Search

Purpose: While lymph node dissection (LND) at radical cystectomy (RC) for muscle-invasive bladder cancer has been studied extensively, the role of LND for nonmuscle-invasive bladder cancer (NMIBC) remains incompletely defined. Herein, we aim to assess the association between extent of LND during RC for NMIBC and local pelvic recurrence-free survival (LPRS), cancer-specific survival (CSS) and overall survival (OS)., Materials and Methods: A multi-institutional retrospective review was performed of patients with NMIBC undergoing RC at 3 large tertiary referral centers. To identify a threshold for lymph node yield (LNY) to optimize LPRS, CSS and OS, separate Cox regression models were developed for each possible LNY threshold. Model performance including Q-statistics and hazard ratios (HRs) were used to identify optimal LNY thresholds., Results: A total of 1,647 patients underwent RC for NMIBC, with a median LNY of 15 (quartiles 9,23). Model performance curves suggested LNY of 10 and 20 to optimize LPRS and CSS/OS, respectively. On multivariable regression, LNY >10 was associated with lower risk of LPR compared to LNY ≤10 (HR 0.63, 95% CI 0.42-0.93, p=0.02). Similarly, LNY >20 was associated with improved CSS (HR 0.67, 95% CI 0.52-0.87, p=0.002) and OS (HR 0.75, 95% CI 0.64-0.88, p <0.001) compared to LNY ≤20. Similar results were observed in the cT1 and cTis subgroups., Conclusions: Greater extent of LND during RC for NMIBC is associated with improved LPRS, CSS and OS, supporting the inclusion of LND during RC for NMIBC, particularly among patients with cTis or cT1 disease. Future prospective studies are warranted to assess the ideal anatomical template of LND in NMIBC.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Data from the pre-neoadjuvant chemotherapy (NAC) era suggests patients who progress on bacillus Calmette-Guérin (BCG) to muscle-invasive bladder cancer (P-MIBC) exhibit worse outcomes compared to de novo MIBC (D-MIBC). Herein, we investigate whether P-MIBC is an independent poor risk factor in the setting of contemporary NAC use., Materials and Methods: A review of patients who underwent radical cystectomy (RC) for cT2-3 MIBC from 2005 to 2018 was performed. Patients were stratified into high risk (lymphovascular invasion, variant histology, hydronephrosis, cT3b) vs low risk (no risk factors) and P-MIBC (≤pT1 treated with at least induction BCG who progressed to ≥cT2) vs D-MIBC., Results: Among 801 patients who underwent RC 20.3% had P-MIBC and 79.7% had D-MIBC. In low-risk patients treated without NAC, P-MIBC was associated with pathological upstaging (64.9% vs 42.7%, p=0.004) and worse overall (OS, p=0.006) and cancer-specific survival (CSS, p=0.001) compared to D-MIBC. P-MIBC status conferred uniformly poor survival outcomes to patients who did not receive NAC compared to D-MIBC without NAC (median OS 51.5 months [95% CI 40.0-81.0] vs 85.1 months [95% CI 62.8-96.0], p=0.040; median CSS not reached, p=0.014). However, P-MIBC status did not remain a negative prognostic factor in the setting of NAC (median OS 90.5 months [95% CI 34.0-not estimable] vs 87.8 months [95% CI 68.7-not estimable], p=0.606; median CSS not reached, p=0.448)., Conclusions: P-MIBC confers a poor prognosis when managed with RC alone. Treatment with NAC results in equivalent pathological response and survival outcomes compared to D-MIBC. P-MIBC should be included in risk-stratified approaches to NAC selection.

Background: To describe self-reported medication patterns and fertility rates in a population of anabolic steroid (AS) users., Methods: We reviewed data from an online survey of AS users and identified a sub-group who had attempted to achieve a pregnancy with their partners while using AS. The online survey consisted of questions addressing demographics, AS use, ancillary medications, and fertility outcomes., Results: A total of 97 men (of 231 total respondents) had attempted to achieve a pregnancy while taking AS and comprise the current cohort. The majority of men were 25-44 years old (63.9%), married (75.5%) and Caucasian (88.7%). Ancillary drug use was common with only 5.2% denying drug use other than ASs. The most common reported ancillary drugs were antiestrogens (89.7%) and sexual enhancement medications (SEMs) (68%). The fertility rate was 92.8%, with 82.4% achieving pregnancy within one year. Interestingly, only 13.5% sought fertility evaluation with treatment required in 8.3%. Age at initiation of AS use, maximum dosage utilized, yearly duration of supplementation, and number of years using steroids were not associated with a prolonged duration to pregnancy or decreased rate of pregnancy., Conclusions: Despite continued use of ASs, this cohort's self-reported fertility rates are unexpectedly high. This is presumably related to cycling of therapy and concomitant use of fertility preserving medications., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The objectives of patient selection and counseling are ultimately to enhance successful outcomes. However, the definition for success is often narrowly defined in published literature (ability to complete surgery, complications, satisfaction) and fails to account for patient desires and expectations, temporal changes, natural history of underlying diseases, or independent validation. Factors associated with satisfaction and dissatisfaction are often surgery-specific, although correlation with pre-operative expectations, revisions, and complications are common with most procedures. The process of appropriate patient selection is determined by the integration of patient and surgeon factors, including psychological capacity to handle unsatisfactory results, baseline expectations, complexity of case, and surgeon volume and experience. Using this model, a high-risk scenario includes one in which a low-volume surgeon performs a complex case in a patient with limited psychological capacity and high expectations. In contrast, a high-volume surgeon performing a routine case in a male with low expectations and abundant psychiatric reserve is more likely to achieve a successful outcome. To further help identify patients who are at high risk for dissatisfaction, a previously published mnemonic is recommended: CURSED Patient (compulsive/obsessive, unrealistic, revision, surgeon shopping, entitled, denial, and psychiatric). Appropriate patient counseling includes setting appropriate expectations, reviewing the potential and anticipated risks of surgery, post-operative instruction to limit complications, and long-term follow-up. As thorough counseling is often a time-consuming endeavor, busy practices may elect to utilize various resources including educational materials, advanced practice providers, or group visits, among others. The consequences for poor patient selection and counseling may range from poor surgical outcomes and patient dissatisfaction to lawsuits, loss of credibility, or even significant patient or personal harm., Competing Interests: Conflicts of Interest: Dr. Köhler is a consultant for both Boston Scientific and Coloplast Corporation. All other authors have no relevant disclosures.

Background: From 2014-2016, our clinical practice progressively incorporated several male infertility and andrology procedures performed under local anesthesia, including circumcision, hydrocelectomy, malleable penile prostheses, orchiectomy, penile plication, spermatocelectomy, testicular prostheses, varicocelectomy, vasectomy reversal (VR), and testicular and microepididymal sperm aspiration (TESE/MESA). Given the observed outcomes and potential financial and logistical benefits of this approach for surgeons and patients, we sought to describe our initial experience., Methods: A retrospective analysis was performed of all andrologic office-based (local anesthesia only) and select OR (general or monitored anesthesia care) procedures performed from 2014-2016. Financial and outcomes analyses were performed for infertility cases due to the homogeneity of payment modalities and number of cases available. Demographic, clinicopathologic, and procedural costs (direct and indirect) were reviewed and compared., Results: A total of 32 VRs, 24 hydrocelectomies, 24 TESEs, 10 circumcisions, 9 MESA/TESEs, 4 spermatocelectomies, 3 orchiectomies (1 inguinal), 2 microTESEs, 2 testicular prostheses, 1 malleable penile prosthesis, 1 penile plication, and 1 varicocelectomy. Compared to the OR, male infertility procedures performed in the clinic with local anesthesia were performed for a fraction of the cost: MESA/TESE (78% reduction), TESE (89% reduction), and VR (62% reduction). All office-based procedures were completed successfully without significant modifications to technique. Outcomes were similar between the office and OR including operative time (VR: 181 vs. 190 min, P=0.34), rate of vasoepididymostomy (VE) (23% vs. 32%, P=0.56), total sperm counts (72.2 vs. 50.9 million, P=0.56), and successful sperm retrieval (MESA/TESE 100% vs. 100%, P=1.00; TESE 80% vs. 100%, P=0.36). To our knowledge, the current study also represents the first report of office-based VE under local anesthesia alone. For hydrocelectomy procedures, recurrence (4%) and hematoma (4%) rates were low (mean 4.2 months follow-up), although this likely relates to modifications with technique and not the anesthesia or operative setting. Overall, when given the choice, 86% of patients chose an office-based approach over the OR., Conclusions: Office-based andrology procedures using local anesthesia may be successfully performed without compromising surgical technique or outcomes. This approach significantly reduces costs for patients and the overall healthcare system and has become our treatment modality of choice., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Oncolytic measles viruses (MV) derived from the live attenuated vaccine strain have been engineered for increased tumor-cell specificity, and are currently under investigation in clinical trials including a phase I study for glioblastoma multiforme (GBM). Recent preclinical studies have shown that the cellular tropism of several viruses can be controlled by inserting microRNA-target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. Since neuron-specific microRNA-7 is downregulated in gliomas but highly expressed in normal brain tissue, we engineered a microRNA-sensitive virus containing target sites for microRNA-7 in the 3'-untranslated region of the viral fusion gene. In presence of microRNA-7 this modification inhibits translation of envelope proteins, restricts viral spread, and progeny production. Even though highly attenuated in presence of microRNA-7, this virus retained full efficacy against glioblastoma xenografts. Furthermore, microRNA-mediated inhibition protected genetically modified mice susceptible to MV infection from a potentially lethal intracerebral challenge. Importantly, endogenous microRNA-7 expression in primary human brain resections tightly restricted replication and spread of microRNA-sensitive virus. This is proof-of-concept that tropism restriction by tissue-specific microRNAs can be adapted to oncolytic MV to regulate viral replication and gene expression to maximize tumor specificity without compromising oncolytic efficacy.

RNAi is a powerful technology for analyzing gene function in human cells. However, its utility can be compromised by inadequate knockdown of the target mRNA or by interpretation of effects without rigorous controls. We review lentiviral vector-based methods that enable transient or stable knockdowns to trace mRNA levels in human CD4+ T cell lines and other targets. Critical controls are reviewed, including rescue of the pre-knockdown phenotype by re-expression of the targeted gene. The time from thinking about a potential knockdown target to analysis of phenotypes can be as short as a few weeks.

The current model of measles virus (MV) pathogenesis implies that apical infection of airway epithelial cells precedes systemic spread. An alternative model suggests that primarily infected lymphatic cells carry MV to the basolateral surface of epithelial cells, supporting MV shedding into the airway lumen and contagion. This model predicts that a mutant MV, unable to enter cells through the unidentified epithelial cell receptor (EpR), would remain virulent but not be shed. To test this model, we identified residues of the MV attachment protein sustaining EpR-mediated cell fusion. These nonpolar or uncharged polar residues defined an area located near the binding site of the signaling lymphocytic activation molecule (SLAM), the receptor for MV on lymphatic cells. We then generated an EpR-blind virus maintaining SLAM-dependent cell entry and inoculated rhesus monkeys intranasally. Hosts infected with the selectively EpR-blind MV developed rash and anorexia while averaging slightly lower viremia than hosts infected with wild-type MV but did not shed virus in the airways. The mechanism restricting shedding was characterized using primary well-differentiated human airway epithelial cells. Wild-type MV infected columnar epithelial cells bearing tight junctions only when applied basolaterally, while the EpR-blind virus did not infect these cells. Thus, EpR is probably a basolateral protein, and infection of the airway epithelium is not essential for systemic spread and virulence of MV.

Virotherapy is currently undergoing a renaissance, based on our improved understanding of virus biology and genetics and our better knowledge of many different types of cancer. Viruses can be reprogrammed into oncolytic vectors by combining three types of modification: targeting, arming and shielding. Targeting introduces multiple layers of cancer specificity and improves safety and efficacy; arming occurs through the expression of prodrug convertases and cytokines; and coating with polymers and the sequential usage of different envelopes or capsids provides shielding from the host immune response. Virus-based therapeutics are beginning to find their place in cancer clinical practice, in combination with chemotherapy and radiation.