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PURPOSE Programmed cell death protein-1 (PD-1) receptor and ligand interactions are the target of immunotherapies for more than 20 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and programmed death ligand-1 (PD-L1) immunohistochemistry. Structural variations (SVs) in PD-L1 ( CD274) and PD-L2 ( PDCD1LG2) have been observed in cancer, but the comprehensive landscape is unknown. Here, we describe the genomic landscape of PD-L1 and PD-L2 SVs, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. METHODS We analyzed sequencing data from cancer cases with PD-L1 and PD-L2 SVs across 22 publications and four data sets, including Foundation Medicine Inc, The Cancer Genome Atlas, International Cancer Genome Consortium, and the Oncology Research Information Exchange Network. We leveraged RNA sequencing to evaluate immune signatures. We curated literature reporting clinical outcomes of patients harboring PD-L1 or PD-L2 SVs. RESULTS Using data sets encompassing 300,000 tumors, we curated 486 cases with SVs in PD-L1 and PD-L2 and observed consistent breakpoint patterns, or hotspots. Leveraging The Cancer Genome Atlas, we observed significant upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, T cells, and immune cell proliferation in samples harboring PD-L1 or PD-L2 SVs. Retrospective review of 12 studies that identified patients with SVs in PD-L1 or PD-L2 revealed > 50% (52/71) response rate to PD-1 immunotherapy with durable responses. CONCLUSION Our findings show that the 3′-UTR is frequently affected, and that SVs are associated with increased expression of ligands and immune signatures. Retrospective evidence from curated studies suggests this genomic alteration could help identify candidates for PD-1/PD-L1 immunotherapy. We expect these findings will better define PD-L1 and PD-L2 SVs in cancer and lend support for prospective clinical trials to target these alterations.

Urothelial carcinoma (UC) presents most frequently as bladder cancer and is the most common cancer of the urinary system in the United States. UC relapse and progression are common and impose a significant negative impact on the lives of patients and healthcare resources. To elucidate the biological mechanisms of UC and find novel biomarkers, we analyzed the clinical and genomic data in the Oncology Research Information Exchange Network (ORIEN). We conducted gene-based and gene-set based association tests on rare germline variants comparing the exome sequencing of 336 UC patients and genome sequencing of 366 healthy controls (42 unrelated individuals from the Centre d'Etudes du Polymorphisme Humain [CEPH] families and 324 from the University of Utah Heritage 1000 [H1K] Projects). The analysis of loss-of-function (LoF) variants revealed that the forkhead box (FOX) J2 gene set was significantly associated with UC at the genome-wide level (Bonferroni-corrected p-value=0.01). Genes in this gene set contain a motif that matches the FOXJ2 transcription factor binding site. Firth-penalized Cox proportional hazard regression on overall survival identified LoF variants in genes down-regulated in naive CD8 T cells to be associated with worse prognosis (Bonferroni-corrected p-value=0.032, hazard ratio=28.2, and 95% confidence interval 6.66 to 119.0). In exome sequencing of tumor tissues, we searched for driver genes and pathways by testing for higher variant allelic fractions than the genome average. The tests yielded eleven genes with genome-wide significance (Table 1). By gene set analysis using the MSigDB Hallmark database, significant pathways included the P53 pathway (p Table 1. Genes with high allelic fractions Gene P-value Number of Variants TP53 Citation Format: Bing-Jian Feng, Wendy Kohlmann, David A. Nix, Aaron Atkinson, Kenneth M. Boucher, Courtney Carroll, Jill Kolesar, Eric A. Singer, Stephen B. Edge, Kamal Sahu, Alejandro Sanchez, Mikaela Larson, Michelle L. Churchman, Laura Graham, John D. Carpten, Yousef Zakharia, Lindsey Byrne, Rohit K. Jain, Kenneth G. Nepple, Ahmad Shabsigh, Jad Chahoud, Sumati Gupta. Germline and somatic genomic profiling of urothelial carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6074.

Bacillus Calmette-Guérin (BCG) is currently recommended as adjuvant therapy following complete transurethral resection of bladder tumor for high-risk nonmuscle-invasive bladder cancer (NMIBC). In response to the BCG shortage, gemcitabine plus docetaxel (Gem/Doce) has been utilized at our institution in the BCG-naïve setting. We report the outcomes of patients with high-risk BCG-naïve NMIBC treated with Gem/Doce.We retrospectively reviewed patients with BCG-naïve high-risk NMIBC treated with Gem/Doce from May 2013 through April 2021. Patients received 6 weekly intravesical instillations of sequential 1 gm gemcitabine and 37.5 mg docetaxel after complete transurethral resection of bladder tumor. Monthly maintenance of 2 years was initiated if disease-free at first followup. The primary outcome was recurrence-free survival. Survival was assessed with the Kaplan-Meier method, indexed from the first Gem/Doce instillation. Adverse events were reported using CTCAE (Common Terminology Criteria for Adverse Events) v5 (National Cancer Institute, Bethesda, Maryland). Differences were assessed with the log-rank test.There were 107 patients with a median followup of 15 months included in the analysis. Patients had high-risk characteristics including 47 with any carcinomaGem/Doce is an effective and well-tolerated therapy for BCG-naïve NMIBC. Further investigation is warranted.

Intravesical gemcitabine-docetaxel has emerged as an efficacious and well-tolerated salvage therapy for non-muscle-invasive bladder cancer. However, further rescue therapies are needed for subsequent recurrences or intolerance, particularly when cystectomy is refused or precluded. Valrubicin is a U.S. Food and Drug Administration-approved agent for bacillus Calmette-Guérin unresponsive disease, yet as monotherapy has demonstrated poor efficacy. We report our experience with sequential intravesical valrubicin and docetaxel as a rescue therapy for non-muscle-invasive bladder cancer.We retrospectively identified all patients with recurrent non-muscle-invasive bladder cancer treated with valrubicin and docetaxel between April 2013 and June 2021. Patients received weekly sequential intravesical instillations of 800 mg valrubicin and 37.5 mg docetaxel for 6 weeks. If disease-free at first follow-up, monthly maintenance of 2 years was initiated. The primary outcome was recurrence-free survival, assessed using the Kaplan-Meier method.The analysis included 75 patients with median follow-up of 21 months (IQR: 13-37). Twelve patients with low-grade disease had a 73% recurrence-free survival at 2 years. Sixty-three patients with recurrent high-grade disease had a 38% 2-year high-grade recurrence-free survival. Forty-two (56%) patients had carcinoma in situ present; recurrence-free survival was similar for those with and without carcinoma in situ (In a heavily pretreated population, our results suggest valrubicin and docetaxel is an effective rescue treatment for patients with recurrent non-muscle-invasive bladder cancer. Further prospective evaluation is needed.

Introduction:Understanding best practices in perioperative care is critical for quality of care for our urology patients. We compiled a single, concise resource that provides recommendation...

Rescue intravesical therapies for patients with bacillus Calmette-Guérin failure nonmuscle invasive bladder cancer remain a critical focus of ongoing research. Sequential intravesical gemcitabine and docetaxel therapy has shown safety and efficacy in 2 retrospective, single institution cohorts. This doublet has since been adopted as an intravesical salvage option at multiple institutions. We report the results of a multi-institutional evaluation of gemcitabine and docetaxel.Each institution retrospectively reviewed all records of patients treated with intravesical gemcitabine and docetaxel for nonmuscle invasive bladder cancer between June 2009 and May 2018. Only patients with recurrent nonmuscle invasive bladder cancer and a history of bacillus Calmette-Guérin treatment were included in the analysis. If patients were disease-free after induction, maintenance was instituted at the treating physician's discretion. Posttreatment surveillance followed American Urological Association guidelines. Survival analysis was performed using the Kaplan-Meier method and risk factors for treatment failure were assessed with Cox regression models.Overall 276 patients (median age 73 years, median followup 22.9 months) received treatment. Nine patients were unable to tolerate a full induction course. One and 2-year recurrence-free survival rates were 60% and 46%, and high grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection. Forty-three patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion. Analysis identified no patient, disease or prior treatment related factors associated with gemcitabine and docetaxel failure.Intravesical gemcitabine and docetaxel therapy is well tolerated and effective, providing a durable response in patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin therapy. Further prospective study is warranted.

The PET radiotracer 68Ga-PSMA (prostate-specific membrane antigen)-HBED-CC (N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) shows potential as an imaging biomarker for recurrent and metastatic prostate cancer. The purpose of this study was to determine the repeatability of 68Ga-PSMA-HBED-CC in a test-retest trial in subjects with metastatic prostate adenocarcinoma. Methods: Subjects with metastatic prostate cancer underwent 2 PET/CT scans with 68Ga-PSMA-HBED-CC within 14 d (mean, 6 ± 4 d). Lesions in bone, nodes, prostate/bed, and visceral organs, as well as representative normal tissues (salivary glands and spleen), were segmented separately by 2 readers. Absolute and percentage differences in SUVmax and SUVmean were calculated for all test-retest regions. Repeatability was assessed using percentage difference, within-subject coefficient of variation (wCV), repeatability coefficient (RC), and Bland-Altman analysis. Results: Eighteen subjects were evaluated, 16 of whom demonstrated local or metastatic disease on 68Ga-PSMA-HBED-CC PET/CT. In total, 136 lesions were segmented in bone (n = 99), nodes (n = 27), prostate/bed (n = 7), and viscera (n = 3). The wCV for SUVmax was 11.7% for bone lesions and 13.7% for nodes. The RC was ±32.5% SUVmax for bone lesions and ±37.9% SUVmax for nodal lesions, meaning 95% of the normal variability between 2 measurements will be within these numbers, so larger differences are likely attributable to true biologic changes in tumor rather than normal physiologic or measurement variability. wCV in the salivary glands and spleen was 8.9% and 10.7% SUVmean, respectively. Conclusion: Repeatability measurements for PET/CT test-retests with 68Ga-PSMA-HBED-CC showed a wCV of 12%-14% SUVmax and an RC of ±33%-38% SUVmax in bone and nodal lesions. These estimates are an important aspect of 68Ga-PSMA-HBED-CC as a quantitative imaging biomarker. These estimates are similar to those reported for 18F-FDG, suggesting that 68Ga-PSMA-HBED-CC PET/CT may be useful in monitoring response to therapy.

BACKGROUND: Expectant management (EM) has been widely recommended for men with low-risk prostate cancers (PCa). We evaluated trends in EM and the sociodemographic and clinical factors associated with EM, initiating a National Comprehensive Cancer Network guideline-concordant active surveillance (AS) monitoring protocol, and switching from EM to active treatment (AT). METHODS: We used the SEER-Medicare database to identify men ages 66+ diagnosed with a low-risk PCa (PSA < 10 ng/mL, Gleason ≤ 6, stage ≤ T2a) in 2010–2013 with ≥1 year of follow-up. We used claims data to capture (1) PCa treatments, including surgical procedures, radiotherapy, and hormone therapy, and (2) AS monitoring procedures, including PSA tests and prostate biopsy. We defined EM as receiving no AT within 1 year of diagnosis. We used multivariable regression techniques to identify factors associated with EM, initiating AS monitoring, and switching to AT. RESULTS: During the study period, EM increased from 29.4% to 49.0%, p < 0.01. Age < 77, being married/partnered, non-Hispanic ethnicity, higher median ZIP code income, lower PSA levels, stage T1c, and more recent year of diagnosis were associated with EM. Nearly 39% of the EM cohort initiated AS monitoring; age 10 years, implying that a substantial proportion was being managed by watchful waiting. AS monitoring was associated with switching to AT, suggesting that treatment decisions likely were based on cancer progression.

Recent studies have shown that using minimally invasive surgical techniques (conventional laparoscopy or robotic) for prostatectomy is associated with lower perioperative complication rates compared with open radical retropubic prostatectomy. However, differences in infectious complications between these minimally invasive approaches are not well characterized. To study this further, we performed a systematic review of the literature and meta-analysis of the infectious complications of prostatectomy, comparing robotic prostatectomy (RP) with conventional laparoscopic prostatectomy (LP).We searched PubMed, CINAHL, CDSR, and EMBASE through September 2018 for studies evaluating minimally invasive prostatectomy and infectious complications. We employed random-effect models to obtain pooled odds ratio (pOR) estimates. Heterogeneity was evaluated with IFifteen studies were included in the final review for the meta-analysis with 14,121 patients undergoing minimally invasive prostatectomy. There was no statistically significant difference in the number of infectious complication events between RP and LP (pOR 0.94; 95% CI 0.50, 1.76). When we performed a stratified analysis, similar results were found with no statistically significant difference in infectious complications comparing RP with LP among patients with prostate cancer (pOR 0.73; 95% CI 0.43, 1.24). We observed that infectious complications were nearly threefold higher with the robotic approach in earlier studies (published between 2007 and 2012, pOR 2.81; 95% CI 1.07, 7.39), but no significant difference was found in later studies (between 2013 and 2018, pOR 0.80, 95% CI 0.40, 1.57).The rate of infectious complications associated with RP was no different than that associated with conventional LP.

Purpose: To report a case of autoimmune retinopathy and optic neuropathy associated with an enolase-positive renal oncocytoma. Observations: A 41-year-old man presented with subacute, painless, bilateral vision loss. On initial examination, visual acuity measured 20/125 OD and 20/1250 OS, and telangiectatic vessels were noted on the optic nerves and in the maculae. Goldmann perimetry showed bilateral, cecocentral scotomas, and electroretinography demonstrated reduced photopic and scotopic signals, concerning for autoimmune retinopathy. Serum testing showed multiple positive anti-optic nerve and anti-retinal antibodies, including to alpha-enolase. Extensive systemic workup was negative except for a large, exophytic, right renal mass. Biopsy was consistent with a benign oncocytoma, and immunohistochemical staining showed diffusely positive alpha-enolase staining. The patient was treated with a five-day course of intravenous methylprednisolone and plasmapheresis with minimal improvement. Surgical excision of the oncocytoma was performed. At 9-months post-operatively, visual acuity had improved to 20/40 OU, with corresponding improvement on visual field and electroretinography testing. Conclusions and importance: To our knowledge, this is the first report of autoimmune retinopathy and optic neuropathy associated with a renal oncocytoma. The case highlights the importance of a thorough systemic workup in cases of suspected autoimmune retinopathy and reminds clinicians that even tumors considered benign can have distal effects on other organs. Keywords: Autoimmune retinopathy, Optic neuropathy, Oncocytoma

Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45+ lymphoid and myeloid cells in matched tumor and blood from three patients with ccRCC. We also included 11,367 immune cells from four other individuals derived from the kidney and peripheral blood to facilitate the identification and assessment of ccRCC-specific differences. There is an overall increase in CD8+ T-cell and macrophage populations in tumor-infiltrated immune cells compared to normal renal tissue. We further demonstrate the divergent cell transcriptional states for tumor-infiltrating CD8+ T cells and identify a MKI67 + proliferative subpopulation being a potential culprit for the progression of ccRCC. Using the SCRS gene expression, we found preferential prediction of clinical outcomes and pathological diseases by subcluster assignment. With further characterization and functional validation, our findings may reveal certain subpopulations of immune cells amenable to therapeutic intervention., Borcherding and Vishwakarma et al. characterize the tumor immune microenvironment in treatment-naïve clear cell renal carcinoma patients using single-cell RNA- and T-cell receptor sequencing. They find CD8 + T cells and macrophages are enriched in tumor tissue, and identify a proliferative CD8 + T-cell population, which may be relevant for anti-cancer responses.

BackgroundObesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes.MethodsWe investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, ‘BMI’ ≥30 kg/m2) or non-obese (BMI 2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString.ResultsWith obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1β in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors.ConclusionsWe find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1β levels, highlighting the need for continued study of this critical issue.

INTRODUCTION AND OBJECTIVE:The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tu...

INTRODUCTION AND OBJECTIVE:After the recurrence of NMIBC following BCG therapy, risk stratified management directs patients toward radical cystectomy, clinical trial enrollment, and off-label use o...

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

497 Background: Bacillus Calmette-Guerin (BCG) is currently recommended as adjuvant therapy following complete transurethral resection of bladder tumor (TURBT) for high-risk non-muscle invasive bladder cancer (NMIBC). However, continued BCG production shortages have precluded the use of BCG in many urologic practices. Efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) in the BCG failure setting has been reproduced across multiple institutions. In response to the continuing BCG shortage, Gem/Doce has been utilized at our institution in the BCG-naïve setting. We report the outcomes of a large cohort of patients with high-risk BCG-naïve NMIBC treated with Gem/Doce. Methods: We retrospectively identified all patients with BCG-naïve high-risk NMIBC who were treated with Gem/Doce from May 2013 through April 2021. We included patients with intent to receive 6 weekly intravesical instillations of sequential 1 gram gemcitabine and 37.5mg docetaxel after complete TURBT. Monthly maintenance of 2 years was initiated if disease free at first follow-up. The primary outcome was recurrence-free survival (RFS) and efficacy was evaluated in an intention-to-treat manner. Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as T-stage increase from Ta or CIS to T1 or development of muscle invasive or metastatic disease. Survival was assessed using the Kaplan-Meier method and log rank test, indexed from the first Gem/Doce instillation. Results: One hundred seven patients with median follow-up of 15 months were included in the analysis. There were 47 with any CIS, 55 with T1 disease, and 7 with micropapillary variant histology. Four patients did not complete a full induction cycle due to hematuria (3) and severe frequency/nocturia (1). 19 patients sustained a recurrence at any point during follow-up. RFS was 89%, 85%, and 82% at 6, 12, and 24 months, respectively. No difference in RFS was seen in patients with or without CIS (p = 0.42). No patients met criteria for either form of disease progression. One patient underwent cystectomy due to end-stage lower urinary tract symptoms, with final pathology pTisN0. No patients died of bladder cancer. Overall survival was 84% at 24 months. 46 patients reported any symptoms during treatment. Common side effects included urinary frequency/urgency (36%), hematuria (11%), and dysuria (8%). Conclusions: In a large cohort of high-risk, BCG-naïve NMIBC patients, Gem/Doce showed excellent efficacy (84% 2-year HG-RFS). These rates are similar to modern treatment naïve cohorts receiving BCG. Prospective comparative analysis of Gem/Doce in BCG-naïve populations is warranted.[Table: see text]

496 Background: Intravesical gemcitabine-docetaxel (Gem/Doce) has emerged as an efficacious and well-tolerated therapy for NMIBC. At first cytoscopic evaluation, success rate for BCG failures is 75-80% with 60% of responders remaining disease free at 24 months. Success rates are even higher for BCG naïve patients with close to 90% disease free at 3 months, and 93% of responders HG disease free at 24 months. There is an unmet need for effective bladder-sparing regimens for Gem/Doce failures. FDA-approved agents in this setting have poor long-term efficacy; Valrubicin has an 8% 24-month disease free rate, and recently approved Pembrolizumab has less than 20% complete response at 1 year. Based on poor efficacy of alternatives, we evaluated sequential intravesical valrubicin-docetaxel (Val/Doce) as a rescue therapy for NMIBC. Methods: We retrospectively identified all patients with NMIBC who were treated with Val/Doce between April 2013 and June 2021. Patients were included with intent to receive 6 weekly intravesical instillations of sequential 800 mg valrubicin and 37.5 mg docetaxel after complete TURBT. Monthly maintenance of 2 years was initiated if disease free at 3-month cytoscopic evaluation. The primary outcome was recurrence-free survival (RFS). Progression events included the development of muscle invasive or metastatic disease as well as any cystectomy. Survival was assessed using the Kaplan-Meier method and log rank test, indexed from start of Val/Doce induction. Surveillance was performed according to AUA guidelines. Results: The final cohort included 75 patients with median follow-up of 21 months. Of these patients, 12 were treated with Val/Doce for low-grade Ta disease, with 60% disease free at 2 years and no subsequent HG occurrences. The remaining 63 patients had high-grade disease of which 86% were BCG failures and 89% were Gem/Doce unresponsive. The 2 year RFS for high-grade patients was 39%. CIS was present in 56% of the cohort. RFS was similar for those with and without CIS. Progression occurred in 12 of the patients with high-grade disease. Of note, 10 underwent cystectomy and 2 died of metastatic bladder cancer, yielding a bladder cancer specific death rate of 3%. Overall and cystectomy-free survival was 88 and 85% at 24 months, respectively. The most commonly reported side effects were bladder spasms (24%), urinary frequency (13%), and dysuria (11%). There were 3 patients who could not tolerant a full induction course. Conclusions: Sequential intravesical valrubicin-docetaxel will rescue a substantial portion of patients with HG NMIBC failing Gem/Doce or BCG. Thus, the regimen allows a high proportion of patients ( > 80%) to retain their bladders with an acceptable ( < 20%) progression rate without succumbing to bladder cancer-related death ( < 5%).[Table: see text]

451 Background: Outside of Lynch syndrome, few genetic factors have been associated with urothelial cancer (UC). This project seeks to describe the frequency of germline variants in a multi-center UC cohort. Methods: Patients diagnosed with UC from 1980 to 2019 and consented to the Total Cancer Care protocol by members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. The ORIEN program includes a convenience sample of cases with both germline and tumor samples available, though this analysis was germline only. Whole exome sequencing data were analyzed using a GATK best practices for germline variant analysis. A series of quality control (allele frequency > = 0.3, read depth > = 20, genotype quality > = 20), annotation, functional impact (loss of function/splicing), and region (cancer predisposition genes/pathways) filters were applied to identify variants of significant consequence. Results: 348 exomes were evaluated. This identified 60 variants classified as pathogenic/likely pathogenic (P/LP) and 17 novel, high impact variants in genes associated with high, moderate, or recessively inherited cancer risk in 77 individuals (22.1%). 15 (4.5%) had P/LP variants in genes associated with a high or moderate cancer risk, and 10 (3%) of these variants were considered to be clinically actionable with associated with cancer screening, risk reduction or treatment recommendations. The high/moderate risk genes with P/LP variants included CHEK2 (n = 5), FANCM (n = 4), MSH6 (n = 2) and single cases of MSH2, BRCA2, ERCC3, and BRIP1. The average age of diagnosis in those with and without a high/moderate risk P/LP variant was 67.6 (57-80 yrs) and 68.9 (45-91 yrs). Family history of cancer was reported for 73% of those with a germline LP/PV and 60% of those without, but this trend was not significant (p =.44). Conclusions: Individuals with UC have a high frequency of germline variants that warrant further study for association with cancer risk. A smaller, but significant portion also carry germline variants that may be clinically relevant to them and/or family members. Currently UC is not included in genetic testing criteria. This study adds to the growing body of research indicating that diverse types of cancer patients harbor germline variants. Strategies for expanding testing should be considered.

573 Background: Intravesical bacillus Calmette-Guérin (BCG) is the first-line treatment for high-risk non-muscle invasive bladder cancer (NMIBC). Unfortunately, disease recurrence/progression is common and associated with increased risk of death from bladder cancer. While radical cystectomy remains the preferred treatment for BCG unresponsive NMIBC, many patients are either unwilling or unfit to undergo surgery. Previous retrospective studies have demonstrated the efficacy of intravesical gemcitabine and docetaxel (Gem/Doce) for treating NMIBC after BCG failure. However, the long-term outcomes of this cohort are unknown. We report 5-year survival outcomes of patients treated with intravesical Gem/Doce after BCG failure. Methods: We retrospectively identified patients at our institution who were treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Initial responders received monthly maintenance instillations for 2 years. Surveillance was performed according to American Urological Association guidelines. Survival time was measured from start of Gem/Doce induction. Outcomes included high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS) and overall survival (OS). Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as recurrence of disease with stage T2 or greater, cystectomy or death due to bladder cancer. Survival probabilities were calculated with the Kaplan-Meier method. Results: A total of 97 patients with a median age of 73 years were treated with Gem/Doce after BCG failure. Median follow-up was 49 months. BCG failure was further stratified as BCG unresponsive (35%), BCG relapsing (38%), BCG intolerant (11%) or unspecified (16%). 71% and 21% of patients had carcinoma in-situ and high-grade T1 disease, respectively. Complete response at initial surveillance was 74% and median duration of response was 26 months. Overall HG-RFS at 1, 2 and 5 years was 60%, 51% and 31%, respectively. HG-RFS was similar among BCG unresponsive patients and the overall cohort (see table). During follow-up, 18 patients (19%) underwent radical cystectomy and 28 patients (29%) experienced disease progression. PFS, CFS, CSS and OS at 5 years was 68%, 75%, 91% and 64%, respectively. Conclusions: Intravesical Gem/Doce for high-risk NMIBC after BCG failure offers long-term efficacy and substantial durability of response with a high likelihood of bladder preservation at five years after induction. Future prospective trials assessing Gem/Doce are warranted.[Table: see text]

Repeat BCG induction remains an option for select non-muscle invasive bladder cancer (NMIBC) patients who fail initial therapy. Alternative salvage intravesical regimens such as Gemcitabine and Docetaxel (Gem/Doce) have been investigated. We aimed to compare the efficacy BCG plus interferon a-2b (BCG/IFN) and Gem/Doce in patients with recurrent NMIBC after a single prior BCG course.The National Phase II BCG/IFN trial database and multi-institutional Gem/Doce database were queried for patients with recurrent NMIBC after one prior BCG induction course, excluding those with BCG unresponsive disease. Stabilized inverse probability treatment weighted survival curves were estimated using the Kaplan-Meier method and compared. Propensity scores were derived from a logistic regression model. The primary outcome was recurrence free survival (RFS); secondary outcomes were high-grade (HG) RFS and risk factors for treatment failure.We identified 197 BCG/IFN and 93 Gem/Doce patients who met study criteria. Patients receiving Gem/Doce were older and more likely to have HG disease, CIS, and persistent disease following induction BCG (all P0.01). After propensity score-based weighting, the adjusted 1- and 2-year RFS was 61% and 53% after BCG/IFN versus 68% and 46% after Gem/Doce (P = 0.95). Adjusted 1- and 2-year HG-RFS was 60% and 51% after BCG/IFN versus 63% and 42% after Gem/Doce (P = 0.68). Multivariable Cox regression revealed that Gem/Doce treatment was not associated with an increased risk of failure (HR = 0.97, P = 0.89) as compared to BCG/IFN.Patients with recurrent NMIBC after a single induction BCG failure and not deemed BCG unresponsive had similar oncologic outcomes with Gem/Doce and BCG/IFN in a post-hoc analysis. Additional prospective studies are needed.

Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins involved in tissue mechanical stability and matrix organization. Initial work has demonstrated that alpha-DG expression is decreased in many types of adenocarcinoma, including prostate, and potentially associated with the development of metastatic disease. However, the consistency between prostate and lymph node alpha-DG staining has not been previously reported. In addition, identification of an immunohistochemical marker associated with prostate cancer grade, stage, need for adjuvant or salvage therapy and mortality would have potential clinical value.Node positive, margin negative radical prostatectomy specimens at a single institution from 1982 to 2012 were reviewed and identified 35 prostate specimens, including 26 patients with available tissue from both the primary prostatectomy and lymph node specimens. The expression levels of the alpha-DG subunit were analyzed using immunohistochemistry and graded from 0 to 4. Survival was compared in different staining pattern groups.Strength of alpha-DG staining was found to be consistent between prostate and lymph node specimens (p0.004). The median overall survival was shorter in those without alpha-DG staining in the prostate compared to those with positive staining, but this difference was not statistically significant (13.2 years versus 19.4 years, p = 0.21). In addition, negative staining was associated with higher mean PSA, pathologic T stage, Gleason grade and the need for adjuvant or salvage therapy compared to positive group but none reached statistical significance (16.06 ng/mL versus 11.67 ng/mL, p = 0.79; 89% versus 68%, p = 0.38; 33.3% versus 23.1%, p = 0.66; 88.9% versus 76.9%, p = 0.44).DG expression by immunohistochemistry staining was consistent between prostate and metastatic lymph node specimens. In a small cohort of prostate cancer patients with margin negative but node positive disease, DG staining was not associated with Gleason grade or with overall mortality.

To provide a comprehensive update of the joint consultation of the International Consultation on Urological Diseases (ICUD) for the diagnosis and management of non-urothelial cancer of the urinary bladder. A detailed analysis of the literature was conducted reporting on the epidemiology, etiology, diagnosis, treatment and outcomes of non-urothelial cancer of the urinary bladder. An international, multidisciplinary expert committee evaluated and graded the evidence according to the Oxford System of Evidence-based Medicine modified by the ICUD. The major non-urothelial cancers of the urinary bladder are squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors. Several other non-urothelial tumors are rare but important to identify because of their aggressive behavior when compared to urothelial bladder tumors. Radical cystectomy and urinary diversion, preceded by neoadjuvant radiation or chemotherapy in some of these tumors, is the main method or treatment for resectable disease. Adjuvant therapy is not usually successful and no novel targeted or immunotherapeutic agents have been identified to provide benefit. Patients with small cell neuroendocrine tumors of the bladder should be offered chemotherapy before surgery. Because non-urothelial cancers are usually locally advanced and/or metastatic at the time of diagnosis, 5-year survival is generally poor. Non-urothelial cancers of the urinary bladder are rare and mostly lack established protocols for treatment. The prognosis of most of these tumors is poor because they are usually advanced at the time of diagnosis. A multimodal treatment approach should be considered to improve outcomes.

Introduction We reviewed the safety and effectiveness of our hospital’s urological telemedicine program that has been used for the Iowa prisoner population for more than a decade. Methods A retrospective review was performed of telemedicine visits of male prisoners from 2007 to 2014. The effectiveness of these visits was assessed by 1) concordance of telemedicine and in-person diagnoses, 2) compliance with radiologic and medication orders, and 3) in-person visits saved with telemedicine. Safety was assessed by analyzing the number of patients for whom an emergency department visit was required after the telemedicine visit, and missed or delayed cases of malignancy. Estimates were then made of the number of cases that could safely be managed with telemedicine alone. Results The most common diagnosis was voiding dysfunction (24%), followed by genitourinary pain (23%). Diagnoses were concordant in 90% of patients, compliance was high (radiology 91%, medications 89%) and in-person visits were estimated to be saved in 80% to 94%. No men required emergency department visits after telemedicine visits and no cases of malignancy were missed in the population that returned for an in-person visit. We estimated that more than 50% of urological complaints in this cohort could have been managed with telemedicine alone. Conclusions Telemedicine was shown to be a safe and effective method of providing general urological care that obviated the initial in-person visits for nearly 90% of patients. It is likely that telemedicine could safely replace in-person visits for many urological conditions, especially for younger men and those for whom access to specialized care may be limited.

Malnutrition is a significant problem for hospitalized patients. However, the true prevalence of reported malnutrition diagnosis in real-world clinical practice is largely unknown. Using a large collaborative multi-institutional database, the rate of malnutrition diagnosis was assessed and used to assess institutional variables associated with higher rates of malnutrition diagnosis.The aim of this study was to define the prevalence of malnutrition diagnosis reported among inpatient hospitalizations.The University Health System Consortium (Vizient) database was retrospectively reviewed for reported rates of malnutrition diagnosis.All adult inpatient hospitalization at 105 member institutions during fiscal years 2014 and 2015 were evaluated.Malnutrition diagnosis based on the presence of an International Classification of Diseases-Ninth Revision diagnosis code.Hospital volume and publicly available hospital rankings and patient satisfaction scores were obtained. Multiple regression analysis was performed to assess the association between these variables and reported rates of malnutrition.A total of 5,896,792 hospitalizations were identified from 105 institutions during the 2-year period. It was found that 292,754 patients (5.0%) had a malnutrition diagnosis during their hospital stay. By institution, median rate of malnutrition diagnosis during hospitalization was 4.0%, whereas the rate of severe malnutrition diagnosis was 0.9%. There was a statistically significant increase in malnutrition diagnosis from 4.0% to 4.9% between 2014 and 2015 (P0.01). Institutional factors associated with increased diagnosis of malnutrition were higher hospital volume, hospital ranking, and patient satisfaction scores (P0.01).Missing a malnutrition diagnosis appears to be a universal issue because the rate of malnutrition diagnosis was consistently low across academic medical centers. Institutional variables were associated with the prevalence of malnutrition diagnosis, which suggests that institutional culture influences malnutrition diagnosis. Quality improvement efforts aimed at improved structure and process appear to be needed to improve the identification of malnutrition.

Malnutrition is emerging as a significant factor in patient outcomes. A contemporary review of malnutrition has not been performed for the urologist. We review the available literature and current standards of care for malnutrition screening, assessment and intervention, focusing on patients with bladder cancer treated with cystectomy.Our multidisciplinary team searched PubMed® for available literature on malnutrition, focusing on definition and significance, importance to urologists, screening, assessment, diagnosis, immunological and economic impacts, and interventions.The prevalence of malnutrition in hospitalized patients is estimated to range from 15% to 60%, reaching upward of 71% in those with cancer. Malnutrition has been shown to increase inflammatory markers, further intensifying catabolism and weight loss. Bladder cancer is catabolic and patients undergoing cystectomy have increased resting energy expenditure postoperatively. Data are emerging on the impact of malnutrition in the cystectomy population. Recent studies have identified poor nutritional status based on low albumin or sarcopenia (loss of muscle) as having an adverse impact on length of hospitalization, complications and survival. The current standard of care malnutrition assessment tool, the 2012 consensus statement of the Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition, has not been evaluated in the urological literature. Perioperative immunonutrition in patients undergoing colorectal surgery has been associated with significant decreases in postoperative complications, and recent pilot work has identified the potential for immunonutrition to positively impact the cystectomy population.Malnutrition has a significant impact on surgical patients, including those with bladder cancer. There are emerging data in the urological literature regarding how best to identify and improve the nutritional status of patients undergoing cystectomy. Additional research is needed to identify malnutrition in these patients and interventions to improve surgical outcomes.

Objective To characterize changes in surgical assistance patterns over time for commonly performed urologic operations. Materials and Methods This study used the Medicare Physician/Supplier Procedure Summary Master File to identify cases performed by urologists from 2003 to 2014. Current Procedural Terminology modifiers were used to identify operations assisted by second surgeons and advanced practice providers (APPs). Rates were reported annually for 6 common urologic operations, and average annual rates of change were determined using least squares regression and tested using t tests (α = .05). Results Of the urologic operations analyzed, 5.0% of cases (n = 33,895) were assisted by APPs compared with 27.0% (n = 182,842) assisted by a second surgeon. The proportion of cases assisted by an APP rose significantly for all procedures; conversely, the proportion of cases assisted by a second surgeon declined significantly for all procedures, except for open partial nephrectomy. The largest changes were seen in robotic prostatectomies for which second surgeon assistance fell from 26% in 2004 to 15% in 2014, whereas APP assistance rose from Conclusion Urologists are increasingly using APPs as assistants in surgery, particularly in robotic and laparoscopic operations. This trend will likely continue as the shortage of urologists worsens in the coming years.

Introduction The United States population is aging, with increasing demand on the limited supply of urologists. Use of advanced practice providers could partly offset the growing demand for urological care. We evaluated the trends of independently performed/billed urological office procedural care by advanced practice providers. We hypothesized that the percentage and complexity of procedures performed independently by advanced practice providers is increasing. Methods We analyzed data from the 2003 to 2014 Medicare Physician/Supplier Procedure Summary Master File, available through the Centers for Medicare and Medicaid Services, for urological procedures with CPT® (Current Procedural Terminology) specialty codes of 97 (physician assistant) and 50 (nurse practitioner) for independently performed procedures. Trends through time for procedures were analyzed using the Mann-Kendall test. Results Independently performed simple advanced practice provider procedures increased from 54,549 to 230,683 yearly from 2003 to 2014, with the most common procedures being measurement of post-void residual, insertion of catheter and interpretation of uroflowmetry. Only 328 cystoscopies were billed independently by advanced practice providers in 2003 but this number increased to 2,284 in 2014. The largest increase in technical procedures performed by advanced practice providers was for cystoscopic stent removal, which accounted for 0.05% of all procedures in 2003 and 1.3% in 2014 (24-fold increase). Conclusions With the relative shortage of urologists more practices are relying on advanced practice providers for patient care. Independently performed procedures by these practitioners are increasing with time, including procedures of moderate complexity, clearly showing their evolving roles and responsibilities in the urology office.