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Introduction: We evaluated surgical trends, perioperative management evolution, and oncologic outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) at a tertiary cancer center over a 24-year period., Methods: Between 1995 and 2018, we evaluated 743 consecutive patients with UTUC who underwent RNU. Generalized additive models were used to estimate the associations between date of surgery and continuous outcomes using a linear model, dichotomous outcomes using a logit link, categorical outcomes using multinomial models, and 2- and 5-year survival outcomes using Cox proportional hazards models., Results: Over the study period, preoperative diagnostic endoscopic biopsies increased from 10% to 66%, along with the proportion of patients who underwent RNU for high-grade disease from 55% to 91%. The rate of open RNU declined from 100% to 56% with a rise in minimally invasive approaches. Median lymph node yield increased with more retroperitoneal lymph node dissections performed. Neoadjuvant chemotherapy utilization increased with a contemporary utilization rate of 32%, coinciding with an increase in pT0 rate from 2% to 8%. Cancer-specific survival probabilities improved over the study period, while metastasis-free and overall survival remained stable., Conclusions: We found several changes in treatment patterns and outcomes for patients with UTUC over the past 2 decades. How individual alterations in management factors, such as patient selection, perioperative chemotherapy, lymphadenectomy, and salvage therapies, impact patient outcomes is challenging in the setting of multiple overlapping practice changes for this rare disease and warrants further investigation.

Background: This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention)., Methods and Results: This was a pooled participant-level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. The CANVAS Program included participants with type 2 diabetes at elevated cardiovascular risk, whereas the CREDENCE trial included participants with type 2 diabetes and albuminuric chronic kidney disease. Hazard ratios (HRs) with interaction terms were obtained from Cox regression models to estimate relative risk reduction with canagliflozin versus placebo across the primary and secondary prevention groups. We analyzed 5616 (38.9%) and 8804 (61.1%) individuals in the primary and secondary prevention subgroups, respectively. Primary versus secondary prevention participants were on average younger (62.2 versus 63.8 years of age) and more often women (42% versus 31%). Canagliflozin reduced the risk of major adverse cardiovascular events (HR, 0.84 [95% CI, 0.76-0.94]) consistently across primary and secondary prevention subgroups ( P interaction =0.86). Similarly, no treatment effect heterogeneity was observed with canagliflozin for hospitalization for heart failure, cardiovascular death, end-stage kidney disease, or all-cause mortality (all P interaction >0.5)., Conclusions: Canagliflozin reduced cardiovascular and kidney outcomes with no statistical evidence of heterogeneity for the treatment effect across the primary and secondary prevention subgroups in the CANVAS Program and CREDENCE trial. Although studies on the optimal implementation of canagliflozin within these populations are warranted, these results reinforce canagliflozin's role in cardiorenal prevention and treatment in individuals with type 2 diabetes., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.

Antibodies produced by antibody-secreting plasma cells (ASCs) underlie multiple forms of long-lasting immunity. Here we examined the mechanisms regulating ASC turnover and persistence using a genetic reporter to time-stamp ASCs. This approach revealed ASC lifespans as heterogeneous and falling on a continuum, with only a small fraction surviving for >60 days. ASC longevity past 60 days was independent of isotype but correlated with a phenotype that developed progressively and ultimately associated with an underlying "long-lived" ASC (LL ASC)-enriched transcriptional program. While some of the differences between LL ASCs and other ASCs appeared to be acquired with age, other features were shared with some younger ASCs, such as high CD138 and CD93. Turnover was unaffected by altered ASC production, arguing against competition for niches as a major driver of turnover. Thus, ASC turnover is set by intrinsic lifespan limits, with steady-state population dynamics governed by niche vacancy rather than displacement., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cellular heterogeneity in cancer is linked to disease progression and therapy response, although mechanisms regulating distinct cellular states within tumors are not well understood. We identified melanin pigment content as a major source of cellular heterogeneity in melanoma and compared RNAseq data from high-pigmented (HPCs) and low-pigmented melanoma cells (LPCs), suggesting EZH2 as a master regulator of these states. EZH2 protein was found to be upregulated in LPCs and inversely correlated with melanin deposition in pigmented patient melanomas. Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA or degradation by DZNep or MS1943 inhibited growth of LPCs and induced HPCs. As the proteasomal inhibitor MG132 induced EZH2 protein in HPCs, we evaluated ubiquitin pathway proteins in HPC vs LPCs. Biochemical assays and animal studies demonstrated that in LPCs, the E2-conjugating enzyme UBE2L6 depletes EZH2 protein in cooperation with UBR4, an E3 ligase, via ubiquitination at EZH2's K381 residue, and is downregulated in LPCs by UHRF1-mediated CpG methylation. Targeting UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 offers potential for modulating the activity of this oncoprotein in contexts in which conventional EZH2 methyltransferase inhibitors are ineffective., (© 2023. The Author(s).)

Purpose: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability., Methods: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability., Results: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001)., Conclusion: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Urinary tract leiomyomas are rare, benign mesenchymal tumors that are traditionally treated with complete surgical excision. We present three cases of urinary tract leiomyoma - two located in the bladder and one in the ureter. Both bladder leiomyomas were treated with transurethral resection of bladder tumor (TURBT) with no evidence of recurrent disease, while the upper tract leiomyoma was managed with surveillance by patient preference, which to our knowledge, has not been previously described. The ureteral leiomyoma has remained stable at five years followup from initial diagnosis. Given the benign nature of leiomyomas and the overall low recurrence rate reported in the literature, bladder-sparing options should be emphasized when feasible, with active surveillance potentially applicable for highly select patients.

Objective: To describe litigation patterns of transurethral surgery in the treatment of benign prostatic hyperplasia including verdicts, types of lawsuits, plaintiff claims, and timing of the claims., Methods: Data was gathered by searching for litigation cases between January 1, 1980 and December 1, 2021 in the Westlaw legal database using keywords for transurethral surgeries for benign prostatic hyperplasia. Extracted data included case type, general description of the plaintiffs and defendants, plaintiff claims, and whether the claim involved preoperative, perioperative, or postoperative management, verdict, and indemnity awards., Results: The Westlaw search yielded 44 unique cases after removing duplicate and irrelevant cases. The most common surgery resulting in a lawsuit was transurethral resection of the prostate (70%) and urologists were the most frequently named defendant (80%). The most common plaintiff claims were sexual dysfunction (36%), irritative lower urinary tract symptoms (32%), and lack of consent (27%). Among malpractice cases, the verdict was in favor of the defendant in most cases (71%) and among Eighth Amendment violation cases, the verdict was in favor of the defendant in every case. The average indemnity payment was $565,845 and the highest indemnity payment was $1,020,000., Conclusion: Complications of transurethral surgeries and lack of consent are common reasons for patient's filing a lawsuit. Healthcare providers should ensure patient understanding of surgical risks and thoroughly document the conversation. Providers should be aware of the causes for litigation among transurethral surgeries for benign prostatic hyperplasia and of the possibility of Eighth Amendment violation lawsuits when treating prison inmates., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Little is known regarding the prognostic implications of variant histology in upper tract urothelial carcinoma (UTUC). We sought to evaluate the impact of variant histology UTUC on patient survival outcomes at our institution., Materials and Methods: We identified 705 patients who underwent nephroureterectomy for UTUC at our institution between January 1995 and December 2018. We tested the association between variant histology and cancer-specific survival (CSS) and overall survival (OS) using separate multivariable Cox models after adjusting for pathological stage., Results: Forty-seven patients (6.7%) had variant histology, with prevalence increasing over time (p=0.003). Other demographic and surgical characteristics were similar between variant histology and pure urothelial carcinoma groups. While patients with variant histology were more likely to receive neoadjuvant chemotherapy (38% vs 15%, p <0.001), they were also more likely to have a higher pathological T stage (p <0.001). Variant histology was associated with significantly worse CSS (HR: 2.14; 95% CI 1.33, 3.44; p=0.002) and OS (HR: 1.74; 95% CI 1.15, 2.63; p=0.008). After adjusting for pathological T stage, variant histology was not significantly associated with CSS (HR: 1.17; 95% CI 0.72, 1.89; p=0.5) or OS (HR: 1.20; 95% CI 0.79, 1.84; p=0.4)., Conclusions: Variant histology UTUC is associated with advanced stage and poor survival, and could serve as a useful biomarker for high-risk disease when pathological stage is unknown. However, the inferior CSS and OS with variant histology can be explained by the higher tumor stage on nephroureterectomy. Thus, finding variant histology on surgical pathology does not provide additional prognostic information beyond stage.

The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Barrier integrity is central to the maintenance of healthy immunological homeostasis. Impaired skin barrier function is linked with enhanced allergen sensitization and the development of diseases such as atopic dermatitis (AD), which can precede the development of other allergic disorders, for example, food allergies and asthma. Epidemiological evidence indicates that children suffering from allergies have lower levels of dietary fibre-derived short-chain fatty acids (SCFA). Using an experimental model of AD-like skin inflammation, we report that a fermentable fibre-rich diet alleviates systemic allergen sensitization and disease severity. The gut-skin axis underpins this phenomenon through SCFA production, particularly butyrate, which strengthens skin barrier function by altering mitochondrial metabolism of epidermal keratinocytes and the production of key structural components. Our results demonstrate that dietary fibre and SCFA improve epidermal barrier integrity, ultimately limiting early allergen sensitization and disease development.The Graphical Abstract was designed using Servier Medical Art images ( https://smart.servier.com )., (© 2022. The Author(s).)

Objective: To evaluate whether urothelial carcinoma (UC) with sarcomatoid differentiation is associated with a lower pathological response rate to neoadjuvant chemotherapy (NAC) and worse oncological outcomes compared to UC without variant histology among patients undergoing radical cystectomy., Patients and Methods: Patients with UC undergoing cystectomy from 1995 to 2018 at the Memorial Sloan Kettering Cancer Centre were identified. Patients with sarcomatoid differentiation at transurethral resection (TUR) or cystectomy, and patients without variant histology were selected. Downstaging from ≥cT2 to ≤pT1N0 defined partial response and pT0N0 defined complete response. Recurrence-free, cancer-specific and overall survival were modelled., Results: We identified 131 patients with sarcomatoid differentiation and 1722 patients without variant histology, of whom 25 with sarcomatoid histology on biopsy and 313 without variant histology received NAC. Those with sarcomatoid differentiation presented with higher consensus tumour stage (94% ≥T2 vs 62%; P < 0.001) and were, therefore, more likely to receive NAC (29% vs 18%; P = 0.003). We found no evidence to support a difference in partial (24% vs 31%) or complete (20% vs 24%) response between patients with sarcomatoid histology and those with pure UC at TUR (P = 0.6). Among patients with sarcomatoid differentiation, 5-year recurrence-free survival was 55% (95% confidence interval [CI] 41-74) among patients receiving NAC and 40% (95% CI 31-52) among patients undergoing cystectomy alone (P = 0.1). Adjusting for stage, nodal involvement, margin status and receipt of NAC, sarcomatoid differentiation was associated with worse recurrence-free (hazard ratio [HR] 1.82, 95% CI 1.39-2.39), disease-specific (HR 1.66, 95% CI 1.23-2.22), and overall survival (HR 1.37, 95% CI 1.06-1.78)., Conclusions: Sarcomatoid differentiation was associated with higher stage at presentation and independently associated with worse survival. Given similar pathological response rates if sarcomatoid differentiation is detected at initial resection, and greater survival among patients receiving NAC, treatment with NAC appears warranted. Other drivers of the poor outcomes of this histology must be investigated., (© 2021 The Authors BJU International © 2021 BJU International.)

Introduction: We sought to better understand the baseline knowledge and practices of the general population regarding testicular cancer (TC) and testicular self-examination (TSE) in an effort to understand whether current screening guidelines reflect their viewpoint. The U.S. Preventive Services Task Force (USPSTF) currently recommends against TSE for TC screening due to a lack of data to support a benefit. Early detection of TC may reduce the required burden of therapy and associated long-term toxicities., Methods: This was a cross-sectional survey study. Participants (median age 33 years, IQR 28-39) were recruited via Amazon Mechanical Turk, a validated crowdsourcing platform used to recruit minimally compensated participants., Results: A total of 250 men rated themselves as "somewhat unknowledgeable" about TC, with no respondents considering themselves "very knowledgeable." Only 26.4% of men knew that TC was curable most of the time. Despite 90.8% of men feeling that their doctor had some role in discussing TC/TSE, only 17.2% had discussed these topics with their doctor. Even after being informed of the rationale behind USPSTF recommendations, only 8% of men thought that potential false positives of TSE would be more important than the rare chance of finding early TC., Conclusions: American men do not feel knowledgeable about TC, have a favorable attitude toward TSE and want their doctor to discuss these topics. Shared decision making regarding TC screening is warranted given the low risk of harm and patient interest, and continued accrual of data on this topic is necessary given the lack of prospective work to date., Competing Interests: The Authors have no conflicts of interest to declare., (© 2021 by American Urological Association Education and Research, Inc.)

Alveologenesis requires the coordinated modulation of the epithelial and mesenchymal compartments to generate mature alveolar saccules for efficient gas exchange. However, the molecular mechanisms underlying the epithelial-mesenchymal interaction during alveologenesis are poorly understood. Here, we report that Wnts produced by epithelial cells are crucial for neonatal alveologenesis. Deletion of the Wnt chaperone protein Wntless homolog (Wls) disrupts alveolar formation, resulting in enlarged saccules in Sftpc-Cre/Nkx2.1-Cre; Wlsloxp/loxp mutants. Although commitment of the alveolar epithelium is unaffected, α-SMA+ mesenchymal cells persist in the alveoli, accompanied by increased collagen deposition, and mutants exhibit exacerbated fibrosis following bleomycin challenge. Notably, α-SMA+ cells include a significant number of endothelial cells resembling endothelial to mesenchymal transition (EndMT), which is also present in Ager-CreER; Wlsloxp/loxp mutants following early postnatal Wls deletion. These findings provide initial evidence that epithelial-derived Wnts are crucial for the differentiation of the surrounding mesenchyme during early postnatal alveologenesis., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Objective: To describe the safety and efficacy of partial nephrectomy (PN) in comparison to radical nephrectomy (RN) for surgically managed renal hilar tumors., Materials and Methods: We retrospectively reviewed institutional records of patients with a small (<5 cm) solitary renal (hilar or non-hilar) mass who underwent PN or RN between 2008 and 2018. Hilar tumors were defined as those at medial position, abutting the renal vessels. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method., Results: Of 1,951 eligible patients, 399 had hilar tumors (292 scheduled for PN, 107 RN) and 1,552 had non-hilar tumors (scheduled for PN). We found no significant differences in survival measures between hilar and non-hilar tumors in patients selected for PN. Patients scheduled for PN for hilar tumors had higher rates of ≥grade II postoperative surgical complications compared to patients scheduled to receive PN for non-hilar tumors (13% vs 8.6%; log-rank P = .018) and non-statistically significantly elevated rates of ≥grade II complications compared to patients scheduled for RN for hilar tumors (13% vs 6.5%; difference 6%, 95% CI 0.4%, 13%; log-rank P = .07)., Conclusion: PN for hilar and non-hilar renal masses (<5cm) experience comparable oncologic outcomes though increased risk of complications for hilar masses. PN for hilar tumors was associated with better renal function and overall survival with non-statistically elevated risk of grade II or higher complications than RN. A renal tumor located at the hilum should not be a contra-indication for performing PN., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To assess interviewing applicant perceptions of a virtual urology residency interview in the setting of changes mandated by COVID-19 and to determine applicant preference for virtual or in person interviews. Applicant perceptions of multiple interview components were queried to identify program specific and interview modality specific strengths or weaknesses in the 2020 to 2021 Urology Match., Methods: A 12 question multiple choice and free text survey was emailed to 66 virtually interviewed applicants for open residency positions at a metropolitan training program after conclusion of interviews. Items of interest included interview type preference, overall interview impression, and recommendations for improvement., Results: A total of 50 of 66 (76%) applicants completed the survey corresponding to approximately 11% of the 2020 national urology applicant pool. A total of 49 of 50 (96%) respondents assessed faculty interaction and the virtual platform positively. A total of 38 of 50 (76%) was satisfied with their resident interaction and 32 of 50 (64%) applicants stated they were able to satisfactorily evaluate the site and program. Ultimately, 39 of 50 (78%) respondents would have preferred an in person interview to our virtual interview. Respondents cited challenges in assessing program culture and program physical site virtually., Conclusion: The majority of survey respondents indicated a preference for in person interviews. A smaller proportion of applicants preferred virtual interviews citing their convenience and lower cost. Efforts to improve the virtual interview experience may focus on improving applicant-resident interaction and remote site assessment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To review medical malpractice trends and to identify the most common claims filed against medical providers for the management of patients with priapism., Methods: Using the Westlaw legal database, a search was done for the keyword "priapism" between July 1, 1980 and July 1, 2020. Cases were evaluated for plaintiff demographics, reasons for filing claims, management outcomes, legal verdicts and awards and further categorized based upon the timing of the alleged malpractice., Results: Alleged negligence during the pre-management period was cited in 30 cases. Administration of psychotropic medications was the most common reasons for filing pre-management claims 22/56 (39.3%). Delay in care accounted for 18/56 (32.1%) and complications of surgery were 5/56 (8.9%) of claims. The majority of the completed cases were in favor of the defendants (39/47; 83.0%). There was no association between type of health care provider or timing of alleged malpractice and ultimate verdict., Conclusions: Prescribing psychoactive medications without warning of the adverse effect profile is the most common reason for claims filed against providers with trazodone as the leading medication. Medical providers should ensure that patients are well informed of this adverse effect prior to prescription. Regardless, the majority of medical malpractice cases carry a verdict in favor of the defendant., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Rezūm vapor ablation is a minimally invasive treatment for benign prostatic hyperplasia (BPH) that uses injections of sterile water vapor directly into the prostate for tissue ablation. Although Rezūm is currently indicated for use in men with prostate sizes ≥30 and ≤80 ml, it is unclear how effective Rezūm is for men in urinary retention. We sought to determine whether Rezūm is effective in the treatment of catheter-dependent urinary retention secondary to BPH., Methods: A retrospective chart review was conducted on consecutive patients who presented for urinary retention and subsequently treated with Rezūm. We evaluated procedural details and examined variables pre- and post-Rezūm (at 6 months) including International Prostate Symptom Score (IPSS), IPSS quality of life (IPSS-QOL), maximum flow (Q max ), post void residual volume (PVR), prostate specific antigen, rate of retention, and use of alpha blockers and 5-alpha reductase inhibitor (5ARI)., Results: Of the 49 patients included in this study, median age of was 73 years, median prostate volume was 73cc (Interquartile range [IQR]: 50, 103) and a median lobe was present in 80% of patients. All patients were in urinary retention before treatment with a median PVR of 900 ml (IQR: 566, 1146). Following Rezum, IPSS (17 pre-Rezūm, 4 post-Rezūm) and IPSS-QOL (4 pre-Rezūm, 1 post-Rezūm) both improved at 6 months (p < 0.01). Q max increased from 3 to 6 ml/s (p = 0.03) and PVR decreased from 900 to 78 ml (p < 0.01). Only 17/38 patients taking alpha-blockers and 7/15 patients on 5ARIs continued therapy at 6 months following Rezūm (p < 0.01). Of the 49 patients treated, 10 (20.4%) remained in catheter dependent urinary retention following the procedure, and 6 remained in retention at 6 months (12.2%) even after further surgical therapies for BPH (p < 0.01)., Conclusion: Rezūm is a safe and effective therapy for treating catheter dependent urinary retention in patients with BPH, including those with median lobes. As a minimally invasive therapy, it is a promising option in patient, particularly those who are not suitable for prolonged anesthesia., (© 2021 Wiley Periodicals LLC.)

The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The level of expression of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) is a predictive biomarker for cancer immunotherapy, however, its detection remains challenging due to tumour heterogeneity and the influence from the binding of therapeutic agents. We recently developed [ 99m Tc]-NM-01 as a companion diagnostic imaging agent for non-invasive molecular imaging of PD-L1 by single-photon emission computed tomography (SPECT). The aim of the study was to evaluate the [ 99m Tc] radiolabelling of GMP graded NM-01 and its pharmacology, pharmacokinetics and toxicology. NM-01 bound specifically to human PD-L1 (K d =0.8 nM) and did not interfere with the binding of the anti-PD-L1 antibody atezolizumab. NM-01 can bind various PD-L1-positive cancer cell lines and only interact with PD-L1 expressed on the cell surface. In SPECT/CT imaging, high [ 99m Tc]-NM-01 accumulation was observed in the HCC827 mouse xenografted tumour model (30-min: 1.50 ± 0.27 %ID/g; 90-min: 1.23 ± 0.18 %ID/g), demonstrated a predominantly renal elimination (high uptake in bladder and kidney), while activity in the blood pool and other major organs remained low. The tumour-to-muscle and tumour-to-blood ratios were comparable with/without atezolizumab (P<0.04) but were significantly lowered when co-injected with excess NM-01 (P=0.04 and P=0.01, respectively.) The blood clearance of [ 99m Tc]-NM-01 is bi-phasic; consisting of an initial fast washout phase with half-life of 2.1 min and a slower clearance phase with half-life of 25.4 min. In an intravenous extended single-dose toxicity study, no treatment-related changes were observed and the maximum tolerated dose of [ 99m Tc]-NM-01 was 2.58 mg/kg. [ 99m Tc]-NM-01 has suitable properties as a potential candidate for SPECT/CT imaging of PD-L1 assessment in cancer patients., Competing Interests: N.C.L.W., Y.C., L.K.M. and H.H.T. are employees of NanoMab Technology Ltd. H.J.B. is an advisor for NanoMab Technology Ltd. G.J.R.C. is a consultant and receive research support for NanoMab Technology Ltd, Theragnostics Ltd and Serac Healthcare Ltd. F. M. M is on the advisory board of Advanced Accelerator Applications GmbH and has received institutional grants from GE Healthcare, Siemens, and NanoMab Technology Ltd., (AJNMMI Copyright © 2021.)

Objectives: To review perioperative, renal functional, and oncological outcomes of the kidney split technique in performing partial nephrectomy (PN) to resect completely endophytic renal tumors., Methods: All consecutive patients who underwent open PN with kidney split between 2015 and 2019 at our institution were included. In this approach the kidney is incised along Brodel's line in an avascular plane to locate and then resect the endophytic tumor. Clinicopathologic data, perioperative metrics, complications, renal function, recurrence, and mortality were analyzed using descriptive statistics., Results: Forty-two open PN with kidney split were performed in 40 patients. No patients required conversion to radical nephrectomy. Most tumors were pT1a renal cell carcinoma (76%), with no recurrences or deaths after a median follow-up of 15 months. All patients had tumors of moderate or high complexity by R.E.N.A.L. nephrometry score. Median cold ischemia time, operative time, estimated blood loss, and inpatient length-of-stay were 34 minutes, 152 minutes, 225 ml, and 2 days, respectively. No patients experienced any Clavien-Dindo grade 4 or 5 complications. Postoperative estimated glomerular filtration rate (eGFR) at last follow-up was >30 ml/min/1.73m 2 in all but one patient, and no patients required dialysis., Conclusions: The kidney split represents an effective PN technique to resect complex, endophytic renal tumors. In our experience, this technique affords acceptable perioperative outcomes, preserved renal function, and no short-term recurrences or mortality events. Our series highlights the importance of adapting classical surgical techniques, using cold ischemia, and relying on preoperative and intraoperative ultrasonography to effectively guide this complex kidney-sparing operation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The Royal College of Physicians and Surgeons of Canada's Competence by Design (CBD) initiative presents curricula challenges to ensure residents gain proficiency while progressing through training. To prepare first-year urology residents (R1s), we developed, implemented, and evaluated a didactic and simulation-focused boot camp to implement the CBD curriculum. We report our experiences and findings of the first three years., Methods: Urology residents from two Canadian universities participated in the two-day boot camp at the beginning of residency. Eleven didactic and six simulation sessions allowed for instruction and deliberate practice with feedback. Pre-and post-course multiple-choice questionnaires (MCQs) and an objective structured clinical exam (OSCE) evaluated knowledge and skills uptake. For initial program evaluation, three R2s served as historical controls in year 1., Results: Nineteen residents completed boot camp. The mean age was 26.4 (±2.8) and 13 were male. Participants markedly improved on the pre- and post-MCQs (year 1: 62% and 91%; year 2: 55% and 89%; year 3: 58% and 86%, respectively). Participants scored marginally higher than the controls on four of the six OSCE stations. OSCE scores remained >88% over the three cohorts. All participants reported higher confidence levels post-boot camp and felt it was excellent preparation for residency., Conclusions: During its first three years, our urology boot camp has demonstrated high feasibility and utility. Knowledge and technical skills uptake were established via MCQ and OSCE results, with participants' scores near or above those of R2 controls. This boot camp will remain in our CBD curriculum and can provide a framework for other urology residency programs.

Much about the range of pathogens, frequency of coinfection, and clinical effects of reproductive tract infections (RTIs) among pregnant women remains unknown. We report on RTIs (Mycoplasma genitalium, Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Treponema pallidum subspecies pallidum, bacterial vaginosis, and vulvovaginal candidiasis) and other reproductive health indicators in 699 pregnant women in Papua New Guinea during 2015-2017. We found M. genitalium, an emerging pathogen in Papua New Guinea, in 12.5% of participants. These infections showed no evidence of macrolide resistance. In total, 74.1% of pregnant women had >1 RTI; most of these infections were treatable. We detected sexually transmitted infections (excluding syphilis) in 37.7% of women. Our findings showed that syndromic management of infections is greatly inadequate. In total, 98.4% of women had never used barrier contraception. These findings will inform efforts to improve reproductive healthcare in Papua New Guinea.

Background: Allergic skin inflammation often presents in early childhood; however, little is known about the events leading to its initiation and whether it is transient or long-term in nature., Objective: We sought to determine the immunologic rules that govern skin inflammation in early life., Methods: Neonatal and adult mice were epicutaneously sensitized with allergen followed by airway allergen challenge. Epicutaneous application of labeled allergen allowed for determination of antigen uptake and processing by antigen-presenting cells. RNAseq and microbiome analysis was performed on skin from neonatal and adult specific pathogen-free and germ-free mice., Results: A mixed T H 2/T H 17 inflammatory response in the skin and the lungs of adult mice was observed following sensitization and challenge. Comparatively, neonatal mice did not develop overt skin inflammation, but exhibited systemic release of IL-17a and a T H 2-dominated lung response. Mechanical skin barrier disruption was not sufficient to drive allergic skin inflammation, although it did promote systemic immune priming. Skin of neonatal mice and adult germ-free mice was seeded with low numbers of antigen-presenting cells and impaired chemokine and alarmin production. Enhanced chemokine and alarmin production, and seeding of the skin with antigen-presenting cells capable of instructing recruited cells to elicit their effector function, was, at least in part, dependent on formation of the microbiome, and consequently contributed to the development of overt skin disease., Conclusions: These data shed light on the principles that underlie allergic inflammation in different tissues and highlight a window of opportunity that might exist for early-life prevention of allergic diseases., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Low-coverage whole-genome sequencing (LC-WGS) can provide insight into oncogenic molecular changes. Serum extracellular vesicles (EV) represent a novel liquid biopsy source of tumoral DNA. This study compared copy number alteration (CNA) profiles generated from LC-WGS of formalin-fixed paraffin-embedded (FFPE) tumoral DNA and EV-DNA obtained from cancer patients. Patients with squamous cell carcinoma of the base of tongue (n = 3) and cutaneous squamous cell carcinoma (n = 2) were included. LC-WGS (0.5-1X coverage) was performed on FFPE-DNA and serum EV-DNA. Similarity between CNA profiles was analysed using QDNAseq. FFPE samples had a mean CNA of 31 (range 17-50) over 1.9 × 10 9 (range 1.0-2.6 × 10 9 ) bp in length, and EV samples had a mean CNA value of 17 (range 7-19) over 7.6 × 10 8 (range 2.9-15 × 10 8 ) bp in length. A mean of 8 (range 0-21) CNA over 5.9 × 10 8 (range 1.6-14 × 10 8 ) bp in length was found to overlap between EV and FFPE-derived samples per patient. Although the mean correlation efficient between samples was r = 0.34 (range - .08 to 0.99), this was not statistically significant (p > 0.05). Regions of highest deletion and duplication in FFPE samples were not well reflected in the EV-DNA. Selected CNA regions in EV-associated DNA were reflective of the primary tumor, however appreciation of global CNA and areas of most significant change was lost. The utility of LC-WGS of EV-derived DNA is likely limited to molecular alterations of known interest.

Introduction: Small renal masses (SRMs), enhancing tumors <4 cm in diameter, are suspicious for renal cell carcinoma (RCC). The incidence of SRMs have risen with the increased quality and frequency of imaging. Partial nephrectomy is widely accepted as a nephron-sparing approach for the management of clinically localized RCC, with a greater than 90% disease-specific survival for stage T1a. Radiofrequency ablation (RFA) has been emerging as an alternative management strategy, with evidence suggesting RFA as a safe alternative for SRMs. We aimed to evaluate the time to recurrence and recurrence rates of SRMs treated with RFA at our institution., Methods: A retrospective review between October 2011 and May 2019 identified 141 patients with a single SRM treated with RFA at Hamilton Health Sciences and St. Joseph's Healthcare Hamilton. Patients with familial syndromes and distant metastases were excluded. Repeat RFAs of the ipsilateral kidney for incomplete ablation were not considered a new procedure. The primary variable measured was time from initial ablation to recurrence. A Cox proportional hazard regression model was used to identify possible prognostic variables for tumor recurrence defined a priori, including age, gender, mass size, RENAL nephrometry, and PADUA scores., Results: The overall average age of our patients was 69.0±11.1 years, with 71.6% being male. Average tumor size was 2.6±0.8 cm. There were 22/154 total recurrences (15.6%) post-RFA. Median followup time was 67 (18-161) months. Those with new recurrences had median time to recurrence of 15 months and no recurrence beyond 53 months. Thirteen of 141 patients had residual disease (9.2%) and were identified within the first eight months post-RFA. The only prognostic variable identified as a predictor of residual disease was tumor size (hazard ratio 2.265; p<0.001)., Conclusions: This study shows the risk of a new recurrence following RFA for SRMs is 6.4%. Most recurrences (9.2%) were a result of residual tumor at the ablation site identified within the first eight months post-RFA. No recurrences were identified beyond 53 months, with a total median followup time of 67 months. Tumor size alone, without need for complex scoring systems, may serve as a predictor of incomplete ablation following RFA and could be used to assist in shared decision-making on management strategies.

Purpose: Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease., Patients and Methods: Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients., Results: The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype., Conclusion: Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs., Competing Interests: Conflicts of Interest Statement:The authors have declared that no competing interests exist.Conflicts of Interest Statement:Authors’ disclosures of potential conflicts of interest and contributions are found at the end of this article.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Michael L. ChengHonoraria: The Lynx Group (supported by Bristol Myers Squibb), WebMD (supported by AstraZeneca), PCME (supported by Merck and Lilly) Consulting or Advisory Role: AstraZeneca, Inivata Travel, Accommodations, Expenses: Daiichi Sankyo, Allergan, Sanofi, Natera, AstraZeneca, Guardant Health, WebMD, PCMEFrançois AudenetHonoraria: Nucleix Travel, Accommodations, Expenses: Ferring, IpsenEugene J. PietzakHonoraria: UpToDate Consulting or Advisory Role: Merck, Chugai PharmaSumit IsharwalOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1232544Gopa IyerConsulting or Advisory Role: Bayer, Janssen, Mirati Therapeutics Research Funding: Mirati Therapeutics (Inst), Novartis (Inst), Debiopharm Group (Inst), Bayer (Inst)Samuel FuntStock and Other Ownership Interests: Kite Pharma, Urogen Pharma (I), Allogene Therapeutics, Neogene Therapeutics (I), Kronos Bio (I), Vida Ventures (I), Vaxigene Consulting or Advisory Role: AstraZeneca/MedImmune, Merck, Immunai Research Funding: Genentech (Inst), AstraZeneca (Inst), Decibel Therapeutics (Inst) Travel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmuneDean F. BajorinHonoraria: Merck Sharp & Dohme Consulting or Advisory Role: Merck, Fidia Farmaceutici, Hoffman-La Roche, Dragonfly Therapeutics Research Funding: Novartis (Inst), Genentech (Inst), Merck (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Seattle Genetics/Astellas (Inst) Travel, Accommodations, Expenses: Genentech, MerckVictor E. ReuterConsulting or Advisory Role: Cepheid Uncompensated Relationships: PaigeAIGabriella JosephStock and Other Ownership Interests: AmgenMaria E. ArcilaHonoraria: Invivoscribe, Biocartis Consulting or Advisory Role: AstraZeneca Travel, Accommodations, Expenses: AstraZeneca, Invivoscribe, Raindance TechnologiesDana W.Y. TsuiHonoraria: Cowen, BofA Merrill Lynch Patents, Royalties, Other Intellectual Property: I am a co-inventor on a provisional patent application filed by Memorial Sloan Kettering Cancer CenterAhmet ZehirHonoraria: IlluminaMichael F. BergerConsulting or Advisory Role: Roche Research Funding: Grail Patents, Royalties, Other Intellectual Property: Provisional patent pending for “Systems and Methods for Detecting Cancer via cfDNA Screening”Eliezer Van AllenStock and Other Ownership Interests: Syapse, Tango Therapeutics, Genome Medical, Microsoft, Ervaxx Consulting or Advisory Role: Syapse, Roche, Third Rock Ventures, Takeda, Novartis, Genome Medical, InVitae, Illumina, Tango Therapeutics, Ervaxx, Janssen Speakers' Bureau: Illumina Research Funding: Bristol Myers Squibb, Novartis Patents, Royalties, Other Intellectual Property: Patent on discovery of retained intron as source of cancer neoantigens (Inst); patent on discovery of chromatin regulators as biomarkers of response to cancer immunotherapy (Inst); patent on clinical interpretation algorithms using cancer molecular data (Inst) Travel, Accommodations, Expenses: GenentechBarry S. TaylorConsulting or Advisory Role: Boehringer Ingelheim, Loxo Oncology at Lilly Research Funding: GenentechHikmat Al-AhmadieConsulting or Advisory Role: Bristol Myers Squibb, EMD Serono, AstraZeneca/MedImmune, Janssen BiotechDavid B. SolitStock and Other Ownership Interests: Loxo Consulting or Advisory Role: Pfizer, Loxo, Illumina, Vivideon Therapeutics, Lilly Oncology, QED Therapeutics, BridgeBio PharmaDarren R. FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics (Inst), Astellas Pharma Other Relationship: UpToDate No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML., (© 2020 by The American Society of Hematology.)

Purpose: We determined the diagnostic performance of 18 F-FDG (fluorodeoxyglucose) positron emission tomography/computerized tomography for detecting nodal metastases in patients with muscle invasive urothelial bladder cancer before radical cystectomy., Materials and Methods: Preoperative 18 F-FDG positron emission tomography/computerized tomography scans (208) were retrospectively reviewed. Scans were routinely performed in 185 patients with muscle invasive urothelial bladder cancer between August 2012 and February 2017, all of whom underwent radical cystectomy and pelvic lymph node dissection. Analyses were stratified by clinical node involvement and chemotherapy status. The diagnostic performance of 18 F-FDG positron emission tomography/computerized tomography was assessed according to sensitivity, specificity, positive predictive value and negative predictive value., Results: Lymph node metastases at time of pelvic lymph node dissection were present in 21.8% of those without suspicious nodes on computerized tomography (clinically node negative) and 52.6% of those with suspicious nodes on computerized tomography (clinically node positive). Median metastatic focus size was 5 mm. In clinically node negative cases 18 F-FDG positron emission tomography/computerized tomography rarely detected nodal metastases (sensitivity 7% to 23%). In clinically node positive cases negative 18 F-FDG positron emission tomography/computerized tomography was useful in ruling out lymph node metastases (sensitivity 92% to 100%). This study was limited by its mixed population and focus on pelvic nodal metastases only., Conclusions: 18 F-FDG positron emission tomography/computerized tomography appears to be most useful for better characterization of enlarged nodes identified by computerized tomography. Routine preoperative 18 F-FDG positron emission tomography/computerized tomography has limited utility in clinically node negative cases.

We investigated whether a unique immune response was instigated with the development of oral tongue squamous cell carcinomas (OTSCC), with/without nodal involvement, with/without recurrent metastatic disease, or within tumor involved nodes. One hundred and ten formalin-fixed paraffin-embedded samples were collected from a retrospective cohort of 67 OTSCC patients and 10 non-cancerous tongue samples. Targets including CD4, CD8, FOXP3, PD-L1, and PD-1 were analyzed by immunohistochemistry. The Nanostring PanCancer Immune Profiling Panel was used for gene expression profiling. Data were externally validated in the The Cancer Genome Atlas (TCGA) head and neck (HNSCC), melanoma and lung squamous cell carcinoma (LSCC) cohorts. A 24-immune gene signature was identified that discriminated more aggressive OTSCC cases, and although not prognostic in HNSCC was associated with survival in other TCGA cohorts (improved survival for melanoma, P < .001 and worse survival for LSCC, P = .038). OTSCC exhibited concordant gene and immunohistochemical (IHC) features characterized by a TH-2 biased, proinflammatory profile with upregulated B cell and neutrophil gene activity and increased CD4, FOXP3, and PD-L1 expression (P < .001 for all by IHC). Compared to less advanced disease, nodal involvement and recurrent OTSCC did not induce a different immune response although recurrent disease was characterized by significantly higher PD-L1 expression (P = .004 by SP263, P = .013 by 22C3, P = .004 for gene expression). Identification of a gene signature associated with different prognostic effects in other cancers highlights common pathways of immune dysregulation that are impacted by the tumor origin. The significant immunosuppressive signaling in OTSCC indicates primary failure of immune system to control carcinogenesis emphasizing the need for early, combination therapeutic approaches., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Assay of Transposase Accessible Chromatin sequencing (ATAC-seq) is widely used in studying chromatin biology, but a comprehensive review of the analysis tools has not been completed yet. Here, we discuss the major steps in ATAC-seq data analysis, including pre-analysis (quality check and alignment), core analysis (peak calling), and advanced analysis (peak differential analysis and annotation, motif enrichment, footprinting, and nucleosome position analysis). We also review the reconstruction of transcriptional regulatory networks with multiomics data and highlight the current challenges of each step. Finally, we describe the potential of single-cell ATAC-seq and highlight the necessity of developing ATAC-seq specific analysis tools to obtain biologically meaningful insights.

Background: Off-pump coronary artery bypass grafting (CABG) negates the requirement for extracorporeal circulation used with the traditional on-pump approach. However, off-pump CABG is technically more challenging and may theoretically lead to less complete revascularisation. Recent data suggests a prognostic benefit for traditional on-pump CABG, but the mechanism for this remains unclear. We hypothesised that the inferior outcomes with off-pump CABG could be driven by the need for repeat revascularisation, with this benefit only becoming clear at long-term follow-up. We therefore evaluated short, medium and long-term outcomes of patients undergoing revascularisation with on vs. off-pump CABG., Methods: Electronic databases were searched to identify suitable randomised controlled trials enrolling ≥100 patients in each arm. Clinical outcomes were extracted at 30-days, 12-months or >4years. The primary outcome was long-term all-cause death, while secondary outcomes included 30-day, 12-month and >4-year cardiac death, stroke, myocardial infarction or revascularisation., Results: Thirteen (13) studies comprising 13,234 patients were included. Off-pump CABG was associated with an increased risk of all-cause death (Odds Ratio [OR] 1.18, 95% confidence interval [CI] 1.02-1.32, p=0.01) and repeat bypass surgery (OR 2.57, 95%CI 1.23-5.39, p=0.01) at long-term follow-up. A significant, increased requirement for revascularisation in off-pump was seen at 12-month follow-up (OR 1.59, 95%CI 1.09-2.33, p=0.02). No differences were noted between groups at 30-days, 12-months and >4years for myocardial infarction or stroke., Conclusions: Off-pump CABG is associated with significantly higher rates of all-cause mortality rate at long-term follow-up. These outcomes demonstrate a temporal relationship that may be driven by a greater requirement for repeat revascularisation at 1- and 5-year follow-up., Study Registration: CRD42018102019 (PROSPERO)., (Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Our recently reported phase III trial demonstrated that patients undergoing nephron-sparing surgery (NSS) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m 2 who received mannitol had no improvement in renal function at 6 mo compared with those who received placebo. Some authors have suggested that benefit is restricted to subgroups, such as those with comorbidities. We assessed whether preoperative eGFR, or other patient and surgical factors modified the effect of mannitol on postoperative outcomes at 6 mo and with extended follow-up. We also assessed whether mannitol was associated with differences in long-term GFR years after surgery. No significant difference between the mannitol or placebo groups (mean eGFR difference: 1.4; 95% confidence interval: -2.6, 5.3; p = 0.5) was found in the 134 patients with known eGFR at 3 yr after NSS. At both 6 mo and 3 yr, the effect of mannitol was not significantly modified by patient or surgical factors including preoperative eGFR. In summary, we validated our original trial conclusions by finding that intraoperative use of mannitol does not improve either short- or long-term renal function in patients undergoing NSS. Specifically, there is no evidence that comorbidities, including lower preoperative eGFR, modify the effect of mannitol. PATIENT SUMMARY: Use of mannitol at the time of partial nephrectomy does not improve either short- or long-term renal function even in patients with comorbidities, including lower preoperative renal function. The routine use of intraoperative mannitol should be discontinued., (Copyright © 2019. Published by Elsevier B.V.)

Objective: The objective of this study was to examine the impact of dehydrated human amnion/chorion membrane (dHACM) allografts on prostate and bladder cancer growth in the setting of residual disease and positive surgical margins., Materials and Methods: A commercially available version of dHACM was used. Cytokines were identified and quantified, followed by comparative analysis of cell growth in two different human cell lines: prostate cancer (LNCaP) and bladder cancer (UM-UC-3), in vitro and in vivo. Tumor growth between the two groups, membrane versus no membrane implant, was compared and immunohistochemistry studies were conducted to quantify CD-31, Ki-67, and vimentin. A Student's unpaired t -test was used to determine statistical significance., Results: The UM-UC-3 and LNCaP cells grew quicker in medium plus 10% serum and dHACM extract than in the other media ( p = 0.03). A total of 28 distinct cytokines were found in the extract, 11 of which had relatively high concentrations and are associated with prostate and bladder cancer tumor progression. In vivo LNCaP model, after 10 weeks, the median tumor volume in the membrane group was almost threefold larger than the partial resection alone ( p = 0.01). Two weeks after resection, in the UM-UC-3 model, the membrane group reached fourfold larger than the partial resection without membrane group ( p < 0.01). In both groups, the expression of CD-31 and Ki-67 markers were similar and showed no statistical significance ( p > 0.05). It was only in the LNCaP tumors that vimentin expression was significantly higher in the group without membrane compared with the membrane group ( p = 0.008)., Conclusion: The use of dHACM after partial tumor resection is related to faster tumor relapse and growth in prostate and urothelial cancer in vivo models, showing a potential risk of rapid local recurrence in patients at high risk of positive margins., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Ectopic upper-pole (UP) ureters in duplex kidneys can be managed surgically by ipsilateral distal ureteroureterostomy (U-U) with or without ureteric stenting. Evidence to support routine stenting during this procedure is lacking., Objective: The authors present their outcomes of children with ectopic UP ureters who underwent ipsilateral distal U-U. They also compared outcomes of those who underwent routine ureteric stenting to those who did not., Study Design: Between 2009 and 2015, the authors performed a prospective analysis on consecutive patients with duplex collecting systems who underwent distal U-U via an inguinal incision for ectopic UP ureters by one of two pediatric urologists. The demographic information, operative factors, and any postoperative complications on follow-up were recorded., Results: The study included 47 patients (28 female) who underwent distal U-U with a mean age of 9.8 months. There were 30 patients who were routinely stented, and 17 who were not based on the routine practices of the operating surgeons without any selection bias. The mean operative time was 90 min, and the mean hospital stay was 0.9 days. No major complications were observed in this series, with 96% of patients showing resolution of hydronephrosis. There were no statistical differences between the stented and stentless U-U groups in terms of operative time, hospital stay, hydronephrosis resolution, time to resolution of hydronephrosis, and major complications. Only stented patients were found to have minor complications (2-urinary tract infection, 2-dysuria, and 2-stent displacement). All patients who underwent routine stent placement required a secondary planned procedure under general anesthesia for the cystoscopic removal of stent., Conclusion: Stenting was associated with a higher number of minor complications compared to the stentless group and thus, may not be routinely necessary when performing distal U-U for management of UP ectopic ureters associated with duplicated collecting systems., (Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)