Faculty Bibliography

BACKGROUND/UNASSIGNED:Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell (EC) barrier. This process allows the heart to obtain fatty acids, its chief source of energy, and apoB-containing lipoproteins to cross the arterial endothelial barrier, leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial TRLs (triglyceride-rich lipoproteins) as an independent risk factor for cardiovascular disease. We explored how chylomicrons affect ECs and transfer their fatty acids across the EC barrier. METHODS/UNASSIGNED:C]oleate, we studied the uptake and release of this labeled by ECs. RESULTS/UNASSIGNED:]C labeled chylomicron triglycerides exited ECs primarily in phospholipids. EVs from chylomicron-treated versus untreated ECs were larger, more abundant, and contained specific microRNAs. Treatment of macrophages and naive ECs with media from chylomicron-treated ECs increased expression of inflammatory genes. CONCLUSIONS/UNASSIGNED:EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. Fatty acids within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition.

OBJECTIVES/BACKGROUND/OBJECTIVE:This study was undertaken to review the published literature and provide a position statement from the American Headache Society regarding the safety, efficacy, and impact on access to care of telemedicine for the clinical management of patients with headache disorders. Access to specialized care in headache medicine is severely limited in the United States and worldwide. Telemedicine has been used as an approach to care delivery in headache medicine for more than a decade, with accelerated adoption during the COVID-19 pandemic. There is now uncertainty regarding the extent to which telemedicine will be accepted by health systems and reimbursed by payers moving forward. The purpose of this position statement is to summarize evidence and clinical experience supporting the utility of telemedicine in headache medicine. METHODS:Evidence regarding the safety and efficacy of telemedicine, and patient and clinician satisfaction with the use of telemedicine for headache specialty care, was gathered from a variety of sources, including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the authors and the Board of Directors of the American Headache Society to confirm consistency with clinical experience and to achieve consensus. RESULTS:Several randomized clinical trials and observational studies have been performed to compare telemedicine with in-person visits in the management of patients with headache disorders. These studies showed consistently that telemedicine is noninferior to in-person care based upon multiple outcome measures, including disability measures, patient satisfaction, and clinician satisfaction. In addition, these studies found that telemedicine rarely leads to a missed diagnosis of secondary headache or mismanagement of primary headache. Telemedicine has substantial advantages for patients, including improved access to care and reduced costs associated with obtaining care. Studies evaluating health care utilization indicate no significant differences between patients evaluated and treated virtually versus in person. Obvious limitations of telemedicine include the inability to perform an in-person physical exam or to perform injections. For a substantial number of patients, however, these limitations are outweighed by its advantages. The experience with telemedicine reported in the literature is consistent with the experience of the Board of Directors of the American Headache Society, who endorse its use for patients when feasible and appropriate. CONCLUSION/CONCLUSIONS:Telemedicine has significantly advanced the care of patients with headache disorders. Its further development and deployment should be supported and reimbursed.

BACKGROUND/UNASSIGNED:Endocrine findings in premature adrenarche have been characterized by elevated DHEAS levels in the past. METHODS/UNASSIGNED:We reviewed 44 female patients, aged 4 to 8 years, with premature adrenarche who were seen at our center between 2019 and 2023. Data were collected on the traditional androgens (DHEA and DHEAS) and novel 11-oxo-androgens. 11-oxo-androgens, DHEAS, and DHEA levels were measured using Liquid chromatography/tandem mass spectrometry (LC/MS-MS) assays in commercial laboratories (Lab Corp). RESULTS/UNASSIGNED:The majority, 89% of patients from the youngest group (4-5year olds), presented with apocrine odor as the only symptom of premature adrenarche. We have demonstrated that DHEA and DHEAS levels were within the normal range in many girls with premature adrenarche, whereas 11-oxo-androgens, particularly 11-hydroxyandrostenedione and 11β-hydroxytestosterone, were elevated. Out of those with normal DHEAS, 75 % had elevated 11-hydroxyandrostenedione, and 77.8% of those patients with normal DHEA had the same elevated oxo-adrogen. Additionally, advanced bone age greater than 1 year compared to chronological age was positively associated with 11-ketotestosterone (Spearman correlation coefficient = 0.32, 95% CI: 0.01-0.57, p=0.0429) and 11β-hydroxy testosterone (Spearman correlation coefficient=0.32, 95% CI: 0.01-0.58, p=0.0395). CONCLUSION/UNASSIGNED:We propose that 11-oxoandrogens are a more sensitive steroid to be measured in premature adrenarche.

PURPOSE/OBJECTIVE:This prospective, non-randomized phase II single-arm pilot trial aimed to explore favorable mid-treatment nodal response (FMNR) through CT imaging to guide de-escalated chemoradiation therapy (CRT) in patients with favorable risk, node-positive HPV-associated oropharyngeal cancer (OPC). MATERIALS AND METHODS/METHODS:. At week 4, CT imaging evaluated nodal response: ≥40% reduction warranted de-escalation to 60 Gy, while <40% reduction continued standard CRT. Primary endpoint was 2-year PFS from initiation of dose de-escalated CRT. Tissue tumor modified viral (TTMV) HPV DNA samples and DW-MRI were collected at baseline and week 4. MDADI questionnaires were collected at baseline, 1, 3, 6, 12, and 24 months. RESULTS:Of 39 patients, 26 had FMNR and underwent de-escalated treatment. 13 pts had slow mid-treatment nodal shrinkage and received standard dose. At a median follow-up of 47.4 months, the 2-year PFS was 92.1% (95% CI: 0.72-0.98) for the deescalated dose group and 92.3% for the standard dose patients (95% CI: 0.57-0.99), p=0.96. With a median survival follow up of 48.9 months (range: 16.7-77.8 months), there were no deaths or distant failures. FMNR was associated with rapid TTMV HPV DNA clearance, reduced TTMV HPV DNA flare, lower baseline and week 4 MRI diffusivity, and higher baseline and week 4 MRI diffusional kurtosis. No differences in acute or late maximum grade 3-4 toxicity by patient were noted. MDADI composite scores showed minimal clinical important difference (MCID) in the de-escalated group at 1-month post-treatment while the standard group had MCID up to 1-year post-treatment. No patients required feeding tube placement. CONCLUSIONS:De-escalated CRT using CT-based mid-treatment nodal response in favorable risk, node-positive HPV-associated OPC achieved excellent 2-year PFS and OS rates and represents a potential approach in better selecting patients for treatment de-escalation.

BACKGROUND:Black men are underrepresented in hypertension trials, even though this population has higher prevalence and more adverse sequelae from hypertension, compared to other groups. In this article we present recruitment and community engagement strategies for the Community-to-Clinic Linkage Implementation Program (CLIP), a cluster-randomized trial on hypertension prevention among Black men. METHODS:Using a 2-stage recruitment process: 1) we enrolled Black-owned barbershops from zip-codes with high hypertension prevalence; and 2) recruited Black male participants who fulfilled the eligibility criteria and were customers of the barbershops. Barbershop and participant recruitment was conducted by a partner community-based organization. RESULTS:The study met the recruitment goals for barbershop enrollment (N=22) and individual participants. Of eligible individuals (N=461), 430 enrolled in the study (93% consent rate, exceeding the original enrollment goal of N=420 participants). Throughout recruitment, the study team conducted 101 unique engagements (41 prior to recruitment, 60 during recruitment), totaling engagement with180 partners across all events, including individual and group meetings, attendance at community events, and educational presentations. In addition to a primary partner community organization, the study team collaborated with a Community Advisory Council, comprised of residents, and civic and community leaders, and with the local health department and varied other organizations. CONCLUSIONS:In CLIP, a high number of academic-community engagement encounters and close collaboration with community partners contributed to successful recruitment of Black men at risk for hypertension and with adverse social determinants. Our experience may serve as to inform investigators focused on recruiting underserved populations in hypertension research trials.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

BACKGROUND:Meningiomas represent the most common primary intracranial tumors in adults, with WHO grade 1 typically associated with favorable outcomes following gross total resection (GTR). METHODS:This retrospective study included patients with CNS WHO grade 1 meningioma and available DNA methylation profiles (n=210). Clinical tumor characteristics and treatment course (e.g., surgical resection, extent of resection, radiotherapy) were evaluated. Integrated Scores (InS) were calculated based on methylation family using the DKFZ brain tumor classifier, CNS WHO grading, and chromosomal losses, categorized as low, intermediate, or high. Survival analyses employed Kaplan-Meier and Cox regression methods, with local progression-free survival defined as primary endpoint. RESULTS:In newly diagnosed cases, GTR was associated with a 93.0% 3-year progression-free survival (PFS), compared to 69.3% following subtotal resection (STR). Stratification by IntS showed that patients in the IntS-low group had superior outcomes: 3-y PFS of 93.4 after GTR and 77.4% after STR. In contrast, patients with IntS-intermediate/high profiles showed significantly worse outcomes, with PFS of 85.9% after GTR and 40.0% after STR. Following tumor recurrence, particularly those with IntS-intermediate/high, postoperative radiotherapy (RT) after STR may improve 3-year PFS to 88.9%, compared to much lower PFS rates in newly diagnosed cases managed without adjuvant RT after STR (3-year PFS: 40.0%). CONCLUSION/CONCLUSIONS:Our findings highlight the combined impact of both the extent of resection (EoR) and molecular risk profile on prognosis in newly diagnosed cases. While conservative management is feasible in lower-risk primary cases, recurrent or higher-risk patients may benefit from early postoperative RT.

PURPOSE/OBJECTIVE:Financial toxicity can negatively affect treatment adherence, quality of life, and survival in patients with cancer. Although screening for financial toxicity is increasingly implemented across oncology practices and cancer centers, less is known about challenges in delivering timely interventions after a positive screen. We evaluated outcomes and barriers in a systematic financial toxicity screening and referral program at a large comprehensive cancer center. METHODS:From March 2023 to December 2024, patients in breast, gynecologic, GI, and thoracic oncology clinics at Memorial Sloan Kettering Cancer Center completed an electronic survey assessing health-related social risks and the 12-item Comprehensive Score for Financial Toxicity (COST). A positive screen was defined as COST <16, unmet essential need, or new loan/borrowing for treatment. Patients screening positive and requesting assistance were referred to Patient Financial Services (PFS) for follow-up. Outcomes included proportions with documented outreach, receipt of any intervention, intervention types, and barriers. RESULTS:A total of 83,978 patients were eligible; of whom 50,949 (61%) completed screening. Of 9,724 positive screens, 8,004 (82%) requested follow-up, and 6,987 referrals were placed. PFS attempted follow-up in 3,383 patients (of the 6,987 = 48%), with documented interventions in 1,510 of 3,383 (45%). Counseling on financial resources (983/3,383 = 29%) was most common, followed by insurance-related counseling (402/3,383 = 12%) and formal program referrals (823/3,383 = 24%). Among patients referred to assistance programs, this was most often to the institutional Financial Assistance Program (438/796 = 55%) or social work (318/796 = 40%). The most frequent barrier was the inability to contact patients (1,464/3,383 = 43%). CONCLUSION/CONCLUSIONS:Routine financial toxicity screening was implemented at scale and connected many patients to meaningful financial support. However, 81% of those who screened positive did not receive an intervention, underscoring the need for expanded infrastructure and policy reforms to address financial toxicity in cancer care.

Pathogens infecting humans continue to emerge or reemerge to cause outbreaks and widespread disease. The National Institute of Allergy and Infectious Diseases has funded Vaccine Treatment and Evaluation Units (VTEUs) for more than 50 years. VTEUs perform clinical studies to assess the safety and immunogenicity of candidate vaccines and other interventions to mitigate the impact of emerging and ongoing infectious diseases. Here, we review clinical studies conducted in the VTEUs since 2000 that have addressed emerging pathogens and other infectious agents with pandemic potential or of bioterrorism concern. The studies conducted range from phase 1 to phase 3 clinical trials, and they have included vaccines, therapeutics, and epidemiological studies. The results of the trials have guided national and often international recommendations for treatment and prevention of many of the evaluated pathogens, culminating in coronavirus disease 2019 studies that began within three months of severe acute respiratory syndrome coronavirus 2 identification. The VTEU network continues to be a critical public health resource for addressing emerging pathogens and expediting the development of safe and effective vaccines and treatments to protect at-risk populations.

PURPOSE/OBJECTIVE:The purpose of this study was to evaluate the effect that associated glenohumeral dislocations have on outcomes following surgical treatment of proximal humerus fractures. METHODS:This IRB-approved study reports on 301 patients, who underwent operative treatment for proximal humerus fractures at an academic medical center from January 2006 to January 2023. Fractures were classified according to the Neer system. Patients were separated into two cohorts based on whether a glenohumeral dislocation was present at the time of initial injury. Outcomes measured included the Disabilities of the Arm, Shoulder, and Hand (DASH) score, shoulder range of motion (forward elevation, external rotation, internal rotation), readmission rates, complications, hardware removal, and need for revision surgery. Independent samples t-tests and chi-squared analysis were used for continuous and categorical variables, respectively. A binary logistic regression was performed to analyze the influence of these factors on complication rate. RESULTS:230 patients sustained an isolated fracture (PHF) and 71 sustained a fracture-dislocation (FD). Significant differences were observed between the FD and PHF groups in all measured outcomes. The FD group had a poorer DASH score (24.38 ± 19.09 vs 10.54 ± 13.67; P < 0.001) and reduced range of shoulder motion in forward elevation (114° ± 40° vs 162° ± 19°; P < 0.001), external rotation (40° ± 19° vs 66° ± 19°; P < 0.001), and internal rotation (57° ± 26° vs 82° ± 21°; P < 0.001). Readmission rates were higher in the FD group (0.28 ± 0.85 vs 0.05 ± 0.28; P < 0.001). The FD cohort also had a higher rate of complications (25.35% vs 6.52%; P < 0.001), need for removal of hardware (14.08% vs 3.04%; P = 0.002), and overall revision surgery (11.27% vs 1.30%; P < 0.001). The FD cohort demonstrated a greater incidence of AVN (12.68% vs 4.35%; P = 0.012). No significant difference was observed regarding rates of fracture healing and recurrent dislocation. Multivariate analysis in the form of binary logistic regression indicated that fracture-dislocation significantly increased the complication risk (OR = 3.310, 95% CI = 1.42-7.70; P = 0.005). CONCLUSION/CONCLUSIONS:Proximal humerus fracture-dislocations are associated with worse functional outcomes and higher complication rates compared to those without dislocations. These findings highlight the potential need for specialized treatment strategies to mitigate the impact of dislocation on recovery.