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BACKGROUND: Evidence-based guidelines for the management of systemic therapy naïve oligometastatic renal cell carcinoma (RCC) are lacking. This prospective phase II single-arm trial evaluated the potential of stereotactic ablative radiotherapy (SAbR) to provide longitudinal disease control while preserving quality of life in patients with systemic therapy naïve oligometastatic RCC. PATIENTS AND METHODS: RCC patients with ≤3 extracranial metastases were eligible. SAbR was administered longitudinally to all upfront and, as applicable, subsequent metastases. The study was powered to achieve a primary objective of freedom from systemic therapy >1 year in >60% of patients (using Clopper and Pearson methodology). Secondary endpoints included progression-free survival (PFS), defined as time from first SAbR to progression not amenable to SAbR (local failure at SAbR-treated sites; new metastases not amenable to SAbR; >3 new metastases; or brain metastases); patient-reported quality of life (QOL) metrics; local control (LC) rates; toxicity; cancer-specific survival (CSS); and overall survival (OS). RESULTS: Twenty-three patients received SAbR to 33 initial and 57 total sites. Median follow-up was 21.7 months (interquartile range 16.3–30.3). Exceeding the pre-specified 60% benchmark, freedom from systemic therapy at one-year was 91.3% (95%CI: 69.5, 97.8). One-year PFS was 82.6% (95%CI: 60.1, 93.1). QOL was largely unaffected. LC was 100%. There were no grade 3/4 toxicities, but there was one death due to immune-related colitis three months after SAbR while on subsequent checkpoint inhibitor therapy where a SAbR contribution could not be excluded. One-year CSS and OS were both 95.7% (95%CI: 72.9, 99.4). CONCLUSIONS: SAbR for oligometastatic RCC was associated with meaningful longitudinal disease control while preserving quality of life. These data support further evaluation of SAbR for systemic therapy naïve oligometastatic RCC. PATIENT SUMMARY: Sequential stereotactic radiation therapy can safely and effectively control metastatic kidney cancer with limited spread for over a year without compromising patients’ quality of life. TAKE HOME MESSAGE: This phase II trial provides prospective evidence that sequential SAbR to all sites of oligometastatic RCC while the disease remains oligometastatic in a selected (and predefined) systemic therapy naïve patient population offers disease control in >90% of patients while maintaining health-related quality of life.

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1–21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) treated with systemic therapy sometimes progress at limited sites. The best treatment approach for patients with oligoprogression remains unclear. OBJECTIVE: To determine the ability of stereotactic ablative radiation (SAbR) to extend ongoing systemic therapy in mRCC patients with oligoprogression. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase II clinical trial was conducted at a university medical center and county hospital, including 20 patients with mRCC on first- to fourth-line systemic therapy with three or fewer sites of progression (including new sites) involving ≤30% of all sites. INTERVENTION: SAbR to oligoprogressing metastases at outset and longitudinally, while radiated sites remain controlled and overall disease oligoprogressive. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was to extend ongoing systemic therapy by >6 mo in >40% of patients. Secondary endpoints included overall survival, toxicity, and patient-reported quality of life. RESULTS AND LIMITATIONS: Twenty patients were enrolled. Upfront and sequential SAbR was administered to a total of 37 sites. The local control rate was 100%. At a median follow-up of 10.4 mo (interquartile range: 5.8–16.4), SAbR extended the duration of the ongoing systemic therapy by >6 mo in 14 patients (70%, 95% confidence interval [CI]: 49.9–90.1). The median time from SAbR to the onset of new systemic therapy or death was 11.1 mo (95% CI: 4.5–19.3). The median duration of SAbR-aided systemic therapy was 24.4 mo (95% CI: 15.3–42.2). Median overall survival was not reached. One patient developed grade 3 gastrointestinal toxicity possibly related to treatment. There was no significant decline in quality of life. Limitations include nonrandomized design and a small patient cohort. CONCLUSIONS: SAbR extended the duration of the ongoing systemic therapy for patients with oligoprogressive mRCC without undermining quality of life. These data support the evaluation of SAbR for oligoprogressive mRCC in a prospective randomized clinical trial. PATIENT SUMMARY: Patients with metastatic kidney cancer on systemic therapy but progressing at limited sites may benefit from focused radiation to progressive sites. Focused radiation was safe and effective, and extended the duration of the ongoing systemic therapy.

In a 2005 article commemorating five hundred years since the estimated date of Thomas Tallis’s birth, Peter Phillips (conductor of the appropriately-named Tallis Scholars) lamented the lack of published scholarship on the composer. At that time, the only book dedicated solely to Tallis was Paul Doe’s extremely slim (seventy-one page) book, published in 1968. This gap has since been filled by not one but two books on Tallis: John Harley’s 2015 Thomas Tallis (Ashgate), and Kerry McCarthy’s 2020 addition to the Oxford University Press (OUP) Master Musicians series, Tallis…

Hereditary hemochromatosis (HHC), a disorder of iron overload, presents with clinical phenotypic heterogeneity. Complications can be mitigated with early intervention. The association between HHC and alopecia areata (AA) is unknown. We report 4 patients with HHC concurrent with AA. In 2 patients, the HHC diagnosis was revealed from the results of laboratory iron studies as part of an alopecia consultation workup. Alopecia areata may be a rare early cutaneous manifestation of HHC in individuals with a predisposition for autoimmunity; however, the genetic relationship between the 2 disorders is currently unknown. Patients at high risk for HHC such as those with a family history and/or those who fit the demographic profile may benefit from laboratory iron screening if they present to the clinic with AA.

Introduction Adrenocortical Carcinoma (ACC) is a rare and often aggressive malignancy arising from the adrenal cortex. Rarely, ACC can be associated with a paraneoplastic syndrome, such as tumor-associated hypoglycemia due to insulin-like growth factor-2 secretion, hyperreninemic hyperaldosteronism, erythropoietin-associated polycythemia, and leukocytosis due to chemokine release from the tumor. Stauffer syndrome is a paraneoplastic syndrome characterized by reversible cholestasis in the absence of liver metastases, most frequently described in the context of renal cell carcinoma. Our case is the first reported association between Stauffer syndrome and ACC. Clinical Case A 38-year-old man presented with nausea, vomiting, painless jaundice, pruritus, and weight loss. Laboratory evaluation revealed an elevated total bilirubin of 8.7 mg/dL (N Conclusion Our case highlights a unique presentation of paraneoplastic hepatic dysfunction with jaundice associated with newly diagnosed ACC. Although Stauffer syndrome is one of the most characteristic paraneoplastic syndromes associated with renal cell carcinoma and other malignancies, paraneoplastic hepatic dysfunction associated with ACC has not been previously reported. The patient had rapid improvement of hyperbilirubinemia after surgical resection of the tumor. Stauffer syndrome should be considered in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Background Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. While ACC can be associated with adrenal hormone excess syndromes, classic paraneoplastic syndromes are rarely seen. Stauffer syndrome, a paraneoplastic phenomenon characterized by reversible cholestasis in the absence of liver metastases, has been described with renal carcinoma and other malignancies but has not been previously reported in ACC. Case Presentation A 38-year-old man presented with emesis, painless jaundice, pruritus, and weight loss. Laboratory evaluation demonstrated elevated total bilirubin of 8.7 mg/dL (N Conclusion This is the first report of a unique presentation of paraneoplastic-related hyperbilirubinemia in the setting of ACC. While extremely rare, Stauffer syndrome should still be considered in differential diagnosis in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases.

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptibleCancers of the bladder and other parts in the urinary system, especially those that are invasive and grow into the muscle layer, may need extra treatment after surgical removal of the tumor, particularly if there is a high risk of the cancer coming back. Chemotherapy regimens that include cisplatin are often used postoperatively, although some patients are unable to tolerate this treatment or refuse it. FGFR3, a protein that is encoded by the

To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis.Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase.Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (82%).Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis.

Background Synchronous video visits (“telehealth”) were rapidly adopted by many cancer centers across the nation to facilitate provision of care during the COVID-19 pandemic; however, in many cases, there was little time to comprehensively assess patient and provider needs related to this rollout. In addition, attitudes toward telehealth use among older patients with cancer, who may face increased vulnerability to inequities in access to care due to limited digital literacy, were largely unknown at that time. Objective The objectives of this concurrent mixed methods study were to (1) assess stakeholder experiences with telehealth since its rollout during the COVID-19 pandemic at an urban comprehensive cancer center and (2) solicit suggestions to optimize workflow and enhance telehealth implementation beyond the pandemic. Methods We conducted surveys and critical incident interviews with providers, staff, and older patients (aged ≥60 years) from a comprehensive cancer center in a large urban area. Data collection occurred from December 2020 to November 2021. We analyzed survey data using descriptive statistics and qualitative data using deductive and inductive thematic content analysis facilitated by NVivo 12.0 (QSR Australia). Results We completed a total of 106 provider or staff surveys, 128 patient surveys, 20 provider or staff interviews, and 14 patient interviews. While the majority (70.7%) of surveyed providers and staff agreed or strongly agreed that the technology used to support telehealth visits at Simmons fit well within their clinical workflow, several suggestions were offered to enhance telehealth implementation, including conducting proactive, systematic training and technical assistance; making appointment scheduling and rooms flexible for in-person or telehealth conversion in real time to streamline workflow; expanding availability of telehealth to supportive care services and physically frail patients; and increasing provider engagement via telehealth meetings and conferences. Less than a third (30.8%) of providers or staff agreed or strongly agreed that the institution did a good job of preparing patients for their first telehealth encounter, and patients reported experiencing challenges with joining video visits (29%) and understanding the telehealth process (28%). Participants suggested several strategies to assist patients with limited digital literacy, including offering video tutorials of the connection process, creating “fake appointments” to practice web-based connections, and hiring a digital navigator to assist with technical difficulties and setup of the web-based portal. Despite challenges, a majority of surveyed patients (65.7%) and providers or staff (76.9%) intend to continue using telehealth after the COVID-19 pandemic passes. Conclusions Use of telehealth for cancer care was received positively by older patients and providers or staff. Taking targeted steps to support enhanced implementation post pandemic could reduce barriers to care, including among older adults and other populations with limited digital literacy, thereby promoting greater equity of access to telehealth and the potential benefits it offers.

Race and ethnic backgrounds affect the disease characteristics and clinical outcomes in many cancers, including acute myeloid leukemia; however, the association of race/ethnicity on myelodysplastic syndrome (MDS) is still controversial. Therefore, we aimed to study the impact of race/ethnicity on the disease characteristics and survival outcomes in patients with MDS. Adult patients with MDS diagnosed in 2004-2016 were selected using the SEER database. Race/ethnicity was categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic. Hispanic and NHB patients had significantly lower incidence rate ratio (IRR) in age group ≥01 years (

Primary Sjögren’s syndrome (SjS) is an inflammatory autoimmune disorder which targets the lacrimal and salivary glands, resulting in glandular dysfunction. Currently, the immune drivers of SjS remain poorly understood and peripheral biomarkers of disease are lacking. The present study therefore sought to investigate the immune cell constituents of the SjS peripheral blood, and to assess the role of the BTLA/HVEM/CD160 co-stimulatory network by characterizing expression within the periphery. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of n = 10 patients with SjS and n = 10 age- and sex-matched healthy control donors. Cells were divided and stained with three panels of antibodies, allowing assessment of T, B, and myeloid cell subsets, and measurement of BTLA, HVEM, and CD160 surface expression by flow cytometry. We identified distinct alterations in proportions of peripheral T, B, and myeloid cell types in SjS compared with healthy controls. Expression of BTLA/CD160/HVEM and frequency of BTLA/CD160/HVEM-expressing cells were significantly altered in peripheral SjS lymphocytes. The proportion of T cells co-expressing BTLA/HVEM and CD160/HVEM were significantly reduced in SjS. We found decreased BTLA and HVEM levels on peripheral B and T cells of SjS patients, and decreased BTLA/HVEM and CD160/HVEM co-expression, demonstrating dysregulation of the BTLA/HVEM axis in the peripheral blood of SjS patients. These results indicate the potential of targeting the BTLA-HVEM axis for the treatment of SjS.

Key Points Question What factors are associated with female oncologists’ decision to pursue academic or nonacademic practice? Findings In this survey study of 667 female oncologists in the US, a spouse or partner and/or family were factors in the career choice of both academic and nonacademic oncologists. Most respondents perceived their gender to adversely affect job promotion, and more than 20% of respondents were considering leaving academia. Meaning The findings suggest that gender inequality in academic oncology will continue if the culture is not addressed., Importance Women outnumber men in US medical school enrollment, but they represent less than 40% of academic oncology faculty. Objective To identify the key factors associated with female oncologists’ decision to pursue academic or nonacademic oncology practice and to characterize their perceptions about their current career. Design, Setting, and Participants This cross-sectional survey study was distributed through email and social media to female physicians in academic and nonacademic oncology practice in the United States. The survey was open for 3 months, from August 1 to October 31, 2020. Main Outcomes and Measures No single primary study outcome was established because of the cross-sectional nature of the survey. Data were collected anonymously and analyzed using t tests for continuous variables and χ2 tests for categorical variables. Results Among the 667 female respondents, 422 (63.2%) identified as academic oncologists and 245 (36.8%) identified as nonacademic oncologists. Approximately 25% of respondents reported that their spouse or partner (156 [23.5%]) and/or family (176 [26.4%]) extremely or moderately affected their decision to pursue academic practice. Academic oncologists perceived the biggest sacrifice of pursuing academics to be time with loved ones (181 [42.9%]). Nonacademic oncologists perceived the biggest sacrifice of pursuing academics to be pressure for academic promotion (102 [41.6%]). Respondents had different perceptions of how their gender affected their ability to obtain a chosen job, with 116 academic oncologists (27.6%) and 101 nonacademic oncologists (41.2%) reporting a positive or somewhat positive impact (P = .001). More than half of the women surveyed (54.6% academic oncologists [230]; 50.6% nonacademic oncologists [123]; P = .61) believed they were less likely to be promoted compared with male colleagues. Academic and nonacademic oncologists reported rarely or never having a sense of belonging in their work environment (33 [7.9%] and 5 [2.0%]; P, This survey study examines the role of family, personal priorities, and sense of professional belonging and fulfillment in career building or planning among female oncologists.

ObjectivesImmune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation.MethodsSingle cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters.ResultsGlobal transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor–ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-β and macrophage interleukin (IL)-1β synergy in driving the transcriptional profile of FAPα+THY1+invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-β and IL-1β treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.

Expanded use of immuno-oncology (IO) therapy to treat cancer has led to an increased frequency of novel toxicities known as immune-related adverse events (irAEs). Delayed recognition of IO toxicity can be life-threatening or even fatal. To address this issue, intervention is possible at three levels: patients, medical providers, and institutions. Patients and the medical community need institutional safeguards in place to promote swift recognition, assessment, and treatment of IO toxicity. Patients receiving IO therapy must be educated to identify the drugs they have received and to recognize potential IO toxicity, and they must know how to report symptoms. Medical providers must be able to reliably identify that patients have received IO therapy as well as recognize rare or subtle symptoms of IO toxicity. Institutions can establish guidelines and order sets to standardize the treatment of patients receiving IO therapy with irAEs, including the complex management of steroid-refractory irAEs. Additional interventions at an institutional level include identification of IO toxicity champions (subspecialists with expertise in IO toxicity), creating immunotherapy-specific tumor boards and lecture series to educate clinicians and staff, and establishing research programs to evaluate IO toxicity. IO therapy and toxicity experiences must be published and shared with both oncology and nononcology providers in the local, national, and international medical community. These efforts aim to improve patient-related outcomes, increase provider education and awareness, and build institutional safety standards for our oncology patients.

1591 Background: Synchronous video visits (“telehealth”) were rapidly adopted to facilitate provision of cancer care during the COVID-19 pandemic, with little time to comprehensively assess patient and provider needs. Attitudes toward telehealth use during active treatment (vs. survivorship care) were largely unknown, as were perceptions of, experiences with, and needed support for telehealth use among older adults with cancer. Older adults in particular may face increased vulnerability to inequities in access to care due to limited digital literacy. Methods: We conducted surveys and semi-structured interviews with providers, staff, and older patients (age ≥60) from a comprehensive cancer center. Data collection occurred between Dec 2020 - Nov 2021. Results: We completed a total of 106 provider/staff surveys, 128 patient surveys, 20 provider/staff interviews, and 15 patient interviews. A majority of surveyed providers/staff felt that telehealth should “definitely be offered” during treatment-phase encounters (55.9% treatment follow-up; 69.1% results communication; 70.2% discussing treatment side effects). Similarly, most patients indicated they would be willing to have video visits with a member of their care team for: discussing treatment side-effects (73.5%), results communication (69.6%), and treatment follow-up (65.7%). Patients reported experiencing challenges with joining video visits (29%) and understanding the telehealth process (28%). Similarly, less than a third (30.8%) of providers/staff agreed or strongly agreed that the institution did a good job of preparing patients for their first telehealth encounter. Patients felt the institution should do more to communicate the advantages of telehealth to older adults in handouts and videos, which included: engaging multiple family members in critical appointments (e.g., treatment decisions, end-of-life), seeing their doctor when they were too sick to travel, and reducing potential exposure to infectious disease at the clinic. Participants suggested several strategies to assist patients with limited digital literacy: offering video tutorials of the connection process, creating “fake appointments” to practice online connections, and hiring a digital navigator to assist with technical difficulties and setup of the online portal. Despite challenges, a majority of surveyed patients (65.7%) and providers/staff (76.9%) intend to continue using telehealth after the COVID-19 pandemic passes. Conclusions: Use of telehealth for cancer care was received positively by older patients and providers/staff. Taking targeted steps to enhance implementation could reduce barriers to care, including among older adults and other populations with limited digital literacy, thereby promoting greater equity of access to telehealth benefits beyond the pandemic.

Purpose: Meaningful connections are an important aspect of career satisfaction. The Hematology Oncology Women Physician Group (HOWPG) is a private Facebook (FB) group of 936 women who practice within the hematology/oncology (H/O) field. We hypothesized that HOWPG adds value to education, emotional wellness, and practice of oncology for its membership. A survey was conducted within HOWPG to define group impact on members. Materials and Methods: A voluntary, anonymous 12-question online survey was distributed to members of HOWPG by sharing the survey link within the FB group. Participants were surveyed regarding demographics, general FB versus exclusive HOWPG use, and opinions regarding HOWPG value and impact. Results: A total of 169 members completed the survey; 9% were fellows, 65% had been in practice less than 10 years, and 26% had been in practice 10 years or more; 97% were age younger than 50 years; 85% practiced adult H/O, and the remainder divided their practice among pediatric H/O, radiation oncology, surgical specialty, and palliative care; 90% used FB at least daily, with 82% accessing HOWPG at least daily. The most common uses for the site included education (65% to 89%), advice on complex cases (65%), emotional support (65%), and networking (55%). On a scale of 1 to 10, learning from clinical cases (9.0) and emotional support (8.4) were rated the most beneficial aspects. Respondents felt HOWPG, when compared with FB in general, was more likely to improve career satisfaction and reduce professional burnout. Conclusion: HOWPG provides an opportunity for education and clinical and emotional support. Social media can be an effective venue to educate physicians, augment patient care via advice, foster networking, reduce burnout, and improve career satisfaction among female physicians in the field of H/O.

ObjectivesA number of immune populations have been implicated in psoriatic arthritis (PsA) pathogenesis. This study used mass cytometry (CyTOF) combined with transcriptomic analysis to generate a high-dimensional dataset of matched PsA synovial fluid (SF) and blood leucocytes, with the aim of identifying cytokine production ex vivo in unstimulated lymphoid and myeloid cells.MethodsFresh SF and paired blood were either fixed or incubated with protein transport inhibitors for 6 h. Samples were stained with two CyTOF panels: a phenotyping panel and an intracellular panel, including antibodies to both T cell and myeloid cell secreted proteins. Transcriptomic analysis by gene array of key expanded cell populations and single-cell RNA-seq, and ELISA and LEGENDplex analysis of PsA SF were also performed.ResultsWe observed marked changes in the myeloid compartment of PsA SF relative to blood, with expansion of intermediate monocytes, macrophages and dendritic cell populations. Classical monocytes, intermediate monocytes and macrophages spontaneously produced significant levels of the proinflammatory mediators osteopontin and CCL2 in the absence of any in vitro stimulation. By contrast minimal spontaneous cytokine production by T cells was detected. Gene expression analysis showed the genes for osteopontin and CCL2 to be amongst those most highly upregulated by PsA monocytes/macrophages; and both proteins were elevated in PsA SF.ConclusionsUsing multiomic analyses we have generated a comprehensive cellular map of PsA SF and blood to reveal key expanded myeloid proinflammatory modules in PsA of potential pathogenic and therapeutic importance.

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

TPS580 Background: Radical surgery is the mainstay of treatment for muscle-invasive upper tract urothelial cancer (UTUC) and urothelial bladder cancer (UBC). However, even when surgery is combined with cisplatin‐based (neo)adjuvant chemotherapy, recurrence rates are high. Many patients (pts) are ineligible for, do not respond to, or refuse cisplatin-based chemotherapy because of toxicity concerns. Fibroblast growth factor receptor 3 ( FGFR3) genetic alterations occur in 21–38% of muscle-invasive UTUC, and in approx. 20% of invasive UBC. Infigratinib (BGJ398) is an ATP-competitive FGFR1–3 selective oral tyrosine kinase inhibitor that has clinical activity and tolerability in pts with advanced/metastatic urothelial carcinoma (UC) harboring susceptible FGFR3 alterations. PROOF 302 was designed to investigate the efficacy and safety of adjuvant infigratinib in pts with high-risk, muscle-invasive UC (85% UTUC) and susceptible FGFR3 alterations. Methods: PROOF 302 is a global, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (NCT04197986). Eligible pts have high-risk, muscle-invasive UTUC (85%) or UBC (15%) with susceptible FGFR3 alterations (mutations, gene fusions or rearrangements) confirmed by FoundationOne CDx test, and are ≤120 days following nephroureterectomy, distal ureterectomy, or cystectomy. The study protocol was amended to include pts with carcinoma in situ at surgical margins and those who refuse cisplatin-based chemotherapy (in addition to pts allowed to enroll if ineligible for perioperative cisplatin-based chemotherapy). Eligible pts are M0 and have either disease stage ≥ypT2 and/or yN+ after cisplatin-based neoadjuvant chemotherapy or ≥pT2 pN0–2 or pN+ (UTUC); and ≥pT3 or pN+ (UBC) if not treated with cisplatin-based neoadjuvant chemotherapy. Pts are randomized 1:1 to receive oral infigratinib 125 mg or placebo QD on days 1–21 of a 28-day cycle for up to 52 weeks (13 cycles) or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS) analyzed via stratified log-rank test and Cox model (hazard ratio). Secondary endpoints: investigator-reviewed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints: quality of life, pharmacokinetics, determination of the prevalence of genomic alterations and correlation with features of UC, genomic and proteomic assessment of tumor tissue and cell-free DNA samples from baseline and at recurrence to identify the predictive/prognostic value of biomarkers. PROOF 302 is actively enrolling as of Sep 2021. A second Data Monitoring Committee meeting is planned for Dec 2021. The last pt is expected to complete treatment in 2024. Clinical trial information: NCT04197986.

TPS591 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in cisplatin-eligible patients (pts) with muscle invasive bladder cancer (MIBC). An unmet need exists in cisplatin-ineligible pts with MIUC who are offered upfront surgery. Neoadjuvant immune checkpoint inhibitors (ICIs) have been demonstrated to be safe and active although the benefit may not extend to the majority of pts. The combination of GCa and an ICI has been demonstrated to be safe and active in cisplatin-ineligible metastatic urothelial carcinoma. In the neoadjuvant setting, combination GCa and an ICI may improve outcomes across a broad group of MIUC by delivering early systemic therapy to pts with cisplatin-ineligible MIUC. We hypothesized that the combination of GCa and avelumab, a PD-L1 inhibitor, may improve pathologic complete remissions (pCR) and long-term outcomes compared to upfront surgery for MIUC (S2011, NCT04871529). Methods: This multicenter, randomized (1:1), open-label phase II trial is comparing the combination of GCa and avelumab (Arm A) as neoadjuvant therapy vs. upfront surgery (Arm B) for pts with cisplatin-ineligible MIUC including MIBC and high-risk upper tract urothelial carcinoma (UTUC). Adjuvant therapy following radical cystectomy, nephroureterectomy or ureterectomy is deferred to investigator discretion in both arms. Eligible pts include those with MIBC or high-grade UTUC with a predominant urothelial component who are cisplatin-ineligible (≥1 of: Zubrod performance status [PS] = 2, creatinine clearance [CrCl] 30 to < 60 ml/min, neuropathy > grade 1, hearing loss > grade 1, congestive heart failure > grade 2). The primary objective is pCR. The stratification factors include clinical stage (cT2N0M0 vs cT3-4aN0M0), Zubrod-PS (0-1 vs 2), CrCl (30 to < 60 vs ≥ 60 ml/min). With 178 evaluable pts, the trial will have a power of 90% (using a 1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. The secondary objectives are toxicities, resectability rates, surgical complications, event-free survival (EFS) and overall survival (OS). Correlative studies include tumor molecular profiling, blood immune studies, circulating tumor-DNA profiling and radiomics. Arm A receives gemcitabine 1000 mg/m2 IV days 1, 8 every 3 weeks x 4 cycles, carboplatin AUC 4.5 (escalated to AUC 5 from cycle 2 if tolerated in cycle 1) IV day 1 every 3 weeks x 4 cycles and avelumab 800 mg IV day 1 every 2 weeks x 6 cycles. Surgery is performed 4-8 weeks after the last neoadjuvant administration. The trial is funded by NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180868, and in part by EMD Serono, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer. Clinical trial information: NCT04871529.

525 Background: Recent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we used real-world evidence to investigate differences between somatic and germline mutations in localized, early-stage urothelial cancers and advanced urothelial cancers. Methods: We retrospectively analyzed de-identified NGS data from 1,146 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; whole-exome capture RNA-seq). For the subset of patients with tumor-normal match sequencing (n=758), additional incidental germline alterations in 46 different genes were assessed. Results: A total of 1,146 bladder cancer tumors were investigated: stage I-II (n=124), stage III (n=159), and stage IV (n=863)—summarized in Table. Tumor mutational burden (TMB) was calculated for 1,126 tumors, and TMB-high (TMB-H; ≥10 mutations per megabase) was similar across tumor stages. PD-L1 immunohistochemical staining was performed on 698 tumors, and no significant differences were observed. Microsatellite instability high (MSI-H) status was detected in only 2 (1.6%) stage I-II tumors and 8 (0.9%) stage IV tumors. Alterations—single nucleotide variants, insertions/deletions, and copy number variants—in FGFR2/3, homologous recombination repair genes (18 genes including BRCA1/2 and ATM), additional DNA repair gene mutations ( ERCC2, RB1, FANCC) and NTRK fusions were detected at similar frequencies across disease stages. In 758 patients with tumor/normal matched sequencing, we identified a low rate of incidental germline mutations in MUTYH (stage III, 1%; stage IV, 1.9%), BRCA2 (stages I-II, 1.2%; stage III, 1%; stage IV, 0.5%), BRIP1 (stages I-II, 1.2%), ATM (stage III, 1%; stage IV, 0.7%), MSH6 (stage III, 1%; stage IV, 0.2%), and TP53 (stage III, 1%; stage IV, 0.2%). Conclusions: Patients with bladder cancer have similar rates of potentially actionable mutations and genomic landscapes regardless of clinical disease stage. These findings provide a rationale for further investigating targeted therapies among early-stage bladder cancer patients.[Table: see text]

389 Background: Emerging data suggest that active surveillance (AS) may be safely implemented in a subset of patients (pts) with metastatic renal cell carcinoma (RCC) and indolent disease to delay the initiation of systemic therapy without undermining long-term survival. However, widespread adoption of AS has been limited by a lack of data on factors portending favorable outcomes. In this study we sought to characterize pts undergoing AS at a large academic medical center to identify factors associated with time on AS. Methods: We identified pts on AS using Kidney Cancer Explorer (KCE), the data management platform of the Kidney Cancer Program at UT Southwestern Medical Center (2005-2020), as well as input from medical oncologists. The AS cohort was defined by (1) having metastatic RCC (determined by either a suspicious lesion > 1cm or a positive biopsy), and (2) the absence of prior systemic therapy. Baseline characteristics and IMDC criteria were evaluated at the outset. Outcomes of interest included progression free survival (PFS), time to systemic therapy (TST), and overall survival (OS). Survival estimates were generated using Kaplan Meier methods. Cox proportional hazard models were used in univariate and multivariate analyses to identify baseline characteristics associated with TST. Results: We identified 37 pts with metastatic RCC undergoing AS; 31 pts (83.8%) had ccRCC, 28 pts (75.7%) had a favorable IMDC prognostic group, 18 pts (48.6%) had one metastatic lesion at baseline, and the cohort had an average tumor burden of 21mm. The majority of pts had clinical or radiologic progression with a median PFS of 10.8 months (95% CI: 8.13-23.31). The median TST was 37 months (95% CI: 24.3-94.9). In total, there were 11 deaths (none of which occurred prior to the initiation of systemic therapy) and median OS after the initiation of AS was 132.5 months (95% CI: 87.3-NR). Multivariate analyses showed that higher numbers of metastatic lesions at baseline were associated with a shorter TST (HR:1.45; 95% CI: 1.03-2.03, p = 0.03). At a median follow-up of 62.5 months, 11/37 (29%) of pts had not yet started systemic therapy. Conclusions: These results expand upon previous studies and support a role for AS to delay systemic therapy in selected pts with metastatic RCC.

Funder: Kennedy Trust studentship, Funder: Oxford-UCB Prize Fellowship, Funder: National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University and Versus Arthritis Research into Inflammatory Arthritis Centre; ref. 22072)., Funder: NIHR Birmingham BRC at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Funder: St Baldrick’s Foundation, Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

OBJECTIVE. The purpose of this article is to review the utility of 18F-fluciclovine PET/CT in the evaluation of recurrent prostate cancer. CONCLUSION. Fluorine-18-labeled fluciclovine PET/CT has shown promise in the evaluation of recurrent prostate cancer. Its performance has been superior to that of other imaging modalities. It has had good diagnostic accuracy, especially in the detection of extra-prostatic disease recurrence, and the findings have an impact on treatment planning. Gallium-68-labeled prostate-specific membrane antigen PET/CT has also had excellent performance in the detection of biochemically recurrent prostate cancer with detection rates superior to those of fluciclovine PET/CT.

The pro-inflammatory cytokine IL-17A has been implicated in the immunopathology of inflammatory arthritis. IL-17F bears 50% homology to IL-17A and has recently been suggested to play a role in inflammation. We investigated the induction and cytokine profile of IL-17F+ CD4+ T cells, and how IL-17F may contribute to inflammation. Upon culture of healthy donor CD4+ T cells with IL-1β, IL-23, anti-CD3, and anti-CD28 mAb, both IL-17A and IL-17F-expressing cells were detected. In comparison to IL-17A+ IL-17F- CD4+ T cells, IL-17F+ IL-17A- and IL-17A+ IL-17F+ CD4+ T cells contained lower proportions of IL-10-expressing and GM-CSF-expressing cells and higher proportions of IFN-γ-expressing cells. Titration of anti-CD28 mAb revealed that strong co-stimulation increased IL-17F+ IL-17A- and IL-17A+ IL-17F+ CD4+ T cell frequencies, whereas IL-17A+ IL-17F- CD4+ T cell frequencies decreased. This was partly mediated via an IL-2-dependent mechanism. Addition of IL-17A, IL-17F, and TNF-α to synovial fibroblasts from patients with inflammatory arthritis resulted in significant production of IL-6 and IL-8, which was reduced to a larger extent by combined blockade of IL-17A and IL-17F than blockade of IL-17A alone. Our data indicate that IL-17A and IL-17F are differentially regulated upon T cell co-stimulation, and that dual blockade of IL-17A and IL-17F reduces inflammation more effectively than IL-17A blockade alone.

Autoimmune diseases resulting from MHC class II–restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA(323–339) and calcitriol targeted dLN PD-L1(hi) DCs of immunized mice and reduced their MHC class II expression. OVA(323–339)/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3(+) and IL-10(+) peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture’s vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.

Fatigued driving contributes to a substantial number of motor vehicle accidents each year. Music listening is often employed as a countermeasure during driving in order to mitigate the effects of fatigue. Though music listening has been established as a distractor in the sense that it increases cognitive load during driving, it is possible that increased cognitive load is desirable under particular circumstances. For instance, during situations that typically result in cognitive underload, such as driving in a low-traffic monotonous stretch of highway, it may be beneficial for cognitive load to increase, thereby necessitating allocation of greater cognitive resources to the task of driving and attenuating fatigue. In the current study, we employed a song-naming game as a countermeasure to fatigued driving in a simulated monotonous environment. During the first driving session, we established that driving performance deteriorates in the absence of an intervention following 30 min of simulated driving. During the second session, we found that a song-naming game employed at the point of fatigue onset was an effective countermeasure, as reflected by simulated driving performance that met or exceeded fresh driving behavior and was significantly better relative to fatigued performance during the first driving session.

Purpose Oligoprogression, defined as limited sites of progression on systemic therapy, in patients with metastatic renal cell carcinoma (mRCC) is not uncommon, possibly because of inter- and intratumoral heterogeneity. We evaluated the effect of stereotactic ablative radiation therapy (SAbR) for longitudinal control of oligoprogressive mRCC. Methods and Materials Patients with extracranial mRCC were included in this retrospective analysis if they progressed in ≤3 sites on systemic therapy while demonstrating response/stability at other sites and received SAbR to all progressing sites without switching systemic therapy. Our primary endpoint was modified progression-free survival (mPFS), which we calculated from the start of SAbR to the start of a subsequent systemic therapy, death, or loss to follow-up. Results We identified 36 patients with a median follow-up of 20.4 months (interquartile range, 10.9-29.4). Forty-three sites were treated with SAbR with a median dose of 36 Gy (range, 18-50) in 3 fractions (range, 1-5). Median time to SAbR from the start of systemic therapy was 11.4 months (interquartile range, 6.1-17.1). Median mPFS was 9.2 months (95% confidence interval [CI], 5.9-13.2). Patients receiving SAbR while on immunotherapy exhibited a longer median mPFS (>28.4 months, log-rank P = .0001) than patients not on immunotherapy (9.2 months). Median overall survival from SAbR administration was 43.4 months (95% CI, 21.5-not Reached). The 1-year local control rate was 93% (95% CI, 78.7-97.5). Most SAbR-related toxicities were grade 1 to 2 (33% of patients), with one grade 5 hemoptysis event possibly related to SAbR or disease progression. Conclusions SAbR has the potential to extend the the duration of current systemic therapy for selected patients with mRCC, preserving subsequent therapies for later administration possibly enabling longer treatment duration.

Background Race and ethnic differences affect the disease characteristics and clinical outcomes in many tumors, including acute myeloid leukemia (Byrne et al. AJCO, 2011). While earlier population-based studies reported no significant impact of race on survival outcomes in myelodysplastic syndromes (MDS) (Ma et al. Cancer, 2007), this study had a limited number of patients, short duration of follow-up including patients diagnosed from 2001-2003 prior to the approval and routine use of hypomethylating agents (HMA). We hypothesized that there are racial differences in the clinical characteristics and outcomes of patients with MDS. We thus analyzed the differences in disease characteristics and survival outcomes based on race and ethnic background in patients with MDS over 13 years. Methods We used the Surveillance, Epidemiology, and End Results (SEER) database to identify adult patients diagnosed with MDS between 2004 and 2016. Disease characteristics and patient outcomes were analyzed among three groups based on race/ethnicity: non-Hispanic white (NHW), non-Hispanic black (NHB) and Hispanics, Fisher exact test and chi-square test were used to compare categorical variables. SEER*Stat version 8.3.6 was used to calculate the incidence rate (IR) and incidence rate ratio (IRR) for NHW, NHB, and Hispanics. Univariate survival analysis was estimated using the Kaplan-Meier method, and groups were compared using a log-rank test. Multivariable survival analyses were performed using the Cox-proportional regression model after adjusting for age, gender, insurance status, histologic risk classification, marital status, and treatment with chemotherapy. Cause-specific survival (CSS) was calculated from the date of diagnosis to the date of MDS-related death and compared amongst the three groups. Results A total of 52,031 patients with MDS were included in this study; 83.4% were NHW, 8.5% were NHB, and 8.2% Hispanics. The incidence was 7.81, 6.46, and 5.17 per 100,000 among NHW, NHB, and Hispanic patients, respectively. Compared to NHW, NHB and Hispanic patients had a significantly lower incidence rate among the overall population (p Conclusions Myelodysplastic syndromes have significant differences in age at presentation, disease risk, and survival outcomes based on racial and ethnic backgrounds. To our knowledge, this study represents the largest population-based analysis with the longest follow-up, specifically looking at such differences in patients with MDS. Further studies are warranted that incorporate treatment patterns and genomic data in order to identify factors that may account for these differences. Disclosures Wang: Celgene/BMS: Research Funding. Patel:France Foundation: Honoraria; Agios: Consultancy; DAVA Pharmaceuticals: Honoraria; Celgene: Consultancy, Speakers Bureau. Zeidan:Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Astex: Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Ionis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BeyondSpring: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; Agios: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria.

4564 Background: Metastatic renal cell carcinoma (mRCC) patients on systemic therapy may experience oligoprogression. SAbR has been demonstrated to be safe and is associated with high local control rates in mRCC. In this prospective phase II single arm trial, we investigated SAbR to control oligoprogressive mRCC. Methods: Patients with mRCC who demonstrated response to systemic therapy with subsequent radiographic evidence of three or fewer sites of progression were treated with SAbR to all progressive sites. Systemic therapy was held during SAbR at the discretion of the treating oncologist. Follow-up included radiographic imaging at three-month intervals. Sequential SAbR for continued oligoprogression was allowed. The primary objective was extension of ongoing systemic therapy by >6 months in 40% of the patients. Progression was defined by any of these 3 criteria: (1) local failure at a radiated site; (2) progression ineligible for additional SAbR (>3 sites) or involving >30% of metastasis; or (3) progression as clinically determined by treating physicians. An exact binomial test was used to test the probability of postponing systemic therapy. Secondary endpoints focused on overall survival (OS), local control (LC) rates, toxicity, and health-related quality of life (QOL). Results: The trial completed accrual with enrollment of 20 patients who received SAbR to a total of 36 sites. At enrollment four, twelve, three, and one patients were on first, second, third, and fourth line of systemic therapy, respectively. Eleven were on immunotherapy and nine on a tyrosine-kinase inhibitor. Three patients required repeat SAbR to a new site for sequential disease control. At a median follow-up of 8.3 months (interquartile range 3.9 – 15.1), SAbR extended the duration of the ongoing systemic therapy by >6 months in 12 out of 17 patients (70.6%, 95% CI: 48.9%-92.3%). Thirteen out of 20 patients progressed with a median PFS of 8.7 months (95% CI: 3.2-12.4). Five patients died and the OS did not reach the median. LC was 36/36 (100%). Treatment related grade 1 and grade 2 toxicity was experienced by three and one patient, respectively; no grade 3 toxicities were reported. When compared to baseline, no significant decline in QOL was detected. Conclusions: SAbR extended PFS of ongoing systemic by >6 months in oligoprogressive patients with mRCC. SAbR was safe and did not adversely affect QOL. These data support further evaluation of SAbR for oligoproressive mRCC in a prospective randomized setting. Clinical trial information: NCT03696277.

11040 Background: Although women outnumber men in US medical school enrollment, women constitute < 50% of faculty in academic oncology. This study aimed to determine factors affecting women oncologists’ decisions to pursue academic versus non-academic oncology in Hematology/Oncology (HO), Pediatric Oncology (PO), Radiation Oncology (RO), and Surgical Oncology (SO), and to characterize the challenges women oncologists face. Methods: A survey was designed to collect cross-sectional data on factors affecting career choices among US women oncologists. The survey was distributed via email and social media. Data were collected anonymously and analyzed using t-tests for continuous variables and Chi-squared tests for categorical variables. Results: Six hundred sixty-seven women oncologists responded: 245 (45.3%) specialized in HO, 173 (25.9%) RO, 88 (13.2%) PO, 56 (8.4%) SO, and 48 (7.2%) other. Four-hundred twenty-two (63.2%) women identified as an academic oncologist (AO); 245 (36.8%) women identified as a non-academic oncologist (non-AO). Approximately ¼ of women oncologists reported their partner (156, 23.5%) or family (176, 26.4%) extremely or moderately impacted their decision whether to pursue academic practice. There was no difference in the timing of childbearing between AO and non-AO. AO perceived the biggest sacrifice of pursuing academics to be time with loved ones (181, 42.9%). Non-AO perceived the biggest sacrifice for AO to be pressure for academic promotion (102, 41.6%), which was the third most common response (44, 18.0%) among AO. Thirty-three (7.9%) AO and 5 (2.0%) non-AO reported feeling that they rarely or never have a sense of belonging in their work environment (p < 0.01). AO and non-AO had significantly different perceptions on how their gender impacted their ability to obtain a chosen job (p < 0.01), with 100 (23.8%) AO and 52 (21.2%) non-AO reporting a negative or somewhat negative impact, and 116 (27.6%) AO and 101 (41.2%) non-AO reporting a positive or somewhat positive impact. More than half of women surveyed (230 AO, 54.6%; 123 non-AO, 50.6%; p = 0.61) felt that they were somewhat or much less likely to be promoted compared to male colleagues. The majority of women reported they would choose the same career path again (71% of AO, 69% of non-AO); however, 92 (21.9%) of AO responded that they were likely or very likely to pursue a career outside academics in the next 5 years. Conclusions: While partners/family have a substantial impact on 1 in 4 women oncologists, this does not differ between AO and non-AO. Significantly more non-AO find their gender to have positively impacted their ability to obtain their chosen job. In contrast, a meaningful number of AO report a poor sense of belonging and perceived discrimination in obtaining jobs and being promoted; 1 in 5 are considering leaving academia. Academic oncology remains at high risk for continued gender inequality if the culture is not addressed.

4518 Background: Neoadjuvant cisplatin-based chemotherapy (CT) prior to radical cystectomy (RC) improves overall survival (OS) in MIBC, but about half of pts are cisplatin-unfit or refuse it. Neoadjuvant immune checkpoint inhibitors can induce high pathologic complete response rate (ypT0N0). The combination of anti-PD-1 (N) and anti-KIR (L) is hypothesized to be safe and have significant activity based on the complementary and possibly synergistic roles in regulating adaptive and innate immune response in MIBC. Methods: This is a phase Ib multi-institutional trial in pts with localized MIBC treated with 2 neoadjuvant doses (4 weeks apart) of N alone (480 mg) in cohort 1 or N (480 mg) + L (240 mg) in cohort 2 prior to RC without adjuvant therapy (NCT03532451). Cohorts were enrolled sequentially and were not randomized. Key eligibility criteria included stage cT2-4aN0-1M0, ≥20% tumor content at TURBT and cisplatin-ineligibility (Galsky criteria) or refusal. Primary endpoint was safety manifested as rate of ≥G3 treatment related adverse events (TRAE) assessed in each cohort with CTCAE v5.0. Key secondary endpoints included the % of pts who had RC > 6 weeks after last neoadjuvant dose due to TRAE, CD8+ T cell density at RC, ypT0N0 and < ypT2N0 rates, CD8+ T cell density change between TURBT and RC, recurrence-free survival (RFS) and biomarkers in tumor tissue, blood and urine. Results: Among 43 pts enrolled (13 cohort 1, 30 cohort 2), median age was 75 (51-89), 67% were men, all had PS ECOG 0-1. Pts were cisplatin-ineligible due to impaired renal function (47%) and hearing loss (37%), while 14 % refused cisplatin. At baseline, 37 pts had cT2 stage, 2 had cN1 and 3 cNx. In cohort 1 and 2, 13 and 29 pts, respectively, completed intended neoadjuvant treatment, and 41/43 underwent RC (12/13 cohort 1, 29/30 cohort 2). One pt progressed to metastatic disease prior to RC (cohort 1) and 1 withdrew consent prior to being treated (cohort 2). Additionally, 1 patient was found to have cervical cancer at RC. Median time from last neoadjuvant dose to RC was 27 (95%CI: 24-29) days. There was no RC delayed > 6 weeks from treatment completion due to TRAE. G3 TRAEs occurred in 0% with N and 6.7% (90%CI 1.2-19.5%) in N+L (1: arthralgia, 1: gout, 2: hip pain) that all resolved. No G4/5 TRAEs occurred. Of 40 pts with MIBC and RC, ypT0N0 rates for N and N+L were 8% and 18%, while < ypT2N0 rates were 17% and 29%, respectively. Data on RFS and OS, and biomarker data were not yet mature. Conclusions: Neoadjuvant N alone and N+L combination prior to RC were safe, feasible and well tolerated in cisplatin-ineligible pts with MIBC, but ypT0N0 rates were unexpectedly low, especially with N alone. Two phase 3 trials (NCT03661320; NCT04209114) are evaluating the peri-operative role of N + chemotherapy +/- Linrodostat in cisplatin-fit and N +/- Bempeg in cisplatin unfit patients and are also assessing biomarkers. Clinical trial information: NCT03532451.