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BACKGROUND Whether extended lymphadenectomy is associated with improved disease-free and overall survival, as compared with standard lymphadenectomy, among patients with localized muscle-invasive bladder cancer undergoing radical cystectomy is unclear. METHODS We randomly assigned, in a 1:1 ratio, patients with localized muscle-invasive bladder cancer of clinical stage T2 (confined to muscle) to T42 (invading adjacent organs) with two or fewer positive nodes (NO, Nl, or N2) to undergo bilateral standard lymphadenectomy (dissection of lymph nodes on both sides of the pelvis) or extended lymphadenectomy involving removal of common iliac, presciatic, and presacral nodes. Randomization was performed during surgery and stratified according to the receipt and type of neoadjuvant chemotherapy, tumor stage (T2 vs. T3 or T4a), and a Zubrod's performance-status score (0 or 1 vs. 2; assessed on a 5-point scale, with higher scores indicating greater disability). The primary outcome was diseasefree survival. Overall survival and safety were also assessed. RESULTS Of 658 patients who were enrolled, 592 eligible patients were randomly assigned to undergo extended lymphadenectomy (292 patients) or standard lymphadenectomy (300). Surgery was performed by 36 surgeons at 27 sites in the United States and Canada. Neoadjuvant chemotherapy had been received by 57% of the patients. At a median follow-up of 6.1 years, recurrence or death had occurred in 130 patients (45°6) in the extended-lymphadenectomy group and in 127 (42%) in the standard-lymphadenectomy group, and the estimated 5-year disease-free survival was 56% and 60°6, respectively (hazard ratio for recurrence or death, 1.10; 95°/0 confidence interval ICI], 0.86 to 1.40; P=0.45). Overall survival at 5 years was 59% in the extended-lymphadenectomy group and 63% in the standard-lymphadenectomy group (hazard ratio for death, 1.13; 95% CI, 0.88 to 1.45). Adverse events of grade 3 to 5 occurred in 157 patients (54°/o) in the extended-lymphadenectomy group and in 132 (44°/0) in the standard-lymphadenectomy group; death within 90 days after surgery occurred in 19 patients (7°/0) and 7 patients (2°/0), respectively. CONCLUSIONS As compared with standard lymphadenectomy, extended lymphadenectomy did not result in improved disease-free or overall survival among patients with muscle-invasive bladder cancer undergoing radical cystectomy and was associated with higher perioperative morbidity and mortality. (Funded by the National Cancer Institute and the Canadian Cancer Society; SWOG S1011 ClinicalTrials.gov number, NCT01224665.). [ABSTRACT FROM AUTHOR]

Abstract Background Epididymal inflammatory myofibroblastic tumor, also known by various other synonyms is a rare benign disease. Only eight cases have been reported to date. The most common presentation is a scrotal mass of variable duration. For a scrotal mass it is difficult to distinguish a benign or malignant etiology, in addition to the origin whether from testis or epididymis. As a result the definitive diagnosis can only be established by surgical exploration. Case presentation We report the ninth case of epididymal IMT who based on clinical and radiological findings underwent radical orchidectomy, with the histology suggestive of inflammatory myofibroblastic tumor. At 4 years follow up the patient is free of disease recurrence. Conclusion IMT though rare should be considered in the differential diagnosis of epididymal mass. Clinically it is often difficult to distinguish the origin of mass and even though the disease has benign nature and course it is crucial to counsel patients for orchidectomy as definitive diagnosis is established on surgical exploration.

Background: We aimed to investigate the association between selected inflammatory and immune variables and survival of dogs with myxomatous mitral valve disease (MMVD). We evaluated data of 62 client-owned dogs with MMVD, grouped into preclinical, stable congestive heart failure (CHF) and unstable CHF. Univariate Cox proportional hazards regression analysis was used to quantify the association of white blood cell count, concentrations and percentages of T lymphocytes and their subtypes (T helper lymphocytes, cytotoxic T lymphocytes, double positive T lymphocytes, double negative T lymphocytes) and B lymphocytes with survival. P values < 0.1 in individual groups and P values < 0.05 in the group of all patients were considered significant. Spearman correlation coefficients between significant covariates were calculated to assess the relationships among variables and with survival., Results: In the preclinical group, percentage of double positive T lymphocytes was negatively associated with survival (hazard ratio (HR) = 2.328; P = 0.051). In the unstable CHF, T lymphocyte (HR = 1.613; P = 0.085), cytotoxic T lymphocyte (HR = 1.562; P = 0.048), double positive (HR = 1.751; P = 0.042), and double negative T lymphocyte (HR = 1.613; P = 0.096) concentrations were negatively associated with survival, as well as cytotoxic T lymphocyte (HR = 1.502; P = 0.007) concentration in the group of all patients. The percentage of T helper lymphocytes was positively associated with survival in the unstable CHF (HR = 0.604; P = 0.053) and in the group of all patients (HR = 0.733; P = 0.044). The concentration of cytotoxic T lymphocytes positively correlated with left atrial to aortic ratio (LA/Ao) (rho = 0.259, P = 0.037), and peak velocity of early diastolic mitral flow (rho = 0.259, P = 0.039), whereas the percentage of T helper lymphocytes negatively correlated with left atrial to aortic ratio (LA/Ao) (rho = -0.212, P = 0.090) and early to late mitral flow ratio (rho = -0.232, P = 0.072)., Conclusions: Cytotoxic T lymphocytes, T helper lymphocytes, double positive and double negative T lymphocytes as well as biomarkers cardiac troponin I, N-terminal pro-B-type natriuretic peptide, C-reactive protein are implicated in the progression of MMVD., (© 2024. The Author(s).)

Background and Objective: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options., Methods: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions., Key Findings and Limitations: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials., Conclusions and Clinical Implications: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Sterols from cholesterol synthesis are crucial for cholesterol production, but also have individual roles difficult to assess in vivo due to essentiality of cholesterol. We developed HepG2 cell models with knockouts (KOs) for three enzymes of cholesterol synthesis, each accumulating specific sterols. Surprisingly, KOs of CYP51 , DHCR24 , and SC5D shared only 9% of differentially expressed genes. The most striking was the phenotype of CYP51 KO with highly elevated lanosterol and 24,25-dihydrolanosterol, significant increase in G2+M phase and enhanced cancer and cell cycle pathways. Comparisons with mouse liver Cyp51 KO data suggest 24,25-dihydrolanosterol activates similar cell proliferation pathways, possibly via elevated LEF1 and WNT/NFKB signaling. In contrast, SC5D and DHCR24 KO cells with elevated lathosterol or desmosterol proliferated slowly, with downregulated E2F, mitosis, and enriched HNF1A. These findings demonstrate that increase of lanosterol and 24,25-dihydrolanosterol, but not other sterols, promotes cell proliferation in hepatocytes., Competing Interests: Authors declare no competing interests., (© 2024 The Authors.)

Background: Academic and community urology centers participating in a pragmatic clinical trial in non-muscle-invasive bladder cancer completed monthly surveys assessing restrictions in aspects of bladder cancer care due to the COVID-19 Public Health Emergency. Our objective was to describe pandemic-related restrictions on bladder cancer care., Methods: We invited 32 sites participating in a multicenter pragmatic bladder cancer trial to complete monthly surveys distributed through REDCap beginning in May 2020. These surveys queried sites on whether they were experiencing restrictions in the use of elective surgery, transurethral resection of bladder tumors (TURBT), radical cystectomy, office cystoscopy, and intravesical bacillus Calmette-Guerin (BCG) availability. Responses were collated with descriptive statistics., Results: Of 32 eligible sites, 21 sites had at least a 50% monthly response rate over the study period and were included in the analysis. Elective surgery was paused at 76% of sites in May 2020, 48% of sites in January 2021, and 52% of sites in January 2022. Over those same periods, coinciding with COVID-19 incidence waves, TURBT was restricted at 10%, 14%, and 14% of sites, respectively, radical cystectomy was restricted at 10%, 14%, and 19% of sites, respectively, and cystoscopy was restricted at 33%, 0%, and 10% of sites, respectively., Conclusions: Bladder cancer care was minimally restricted compared with more pronounced restrictions seen in general elective surgeries during the COVID-19 pandemic., 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 © 2023 Elsevier Inc. All rights reserved.)

The use of blue light cystoscopy (BLC) has been shown to improve bladder tumor detection. However, data demonstrating the efficacy of BLC across different races are limited. Herein, we aim to evaluate heterogeneity in the characteristics of BLC for the detection of malignant lesions among various races. Clinicopathologic information was collected from patients enrolled in the multi-institutional Cysview ® registry (2014-2021) who underwent transurethral resection or biopsy of bladder tumors. Outcome variables included sensitivity and negative and positive predictive values of BLC and white light cystoscopy (WLC) for the detection of malignant lesions among various races. Overall, 2379 separate lesions/tumors were identified from 1292 patients, of whom 1095 (85%) were Caucasian, 96 (7%) were African American, 51 (4%) were Asian, and 50 (4%) were Hispanic. The sensitivity of BLC was higher than that of WLC in the total cohort, as well as in the Caucasian and Asian subgroups. The addition of BLC to WLC increased the detection rate by 10% for any malignant lesion in the total cohort, with the greatest increase in Asian patients (18%). Additionally, the positive predictive value of BLC was highest in Asian patients (94%), while Hispanic patients had the highest negative predictive value (86%). Our study showed that regardless of race, BLC increases the detection of bladder cancer when combined with WLC.

Background: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC., Objective: On November 18-19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies., Methods: Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment., Results: In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure., Conclusions: The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development., Competing Interests: E.C., J.F., S.A., V.B., A.A.J., P.B., K.S., J.R.B., E.B., R.O., K.B., Z.F., T.M.D., R.B., D.L.S., L.A.K., R.P., P.G.K., and C.W. have no conflicts of interest to report. N.M.H., S.P.L., A.M.K., R.S.S., M.A.O., M.J.R., M.D.G., P.C.B., K.P., C.P.D., R.B., and S.P.P. (Psutka) are Editorial Board members of this journal, but were not involved in the peer-review process nor had access to any information regarding its peer-review. N.M.H. receives consulting compensation from AstraZeneca, Merck, BioGears, Seattle Genetics, Mirati, Incyte, RemGen, Janssen, Pfizer, EMD Serono, Verity Pharmaceuticals, Huron Consulting, Guidepoint, Natera, Protara Therapeutics, Astellas Pharma; research support to the institution from HTG Molecular Diagnostics, AstraZeneca, Bristol Myers-Squibb, Genentech, Seattle Genetics, Pieris, Inovio, Principia Biopharm, Incyte, and Ikena Oncology; and speaking honorarium from Medscape. S.P.L. reports clinical trial involvement with Aura Bioscience, FKD, JBL (SWOG), Genentech (SWOG), Janssen (SWOG), Merck (Alliance), QED Therapeutics, UroGen, Vaxiion, Viventia; is on the advisory board or a consultant for Aura Bioscience, BMS, C2iGenomics, Ferring, Incyte, Pfizer/EMD Serono, Protara, Stimit, UroGen, Vaxiion, Verity; has a patent for a TCGA classifier; and receives honoraria from Grand Rounds Urology and UroToday. A.M.K. reports clinical trial involvement with FKD, Merck, Bristol Myers Squibb, Photocure, SWOG, Adolor, Heat Biologics, Janssen, Taris, Seattle Genetics; reports laboratory research with NIH, SPORE, AIBCCR, PCORI; is on the advisory board or a consultant for TMC Innovation, Arquer Diagnostics, Asieris, Astellas, Biological Dynamics, BMS, CG Oncology, Cystotech, Eisai, Engene, Ferring, InCyte, Imvax, Imagin Medical, Janssen, Medac, Merck, Nonagen, Photocure, ProTara, Pfizer, Roche, Seattle Genetics, Sessen Bio, Theralase, US Biotest, Urogen Inc; is on the editorial board of European Urology Oncology; Journal of Urology, UroToday; is president of International Bladder Cancer Network and International Bladder Cancer Group; and has a joint patent with UT MD Anderson Cancer Center for CyPRIT (Cytokine Predictors of Response to Intravesical Therapy). R.S.S. is a consultant for CG Oncology and Verity Pharma; and receives research support from Japanese BCG Laboratories and Merck. N.S. is a consultant for AbbVie, Accord, Alessa Therapeutics, Amgen, Antev, Arquer, Asieris, Astellas, Astra Zeneca, AuraBiosciences, Bayer, BMS, Bioprotect, Boston Scientific, Clarity, Dendreon, Exact Imaging, FizeMedical, CG Oncology, Genentech/Roche, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myriad, Nonagen, Novartis, Nymox, Pacific Edge, Palette Life, Photocure, Pfizer, PlatformQ, Profound Medical, Promaxo, Propella, Protara, Sanofi, Specialty Networks, Telix, Tolmar, Urogen, and Vessi. M.K. receives grant funding from the American Cancer Society; is a consultant for Merck, Pfizer, Seagen/Astellas, Photocure, Aura, BMS, Nanology, and Janssen; and holds a patent for Nanoparticle Formulations for Enhanced Drug Delivery to the Bladder. M.A.O. receives grant/research/clinical trial support from Abbot Molecular, Photocure, Urogen; and is a consultant or on the advisory board for Fidia Pharmaceuticals, Sesen Bio, Merck, Theralase, and Urogen. G.D.S. is a member of the Clinical Trial Protocol Committee for Merck, BMS, Janssen, CG Oncology, Pfizer, PhotoCure, Fidia, Seagen, Protara; is or has been a scientific advisor /consultant with CG Oncology; PhotoCure; Merck; Taris Biomedical (Now Janssen); Fidia Farmaceuticals; Urogen, Ferring; Fergene, Bristol Myers Squibb; Astra Zeneca; Pfizer, Janssen; Epivax Therapeutics; EnGene Bio; Astellas; SeaGen; Verity Pharmaceuticals, Protara, xCures, Nonagen, Nanology, Imvax, Asieris; and has equity stock/options with Epivax Therapeutics, Urogen, CG Oncology, Engene Bio. M.J.R. has intellectual property with Fina Biotech and is or has been a meeting participant or lecturer for Roche, AstraZeneca, and Bayer. M.D.G. receives research funding from Bristol Myers Squibb, Novartis, Dendreon, Astra Zeneca, Merck, Genentech; and is on the advisory board or a consultant for Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, Rappta Therapeutics, Alligator, Silverback, Fujifilm, Curis, Gilead, Bicycle, Asieris, Abbvie, Analog Devices. P.C.B is a member of the advisory board or equivalent with AbbVie, AstraZeneca, Astellas, Bayer, BMS, EMD-Serono, Ferring, Fergene, Janssen, Merck, miR Scientific, Nonagen, NanOlogy, Pfizer, Photocure, Prokarium, Protara Therapeutics, QED Bioscience, Roche, Sanofi, Sesen Bio, STIMIT, TerSera, Tolmar, Urogen, Verity; is a member of a Speaker’s bureau with Janssen, Minogue, Ferring, TerSera, Pfizer; has received a grant or honorarium from iProgen; and shares a patent with Veracyte. H.A. provides consultation to AstraZeneca, Flare Therapeutics and Paige.AI. K.P. receives consulting fees from Photocure. C.P.D. reports compensation for Scientific/Advisory Committee Member for AstraZeneca Pharmaceuticals, UroGen Pharma (formerly Theracoat Ltd.); consulting fees from STIMIT Corporation; consulting fees from General Atlantic; board member position for DF/HCC Kidney Cancer SPORE Advisory Board; research funding from Cancer Prevention Research Institute of Texas (CPRIT), Department of Defense (DoD), and NIH/NCI. S.P.P. (Porten) receives research support from Photocure, consulting compensation from Pacific Edge, grant funding from PCORI, BCAN, AHRQ, Genentech, Merck, and is on the advisory board for AstraZeneca. A.B.S. receives grant funding from PCORI, BCAN, AHRQ, Genentech, and Merck. S.P.P. (Psutka) reports being on Practice Guidelines Committee (Upper Tract Urothelial Carcinoma) of the American Urological Association (AUA), being AUA Core Curriculum Sr. Editor (2019-2023) and Senior Consultant (2023-); is or has been on Scientific Advisory Boards for Merck (Past), ImmunityBio (Past), Janssen (Current); has received travel funding/honoraria from Medtronic (Past), AstraZeneca (Past); receives research funding from PRIME Education, INC, Bladder Cancer Advocacy Network, National Institute on Aging, and is on the editorial boards for European Urology. N.A. receives research funding to institution from Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon., (© 2023 – The authors. Published by IOS Press.)

Introduction: Effective therapies for patients with nonmuscle invasive bladder cancer that recurs or progresses after Bacille Calmette-Guérin (BCG) are lacking. This unmet need is the focus of many drug development efforts, reflected in many completed/ongoing/planned clinical trials for patients with BCG unresponsive bladder cancer. Though BCG unresponsive criteria are well defined, enrollment criteria are variable such that, even at centers with several open trials in this space, a given patient with BCG unresponsive bladder cancer might not qualify for any. To understand the scope of this dilemma, we systematically analyzed enrollment criteria for all BCG unresponsive protocols registered on ClinicalTrials.gov to quantify heterogeneity in enrollment criteria and to determine what proportion of trials were inclusive to patients meeting U.S. Food and Drug Administration (FDA) BCG unresponsive criteria., Methods: The ClinicalTrials.gov search tool was queried for relevant trials using the terms "bladder cancer" "nonmuscle invasive bladder cancer" and "BCG". Previously published review articles were cross-referenced to ensure that search results were comprehensive. Inclusion and exclusion criteria for the resulting 31 protocols pertaining to distinct categories such as performance status, laboratory parameters, co-morbidities, active medications, and prior therapies were recorded. Based on enrollment criteria, the trial was assessed as fully inclusive or not to patients considered to be BCG unresponsive by the 2018 FDA criteria., Results: Of 31 trials, 15 (48%) had inclusion/exclusion criteria that were fully consistent with (inclusive of patients that met) the BCG unresponsive bladder cancer definition. 18 (58%) of trials excluded patients with a history of prior pelvic radiation therapy. 14 (45%) of trials excluded patients with ECOG performance status >2 (or Karnofsky Performance Status equivalent). The most common disease specific exclusion for patients with BCG unresponsive bladder cancer was a requirement for stage Tis (carcinoma in situ, CIS), which pertained to 7 (23%) of trials., Conclusions: Enrollment criteria for patients with BCG unresponsive bladder cancer are highly variable. Over half of trials evaluated do not meet stringent criteria for this disease state based upon treatment history and cancer staging requirements. For patients who desire to enroll in clinical trials, this restricts access to novel agents. For bladder cancer treating physicians and regulatory bodies, this also hinders comparisons across agents., Competing Interests: Conflicts of interest disclosure Michael Chandra: no relationships to disclose. Roger Li: stock and other ownership interests - crispr therapeutics; Guardant Health. Consulting or Advisory Role - Arquer Diagnostics; Bristol-Myers Squibb; FerGene; Ferring. Research Funding - CG Oncology. Expert Testimony - CG Oncology. Other Relationship – Predicine Anil Parwani: No Relationships to Disclose. William Edgar Carson: No Relationships to Disclose. Kamal S. Pohar: Consulting or Advisory Role - Photocure. Debasish Sundi: Consulting or Advisory Role - Janssen, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Bacille Calmette-Guérin (BCG) is the standard therapy after transurethral resection of bladder tumour for high-risk non-muscle-invasive bladder cancer (NMIBC). However, post-BCG recurrence/progression occurs frequently, and noncystectomy options are limited., Objective: To evaluate the safety and clinical activity of atezolizumab ± BCG in high-risk BCG-unresponsive NMIBC., Design, Setting, and Participants: This phase 1b/2 GU-123 study (NCT02792192) treated patients with BCG-unresponsive NMIBC who had carcinoma in situ with atezolizumab ± BCG., Intervention: Patients in cohorts 1A and 1B received atezolizumab 1200 mg IV q3w for ≤96 wk. Those in cohort 1B also received standard BCG induction (six weekly doses) and maintenance courses (three doses weekly starting at month 3) with optional maintenance at 6, 12, 18, 24, and 30 mo., Outcome Measurements and Statistical Analysis: Coprimary endpoints were safety and 6-mo complete response (CR) rate. Secondary endpoints included 3-mo CR rate and duration of CR; 95% confidence intervals were calculated using the Clopper-Pearson method., Results and Limitations: At data cut-off (September 29, 2020), 24 patients were enrolled (cohort 1A, n = 12; cohort 1B, n = 12), and the recommended BCG dose was 50 mg in cohort 1B. Four patients (33%) had adverse events (AEs) leading to BCG dose modification/interruption. Three patients (25%) in cohort 1A reported atezolizumab-related grade 3 AEs; cohort 1B had no atezolizumab- or BCG-related grade ≥3 AEs. No grade 4/5 AEs were reported. The 6-mo CR rate was 33% in cohort 1A (median duration of CR, 6.8 mo) and 42% in cohort 1B (median duration of CR, not reached [≥12 mo]). These results are limited by the small sample size of GU-123., Conclusions: In this first report of the atezolizumab-BCG combination in NMIBC, atezolizumab ± BCG was well tolerated, with no new safety signals or treatment-related deaths. Preliminary results suggested clinically meaningful activity; the combination favoured a longer duration of response., Patient Summary: We studied atezolizumab with and without bacille Calmette-Guérin (BCG) to determine whether this combination was safe and had clinical activity in patients with high-risk noninvasive bladder cancer (high-grade bladder tumours that affect the outermost lining of the bladder wall) that has previously been treated with BCG and is still present or occurred again. Our results suggest that atezolizumab with or without BCG was generally safe and could be used to treat patients unresponsive to BCG., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate whether a restaging transurethral resection of bladder tumor (TURBT) is necessary in high-risk nonmuscle invasive bladder cancer (NMIBC) if the initial TURBT was performed using blue light (BL) technology., Methods and Materials: Using the multi-institutional Cysview registry between 2014 and 2021, all consecutive adult patients with known NMIBC (Ta and T1 disease) who underwent TURBT followed by a restaging TURBT within 8 weeks were reviewed. Patients were stratified according to their initial TURBT, BL vs. white light (WL), and compared to determine rates of residual disease and upstaging. Univariate analysis was performed using Mann-Whitney U and chi-square tests, with P < 0.05 considered significant., Results: Overall, 115 patients had TURBT for NMIBC followed by a restaging TURBT within 8 weeks and were included in the analysis. Patients who underwent BL compared to WL for their initial TURBT had higher rates of benign pathology on restaging TURBT, although this was not statistically significant (47% vs. 30%; P = 0.08). Of patients with residual tumors on restaging TURBT, there were no differences in rates of Ta (22% vs. 26.5%; P = 0.62), T1 (22% vs. 26.5%; P = 0.62), or CIS (5.5% vs. 13%; P = 0.49) when the initial TURBT was done using BL compared to WL. Rates of upstaging to muscle invasive disease were also not different when initial TURBT was performed using BL compared to WL (3% vs. 4%; P = 0.78)., Conclusions: TURBT using BL does not reduce rates of residual disease or risk of upstaging on restaging TURBT in Ta or T1 disease. Thus, a restaging TURBT is still necessary even if initial TURBT was performed using BL., Competing Interests: Conflict of interest Siamak Daneshmand is a paid consultant for Photocure. Yair Lotan is a paid consultant for Photocure and does research with Storz. Sima Porten is a paid consultant for Photocure. Brian Willard has research funding from and on speakers bureau for Photocure. Additional research funding with Jansseen, Myriad, and Coloplast. Gary D. Steinberg is a paid consultant for Photocure. Also, he is a member of Clinical Trial Protocol Committees for Photocure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Scarce data exist on the effects of coenzyme Q 10 (CoQ 10 ) supplementation in dogs with myxomatous mitral valve disease (MMVD). The purpose of this study was to investigate the effect of CoQ 10 supplementation on oxidative stress markers (glutathione peroxidase, F2-isoprostanes), markers of inflammation (tumor necrosis factor-α, TNF soluble receptor II, leucocytes, and their subtypes), lymphocyte subpopulations (T helper and cytotoxic T lymphocytes, including activated T lymphocytes, and B lymphocytes), and echocardiographic and clinical parameters in dogs with MMVD. In this randomized, controlled, double-blind, longitudinal study, 43 MMVD dogs in stages ACVIM (American College of Veterinary Internal Medicine classification) B2 and ACVIM C and D (congestive heart failure (CHF)) received water-soluble coenzyme Q 10 (100 mg twice daily) or placebo for 3 months, and 12 non-supplemented healthy dogs served as controls. All parameters were measured before and after supplementation in MMVD dogs and once in healthy dogs. CoQ 10 supplementation had a positive impact on neutrophil percentage, lymphocyte percentage, and lymphocyte concentration in our cohort of dogs with CHF (ACVIM C and D). Conclusion: CoQ 10 as an oral supplement may have benefits in terms of decreasing inflammation in dogs with MMVD and CHF.

Objectives: To evaluate the role of blue-light cystoscopy (BLC) in detecting invasive tumours that were not visible on white-light cystoscopy (WLC)., Patients and Methods: Using the multi-institutional Cysview registry database, patients who had at least one white-light negative (WL-)/blue-light positive (BL+) lesion with invasive pathology (≥T1) as highest stage tumour were identified. All WL-/BL+ lesions and all invasive tumours in the database were used as denominators. Relevant baseline and outcome data were collected., Results: Of the 3514 lesions (1257 unique patients), 818 (23.2%) lesions were WL-/BL+, of those, 55 (7%) lesions were invasive (48 T1, seven T2; 47 unique patients) including 28/55 (51%) de novo invasive lesions (26 unique patients). In all, 21/47 (45%) patients had WL-/BL+ concommitant carcinoma in situ and/or another T1 lesions. Of 22 patients with a WL-/BL+ lesion who underwent radical cystectomy (RC), high-risk pathological features leading to RC was only visible on BLC in 18 (82%) patients. At time of RC, 11/22 (50%) patients had pathological upstaging including four (18%) with node-positive disease., Conclusions: A considerable proportion of invasive lesions are only detectable by BLC and the rate of pathological upstaging is significant. Our present findings suggest an additional benefit of BLC in the detection of invasive bladder tumours that has implications for treatment approach., (© 2021 The Authors BJU International © 2021 BJU International.)

Purpose: The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guérin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with non-muscle invasive bladder cancer (NMIBC) undergoing BCG., Materials and Methods: Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence., Results: Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15)., Conclusions: BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.

Background: Data on alterations in peripheral blood lymphocyte (PBL) subtypes in dogs with myxomatous mitral valve disease (MMVD) is lacking., Objectives: To investigate PBL subtypes and their correlation with parameters of inflammation and MMVD progression markers in dogs with different stages of MMVD., Animals: Seventy-eight client-owned dogs: 65 with MMVD (American College of Veterinary Internal Medicine [ACVIM] classification stages B2, C, and D) and 13 healthy controls., Methods: Prospective cross-sectional study. Complete cardiac assessment, flow cytometry (T lymphocytes [CD3+], their subtypes [CD3+CD4+, CD3+CD8+, CD3+CD4+CD8+, CD3+CD4-CD8-], and B lymphocytes [CD45+CD21+]) and measurement of N-terminal pro B-type natriuretic peptide, cardiac troponin I, and C-reactive protein concentrations were performed., Results: The percentage of CD3+CD4+ lymphocytes was significantly lower in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .003), the percentage of CD3+CD8+ lymphocytes was significantly higher in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .01), CD3+CD8+ lymphocyte concentration was significantly higher in unstable ACVIM C and D patients (P = .05), and the CD3+CD4+/CD3+CD8+ ratio was significantly lower in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .01) compared with healthy controls., Conclusions and Clinical Importance: The percentages of CD3+CD4+ and CD3+CD8+ PBL and CD4+/CD8+ ratio were altered in MMVD dogs with congestive heart failure (ACVIM C, D), but not in ACVIM B2, suggesting involvement of these PBL subtypes in the pathogenesis of congestive heart failure in dogs with MMVD., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Recent research has indicated that dysbiosis of the gut microbiota can lead to an altered circadian clock of the mammalian host. Herein we developed an original system that allows real-time circadian studies of human HepG2 hepatoma cells co-cultured with bacteria. The HepG2 cells with stably integrated firefly luciferase reporter under the control of PERIOD2 promoter were co-cultured with E. coli strains isolated from human fecal samples from healthy individuals. The two E. coli strains differ in the phylogenetic group and the number of ExPEC virulence-associated genes: BJ17 has only two, and BJ23 has 15 of 23 tested. In the first 24 h, the E. coli BJ17 affected the HepG2 circadian clock more than BJ23. Cosinor analysis shows a statistically significant change in the amplitude of PER1 and 2 and the phase advance of PER3. A high percentage of necrotic and apoptotic cells occurred at 72 h, while a correlation between the number of ExPEC genes and the influence on the HepG2 core clock gene expression was observed. Our study reveals that the E. coli genetic background is important for the effect on the mammalian circadian clock genes, indicating possible future use of probiotic E. coli strains to influence the host circadian clock.

Extracellular vesicles with their molecular cargo can modulate target cell response and may affect the pathogenesis of diseases. The extracellular vesicles containing micro-RNAs (miRNAs), which are often studied as disease biomarkers, but rarely as mediators of the disease development. The role of extracellular vesicles derived miRNAs in type 1 diabetes is currently not well established. We observed a fraction of blood plasma extracellular vesicles positive for membrane proteins potentially associated with insulin-producing beta-cells and identified differentially expressed extracellular vesicles derived miRNAs in individuals with type 1 diabetes. These differentially expressed extracellular vesicles derived human miRNAs in participants with type 1 diabetes and participants with Langerhans islets beta-cells destruction showed the ability to activate TLR7/8 signaling cascade and increase activation as well as cytotoxicity of the effector blood immune cells with cytokine and chemokine release. Our results illustrate extracellular vesicles derived human miRNAs as modulators of the immune system in type 1 diabetes autoimmunity, providing potentially new insight into the pathogenesis of the disease, and novel molecular targets for intervention and type 1 diabetes prevention., (Copyright © 2020 Tesovnik, Kovač, Pohar, Hudoklin, Dovč, Bratina, Trebušak Podkrajšek, Debeljak, Veranič, Bosi, Piemonti, Ihan and Battelino.)

Blue light cystoscopy (BLC) with hexaminolevulinate (HAL) during transurethral resection of bladder cancer improves detection of non-muscle-invasive bladder cancer (NMIBC) and reduces recurrence rates. Flexible BLC was approved by the FDA in 2018 for use in the surveillance setting and was demonstrated to improve detection. Results of a phase III prospective multicentre study of blue light flexible cystoscopy (BLFC) in surveillance of intermediate-risk and high-risk NMIBC showed that 20.6% of malignancies were identified only by BLFC. Improved detection rates in the surveillance setting are anticipated to lead to improved clinical outcomes by reducing future recurrences and earlier identification of tumours that are unresponsive to therapy. Thus, BLFC has a role in surveillance cystoscopy, and determining which patients will benefit from BLFC and optimal and cost-effective ways of incorporating this technology into surveillance cystoscopy must be developed.

Objective: To evaluate blue-light flexible cystoscopy (BLFC) with hexaminolevulinate in the office surveillance of patients with non-muscle-invasive bladder cancer with a high risk of recurrence by assessing its impact on pain, anxiety, subjective value of the test and patient willingness to pay., Materials and Methods: A prospective, multicentre, phase III study was conducted during which the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, Pain and 'Was It Worth It' questionnaires were administered at baseline, after surveillance with BLFC and after resection for those referred to the operating room. Comparisons of scores were performed between groups., Results: A total of 304 patients were enrolled, of whom 103 were referred for surgical examination. Of these, 63 were found to have histologically confirmed malignancy. Pain levels were low throughout the study. Anxiety levels decreased after BLFC (∆ = -2.6), with a greater decrease among those with negative pathology results (P = 0.051). No differences in anxiety were noted based on gender, BLFC results, or test performance (true-positive/false-positive). Most patients found BLFC 'worthwhile' (94%), would 'do it again' (94%) and 'would recommend it to others' (91%), with no differences based on BLFC results or test performance. Most patients undergoing BLFC (76%) were willing to pay out of pocket., Conclusions: Anxiety decreased after BLFC in patients with negative pathology, including patients with false-positive results. Most of the patients undergoing BLFC were willing to pay out of pocket, found the procedure worthwhile and would recommend it to others, irrespective of whether they had a positive BLFC result or whether this was false-positive after surgery., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Purpose of Review: To summarize the current knowledge about the clinical role of novel urinary markers in bladder cancer (BCa) management, from diagnosis to follow-up, from prognosis of oncological outcomes to response to intravesical therapy., Recent Findings: Urinary markers have been developed to overcome the limitations of the current available tools for the diagnosis and surveillance of BCa patients. However, to date, because of their limited performances, urinary markers are not generally used in clinical practice. For a marker to be of clinical benefit, it needs to be better, easier, faster and cheaper. The differential requirements for a marker's diagnostic performances depend on goals for clinical utility. Their most promising role seems to be in settings such as in case of equivocal cystoscopy/cytology during follow-up of nonmuscle invasive tumors. Newer markers are available or in development using panels of markers of RNA expression or methylation., Summary: To date, there are multiple urine markers that have improved sensitivity over cytology but there is lack of validation of clinical utility. Some of the recently developed markers aim to change the paradigm of BCa follow-up by replacing or reducing the need of invasive investigations. Further prospective validations are needed to confirm these findings.

Introduction: Blue light cystoscopy (BLC) using hexaminolevulinate (HAL/Cysview/Hexvix) has been previously shown to improve detection of non-muscle-invasive bladder cancer (NMIBC). Herein, we evaluated the detection of malignant lesions in a heterogenous group of patients in the real world setting and documented the change in risk category due to upstaging or upgrading., Methods: Prospective enrollment during April 2014 to December 2016 of consecutive adult patients with suspected or known non-muscle-invasive bladder cancer based on prior cystoscopy or imaging, undergoing transurethral resection of bladder tumor at 9 different referral medical centers. HAL was instilled in the bladder for 1 to 3 hours before evacuation and inspection. Sensitivity and specificity of BLC, white light cystoscopy (WLC), and the combination of both BLC and WLC for detection of any malignancy was reported on final pathology. Number of patients with a change in American Urological Association (AUA) risk category based on BLC findings leading to a possible change in management and adverse events were recorded., Results: Overall, 1,632 separate samples from bladder resection or biopsy were identified from 641 BLC procedures on 533 patients: 85 (16%) underwent repeat BLC (range: 2-5). Sensitivity of WLC, BLC, and the combination for diagnosis of any malignant lesion was 76%, 91%, and 98.5%, respectively. Addition of BLC to standard WLC increased detection rate by 12% for any papillary lesion and 43% for carcinoma in-situ. Within the WLC negative group, an additional 206 lesions in 133 (25%) patients were detected exclusively with BLC. In multifocal disease, BLC resulted in AUA risk-group migration occurred in 33 (6%) patients and a change in recommended management in 74 (14%). False-positive rate was 25% for WLC and 30% for BLC. One mild dermatologic hypersensitivity reaction (0.2%)., Conclusions: BLC increases detection rates of carcinoma in-situ and papillary lesions over WLC alone and can change management in 14% of cases. Repeat use of HAL for BLC is safe., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of bladder cancer during surveillance., Materials and Methods: Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and randomization to blue light flexible cystoscopy. All suspicious lesions were documented. Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy. All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel. The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy. Additional end points were the false-positive rate, carcinoma in situ detection and additional tumors detected only with blue light cystoscopy., Results: Following surveillance 103 of the 304 patients were referred, including 63 with confirmed malignancy, of whom 26 had carcinoma in situ. In 13 of the 63 patients (20.6%, 95% CI 11.5-32.7) recurrence was seen only with blue light flexible cystoscopy (p <0.0001). Five of these cases were confirmed as carcinoma in situ. Operating room examination confirmed carcinoma in situ in 26 of 63 patients (41%), which was detected only with blue light cystoscopy in 9 of the 26 (34.6%, 95% CI 17.2-55.7, p <0.0001). Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients (46%). The false-positive rate was 9.1% for white and blue light cystoscopy. None of the 12 adverse events during surveillance were serious., Conclusions: Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer and it is safe when used for surveillance. Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy., Competing Interests: Supported by Photocure ASA, Norway. Yair Lotan and Trinity Bivalacqua have a financial interest and/or other relationship with Photocure. Gary Steinberg has a financial interest and/or other relationship with Photocure, Merck, FKD, MDxHealth, Cold Genesys, UroGen, Heat Biologics, Roche, Nateraand BioCanCell. Siamak Daneshmand is a paid consultant for Photocure., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We describe a case history of a young adult with LRBA deficiency and two independent malignancies., Methods: Family-trio whole exome sequencing with unbiased phenotype ontology approach was used for identification of causative mutations of a primary immune deficiency disorder. Additionally, we sought to identify germline mutations in genes known to be associated with two independent malignancies using a targeted approach. A cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in T lymphocytes was determined by flow cytometry., Results: In the patient with clinical signs of LRBA deficiency multifocal gastric carcinoma and malignant melanoma were diagnosed and surgically treated at 19 and 27 years of age, respectively. Despite refusal of any adjuvant chemotherapy or radiotherapy, the patient demonstrated disease free survival for at least 13 years after the first cancer diagnosis. A homozygous frameshift deletion in LRBA gene (p.Glu946Ter) and two common variants in TYR gene were identified. Reduced CTLA4 expression in a subset of regulatory T lymphocytes was identified in the patient and his unaffected mother carrying a heterozygous LRBA mutation as compared to control in a dose-dependent manner., Conclusion: This is the first description of gastric cancer and malignant melanoma in a young adult with LRBA deficiency. The role of LRBA gene knockout in cancer development and its prognosis remains to be elucidated.

Objectives: To develop a scoring tool, Pelvic Lymphadenectomy Appropriateness and Completion Evaluation (PLACE), to assess the intraoperative completeness and appropriateness of pelvic lymph node dissection (PLND) following robot-assisted radical cystectomy (RARC)., Patients, Subjects and Methods: A panel of 11 open and robotic surgeons developed the content and structure of PLACE. The PLND template was divided into three zones. In all, 21 de-identified videos of bilateral robot-assisted PLNDs were assessed by the 11 experts using PLACE to determine inter-rater reliability. Lymph node (LN) clearance was defined as the proportion of cleared LNs from all PLACE zones. We investigated the correlation between LN clearance and LN count. Then, we compared the LN count of 18 prospective PLNDs using PLACE with our retrospective series performed using the extended template (No PLACE)., Results: A significant reliability was achieved for all PLACE zones among the 11 raters for the 21 bilateral PLND videos. The median (interquartile range) for LN clearance was 468 (431-545). There was a significant positive correlation between LN clearance and LN count (R 2 = 0.70, P < 0.01). The PLACE group yielded similar LN counts when compared to the No PLACE group., Conclusions: Pelvic Lymphadenectomy Appropriateness and Completion Evaluation is a structured intraoperative scoring system that can be used intraoperatively to measure and quantify PLND for quality control and to facilitate training during RARC., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Tomato product consumption and estimated lycopene intake are hypothesised to reduce the risk of prostate cancer. To define the impact of typical servings of commercially available tomato products on resultant plasma and prostate lycopene concentrations, men scheduled to undergo prostatectomy (n 33) were randomised either to a lycopene-restricted control group ( < 5 mg lycopene/d) or to a tomato soup (2-2¾ cups prepared/d), tomato sauce (142-198 g/d or 5-7 ounces/d) or vegetable juice (325-488 ml/d or 11-16·5 fluid ounces/d) intervention providing 25-35 mg lycopene/d. Plasma and prostate carotenoid concentrations were measured by HPLC. Tomato soup, sauce and juice consumption significantly increased plasma lycopene concentration from 0·68 (sem 0·1) to 1·13 (sem 0·09) μmol/l (66 %), 0·48 (sem 0·09) to 0·82 (sem 0·12) μmol/l (71 %) and 0·49 (sem 0·12) to 0·78 (sem 0·1) μmol/l (59 %), respectively, while the controls consuming the lycopene-restricted diet showed a decline in plasma lycopene concentration from 0·55 (sem 0·60) to 0·42 (sem 0·07) μmol/l ( - 24 %). The end-of-study prostate lycopene concentration was 0·16 (sem 0·02) nmol/g in the controls, but was 3·5-, 3·6- and 2·2-fold higher in tomato soup (P= 0·001), sauce (P= 0·001) and juice (P= 0·165) consumers, respectively. Prostate lycopene concentration was moderately correlated with post-intervention plasma lycopene concentrations (r 0·60, P =0·001), indicating that additional factors have an impact on tissue concentrations. While the primary geometric lycopene isomer in tomato products was all-trans (80-90 %), plasma and prostate isomers were 47 and 80 % cis, respectively, demonstrating a shift towards cis accumulation. Consumption of typical servings of processed tomato products results in differing plasma and prostate lycopene concentrations. Factors including meal composition and genetics deserve further evaluation to determine their impacts on lycopene absorption and biodistribution.

Purpose: To apply k-means clustering of two pharmacokinetic parameters derived from 3T dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the chemotherapeutic response in bladder cancer at the mid-cycle timepoint., Materials and Methods: With the predetermined number of three clusters, k-means clustering was performed on nondimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor's chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer., Results: The k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value., Conclusion: The k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor's chemotherapeutic response., (© 2014 Wiley Periodicals, Inc.)

Testicular cancer is the most common malignancy in men aged 20-35 years and accounts for approximately 1% of all male malignancies. Testicular cancer has a propensity to spread via the lymphatic system to the retroperitoneal lymph nodes, and retroperitoneal lymph node dissection remains an essential component in the cure of these patients. This review summarizes the basic principles of surgical management of germ cell tumors.

Purpose: The p63 gene, located on chromosome 3q27-28, is a member of the p53 gene family. The product encoded by the p63 gene has been reported to be essential for normal development., Experimental Design: In this study, we examined the expression pattern of p63 in human normal and tumor tissues by immunohistochemistry using a monoclonal antibody (clone 4A4) that recognizes all p63 splice variants, and by reverse transcription-PCR using isoform-specific primers., Results: We found that p63 expression was restricted to the nucleus, with a nucleoplasmic pattern. We also observed that the expression was restricted to epithelial cells of stratified epithelia, such as skin, esophagus, exocervix, tonsil, and bladder, and to certain subpopulations of basal cells in glandular structures of prostate and breast, as well as in bronchi. Consistent with the phenotype observed in normal tissues, we found that p63 is expressed predominantly in basal cell and squamous cell carcinomas, as well as transitional cell carcinomas, but not in adenocarcinomas, including those of breast and prostate. Interestingly, thymomas expressed high levels of p63. Moreover, a subset of non-Hodgkin's lymphoma was also found to express p63. Using isoform-specific reverse transcription-PCR, we found that thymomas express all isoforms of p63, whereas the non-Hodgkin's lymphoma tended to express the transactivation-competent isoforms. We did not detect p63 expression in a variety of endocrine tumors, germ cell neoplasms, or melanomas. Additionally, soft tissue sarcomas were also found to have undetectable p63 levels., Conclusions: Our data support a role for p63 in squamous and transitional cell carcinomas, as well as certain lymphomas and thymomas.

Because the disease is so often multifocal and has a high likelihood of recurrence, transitional-cell carcinoma of the ureter traditionally has been treated by nephroureterectomy. As reviewed in this article, partial ureterectomy may be a feasible option for some patients, particularly those with a solitary kidney, bilateral tumors, or renal insufficiency. This conservative procedure also may be appropriate for patients with grade 1 and possibly grade 2 tumors in stage Ta/T1.

The INK4a/ARF locus encodes two distinct tumor suppressors, p16INK4a and p14ARF. Although the contribution of p16INK4a to human tumorigenesis through point mutation, deletion, and hypermethylation has been widely documented, little is known about specific p14ARF lesions and their consequences. Recent data indicate that p14ARF suffers inactivation by promoter hypermethylation in colorectal cancer cells. Because it is known that p14ARF prevents MDM2 nucleocytoplasmic shuttling and thus stabilizes p53 by attenuating MDM2-mediated degradation, we studied the relationship of p14ARF epigenetic silencing to the expression and localization of MDM2 and p53. Cancer cell lines with an unmethylated p14ARF promoter showed strong nuclear expression of MDM2, whereas in a colorectal cell line with p14ARF hypermethylation-associated inactivation, MDM2 protein was also seen in the cytosol. Treatment with the demethylating agent 5-aza-2'-deoxycytidine was able to reinternalize MDM2 to the nucleus, and p53 expression was restored. No apparent changes in retinoblastoma localization were observed. We also studied the profile of p14ARF promoter hypermethylation in an extensive collection of 559 human primary tumors of different cell types, observing that in colorectal, gastric, renal, esophageal, and endometrial neoplasms and gliomas, aberrant methylation of p14ARF was a relatively common epigenetic event. MDM2 expression patterns revealed that lack of p14ARF promoter hypermethylation was associated with tumors showing exclusive nuclear MDM2 staining, whereas MDM2 cytosolic staining was frequently observed in neoplasms with aberrant p14ARF methylation. Taken together, these data support that epigenetic silencing of p14ARF by promoter hypermethylation is a key mechanism in the disturbance of the MDM2 nuclear localization in human cancer.