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Introduction: Upper tract urothelial carcinoma (UTUC) is a rare malignancy with poor prognosis. Radical nephroureterectomy (RNU) remains the standard treatment for high-risk UTUC. Considering the decline in renal function with RNU and results from prospective trials, NAC has emerged as a favored perioperative treatment for chemo-eligible patients with UTUC. However, strong evidence of the efficacy of NAC and predictors for its use are scarce. We aimed to assess trends in NAC utilization and pathologic outcomes and survival with NAC use., Methods: The National Cancer Database was queried for patients with high-grade cTanyNanyM0 UTUC treated with RNU from 2004 to 2019. Outcomes included overall survival (OS), pathologic response (pR) and pathologic complete response (pCR), defined as ≤pT1pN0/X and pT0pN0/X, respectively., Results: Of 6,645 patients treated with RNU, 209 received RNU NAC. Greater distance from treatment facility decreased the likelihood of receiving NAC. Higher cT stages (OR 1.72, P = .028), cN+ status (OR 7.40, P < .001) and treatment at an academic facility (OR 2.02, P < .001) predicted NAC treatment. NAC was associated with 34.0% pR and 5.3% pCR. In multivariable analysis, patients with pR and pCR had improved OS (HR = 0.176, P < .014)., Conclusion: We report significant response rates with NAC and improved OS in patients who experienced pR or pCR. Over a 15-year study period, NAC was underutilized, especially in nonacademic settings and among patients living farther from care facilities, underscoring the need for improved regionalization and multidisciplinary approaches in UTUC management., Competing Interests: Disclosures None of the authors have any relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Bladder cancer (BCa) with variant histology (VH) is notably aggressive and not as well studied as pure urothelial carcinoma (UC). The characteristics of variant BCa in the setting of metastatic disease may contribute to treatment response/resistance and subsequent disease progression. In this study, we sought to assess VH's impact on metastasis sites at presentation in metastatic BCa., Methods: The National Cancer Database was queried from 2004 to 2019 to analyze cT1-4 cN0-3 cM1 patients with UC and VH BCa. The primary endpoint was the presence of metastasis to different organs. Binomial multivariable logistic regression was performed to determine the impact of VH on metastatic sites while controlling for multiple variables., Results: Total 6005 eligible patients diagnosed with either UC or VH were included. Patients with small cell histology, the second most common VH, were more likely to have liver metastasis (OR: 4.335) while less likely to have lung metastases (OR: 0.521). Squamous cell carcinoma decreased the odds of bone metastasis (OR: 0.449). Adenocarcinoma increased the odds of lung metastases (OR: 1.690). Micropapillary VH is less likely to metastasize to the lungs (OR: 0.182) but more likely to spread to nonregional lymph nodes (OR: 2.623). Sarcomatoid subtype did not exhibit a statistically significant variation in the odds ratio for any of the metastatic sites., Conclusion: This study comprehensively analyzes the limited research regarding metastatic BCa and VH. Our analysis underscores each subtype exhibiting heterogeneous metastatic tropism. Importantly, these findings illustrate the role of routine somatic gene expression profiling to guide adequate staging and treatment intensification and to offer a foundation for future studies of VH BCa care., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Concern for overtreatment in very low-, low-, and favorable intermediate-risk prostate cancer has promoted a more conservative approach through active surveillance (AS) with comparable survival outcomes. We analyzed the National Cancer Database (NCDB) to determine if delaying radical prostatectomy greater than 6 months is associated with an increase in the rate of adverse pathology or secondary treatment (adjuvant or salvage) at radical prostatectomy., Methods: Utilizing the NCDB from 2004 to 2019, 40 to 75-year-old men with very low-, low-, and favorable-intermediate-risk prostate cancer, as defined by the National Comprehensive Cancer Network, were identified for this study. These individuals received radical prostatectomy either before or after 6 months following diagnosis. Clinical, demographic, and pathologic characteristics were obtained. Adverse pathologic outcomes were defined as pT3-4N0-1 and/or positive surgical margins. Multiple logistic regression models were used to predict delays in treatment, adverse pathologic outcomes, and receipt of secondary therapy. Survival analysis was performed using the Cox Proportional Hazards Model and the Kaplan-Meier Method., Results: Of the 195,397 patients who met inclusion criteria, only 13,393 patients received surgery 6 months after diagnosis. The median time of delay was 7.5 months compared to 2.3 months in the immediate treatment group. Overall, delaying surgery had no statistically significant impact on adverse pathologic outcomes, regardless of risk category. However, when accounting for the interaction between race and delayed treatment, non-Hispanic black patients who received a delay in treatment were more likely to experience adverse features (OR 1.12, 95%CI 1.00-1.26, P = .041). Conversely, patients who had delayed surgery were less likely to receive additional therapy (either adjuvant or salvage) (OR 0.60, 95%CI 0.52-0.68, P < .001). Survival analysis showed that both groups fared well, with a 5-year survival of 97% for both groups. The treatment group was not predictive of survival., Conclusion: Overall, delaying surgery more than 6 months following diagnosis did not have a significant impact on adverse pathologic features or overall survival. However, when specifically looking at non-Hispanic black patients with a treatment delay, these patients were at increased risk for adverse features, suggesting that the negative impact of treatment delay depends on the patient's race. As race is a social construct, this finding likely points to the complex socioeconomic factors that contribute to overall health outcomes rather than any inherent disease characteristics. Lastly, delayed treatment patients were actually less likely to require secondary therapy, regardless of race, possibly reflecting high clinician acumen in selecting patients appropriate for treatment delay. The results suggest that patients who ultimately "fail" AS and require subsequent surgery have overall comparable survival outcomes. However, pathologic outcomes are dependent on the patient's underlying race, with non-Hispanic black patients experiencing an increased risk of adverse outcomes if treatment is delayed., Competing Interests: Disclosure The authors have no financial conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Recent studies have highlighted the overall survival (OS) benefit of cytoreductive radical cystectomy (CRC) in metastatic bladder cancer (mBCa). Cytoreductive surgery has been established in other urologic cancers. However, the efficacy of CRC and optimal criteria for patient selection in mBCa is unclear. This study investigated the oncologic efficacy of CRC, particularly emphasizing the location and number of metastasis sites as a predictor of survival and treatment response., Methods: A retrospective analysis of cT2-4N0-3M1 mBCa patients treated with multiagent chemotherapy between 2004 and 2019 was conducted using the National Cancer Database. Patients were classified by additional treatment with CRC or conservative local treatment (CLT), consisting of transurethral resection of bladder tumor, radiation, or no local treatment and propensity score (PS) matched. Kaplan-Meier analysis and multivariate Cox Proportional Hazards model assessed the effect of CRC or CLT on OS within the matched cohort and in four subgroups (1) patients with only distant lymph node (LN) metastasis vs. any organ metastasis, (2) patients with single metastasis vs. multiple metastases. Sensitivity analysis estimated the influence of unmeasured confounders on CRC OS benefit., Results: Propensity matching yielded 247 and 251 patients treated with CRC and CLT, respectively. Median OS in patients who received CRC was greater than that of patients treated with CLT (20.4 months vs. 12.0 months, P < 0.001). CRC was associated with reduced mortality risk in patients with only distant LN metastases (HR = 0.545, P = 0.039), any organ metastasis (HR = 0.421, P < 0.001), and single visceral metastasis (HR = 0.483, P = 0.002). However, CRC did not significantly improve OS in patients with multiple metastases (HR = 0.501, P = 0.064)., Conclusion: These findings demonstrate an OS benefit of CRC with multiagent chemotherapy and pinpoint multiple visceral metastases as a potential contraindication for CRC. Although limited by the influence of unmeasured confounders, these findings may inform future prospective investigations into CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Numerous studies have shown that both race and insurance status may affect prostate cancer (PCa) workup and treatment. Preliminary investigations have shown that these factors may be associated with treatment delays, which may indicate inequitable care and increase risk of tumor progression. This investigation aimed to assess whether race and insurance impacted the interval between multiparametric MRI (mpMRI)-to-biopsy, and biopsy-to-prostatectomy., Materials and Methods: A single-institution analysis of 261 patients with recorded race and insurance data was performed using an Institutional Review Board-compliant database with information spanning from 2016 to 2022. Race was self-reported during intake, and insurance status was retrieved from the electronic medical record. Insurance was sub-divided into private, Medicare, and Medicaid. Diagnostic or treatment latency was defined as time between mpMRI-to-biopsy, or biopsy-to-surgery., Results: Stratified by race, there was no difference in either latency period when comparing African American (AA) and white patients. Stratified by insurance status, there was no difference in time from mpMRI-to-biopsy (P = .50), but there was a significantly longer interval from biopsy-to-prostatectomy for patients with Medicaid insurance (P = .02). Patients with Medicaid waited on average 168 days to receive surgery, in contrast to 92 days for private and 87 for Medicare. Notably, 82% of Medicaid patients were AA., Conclusion: Insurance status, which is inherently linked to race and social determinants of health, portended a significantly increased interval between biopsy and surgery. Physicians should be aware of the relationship between insurance status and treatment delay, as well as its potential downstream consequences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Despite concerns of atypical recurrence following robotic-assisted radical cystectomy (RARC), utilization of the modality is increasing. The presumed mechanisms of peritoneal immunomodulation and pneumoperitoneum-induced tumor cell intravasation are especially relevant for higher stage, locally advanced disease, where intrinsic metastatic potential of tumor cells may be greater. This study aims to compare the oncologic outcomes and survival after RARC compared to open radical cystectomy (ORC) among patients with stage pT3-4 or node-positive muscle-invasive bladder cancer., Patients and Methods: Retrospective cohort analysis of pT3-4N0-3 and pT(any)N1-3 patients who underwent RARC or ORC was performed using the National Cancer Database (2010-2016) to investigate perioperative and oncologic outcomes., Results: 9,062 ORC cases and 2,544 RARC cases met inclusion criteria. The robotic approach was significantly associated with superior unadjusted survival compared to open as well as lower proportions of unadjusted 30- and 90-day mortality, lower positive margin status, and shorter surgical inpatient stay (all respective P<.05). However, after adjusting for confounding covariates, multivariable analysis revealed no difference in mortality hazard or odds of any of the above secondary outcomes with the exception of shorter inpatient stay and higher lymph node yield. Patients treated with RARC were more likely to have neoadjuvant chemotherapy., Conclusions: RARC is no less safe than ORC for patients with locally advanced bladder cancer on the basis of overall, 30- and 90-day survival. Unadjusted mortality and surgical outcomes demonstrate advantages to RARC, which are attenuated after multivariate analysis. Perioperative benefits may favor the robotic approach, consistent with previous randomized control studies., (Copyright © 2021. Published by Elsevier Inc.)

Brain access remains a major challenge in drug testing. The nearly 'impermeable' blood-brain-barrier (BBB) prevents most drugs from gaining access to brain cells via systematic intravenous (IV) injection. In this study, silk fibroin films were used as drug carrier as well as cell culture substrate to simulate the in vivo interface between drug reservoir and brain cells for testing drug delivery in the brain. In in vitro studies, film-released arabinofuranosyl cytidine (AraC), a mitotic inhibitor, selectively killed glial cells in film-supported mixed neural cell cultures; with widened dosage windows for drug efficacy and tolerance compared to drugs in solution. In the brain, the presence of silk films was well tolerated with no signs of acute neuroinflammation, cell death, or altered brain function. Topical application of silk films on the cortical surface delivered Evans blue, a BBB-impenetrable fluorescent marker, through the intact dura matter into the parenchyma of the ipsilateral hemisphere as deep as the hippocampal region, but not the contralateral hemisphere. In a mouse traumatic brain injury (TBI) model, necrosis markers by film delivery accessed more cells in the lesion core than by con-current IV delivery; whereas the total coverage including the peri-lesional area appeared to be comparable between the two routes. The complementary distribution patterns of co-delivered markers provided direct evidence of the partial confinement of either route's access to brain cells by a restrictive zone near the lesion border. Finally, film-delivered necrostatin-1 reduced overall cell necrosis by approximately 40% in the TBI model. These findings from representative small molecules of delivery route-dependent drug access are broadly applicable for evaluating drug actions both in vitro and in vivo. Combined with its demonstrated role of supporting neuron-electrode interfaces, the film system can be further developed for testing a range of neuromodulation approaches (i.e., drug delivery, electrical stimulation, cell graft) in the brain. STATEMENT OF SIGNIFICANCE: This study demonstrated that silk fibroin films can be used to evaluate drug actions both in vitro and in vivo, partially overcoming the significant delivery barriers of the brain. This system can be adapted for efficient drug access to specific brain regions and/or cell types. The film system can be further developed for testing a range of interventions with drugs, electrical signals or cell graft for analysis of treatment outcomes including cell responses and brain function., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: Seminal vesicle invasion (SVI) is a risk factor for poor oncologic outcome in patients with prostate cancer. Modifications to the pelvic lymph node dissection (PLND) during radical prostatectomy (RP) have been reported to have a therapeutic benefit. The present study is the first to determine if lymph node yield (LNY) is associated with a lower risk of biochemical recurrence (BCR) for men with SVI., Methods: A total of 220 patients from 2 high-volume institutions who underwent RP without adjuvant treatment between 1990 and 2015 and had prostate cancer with SVI (i.e., pT3b) were identified, and 21 patients did not undergo lymph node dissection. BCR was defined as a postoperative PSA>0.2ng/mL, or use of salvage androgen deprivation therapy (ADT) or radiation. Multivariable Cox proportional hazards models were used to determine whether LNY was predictive of BCR, controlling for PSA, pathologic Gleason Score, pathologic lymph node status, NCCN risk category, etc. The Kaplan-Meier method was used to determine 3-year freedom from BCR., Results: Median number of lymph nodes sampled were 7 (IQR: 3-12; range: 0-35) and 90.5% underwent PLND. The estimated 3-year BCR rate was 43.9%. Results from multivariable analysis demonstrated that LNY was not significantly associated with risk of BCR overall (HR = 1.00, 95% CI: 0.98-1.03; P = 0.848) for pN0 (HR = 0.99, 95% CI: 0.97-1.03; P = 0.916) or pN1 patients (HR = 0.96, 95% CI: 0.88-1.06; P = 0.468). Overall, PSA (HR = 1.02, P<0.001) and biopsy Gleason sum ≥ 8 (HR = 1.81, P = 0.001) were associated with an increased risk of BCR, and increasing LNY increased the likelihood of detecting>2 positive lymph nodes (OR = 1.27, 95% CI: 1.06-1.65, P = 0.023)., Conclusion: Seminal vesicle invasion is associated with an increased risk of BCR at 3 years, primarily due to pathologic Gleason score and PSA. Although greater lymph node yield is diagnostic and facilitates more accurate pathologic staging, our data do not show a therapeutic benefit in reducing BCR., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: To compare oncologic outcomes of different definitive treatment (DT) modalities in a cohort of patients with prostate cancer (PCa) after active surveillance (AS)., Methods: We identified 237 patients with National Comprehensive Cancer Network (NCCN) low- and intermediate-risk prostate cancer diagnosed from 1990 to 2012 who did not undergo immediate DT within 12 months of diagnosis (ie, AS patients as well as watchful waiting and those refusing DT). Charts were examined for clinical/pathologic data and type of DT: surgery (RP), radiation including brachytherapy (XRT), cryotherapy, and androgen deprivation therapy monotherapy (ADT). The impact of DT on oncologic outcomes of biochemical recurrence (BCR), metastasis, disease-specific (DSS), and overall survival (OS) was examined with the Cox proportional hazards model, along with the Kaplan-Meier method and log-rank test., Results: After median time on AS of 63.4 months, 40% of patients underwent DT: 47% XRT, 28% RP, 14% ADT, and 11% cryotherapy. On multivariable analysis, the use of XRT predicted higher BCR (hazard ratio [HR] 6.1, P = .001) and worse overall mortality (HR 2.1, P = .03) compared with other treatments, controlling for age, Charlson Comorbidity Index (CCI), stage, Gleason score, and NCCN risk category. Median follow-up was 71.7 months. On Kaplan-Meier analysis, 10-year OS was superior for RP versus XRT among patients with prostatic specific antigen (PSA) velocity >2.0 ng/mL/y., Conclusions: Low- and intermediate-risk patients with PCa who progress to DT after AS may be inadequately treated with radiation therapy compared with other DT modalities, especially when pretreatment PSA velocity is > 2 ng/mL/y., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The significance of a "close" but negative surgical margin after radical prostatectomy (RP) is controversial. We evaluated the effect of a close surgical margin (CSM) on biochemical recurrence (BCR) compared to a negative margin after RP., Materials and Methods: Pathologic records of men who underwent RP from 2005-2011 were retrospectively reviewed. Margin status was classified as "positive" (PSM), "negative" (NSM), or "close" (<1mm from margin). BCR was defined as 2 consecutive postoperative prostate specific antigen measurements >0.2ng/ml. Probability of BCR was estimated using the Kaplan-Meier method and stratified by margin status. Univariable and multivariable Cox proportional hazards models were used to determine whether close margin status was associated with an increased rate of BCR., Results: A total of 609 consecutive patients underwent RP (93% robotic) and had complete pathologic data. A total of 126 (20.7%) had PSM, 453 (74.4%) had NSM, and 30 (4.9%) had CSM (mean<0.44mm). The 3-year BCR-free survival for patients with CSM was similar to those with PSM (70.4% vs. 74.5%, log rank P = 0.66) and significantly worse than those with NSM (90%, log rank P<0.001). On multivariable regression, positive margin status (HR = 3.26, P<0.001) was significantly associated with a higher risk of BCR, along with close margins (HR = 2.7, P = 0.04)., Conclusions: BCR for patients with CSM at RP is tantamount to PSM patients. CSM <1mm should be explicitly noted on pathology reports. Patients with this finding should be followed up closely and offered adjuvant therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: To date, no population studies have been designed to assess the impact of race and gender on the rate of nephron-sparing surgery (NSS) across the United States., Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients with T1a renal cell carcinoma (RCC) treated over the most recent decade, 1998-2007. Baseline socio-demographic data were compared between Caucasian and African-American patients using χ(2) and t-test analysis, and rates of radical nephrectomy (RN) were compared for all permutations of race and gender. A multivariate logistic regression model was in turn created with these variables to predict the odds of undergoing a radical nephrectomy. No prior assumptions were made regarding superiority of partial nephrectomy (PN) over RN as a therapeutic intervention., Results: A total of 14,953 patients were eligible for inclusion in this study, and of these, 1,804 (12%) were African-American. Comparably, African-American patients were younger (<50 years; 23 vs. 28%, P < 0.001), and had an increased rate of high grade disease (13 vs. 16%, P < 0.001). Among different subsets of race and gender, African-American women received PN least often (28%) compared with all other groups, with African-American women at a 47% increased risk of undergoing RN compared with Caucasian male counterparts (95% CI: 1.24-1.73)., Conclusions: Significant racial and gender disparities exist with regard to utilization of nephron-sparing surgery for small renal masses, particularly in African-American women. Further efforts should be directed to elucidating and addressing the rationale behind this disparity to ensure the uniformity of care., (Copyright © 2013 Elsevier Inc. All rights reserved.)