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OBJECTIVE Brainstem cavernous malformations (CMs) often require resection due to their aggressive natural history causing hemorrhage and progressive neurological deficits. The authors report a novel intraoperative neuromonitoring technique of direct brainstem somatosensory evoked potentials (SSEPs) for functional mapping intended to help guide surgery and subsequently prevent and minimize postoperative sensory deficits. METHODS Between 2013 and 2019 at the Stanford University Hospital, intraoperative direct brainstem stimulation of primary somatosensory pathways was attempted in 11 patients with CMs. Stimulation identified nucleus fasciculus, nucleus cuneatus, medial lemniscus, or safe corridors for incisions. SSEPs were recorded from standard scalp subdermal electrodes. Stimulation intensities required to evoke potentials ranged from 0.3 to 3.0 mA or V. RESULTS There were a total of 1 midbrain, 6 pontine, and 4 medullary CMs—all with surrounding hemorrhage. In 7/11 cases, brainstem SSEPs were recorded and reproducible. In cases 1 and 11, peripheral median nerve and posterior tibial nerve stimulations did not produce reliable SSEPs but direct brainstem stimulation did. In 4/11 cases, stimulation around the areas of hemosiderin did not evoke reliable SSEPs. The direct brainstem SSEP technique allowed the surgeon to find safe corridors to incise the brainstem and resect the lesions. CONCLUSIONS Direct stimulation of brainstem sensory structures with successful recording of scalp SSEPs is feasible at low stimulation intensities. This innovative technique can help the neurosurgeon clarify distorted anatomy, identify safer incision sites from which to evacuate clots and CMs, and may help reduce postoperative neurological deficits. The technique needs further refinement, but could potentially be useful to map other brainstem lesions.

There are profound consequences when developing youth do not get adequate sleep. Adolescents who experience poor sleep may be more likely to engage in offending behavior. While there is a documented association between the number of hours youth sleep and their likelihood of offending, it is unclear how youths' perceptions of their sleep quality contribute to offending. Further, scholars have yet to rigorously examine the relation between sleep problems and offending in young adulthood, a developmental stage, which is both critical for desistance and in which sleep may play an important role.Using a sample of 1,216 justice-involved male youth, this study uses within-individual longitudinal methods (fixed-effects Poisson regression models) to examine the relation between changes in perceptions of sleep quality and changes in offending behavior from ages 13 to 24.Increases in sleep problems are associated with increases in offending, particularly aggressive/person-related offenses, for both adolescents and young adults. This holds true even after controlling for time-varying anxiety, substance use, and violence exposure.Improving sleep quality may be critical for reducing aggressive behavior in at-risk adolescents and young adults. Interventions that address sleep quality, and not just quantity, may be particularly beneficial.

PURPOSE The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guerin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with nonmuscle-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 a 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.

When it comes to the treatment of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical bacillus Calmette-Guérin (BCG), two questions must be considered: 1) what dose to give, and 2) for how long? The issue of optimal dose and duration has been the subject of several randomized trials and is especially pertinent in the context of a global BCG shortage. Despite this, there appears to be uncertainty as to whether BCG dose or duration may be compromised in the event of shortage. As such, we wish to summarize the available evidence as an aid to the practicing urologist.

Pathologic specifications of analyzed tumor specimens (formal pathologist review).

Frequencies of mutations in genes previously reported6-8,10 as observed in our panel of bladder carcinoma patients.

Genes calculated to be significantly mutated by Genome MuSic algorithm (p

Clinical characteristics of the 81 patients, according to recurrence status.

Genes calculated to be significantly mutated by MutSigCV algorithm (p

Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators.Experimental Design: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients.Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22–0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage.Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. Clin Cancer Res; 20(24); 6605–17. ©2014 AACR.

Normal adjacent bladder tissue specimens (formal pathologist review).

The field of cancer therapy has undergone a major transformation in less than a decade due to the introduction of checkpoint inhibitors, the advent of next generation sequencing and the discovery of neoantigens. The key observation that the breadth of each patient's immune response to the unique mutations or neoantigens present in their tumor is directly related to their survival has led oncologists to focus on driving immune responses to neoantigens through vaccination. Oncology has entered the era of precision immunotherapy, and cancer vaccine development is undergoing a paradigm shift.Neoantigens are short peptide sequences found in tumors, but not noncancerous tissues, the vast majority of which are unique to each patient. In addition to providing a description of the distinguishing features of neoantigen discovery platforms, this review will address cross-cutting personalized cancer vaccine design themes and developmental stumbling blocks.Immunoinformatic pipelines that can rapidly scan cancer genomes and identify 'the best' neoantigens are in high demand. Despite the need for such tools, immunoinformatic methods for identifying neoepitopes in cancer genomes are diverse and have not been well-validated. Validation of 'personalized vaccine design pipelines' will bring about a revolution in neoantigen-based vaccine design and delivery.

Adolescence is a peak period for risk-taking, but research has largely overlooked positive manifestations of adolescent risk-taking due to ambiguity regarding operationalization and measurement of positive risk-taking. We address this limitation using a mixed-methods approach. We elicited free responses from contemporary college students (N = 74, M

Aim: Spatial compositional turnover varies considerably among co-occurring assemblages of organisms, presumably shaped by common processes related to species traits. We investigated patterns of spatial turnover in a diverse set of marine assemblages using zeta diversity, which extends traditional pairwise measures of turnover to capture the roles of both rare and common species in shaping assemblage turnover. We tested the generality of hypothesized patterns related to ecological traits and provide insights into mechanisms of biodiversity change. Location: Temperate pelagic and benthic marine assemblages of micro- and macroorganisms along south-eastern Australia (30–36° S latitude). Time period: 2008–2021. Major taxa studied: Bacteria, phytoplankton, zooplankton, fish, and macrobenthic groups. Methods: Six marine datasets spanning bacteria to fishes were collated for measures of “species” occurrence, with a 1° latitude grain. For each assemblage, ecological traits of body size, habitat and trophic level were analysed for the form and rate of decline in zeta diversity and for the species retention rate. Results: Species at higher trophic levels showed two to three times the rate of zeta diversity decline compared with lower trophic levels, indicating an increase in turnover from phytoplankton to carnivorous fishes. Body size showed the hypothesized unimodal relationship with rates of turnover for macroorganisms. Patterns of bacterial turnover contrasted with those found for macroorganisms, with the highest levels of turnover in pelagic habitats compared with benthic (kelp-associated) habitats. The shape of retention rate curves showed the importance of both rare and common species in driving turnover; a finding that would not have been observable using pairwise (beta diversity) measures of turnover. Main conclusions: Our results support theoretical predictions for phytoplankton and macroorganisms, showing an increase in turnover rate with trophic level, but these predictions did not hold for bacteria. Such deviations from theory need to be investigated further to identify underlying processes that govern microbial assemblage dynamics.

Antarctic sea-ice forms a complex and dynamic system that drives many ecological processes in the Southern Ocean. Sea-ice microalgae and their associated microbial communities are understood to influence nutrient flow and allocation in marine polar environments. Sea-ice microalgae and their microbiota can have high seasonal and regional (>1000 km2) compositional and abundance variation, driven by factors modulating their growth, symbiotic interactions and function. In contrast, our knowledge of small-scale variation in these communities is limited. Understanding variation across multiple scales and its potential drivers is critical for informing on how multiple stressors impact sea-ice communities and the functions they provide. Here, we characterized bacterial communities associated with sea-ice microalgae and the potential drivers that influence their variation across a range of spatial scales (metres to >10 kms) in a previously understudied area in Commonwealth Bay, East Antarctica where anomalous events have substantially and rapidly expanded local sea-ice coverage. We found a higher abundance and different composition of bacterial communities living in sea-ice microalgae closer to the shore compared to those further from the coast. Variation in community structure increased linearly with distance between samples. Ice thickness and depth to the seabed were found to be poor predictors of these communities. Further research on the small-scale environmental drivers influencing these communities is needed to fully understand how large-scale regional events can affect local function and ecosystem processes.

We report the saturable absorption characterization of mono- to few-layers graphene and bulk exfoliated ReS2 flakes fiber samples, using an automated balanced photodetectors setup and a 150-fs 1560-nm fiber laser.

Kelp forest ecosystems and their associated ecosystem services are declining around the world. In response, marine managers are working to restore and counteract these declines. Kelp restoration first started in the 1700s in Japan and since then has spread across the globe. Restoration efforts, however, have been largely disconnected, with varying methodologies trialled by different actors in different countries. Moreover, a small subset of these efforts are 'afforestation', which focuses on creating new kelp habitat, as opposed to restoring kelp where it previously existed. To distil lessons learned over the last 300 years of kelp restoration, we review the history of kelp restoration (including afforestation) around the world and synthesise the results of 259 documented restoration attempts spanning from 1957 to 2020, across 16 countries, five languages, and multiple user groups. Our results show that kelp restoration projects have increased in frequency, have employed 10 different methodologies and targeted 17 different kelp genera. Of these projects, the majority have been led by academics (62%), have been conducted at sizes of less than 1 ha (80%) and took place over time spans of less than 2 years. We show that projects are most successful when they are located near existing kelp forests. Further, disturbance events such as sea-urchin grazing are identified as regular causes of project failure. Costs for restoration are historically high, averaging hundreds of thousands of dollars per hectare, therefore we explore avenues to reduce these costs and suggest financial and legal pathways for scaling up future restoration efforts. One key suggestion is the creation of a living database which serves as a platform for recording restoration projects, showcasing and/or re-analysing existing data, and providing updated information. Our work establishes the groundwork to provide adaptive and relevant recommendations on best practices for kelp restoration projects today and into the future. Published version This work was supported by a Scientia PhD scholarship to A.M.E., and the Australian Research Council through projects LP160100836 to P.D.S., E.M.M. and A.V., DP180104041 to P.D.S. and E.M.M. and DP190102030 to A.V. Open access funding enabled and organized by Projekt DEAL.

We evaluated two configurations of EDFLs with different lengths and, consequently, different repetition rates as a condition of optimizing the power for the generated number of modes and improving the SNR of the beat frequency.

In this work, we report the first nonlinear refraction (NLR) measurements of CVD monolayer ReS2. Using an 800-nm femtosecond laser, a high nonthermal NLR of 2.39x10−8cm2/W was obtained, 3× higher than that of monolayer WS2.

503 Background: Pts presenting with NMIBC carcinoma in situ (CIS) have a high risk of progression. FGFR inhibition may benefit CIS pts with FGFRalt who are unresponsive to first-line BCG, for whom treatment (tx) options, other than radical cystectomy, are limited. Erdafitinib (erda), an oral selective pan-FGFR tyrosine kinase inhibitor, is approved for locally advanced or metastatic urothelial cancer in adults with FGFR3/2alt who have progressed during or after ≥1 line of platinum-containing chemotherapy. THOR-2 (NCT04172675) is a multicohort phase 2 study of erda in pts with HR-NMIBC. Here we report results from an exploratory cohort of pts with BCG-unresponsive CIS with FGFRalt with or without papillary disease (Cohort 2). Methods: Inclusion criteria: age ≥18 y, with histologically confirmed, BCG-unresponsive HR-NMIBC with FGFR3/2alt (by local/central testing) presenting as CIS, with or without a papillary tumor and who refused or were not eligible for cystectomy. In this cohort, pts received continuous oral erda 6 mg once daily without uptitration in 28-d cycles (dose selected to improve tolerability while maintaining activity to prevent disease recurrence, for this population). Erda was discontinued if no complete response (CR) was observed within 3 mos. Exploratory efficacy end points are CR rates at the Cycle 3 Day 1 (C3D1) disease evaluation and the Cycle 6 Day 1 (C6D1) disease evaluation; safety was a key secondary end point. Results: As of the data cutoff (Sep 2022) (median follow-up of 10 mos), 10 pts have received erda (enrolled population; median age 72 y [range 52-83]; 90% CIS [1 pt with Ta was mis-enrolled]). Pts received erda for a median duration 5.9 mos (range 1.1-17.0). Of 10 enrolled pts, the CR rates at first evaluation (C3D1) and second evaluation (C6D1) were 100% (9/9 evaluable pts) and 75% (6/8 evaluable pts), respectively. The median duration of response was 3.0 mos. The most common tx-emergent adverse events (TEAEs) were dry mouth (60%; n=6), hyperphosphatemia (50%; n=5), dysgeusia (50%; n=5), and diarrhea (50.0%; n=5). 1 pt (10%) had Gr 2 retinal detachment which led to tx discontinuation and 1 pt (10%) had Gr 1 subretinal fluid; both reported as resolved. Gr ≥3 tx-related TEAEs occurred in 3 pts (30%), and included dry mouth, stomatitis, nail disorder, onychomadesis, acute kidney injury, chronic kidney disease, sepsis, and hypotension in 1 pt each. 1 pt (10%) had serious tx-related TEAEs (dry mouth, hypotension, pneumonitis, acute kidney injury, and sepsis), and 1 pt (10%) discontinued tx due to a tx-related TEAE. No tx-related deaths were observed. Conclusions: Data from Cohort 2 of THOR-2 demonstrate efficacy at C3D1 and C6D1 evaluations in pts with HR-NMIBC with FGFRalt. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04172675 .

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

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.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 P0.05 considered significant.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).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.

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 titer800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers800 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 titers800 and peak antibody fold change8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers800 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.

We experimentally investigated the saturable absorption influence of graphene layers with natural stacking order in an erbium-doped fiber laser passive mode-locking. Mechanically exfoliated graphene saturable absorber (MEGSA) samples, ranging from 1 to 6 layers, were fabricated preserving their natural ABA stacking order and precisely characterized by 2D band profile from Raman spectroscopy. By incorporating the samples as saturable absorbers (SA) in the fiber laser, mode-locking performances with pulse duration from 670–780 fs and bandwidth from 3.8–4.6 nm could be generated. Also, we identified a transition in the mode-locking activation mechanism from non-self-starting, for monolayer and bilayer graphene, to self-starting, for trilayer and few-layer graphene, which is a strong indicative of fast-to-slow saturable absorption response dependence on the number of graphene layers.

Contains fulltext : 251844.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Neoadjuvant chemotherapy and radical cystectomy (RC) are underutilized standards of care for the treatment of muscle-invasive bladder cancer (MIBC) due to high patient burden from systemic toxicities and postoperative complications, respectively. TAR-200 is a novel intravesical drug delivery system developed to release gemcitabine into the bladder urine continuously, resulting in distribution of drug into stromal layers of the bladder. The primary aim of the TAR-200-101 study was to evaluate the safety of TAR-200 in patients with MIBC prior to RC (NCT02722538). METHODS AND MATERIALS: This phase I, open-label study was conducted across 6 US and European sites. Eligible patients were aged ≥18 years with histologically confirmed T2a-T3b N0-N1 M0 urothelial cancer and had refusal or were ineligible to receive cisplatin-based combination chemotherapy. Two arms were enrolled serially. Patients in Arm 1 had residual tumor >3 cm after transurethral resection of bladder tumor (TURBT); those in Arm 2 had undergone maximal TURBT (residual tumor

4597 Background: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ̃20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction,viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: A CR rate of 87.5% (14/16) at the 3 m assessment timepoint has been observed thus far. All patients in CR at 3 m remain in CR at downstream timepoints including: 9/9 at 6 m, 6/6 at 9 m, and 3/3 at 12 m. Treatment related AE have been generally limited to transient grade 1-2 local-regional genitourinary adverse events with no reports of grade 3, 4 or SAE attributed to treatment with CG0070/Pembroluzimab. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. Additional data on efficacy as well as safety and biomarker (CAR, E2F, and PDL1) assessment will be presented for at least 25 of the projected 35 patients at the time of the conference. Clinical trial information: NCT04387461.

TPS4614 Background: Bacillus Calmette-Guérin (BCG) therapy is the standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor. However, disease recurrence or progression is common and patients with BCG-unresponsive disease are unlikely to respond to further BCG therapy. In these patients, the current standard of care is radical cystectomy and bladder-preserving treatment options, limited to intravesical chemotherapy or intravenous pembrolizumab. In a phase 1 study, sasanlimab (PF-06801591), a monoclonal antibody to programmed cell death protein 1 (PD-1), was administered subcutaneously at 300 mg every 4 weeks. Sasanlimab had an acceptable safety profile and showed clinical activity aligned to other anti-PD-1/PD-ligand 1 (PD-L1) agents in patients with advanced urothelial carcinoma and non-small cell lung cancer, while offering the convenience of subcutaneous administration. Therefore, CREST Study Cohort B aims to evaluate sasanlimab administered subcutaneously in patients with BCG-unresponsive NMIBC. Methods: CREST Study Cohort B is a non-randomized, multicenter, multinational, open-label, phase 3 study and will enroll ̃160 patients with histologically confirmed BCG-unresponsive, high-risk, non-muscle invasive transitional cell carcinoma of the bladder urothelium (high-grade Ta or T1 tumor, or carcinoma in situ [CIS]) in 2 separate Cohorts, B1 and B2 (̃110 and ̃50 patients, respectively). Cohort B1 will enroll patients with persistent or recurrent CIS with or without concomitant recurrent high-grade Ta/T1 disease, within 12 months of completing adequate BCG therapy. Cohort B2 will enroll patients with recurrent high-grade Ta/T1 disease within 6 months of completing adequate BCG therapy. All patients will receive subcutaneous sasanlimab as a single agent. Efficacy will be assessed at regular intervals by cystoscopy, urine cytology, biopsy, and imaging. The primary endpoint is complete response (CR) and event-free survival (EFS) for Cohort B1 and B2, respectively. Secondary endpoints include duration of CR (Cohort B1 only), EFS (Cohort B1 only), overall survival, time to cystectomy, safety, health-related quality of life, pharmacokinetic parameters, PD-L1 expression, and incidence of anti-drug antibodies. Recruitment of patients in CREST Study Cohort B will be opened in Canada and the United States of America, with other sites in Asia, Australia, and Europe. Clinical trial information: NCT04165317.

454 Background: Patient preference is an important factor in selecting appropriate treatment choices. Although underutilized, the standard of care for MIUC is with NAC, whereas evidence for adjuvant therapy is less clear. With the introduction of novel adjuvant treatments such as immune checkpoint inhibitors, treatment options are expected to expand. This study examines whether preferences for adjuvant therapy is impacted in MIUC patients receiving NAC. Methods: A cross-sectional, web-based survey included patients ≥ 18 years old who self-reported being diagnosed with MIUC and underwent radical cystectomy or nephroureterectomy without recurrence. Patients were recruited from the US, UK, Canada, France, and Germany (May–Sep 2021). A DCE using 2 adjuvant treatment profiles included 8 attributes: cancer-free survival, overall survival (OS), hypothyroidism requiring life-long hormone therapy, risk of a serious adverse event (requiring medical intervention/possible hospitalization), nausea, fatigue, diarrhea, and a dosing regimen (frequency of treatment and monitoring); an opt-out option of no treatment was also shown. Patients were grouped according to self-reported receipt of NAC. Descriptive statistics and hierarchical Bayesian logistic model with estimated preference weights were used. Relative importance estimates (mean ± standard error), or how much the attribute ranges accounted for the variation in preferences, were computed for each attribute. Bivariate comparisons used t-tests. Results: This interim analysis identified 205 patients (70.7% of target sample; US, n = 99; Germany, n = 60; UK, n = 31; Canada, n = 14; France, n = 1). Of 82 patients (40.0%) receiving NAC, 32.7% were patients > 65 years and 55.1% were male; receipt of NAC did not differ by age ( P = 0.248) or sex ( P = 0.731). Patients were willing to accept increased risk in toxicities for increased treatment efficacy. Specifically, mean relative importance of treatment attributes showed that difference in median OS (25 months compared to 78 months) was most important (34.6% ± 1.6), although less so for those who did not receive NAC (30.2% ± 2.4 vs 37.5% ± 2.0; P = 0.022). Patients chose an adjuvant treatment option over ‘no treatment’ 91% of the time, with similar findings by NAC status. Conclusions: Preliminary data indicates that receipt of NAC impacts preferences for adjuvant treatment attributes. However, regardless of these attributes, patients still preferred adjuvant treatment over none. These results suggest that providing standard of care NAC does not reduce patient preference for adjuvant therapy; rather, patient preferences for adjuvant treatment attributes vary by treatment history, with implications for improving quality of care and outcomes.

493 Background: Standard treatment (tx) for high-risk NMIBC is transurethral resection of bladder tumor (TURBT) followed by BCG induction and maintenance. However, ≈50% of pts experience recurrence and/or progression after tx and may be ineligible for or refuse cystectomy. The PD-L1/PD-1 pathway may be involved with immune escape in NMIBC following BCG exposure. Here, we report results of atezo (anti–PD-L1) ± BCG in BCG-unresponsive, high-risk NMIBC. Methods: This multicenter study (NCT02792192) enrolled pts with BCG-unresponsive NMIBC with carcinoma in situ who had repeat TURBT. Cohort 1A and 1B pts received atezo 1200 mg IV q3w for ≤96 wk. Cohort 1B pts also received standard BCG induction (qw × 6 doses) and maintenance (qw × 3 doses at 3 mo), with optional maintenance courses at 6, 12, 18, 24, and 30 mo. For cohort 1B only, de-escalation was allowed for ≤3 BCG dose levels (full dose 50 mg, 66% and 33% of full dose). Co-primary outcomes were safety and complete response (CR) rate at 6 mo (6-mo bladder biopsy required). Duration of CR and 3-mo CR rate (key secondary outcomes) and 12-mo CR rate (exploratory) were also shown. Results: Cohorts 1A and 1B enrolled 12 pts each. Median age was 74 y; most pts had ECOG PS 0 (n = 7 [58%] in each cohort). At data cutoff (Sep 29, 2020), median atezo tx duration was 22.7 wk in cohort 1A and 31.6 wk in 1B. Following dose de-escalation in cohort 1B, the recommended BCG dose was 50 mg. BCG dose modification/interruption occurred in 4 pts (33%) due to an AE. The most common reason for tx discontinuation was disease recurrence or progression in both cohorts. Three pts (25%) in cohort 1A had atezo-related Gr 3 AEs (most common: maculopapular rash, n = 2); no atezo- or BCG-related Gr ≥3 AEs were seen in cohort 1B. Three dose-limiting toxicities occurred (1 [8%] in cohort 1A and 2 [17%] in cohort 1B), all reported as AEs of special interest. No Gr 4/5 AEs were reported. CRs, which appeared durable, were seen in both cohorts (Table). Conclusions: In this first report of atezo + BCG in NMIBC, atezo as mono- and combination therapy was well tolerated, with no new safety signals or tx-related deaths. Preliminary data suggested clinically meaningful activity, especially with atezo + BCG, requiring confirmation in a larger setting. Clinical trial information: NCT02792192. [Table: see text]

TPS597 Background: Cohort A of the phase 2 KEYNOTE-057 study showed that pembrolizumab monotherapy provided effective antitumor activity and acceptable safety in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS). Pembrolizumab in combination with BCG at earlier stages of HR NMIBC might provide benefit superior to that of BCG monotherapy. The open-label, comparator-controlled, phase 3 KEYNOTE-676 study (NCT03711032) will be conducted to investigate the efficacy and safety of pembrolizumab + BCG versus BCG monotherapy in patients with HR NMIBC. Cohort A will enroll patients with persistent or recurrent HR NMIBC after BCG induction. Cohort B is a new, randomly assigned cohort that will help evaluate pembrolizumab + BCG in BCG treatment–naive patients who either never received BCG treatment or received BCG treatment > 2 years before enrollment. Methods: Cohort B of KEYNOTE-676 will enroll approximately 975 patients with blinded independent central review (BICR)–confirmed HR NMIBC (T1, high-grade Ta CIS) and Eastern Cooperative Oncology Group performance status score 0-2 who underwent cystoscopy/transurethral resection of bladder tumor ≤12 weeks before randomization and had not received BCG within the past 2 years. Patients will be randomly assigned 1:1:1 to receive pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) + BCG reduced maintenance (≤6 months), pembrolizumab 400 mg IV Q6W + BCG full maintenance (≤18 months), or BCG monotherapy (BCG full maintenance). Stratification factors include NMIBC stage (CIS or no CIS) and PD-L1 expression (combined positive score [CPS] ≥10 or CPS < 10), determined by central laboratory. Disease status will be assessed by use of cystoscopy, urine cytology, and biopsy (as applicable) every 12 weeks (Q12W) through year 2, then every 24 weeks through year 5; imaging with computed tomography urography will occur every 72 weeks. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of study treatment (90 days for serious AEs). The primary end point is event-free survival (EFS). Secondary end points include complete response rate by BICR, duration of response (DOR), 12-month DOR rate (CIS only), 24-month EFS rate, disease-specific survival, time to cystectomy, overall survival, and safety. The study is enrolling or planning to enroll at sites in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT03711032.