JC virus (JCV) is the aetiological agent of the demyelinating disease progressive multifocal leukoencephalopathy, an AIDS defining illness and serious complication of mAb therapies. Initial infection probably occurs in childhood. In the working model of dissemination, virus persists in the kidney and lymphoid tissues until immune suppression/modulation causes reactivation and trafficking to the brain where JCV replicates in oligodendrocytes. JCV infection is regulated through binding of host factors such as Spi-B to, and sequence variation in the non-coding control region (NCCR). Although NCCR sequences differ between sites of persistence and pathogenesis, evidence suggests that the virus that initiates infection in the brain disseminates via B-cells derived from latently infected haematopoietic precursors in the bone marrow. Spi-B binds adjacent to TATA boxes in the promoter/enhancer of the PML-associated JCV Mad-1 and Mad-4 viruses but not the non-pathogenic, kidney-associated archetype. The Spi-B-binding site of Mad-1/Mad-4 differs from that of archetype by a single nucleotide, AAAAGGGAAGGGA to AAAAGGGAAGGTA. Point mutation of the Mad-1 Spi-B site reduced early viral protein large T-antigen expression by up to fourfold. Strikingly, the reverse mutation in the archetype NCCR increased large T-antigen expression by 10-fold. Interestingly, Spi-B protein binds the NCCR sequence flanking the viral promoter/enhancer, but these sites are not essential for early viral gene expression. The effect of mutating Spi-B-binding sites within the JCV promoter/enhancer on early viral gene expression strongly suggests a role for Spi-B binding to the viral promoter/enhancer in the activation of early viral gene expression.

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e21568 Background: Adjuvant therapy with single agent anti-PD1 and BRAF/MEK-inhibitors (BRAF/MEKi) is approved for patients diagnosed with high-risk stage III melanoma. The goal of adjuvant therapy is to prevent the growth of the occult metastasis to distant organs. The premise of neoadjuvant therapy in clinical stage III melanoma is to allow for a better antigen exposure when checkpoint inhibitors are administered. We aimed to get an overview of the current state of neoadjuvant therapy in resectable melanoma. Methods: A systematic literature search was conducted in November 2022, using PubMed, American Society of Clinical Oncology (ASCO) Journal of Clinical Oncology and European Society for Medical Oncology (ESMO) abstract databases. Eligible studies included Phase 2 and 3 randomized controlled trials (RCT), single-arm trials, pooled analyses, and planned future trials published between 2018-2022 looking at the efficacy of neoadjuvants in resectable melanoma. Two individuals (CL and MM) screened all the studies, and 3 individuals (CM, MM, MW) went over the list of Abstracts. Primary outcomes and secondary outcomes, as well as median duration of follow up and Grade 3 or above adverse effects (AEs) were recorded. Abstracts with more recent findings or final publications were excluded in the final analysis. Results: A total of 14 published studies (4 RTCs, 5 single-arm, 2 OpACIN-neo and 3 related sub-analysis studies) and 16 abstracts (5 ESMO, 11 ASCO) were identified, representing 34 unique Neoadjuvant arms and a total of 1,496 patients. Thirteen of 27 trials making 71% of patients (n = 1061) tested immune checkpoint inhibitors (ICIs). Four of 27 trials of total n = 112 tested BRAF/MEKi. All ongoing or future studies (7 trials) tested combination of ICI with BRAF/MEKi or other molecules such as MDM2 inhibitors, interferon-α, or oncolytic viruses. Most of studies (54% of ICI studies, 50% of BRAF/MEK inhibitor trials, and 80% of other studies) used pathological response as their primary outcome. Other primary end points included event-free survival (EFS) and relapse-free survival (RFS), and 13/14 published studies and 13/16 abstracts met the primary end point. A pooled analysis of complete pathologic response (pCR) revealed an estimate of 38.3% ± 19.7 (mean ± SD) from 16 unique ICI neoadjuvant arms, 51.9% ± 5.3 for BRAF/MEKi (from 3 data points), and 21.0% ± 7.2 for other agents/combinations (from 3 data points). Rate of ≥ Grade 3 AEs was 28.7% ± 31.0 (from 11 data points) for studies testing ICI, 32.5% ± 14.1 (from 6 data points) for BRAF/MEKi, and 23.6% ± 20.2 (from 3 data points) from studies testing other agents/combinations. Conclusions: Recent studies have shown that neoadjuvant in resectable melanoma can offer increased therapeutic efficacy. While past studies have focused on PD-1 and CTLA-4 inhibitors, ongoing and future studies are beginning to test newer agents and novel molecular targets.

4623 Background: The role of neoadjuvant chemotherapy (NAC) for resectable pancreatic cancer (RPC) remains controversial. We sought to compare the outcomes of NAC with upfront surgery (UFS). Methods: The study retrospectively enrolled patients with RPC who had UFS or received neoadjuvant FOLFIRINOX (FFX) or gemcitabine plus albumin-bound paclitaxel (GA). Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher’s exact test for categorical variables. The overall survival (OS) and recurrence-free survival (RFS) were determined by the Kaplan-Meier method with Wilcoxon test for the difference between groups. The effects of NAC vs. UFS on OS and RFS were further estimated using Cox regression controlling the effects of age and CA 19-9. Results: Between 2011 and 2019, 131 patients with RPC underwent UFS followed by adjuvant chemotherapy (gemcitabine, n = 65; gemcitabine/capecitabine, n = 18; FFX, n = 9). Up to 32 patients (24.4%) could not receive adjuvant chemotherapy due to surgical complications or poor recovery. Total 50 patients with RPC received NAC (FFX, n = 32; GA, n = 18). Median of 5.5 cycles of FFX or 3 cycles of GA were given prior to surgery. Resection rate was 72% (FFX 62.5%; GA 88.9%). The rest (28%) were no longer surgical candidates due to disease progression rather than toxicities from NAC. On surgical pathological review, complete resection (R0) was achieved in 83.3% of resected cases after NAC (FFX 90%; GA 75%) and 79.4% with UFS. The tumor size distribution was: pT1 11.1%, pT2 41.7%, pT3 44.4% with NAC; pT1 5.4%, pT2 18.3%, pT3 76.3% with UFS. The nodal status distribution was: pN0 27.8%, pN1 55.5%, pN2 16.7% with NAC; pN0 23.7%, pN1 71.0%, pN2 5.3% with UFS. Median pre-treatment CA 19-9 was 321.95 unit/mL in the NAC group and 79.99 unit/mL in the UFS group (p = 0.009). Median age was 70.5 in the NAC group and 72 in the UFS group (p = 0.374). There was no significant difference in the performance status between the two groups. In Kaplan-Meier analysis, there was a significant difference of OS between UFS and NAC with median OS of 648 days under UFS versus 884 days under NAC (p = 0.029); the median of RFS was 390 days under UFS versus 392 days under NAC (p = 0.953). The hazard ratio (NAC vs UFS) adjusted for CA19-9 and age was 0.7 (p = 0.176) for OS and 0.98 (p = 0.918) for RFS. Conclusions: We observed a signal of tumor downstaging, higher R0 rate, and improved OS with NAC compared with UFS. Further prospective trials are needed to validate these results.

8588 Background: Small cell lung cancer (SCLC) comprises 10-15% of all lung cancers yet little is known about the impact of social determinants of health (SDOH) on outcomes in patients with SCLC. This study aims to assess the impact of various SDOH on overall survival (OS) in patients diagnosed with SCLC at a single institution. Methods: We have established a large clinical/pathologic/genomic database of all patients diagnosed and treated for SCLC between 1998-2022 at our institution for retrospective study. Demographic data including sex, race, age, stage, address, and smoking status were collected. Poverty index was assessed by percent of school-aged children in poverty at the school district level based off 2021 census using the SAIPE tool and stratified as low (poverty index <=15.1) and high (poverty index >15.1). Water/Air carcinogens were obtained by zip code through EPA TRI Explorer database at year of SCLC diagnosis. Food desert designation was acquired through USDA low income and low access atlas at 0.5 miles for urban residences and 10 miles for rural residences respectively. Violent crime rates were obtained from the FBI Crime Data Explorer by year of diagnosis and police department jurisdiction. OS was computed from date of diagnosis to death or last known follow up date, and univariate Cox proportional hazards (PH) regression analysis was performed. Factors that were significant at significance level of 0.25 in univariate analysis were further evaluated using multivariable Cox PH model. Results: A total of 982 patients with SCLC were included. Univariate PH analysis demonstrated statistically significant improvement in OS with younger age (HR = 1.03, 95% CI 1.02-1.03, p <0.0001), female sex (HR = 0.8, 95% CI 0.7-0.92, p 0.001), low poverty index (HR = 1.12, 95% CI 0.98-1.12, p = 0.097), limited stage disease (HR = 3.12, 95% CI 2.66-3.66, p = <0.0001), and lack of air pollution exposure (HR = 1.09, 95% CI 0.95-1.24, p = 0.227). Multivariable PH analysis showed statistically significant OS improvement for those from lower poverty areas (HR = 1.22, 95% CI: 1.07- 1.4, p = 0.004) as well as in those without air pollution exposure (HR = 1.21, 95% CI: 1.05- 1.39, p = 0.008), controlling for age, sex, stage and smoking. Exposure to water pollution, violent crime rate, food desert designation and pack years smoked were not found to be independent predictors of OS. Conclusions: In this large detailed cohort of 982 patients with SCLC, there was a significantly lower OS for patients living in high poverty areas and for patients exposed to air pollutants. This effect was durable even after for controlling for age, sex, stage, and smoking status, demonstrating that these are independent risk factors associated with poorer OS. Our next research steps will be to examine the biologic basis for these disparities through genomic and transcriptomic analysis.