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AbstractBackgroundExternal‐beam radiation (EBRT) is a noninvasive therapeutic alternative to transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The objective of this study was to conduct a systematic review and meta‐analysis of prospective randomized clinical trials to assess the clinical efficacy of EBRT versus TACE for HCC as either a definitive monotherapy or as a bridge to transplantation/surgery.MethodsA systematic review and meta‐analysis were performed to include prospective randomized trials comparing EBRT versus TACE. Data was analyzed with random and fixed‐effects models. The inconsistency index (I2) was chosen to assess heterogeneity. Three publications were included with a total of 142 patients. Outcomes included local control (LC), overall survival (OS), progression‐free survival (PFS), and occurrences of grade ≥3 toxicity. Comparisons are reported as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).ResultsThere were three randomized trials that met inclusion criteria. The EBRT was delivered in three to 15 fractions with a total dose between 30 and 75 gray(Gy). EBRT was associated with significantly improved LC (HR, 0.16; 95% CI, 0.08–0.34; I2 = 0%) and PFS (HR, 0.37; 95% CI, 0.23–0.60; I2, 0%) compared with TACE. There was no significant difference between EBRT and TACE in OS (RR, 0.79; 95% CI, 0.51–1.22; I2 = 0%) or grade ≥3 toxicity (RR, 0.86; 95% CI, 0.31–2.37; I2 = 57%). None of the analyses had statistically significant heterogeneity.ConclusionsCompared with TACE, EBRT yields superior LC and PFS without providing a survival benefit in early and intermediate stage HCC. Additional larger prospective randomized controlled trials should be conducted to further investigate differences in clinical outcomes amongst patients with more advanced disease.

Abstract Background The opioid crisis and the increasing prevalence of multi-drug resistant organism (MDRO) infections pose a threat to public health. Opioid Use Disorder (OUD) patient are prone to MDRO colonization and infections, thus potentially leading to adverse outcomes during periods of critical illness. Understanding the prevalence and predictors of MDRO infections within this vulnerable population is critical to improving patient outcomes by optimizing interventions and treatment plans. Methods We conducted a retrospective, multicenter, cohort study to evaluate the prevalence of MDRO isolation among adults with OUD admitted to an intensive care unit (ICU) with an infection across four Mayo Clinic regions. Patients were classified to the MDRO cohort if an MDRO was isolated from standard cultures or rapid diagnostic testing within 48 hours of admission. We utilized descriptive statistics, univariate and multivariate least absolute shrinkage and selection operator (LASSO) regression analysis including random effect to account for site variability, to analyze demographic data, clinical characteristics, and outcomes. Results 790 critically ill adult OUD patients with infection-related admission were included in the study cohort. The prevalence of MDRO isolation was 22.5% (n=178), with MRSA being the predominant isolated MDRO. In LASSO regression analyses, we identified homelessness (OR: 1.79, p = 0.022), no Medications for OUD (MOUD) treatment (OR: 1.56, p=0.023), and positive Hepatitis C Virus (HCV) status (OR: 2.19, p = 0.012) as significant predictors for isolation of an MDRO. Intravenous (IV) antibiotic use in the preceding 90 days was also positively associated (OR: 1.04 per 24 hours, p = 0.007), alongside mental health disorders (OR: 2.03, p < 0.001) and diabetes (OR: 1.54, p = 0.023). Conclusion The high prevalence of MDRO isolation in critically ill OUD patients with infection is associated with complex social and clinical factors. Disclosures All Authors: No reported disclosures

Abstract Background Culture-negative native vertebral osteomyelitis (CN-NVO) is increasingly common, rising from 0.3 to 1.8 cases per 100,000 between 1995 and 2008. The lack of microbial identification complicates optimal treatment and creates prognostic uncertainties. We describe our decade-long clinical experience with CN-NVO, focusing on patient characteristics, treatment, and outcomes. Patient Characteristics Methods We retrospectively analyzed adult patients with radiographic evidence of NVO between January 1, 2011, and July 31, 2021. CN-NVO required clinical indicators such as back pain and fever, elevated inflammatory markers, and negative cultures from at least one spine biopsy. Patients with infected instrumentation were excluded. Diagnostic Evaluation Values represent median, lower quartile, and upper quartile for continuous variables unless otherwise specified, 2 whereas frequencies and percentages are presented for categorical variables. ^ All results returned negative *Biopsies number two and three did not result in additional findings or change clinical management. Results Seventy-two patients were included. Their characteristics are presented in Table 1. Most (77.8%) had received antibiotics within the 4 weeks preceding the biopsy. Disc space enhancement on MRI was the primary finding, with the lumbar spine being the most frequently involved (Table 2). Blood cultures were positive in 39.4% of the patients within 3 months of symptom onset. Streptococcus spp. (n=9, median time between positive culture and diagnosis: 6.5 days [IQR 2.25, 26.75]) and Staphylococcus aureus (n=7, 40 days [IQR 37.5, 51.5]) were most common. Definitive antibiotics were administered in 98.6% of the cases, primarily IV β-lactam + vancomycin. Oral antibiotics (PO) were used in 46.5% of the patients, primarily as step-down therapy (91%) (Table 3). Surgery was required in 8.5% of the patients for abscess drainage or relief of spinal cord compression. Treatment failure occurred in 9.4% of patients, and 37.5% died during the median follow-up of 568.5 days, with two deaths related to the infection. Treatment and Outcomes ^ defined as requiring another course of antibiotics and/or surgery for suspected ongoing infection ¶ Clinical findings include back pain or fevers; laboratory findings indicate abnormal or uptrend in inflammatory marker values # Defined as MRI findings concerning ongoing or worsening infection as per the interpretation of the Radiologist, Infectious Disease physician, and/or Orthopedic Surgeon Conclusion Patients with CN-NVO often require prolonged antibiotic therapy, typically combination regimens, with favorable treatment outcomes. Our treatment failure rate is similar to other studies, although comparability may be limited by heterogeneity in definitions. Mortality rates in the range of 6 and 36% have been reported, with the higher end driven mostly by comorbidities. Enhanced diagnostics and standardized treatment protocols are needed to further improve patient outcomes. Disclosures All Authors: No reported disclosures

Abstract Background Optimizing antimicrobial prescribing for urinary tract infections (UTI) represents an area of opportunity for ambulatory antimicrobial stewardship programs. A pre-populated, ambulatory antibiotic order panel for UTI was implemented in the Mayo Clinic Enterprise on 5/16/2022. The order panel provides antimicrobial regimens which align with both institutional and national treatment guidelines based on patient comorbidities, complicating factors, and beta-lactam allergy status. We aimed to assess the impact of panel use on antibiotic prescribing for complicated and uncomplicated cystitis in the ambulatory setting. Methods This retrospective review included ambulatory encounters from the Mayo Clinic Enterprise in 2022 and 2023. Eligible encounters were randomly selected and included those with a primary ICD-10 code of cystitis performed by primary care or urgent care clinicians. Encounters were excluded if patients had symptoms indicative of pyelonephritis, underwent urinary instrumentation within 30 days, or had a urinary pathogen isolated within 90 days. The primary outcome was concordance with institutional guidelines. Secondary outcomes included repeat healthcare contact and therapy duration. Outcomes were analyzed with Pearson's chi-squared and Wilcoxon rank sum tests (α level = 0.05). Results 793 encounters (397 panel vs. 396 non-panel) were included. Prescribing was guideline concordant in 79.3% and 64.9% (p< 0.001) of panel and non-panel encounters, respectively. Inappropriate duration was the most common reason for non-concordance in the panel use cohort. There was no difference between groups for repeat healthcare contact incidence. Antimicrobials prescribed differed between panel and no-panel groups (Table 1), with higher use of sulfamethoxazole/trimethoprim and lower use of cefdinir in the panel cohort. Numerically shorter durations were seen in the panel group, with more 3- and 5-day regimens than the no-panel group. Conclusion Use of a pre-populated antimicrobial order panel for outpatient cystitis encounters resulted in greater adherence to institutional guideline recommendations, particularly in terms of antimicrobial selection, without adversely impacting repeat healthcare contact. Disclosures Paschalis Vergidis, MD, MSc, AbbVie: Advisor/Consultant|Ansun Biopharma: Grant/Research Support|Cidara Therapeutics: Grant/Research Support|F2G: Grant/Research Support|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support

Abstract Purpose: Data on clear-cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of hypoxia-inducible factor-1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients and Methods: Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2,500, 3,000, and 4,000 μg) were administered orally twice daily for 14 days and then once daily concurrently with axitinib 5 mg twice daily using a 3 + 3 design in phase I. Patients were treated at the 4,000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. Results: No dose-limiting toxicities occurred at the 4,000 μg SLM dose level. Among the 27 patients treated with 4,000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent. Conclusions: SLM (4,000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

Introduction Although the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) has been reported, the proportion of patients with CIPN who report chronic moderate-to-severe neuropathy or chronic painful neuropathy remains poorly understood, despite its significant impact on patients’ quality of life and treatment outcomes. Methods A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome was the pooled prevalence of chronic (≥3 months) moderate-to-severe CIPN or painful CIPN among patients diagnosed with CIPN. Estimates from each study were transformed using a double-arcsine transformation and pooled in a meta-analysis using an inverse variance heterogeneity model. Subgroup analysis was conducted based on geographical region, sex, chemotherapy regimen, primary cancer type, and funding source; metaregression analysis was conducted based on study design, human development index (HDI), and publication year. Results 76 studies from 29 countries, encompassing 13 635 patients with CIPN, were included. Among patients diagnosed with CIPN, the pooled prevalence of those reporting chronic moderate-to-severe CIPN or painful CIPN was estimated at 47.76% (95% CI 37.50 to 58.08; 95% prediction interval 24.68–71.84). Substantial heterogeneity was observed across studies ( I² =97.45%; 95% CI for I 2 97.15 to 97.72). Subgroup analysis revealed that patients treated with platinum-based agents and taxanes had the highest prevalence of chronic moderate-to-severe CIPN or painful CIPN (44.47% and 55.68%, respectively), and among primary cancers, those with breast cancer, multiple myeloma, and lung cancer reported the highest prevalence of chronic moderate-to-severe CIPN or painful CIPN (61.31%, 53.55%, and 50.85%, respectively). Study design, HDI, and publication year were non-significant moderators of prevalence estimates. Based on our Grading of Recommendations, Assessment, Development, and Evaluation assessment, the certainty of evidence was considered “very low.” Sensitivity analysis restricted to studies explicitly measuring painful CIPN (40.78%; 95% CI 29.08 to 52.74) or moderate-to-severe CIPN (49.04%; 95% CI 37.16 to 60.95) yielded similar prevalence estimates. Conclusion This study provides the first comprehensive global estimate of the prevalence of chronic moderate-to-severe CIPN or painful CIPN, highlighting its significant burden on patients worldwide. The variation in prevalence across geographical regions, chemotherapy regimens, and primary cancers underscores the need for tailored management strategies and further research to address potential disparities.

A 67-year-old male with positive signals for neuroendocrine and head/neck cancer on a commercially available multicancer detection test underwent an extensive negative diagnostic workup at a local hospital. Referred to our medical center for advanced imaging and endoscopic procedures ultimately led to the diagnosis of an early-stage seminoma with eventual orchiectomy. This case highlights challenges in evaluating positive multicancer detection results, emphasizing the need for a broader understanding of how to interpret these testing results to fully evaluate complex cases, as well as the need for protocolized follow-up approaches to a positive multicancer detection test.

770 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and limited treatment options. A 584 bp deletion in CTRB2 , which impairs chymotrypsin B2 function, has been linked to increased PDAC risk. This study investigates the impact of this deletion on progression and survival outcomes in patients with PDAC. Methods: There were 633 patients in whom CTRB2ex6 deletion was genotyped; 263 patients received chemotherapy and had time to progression (TTP) information. TTP was calculated from diagnosis date until earliest of 1) progression date (event), 2) surgery, death, or next chemotherapy date (competing risk), or 3) date last known to be alive (censor). Overall survival (OS) was calculated for the cohort from diagnosis until date of death (event) or date last known to be alive (censor). TTP was analyzed using cumulative incidence methods accounting for competing risks; OS was analyzed using Kaplan-Meier methods. Cox proportional hazard models adjusted for age and sex were used to test associations and compute hazard ratios (HR) and 95% confidence intervals (CI). Results: Median TTP in those with CTRB2ex6 deletion negative carrier status (n=209) was 1.3 years vs 5.9 years for those with positive carrier status (n=54). Estimated 3-year progression rates were 54.2% for patients with no CTRB2ex6 deletions, 43.7% for patients with one deletion (n=48), and 33.3% for patients with two CTRB2ex6 deletions (n=6). TTP was not associated with CTRB2 deletion carrier status (HR: 0.8, 95% CI: 0.6-1.3). Median OS for CTRB2ex6 deletion negative carriers (n=514) was 1.0 year vs 0.9 years for positive carriers (n=119); within deletion carriers, heterozygous carriers (n=110) had a median OS of 0.9 years, and homozygous carriers (n=9) had a median OS of 2.6 years. OS was not associated with CTRB2 deletion carrier status (HR: 1.0, 95% CI: 0.9-1.3). Conclusions: Although we did not detect statistically significant differences in TTP and OS by CTRB2ex6 deletion carrier status, there was an interesting trend toward longer TTP and OS in the small number of patients who carried homozygous CTRB2ex6 deletions. Larger studies are warranted to validate these findings.

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .