated by fitting alternatively either pDS or pCR, and adjusted for potential confounders. The discrimination of the Cox models for predicting OS was evaluated using Harrell's C‐index. The analyses were repeated in patients diagnosed as having cT2–4N0M0 disease. Results Among 264 patients meeting the inclusion criteria, 72 (27%) and 39 (15%) achieved pDS and pCR, respectively. On multivariable analysis, both pDS (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.13, 0.45; P < 0.001) and pCR (HR 0.37, 95% CI 0.18, 0.79; P = 0.01) were associated with OS. The model including pDS achieved better discrimination with respect to the model including pCR: C‐index 76.4 vs 72.7, respectively. In the 128 patients diagnosed with cT2–4 disease, both pDS (HR 0.19, 95% CI 0.09, 0.40; P < 0.001) and pCR (HR 0.31, 95% CI 0.11, 0.85; P = 0.023) were confirmed as predictors of OS. The model including pDS was confirmed to discriminate better than the model including pCR: C‐index 75 vs 68.9, respectively. Conclusion The study showed that pDS after NAC for UTUC was more informative than pCR when predicting OS. These findings, although requiring prospective validation, can aid in the design of clinical trials seeking to refine the use of chemotherapy and other systemic therapies in this setting.

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PURPOSE: Data have indicated that residual disease after neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) may be associated with poor outcomes. OBJECTIVE: Analyze differences in overall survival (OS) of patients with residual MIBC treated with NAC + Radical cystectomy (RC), RC alone, or RC + Adjuvant Chemotherapy(AC). MATERIALS AND METHODS: The National Cancer Database was queried for patients who underwent RC alone, NAC + RC, or RC + AC for MIBC stage cT2-4aN0M0 from 2004-2015. Covariates were balanced using propensity score (PS) weighting. Time to death was evaluated from diagnosis. Weighted cox proportional hazards models and Kaplan-Meier survival curves were created to analyze differences in OS. RESULTS: 8,288 patients were included for analysis, 1,899 (23%) received NAC + RC, 5,529 (67%) received RC alone, and 860 (10%) received RC + AC. Patients were sub-stratified based on pathological staging (≤pT2 or >pT2) and compared against treatment with RC alone. In the ≤pT2 cohort, NAC + RC was associated with a decreased risk of death (HR:0.85, 95% CI:0.79–0.91) and RC + AC was associated with an increased risk of death (HR:1.46, 95% CI:1.34–1.60, both p < 0.001) compared to RC alone. In the >pT2 cohort, these associations reversed, with an increased risk of death seen in the NAC + RC group (HR:1.11, 95% CI:1.05–1.18) and a decreased risk of death in the RC + AC group (HR:0.74, 95% CI:0.7–0.77, both p < 0.001). CONCLUSIONS: Patients with >ypT2 disease after NAC experienced a significant increased risk of death when compared to pathological stage-matched patients who underwent RC alone or RC + AC. Biomarkers predictive of NAC resistance may be important to optimize NAC usage and establish treatment algorithms.

Objective To analyse whether selective arterial clamping (SAC) and off‐clamp (OC) techniques during robot‐assisted partial nephrectomy (RPN) are associated with a renal functional benefit in patients with Stage 3–5 chronic kidney disease (CKD). Patients and methods The change in estimated glomerular filtration rate (eGFR) over time was compared between 462 patients with baseline CKD 3–5 that underwent RPN with main arterial clamping (MAC) (n = 375, 81.2%), SAC (n = 48, 10.4%) or OC (n = 39, 8.4%) using a multivariable linear mixed‐effects model. All follow‐up eGFRs, including baseline and follow‐up between 3 and 24 months, were included in the model for analysis. The median follow‐up was 12.0 months (interquartile range 6.7–16.5; range 3.0–24.0 months). Results In the multivariable linear mixed‐effects model adjusting for characteristics including tumour size and the R.E.N.A.L. (Radius; Exophytic/Endophytic; Nearness; Anterior/Posterior; Location) Nephrometry Score, the change in eGFR over time was not significantly different between SAC and MAC RPN (β = −1.20, 95% confidence interval [CI] −5.45, 3.06; P = 0.582) and OC and MAC RPN (β = −1.57, 95% CI −5.21, 2.08; P = 0.400). Only 20 (15 MAC, two SAC, three OC) patients overall had progression of their CKD stage at last follow‐up. The mean ischaemia time was 17 min for MAC and 15 min for SAC. There was no benefit to SAC or OC in terms of blood loss, perioperative complications, length of stay, or surgical margins. Conclusion SAC and OC techniques during RPN were not associated with benefit in preservation of eGFR in patients with baseline CKD.