Faculty Bibliography

There is limited understanding of the epigenetic drivers of tumor evolution in hepatocellular carcinoma (HCC). Here we characterize the epigenetic contribution of methylation to intra-tumoral heterogeneity (mITH) using regional enhanced reduced-representation bisulfite sequencing DNA methylation data from 47 early stage, treatment-naive HCC biopsies across 9 patients by quantifying regional differential methylation across promoters and CpG islands, while overlapping with methylation age markers. Furthermore, we integrate these data with matching RNA-sequencing, targeted DNA sequencing, tumor-infiltrating lymphocyte (TIL), and hepatitis-B viral expression data. We found substantial mITH signatures in promoter and enhancer sites across 44% of patients in our cohort that highlight a novel axis of ITH that is not otherwise detectable from RNA analysis alone. Additionally, we identify an epigenetic tumoral aging measure that reflects a complex tumor fitness phenotype as a potential proxy for tumor clonality. Associating clinical outcomes with epigenetic tumoral age using 450k array data from 377 patients with HCC in the TCGA-LIHC single-biopsy cohort we found evidence implying that epigenetically old tumors have lower fitness yet higher TIL burden. Our data reveal a novel, unique epigenetic axis of ITH in HCC that merits further exploration.

INTRODUCTION/UNASSIGNED:An emergency general surgery (EGS) service is a crucial component of care in a hospital. Current reviews of EGS focus on procedural-based or diagnosis-driven reviews of administrative data. However, patients evaluated by an EGS service may or may not undergo surgery. Therefore, we sought to determine the feasibility of maintaining an EGS registry to include those who do and do not undergo surgery and determine the contribution of nonoperative care to the service. METHODS/UNASSIGNED:Demographic and clinical data for operative and nonoperative general surgery consult patients extracted from the local medical record were entered into a registry over 12 months from 2018 to 2019. We used descriptive statistics to demonstrate differences in demographics and clinical presentation between operative and nonoperative groups. RESULTS/UNASSIGNED:1065 EGS patients were captured into the registry, only 40 % of whom required an operation. Insurance status and race/ethnicity were different between operative and nonoperative groups. Reasons for consultation varied broadly with the largest group (20 %) being for hepatopancreaticobiliary disease. DISCUSSION/UNASSIGNED:Providing insight into the important contribution of nonoperative care on EGS burden, we present data from an institutional EGS registry. EGS registries can provide direction for future studies to guide optimal management of EGS patients, especially in resource-limited settings. CONCLUSION/UNASSIGNED:Maintaining registries poses challenges but given its importance and the need to determine the contribution of patients who do not undergo procedures to the service load, resources are necessary to ensure they continue.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by a dismal prognosis and limited therapeutic options. Its highly invasive nature and pronounced intratumoral heterogeneity underscores the urgent need for innovative and targeted therapeutic strategies. One promising approach is synthetic lethality, which exploits cancer-specific genetic vulnerabilities to selectively eliminate tumor cells. A well-characterized example involves the deletion of methylthioadenosine phosphorylase (MTAP), commonly observed in GBM and other malignancies. This review focuses on synthetic lethality targeting protein arginine methyltransferase 5 (PRMT5) in MTAP-deleted GBM. Loss of MTAP leads to the accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5, thereby creating a selective vulnerability to PRMT5 inhibition which is used to inhibit the residual function of PRMT5. We critically evaluate preclinical and clinical data on both first- and second-generation PRMT5 inhibitors, with particular emphasis on MTA-cooperative compounds that selectively exploit MTAP deficiency. Despite promising anti-tumor activity in vitro, the clinical efficacy of PRMT5 inhibitors is often limited by the tumor microenvironment, particularly the impact of non-malignant cells that attenuate drug activity. Finally, we explore rational combination strategies that integrate PRMT5 inhibition with existing therapies to enhance clinical outcomes in GBM.

AIMS/UNASSIGNED:Lipedema is a condition often mistaken for other causes of limb swelling including lymphedema and obesity. Lipedema may have a unique metabolic profile. Interrogation of the metabolome is a strategy that could reveal unique biomarkers to distinguish lipedema from lymphedema and obesity. METHODS/UNASSIGNED:Unbiased metabolomics was utilized to examine 38 BMI-matched overweight patients compared with patients with lipedema, lymphedema, and lipolymphedema. Machine learning identified biomarkers to distinguish diseases, and further examined in a validation cohort of 198 patients with each disorders. Adjustments were made for baseline clinical and demographic variables. RESULTS/UNASSIGNED:Plasma metabolomics firstly revealed uric acid as a biomarker that performs well to distinguish between phenotypically similar diseases in patients with elevated BMI. In a validation cohort of 64 patients with lipedema, uric acid (5.05 mg/dL) was compared with 64 patients with lymphedema (5.4 mg/dl), and 70 overweight patients without these conditions (4.6 mg/dL, p < 0.05). Uric acid-to-cystatin c ratio distinguished between all three groups (Lipedema: 5.2; Lymphedema: 6.3; overweight: 4.0, p < 0.01); however, significance was lost after adjustment for renal function. CONCLUSION/UNASSIGNED:Metabolomic analysis revealed uric acid may differentiate between lipedema, lymphedema, lipolymphedema and obese individuals without those conditions. In a validation cohort, while uric acid was higher in lipedema and lymphedema, uric acid adjusted by cystatin c clearance revealed uric acid to be a less useful marker to distinguish lipedema from lymphedema in the context of renal insufficiency.

IMPORTANCE/UNASSIGNED:Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. OBJECTIVE/UNASSIGNED:To develop consensus best practices for delivering NT to patients with localized PDAC. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. MAIN OUTCOME AND MEASURES/UNASSIGNED:Statements that reached 75% agreement or greater were included in final consensus statements. RESULTS/UNASSIGNED:Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). CONCLUSIONS/UNASSIGNED:Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor how they contribute to neuronal dysfunction and disease risk as organisms age. Here, we examine the transcriptional, cell biology, and functional differences in astrocytes across normal aging. Astrocytes at baseline are heterogenous, responsive to their environments, and critical regulators of brain microenvironments and neuronal function. With increasing age, astrocytes adopt different immune-related and senescence-associated states, which relate to organelle dysfunction and loss of homeostasis maintenance, both cell autonomously and non-cell autonomously. These perturbed states are increasingly associated with age-related dysfunction and the onset of neurodegeneration, suggesting that astrocyte aging is a compelling target for future manipulation in the prevention of disease.

In the current study, we assessed whether repeated measurements of a panel of protein biomarkers with relevance to pancreatic ductal adenocarcinoma (PDAC) improves lead time performance for earlier detection over a single timepoint measurement. Specifically, CA125, CEA, LRG1, REG3A, THBS2, TIMP1, TNRFSF1A as well as CA19-9 were assayed in serially collected pre-diagnostic plasma from 242 PDAC cases and 242 age- and sex-matched non-case control participants in the PLCO cohort. We compared performance estimates of a parametric empirical Bayes (PEB) algorithm, which incorporates participant biomarker history, to that of a single-threshold (ST) method. We demonstrated improvements in AUC estimates (2-13 %) for all biomarkers when considering the PEB approach compared to ST. For CA19-9, the PEB^CA19-9 yielded an AUC of 0.88 when at least one repeat measurement was within 3 years of clinical diagnosis. At a specificity of 98.5 %, the PEB^CA19-9 identified 15 of the 41 PDAC cases and signaled positive at an average lead-time of 1.09 years whereas the ST approach captured 11 of the 41 PDAC cases with an average positive signal at 0.48 years. Among CA19-9 low individuals, a PEB algorithm based on repeat measurements of TIMP1 yielded an additional 14 % sensitivity at 98.5 % specificity. An adaptive algorithm that considers repeated CA19-9 measurements improves sensitivity and lead-time detection of PDAC compared to a single-threshold method. Additional protein biomarkers may improve sensitivity for earlier detection of PDAC among cases with low CA19-9.