Citations

Abstract Purpose: Our goal was to determine if the HRDefine biomarker combining methylation and mutation assessment of key homologous recombination repair genes identifies BRCA wildtype (BRCAwt) ovarian cancer (OC) with outcomes similar to BRCA mutated (BRCAm) OC within the context of a frontline PARP inhibitor trial for advanced ovarian cancer. Methods: We performed an exploratory biomarker analysis of blood and neoplastic samples from the VELIA trial, a phase 3 study evaluating the PARP inhibitor veliparib as frontline maintenance therapy in OC. We developed a highly sensitive droplet digital PCR assay for quantitative BRCA1 and RAD51C promoter methylation and assessed germline/somatic mutations using the BROCA next generation sequencing platform. Cases were grouped into: BRCAm, HRDefine positive (BRCAwt HRDefine+), and HRDefine negative (BRCAwt HRDefine-). Carcinomas were considered HRDefine+ if quantitative BRCA1 or RAD51C promoter methylation was >/= 60% or if a germline or somatic pathogenic variant (PV) was identified in the following non-BRCA HRR repair genes: RAD51C, RAD51D, PALB2, BARD1. For this analysis, the control group included the two study arms with placebo maintenance compared to the investigational arm of veliparib with chemotherapy and continued as maintenance (veliparib throughout group). HRDefine was compared to the Myriad genomic instability score (GIS) used as HRD assessment in the trial. Progression free survival (PFS) was compared using log rank tests. Results: Among 1140 VELIA participants, biomarker analysis could be performed for 487 cases. Of these, 255 (52%) were BRCAm, 60 (12%) were BRCAwt HRDefine+, and 172 (35%) were BRCAwt HRDefine-. BRCAwt HRDefine+ was driven by promoter methylation (57%), germline (40%), or somatic (3%) PVs. Median PFS (months, all arms combined) was 26 months (BRCAm), 27 months (BRCAwt HRDefine+), and 15 months (BRCAwt HRDefine-), with corresponding hazard ratios (HR) of 0.50 (95% CI: 0.39-0.65) and 0.50 (0.34-0.73) versus HRDefine-. All HRDefine+ molecular subgroups were associated with longer PFS, including RAD51C/D mutations (HR 0.44, 0.25-0.77) and promoter methylation (HR 0.60, 0.36-0.97). HRDefine positivity was significantly associated with improved PFS compared to HRDefine-/GIS low (n=60 vs n=111, median PFS 27 versus 14 months, HR 0.44, 0.30-0.65), while the HRDefine- cases with high GIS demonstrated a trend toward an intermediate PFS (n=56, median 18 months, HR 0.67, 0.45-1.01). When compared by treatment arm, median PFS was significantly longer in the veliparib throughout arm compared to control only for the BRCAm group (32 months vs 23 months, HR 0.61, 0.42-0.87), though the analysis was underpowered for the BRCAwt HRDefine+ sub-group (30 months vs 25 months, HR 0.79, 0.4-1.57). Conclusions: HRDefine identifies BRCAwt OC associated with a PFS that is like that of BRCAm cases and may improve stratification for PARP inhibitor therapy beyond current HRD assays. GIS may have some, albeit reduced, prognostic implication that is independent of HRDefine. Citation Format: Isabel V. Rodriguez, Marc Radke, Ronit Katz, Persephone Miller, Paula Ladd, Nithisha Khasnavis, Jennifer Ochoa, Melanie Dillon, Heather Lankes, Peter Ansell, Carol Aghajanian, Gini Fleming, Michael Birrer, Scott Kaufmann, Charles Leath, Kathleen Moore, Theresa Werner, Linda Van Le, Robert L. Coleman, Elizabeth M. Swisher. Application of HRDefine: a biomarker for identifying root causes of homologous recombination deficiency to a phase 3, randomized, placebo-controlled trial of veliparib in front-line treatment of advanced ovarian cancer (VELIA/GOG-3005) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A044.

Abstract Multiple Myeloma (MM) is an incurable plasma cell malignancy that progresses from the precursor condition monoclonal gammopathy of undetermined significance (MGUS). African Americans (AA) have the highest incidence of MGUS and MM of any population group in the U.S., with ∼1.5-2-fold higher age-adjusted incidence than European Americans (EA) for reasons that remain unclear. Despite the increased incidence, MM tumors in AA patients show fewer TP53 deletions/mutations and high-risk cytogenetic features compared to EA patients. Studies also show that, with equal access to care, AA patients have better overall survival (OS) independent of age. Given recent studies demonstrating accelerated biological aging in AA individuals, we hypothesize that immunosenescence that occurs with aging reduces the immune pressure on MM cells, resulting in the increased emergence of less aggressive tumors. To test this, we utilized viably frozen bone marrow samples from the Mayo Clinic Myeloma Biobank. We profiled samples from 128 individuals (N= 53 and 75 AA vs. EA, respectively) with either newly diagnosed MM (NDMM) or treated MM (N= 27 and 38 AA vs. EA, respectively), MGUS (N=18 and 23 AA vs. EA, respectively), or healthy controls (N= 8 and 14 AA vs. EA, respectively) by mass cytometry (CyTOF) (N= 17 MGUS, 55 MM and 22 healthy controls) using the CyTOF Human Immune Profile Assay or by single cell RNA-sequencing (scRNA-seq, N= 24 MGUS/SMM and 10 MM). Profiling of the CD45+ non-tumor lymphocytes by scRNA-seq revealed AA patients exhibited increased T cell populations (odds ratio (OR)=2.3), including a reduction in CD8+ effector memory (OR=0.94) and an increase in CD8+ cytotoxic effector (OR=1.02) in a multivariate model adjusting for age and sex. Analysis by CyTOF confirmed an increase in overall CD3+ T cells (49.5% vs. 35.3%, p=0.0001) including increases in CD8+ terminal effector (9.5% vs. 5.2%, p=0.021) and CD4+ terminal effector T cells (5.5% vs. 2.7%, p=5.7x10^-6) among AA patients, and this difference remained after adjusting for age and sex. Within the CD8+ terminal effector T cells, we also noted increases in CD57+/CD28- senescent T cells, consistent with immune exhaustion that occurs with biological aging. We are currently working to assess whether AA patients with MGUS and MM exhibit accelerated biological aging as measured by frailty index, peripheral senescence associated secretory phenotypes, and PBMC epigenetic clock scores. We plan to extend our analysis of the immune microenvironment to assess patient T cell function ex vivo. Finally, we will evaluate whether MM cells from AA patients exhibit increased sensitivity to control cytotoxic T cell induced cell death in vitro compared to cells from EA patients. The results from this study will allow further understanding of components causing the increased risk for MM development seen in AA individuals. Citation Format: Alani Perkin, Megan Moore Weivoda, Linda Baughn. Immunosenescence driven T-cell remodeling may underlie increased risk of Multiple Myeloma in African Americans [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A051.

ABSTRACT Biofilms hinder wound infection healing, making wound infections a healthcare challenge for which innovative treatments are needed. A 1.77 cm 2 electrochemical bandage (e-bandage), which generates the biocide hypochlorous acid (HOCl), has shown promising anti-biofilm activity in vitro , ex vivo , and in vivo . The e-bandage is a three-electrode system operationalized by a hydrogel. In addition to providing a conductive electrolyte for the electrodes, the hydrogel provides a protective barrier for the wound. How different hydrogels impact e-bandage functionality is not completely defined. Here, the in vitro activity of seven clinically available hydrogels (xanthan gum, 3M, Duoderm, Prontosan, Purilon, Skintegrity, and Solosite) was evaluated with 1.77 cm 2 HOCl-generating e-bandages using a potentiostat with a multiplexer in a membrane biofilm model against methicillin-resistant Staphylococcus aureus IDRL-6169 and Acinetobacter baumannii ATCC-17978. When applied with polarized HOCl-producing e-bandages, all evaluated hydrogels except Solosite yielded ≥5.5 log 10 CFU/cm 2 reductions in bacterial quantities after 6 h of treatment, with most being below the detection limit at that time point. Prontosan exhibited antibacterial activity independent of e-bandage. Results of this study inform the selection of clinically available hydrogels that may be suitable for use with a 1.77 cm 2 HOCl-producing e-bandage. IMPORTANCE In this study, it was shown that some clinically available hydrogels, combined with a 1.77 cm 2 HOCl-generating electrochemical bandage, deliver time-dependent antimicrobial activity against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii biofilms, offering a potential approach to treat wound infections, including those caused by antimicrobial-resistant bacteria.

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

ABSTRACT An electrochemical bandage (e‐bandage) that generates hydrogen peroxide (H 2 O 2 ) through a combination of working, counter and reference electrodes used with an electrolyte‐providing hydrogel is being developed for wound infection management. e‐Bandage biocidal activity was previously demonstrated using Xanthan gum hydrogel. For clinical use, clinically used hydrogels would be ideal, but their use with the described e‐bandage has not been shown. The goal of this work was to evaluate the biocidal activity of off‐the‐shelf, clinically used hydrogels when used with a 1.77 cm 2 H 2 O 2 ‐producing e‐bandage. e‐Bandage electrochemical parameters and activity against methicillin‐resistant Staphylococcus aureus IDRL‐6169 and Acinetobacter baumannii ATCC‐17978 biofilms were assessed with six off‐the‐shelf hydrogels. Variations in hydrogel composition affected electrochemical parameters, which was associated with differences in biocidal activity. Results of this study inform the selection of off‐the‐shelf hydrogels for use with H 2 O 2 ‐producing e‐bandages.

Objective: To develop, implement, and evaluate a novel process used for residency application review that deemphasizes metrics known to create bias with the goal of interviewing and matching a more diverse resident cohort. Methods: Between 2020 and 2023, a novel standardized rubric and application review process were developed and implemented at the authors’ academic training program. The rubric deemphasized USMLE scores, honor society membership, and number of publications while utilizing an AI-driven pre-sort of applications, facilitating holistic review. This weighted applicant attributes identified in personal statements, life experiences, achievements in community, leadership roles, otolaryngology-specific impressions highlighted in letters of recommendation, and otolaryngology-specific research and publications similarly to academic metrics (clerkship grades and standardized test scores). Demographics of applicants interviewed and matched into our program were compared pre- and post-implementation using descriptive statistics. Results: Using a standardized rubric to review residency applications that deemphasizes traditional metrics, the authors’ otolaryngology residency program has interviewed, ranked, and matched more diverse candidates. As a result, from 2019 to 2022, the overall resident cohort has diversified from 4% historically marginalized residents to 24%, from 28% female residents to 44%, and from 33% of residents outside our geographic region to 66%. Conclusion: There is significant underrepresentation among otolaryngology residents. Selection based upon USMLE Step 1 scores, honor society membership, and number of publications have been shown to restrict diversity. Purposeful holistic review increases diversity in interviewed and matched resident cohort.

Importance Multiparametric magnetic resonance imaging (MRI), with or without prostate biopsy, has become the standard of care for diagnosing clinically significant prostate cancer. Resource capacity limits widespread adoption. Biparametric MRI, which omits the gadolinium contrast sequence, is a shorter and cheaper alternative offering time-saving capacity gains for health systems globally. Objective To assess whether biparametric MRI is noninferior to multiparametric MRI for diagnosis of clinically significant prostate cancer. Design, Setting, and Participants A prospective, multicenter, within-patient, noninferiority trial of biopsy-naive men from 22 centers (12 countries) with clinical suspicion of prostate cancer (elevated prostate-specific antigen [PSA] level and/or abnormal digital rectal examination findings) from April 2022 to September 2023, with the last follow-up conducted on December 3, 2024. Interventions Participants underwent multiparametric MRI, comprising T2-weighted, diffusion-weighted, and dynamic contrast–enhanced (DCE) sequences. Radiologists reported abbreviated biparametric MRI first (T2-weighted and diffusion-weighted), blinded to the DCE sequence. After unblinding, radiologists reported the full multiparametric MRI. Patients underwent a targeted biopsy with or without systematic biopsy if either biparametric MRI or multiparametric MRI was suggestive of clinically significant prostate cancer. Main outcomes and measures The primary outcome was the proportion of men with clinically significant prostate cancer. Secondary outcomes included the proportion of men with clinically insignificant cancer. The noninferiority margin was 5%. Results Of 555 men recruited, 490 were included for primary outcome analysis. Median age was 65 (IQR, 59-70) years and median PSA level was 5.6 (IQR, 4.4-8.0) ng/mL. The proportion of patients with abnormal digital rectal examination findings was 12.7%. Biparametric MRI was noninferior to multiparametric MRI, detecting clinically significant prostate cancer in 143 of 490 men (29.2%), compared with 145 of 490 men (29.6%) (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points; P = .50). Biparametric MRI detected clinically insignificant cancer in 45 of 490 men (9.2%), compared with 47 of 490 men (9.6%) with the use of multiparametric MRI (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points). Central quality control demonstrated that 99% of scans were of adequate diagnostic quality. Conclusion and relevance In men with suspected prostate cancer, provided image quality is adequate, an abbreviated biparametric MRI scan, with or without targeted biopsy, could become the new standard of care for prostate cancer diagnosis. With approximately 4 million prostate MRIs performed globally annually, adopting biparametric MRI could substantially increase scanner throughput and reduce costs worldwide. Trial registration ClinicalTrials.gov Identifier: NCT04571840

Intravoxel incoherent motion MRI parameters derived from two software packages demonstrated diagnostic value for breast cancer, with multivariable combinations of histogram metrics achieving high diagnostic accuracy.

ABSTRACT The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type‐specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)‐derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single‐cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC‐derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia‐driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.