Medical Specialties Commons^™

Characterization Of Driver Mutations Identifies Gene Signatures Predictive Of Prognosis And Treatment Sensitivity In Multiple Myeloma, Jian-Rong Li, Abinand Krishna Parthasarathy, Aravind Singaram Kannappan, Shahram Arsang-Jang, Jing Dong, Chao Cheng

Faculty, Staff and Students Publications

In multiple myeloma (MM), while frequent mutations in driver genes are crucial for disease progression, they traditionally offer limited insights into patient prognosis. This study aims to enhance prognostic understanding in MM by analyzing pathway dysregulations in key cancer driver genes, thereby identifying actionable gene signatures. We conducted a detailed quantification of mutations and pathway dysregulations in 10 frequently mutated cancer driver genes in MM to characterize their comprehensive mutational impacts on the whole transcriptome. This was followed by a systematic survival analysis to identify significant gene signatures with enhanced prognostic value. Our systematic analysis highlighted 2 significant signatures, TP53 …

Differences In Brain Volume In Military Service Members And Veterans After Blast-Related Mild Tbi: A Limbic-Cenc Study, Emily L Dennis, Jared A Rowland, Carrie Esopenko, Nicholas J Tustison, Mary R Newsome, Elizabeth S Hovenden, Brian B Avants, Jessica Gill, Sidney R Hinds, Kimbra Kenney, Hannah M Lindsey, Sarah L Martindale, Mary Jo Pugh, Randall S Scheibel, Pashtun-Poh Shahim, Robert Shih, James R Stone, Maya Troyanskaya, William C Walker, Kent Werner, Gerald E York, David X Cifu, David F Tate, Elisabeth A Wilde

Faculty, Staff and Students Publications

Importance: Blast-related mild traumatic brain injuries (TBIs), the "signature injury" of post-9/11 conflicts, are associated with clinically relevant, long-term cognitive, psychological, and behavioral dysfunction and disability; however, the underlying neural mechanisms remain unclear.

Objective: To investigate associations between a history of remote blast-related mild TBI and regional brain volume in a sample of US veterans and active duty service members.

Design, setting, and participants: Prospective cohort study of US veterans and active duty service members from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC), which enrolled more than 1500 participants at 5 sites used in …

The Utilization Of Echocardiography In Children With Staphylococcus Aureus Bacteremia, Richard Bui, Lauren M Sommer, Meghan Walther, Kristina G Hulten, Jesus G Vallejo, Sheldon L Kaplan, J Chase Mcneil

Faculty, Staff and Students Publications

The need for echocardiography in pediatric Staphylococcus aureus bacteremia (SAB) remains uncertain. We reviewed 331 pediatric SAB cases. Nine subjects, all with comorbidities, met the echocardiogram criteria for infective endocarditis (IE). IE was associated with congenital heart disease and prolonged bacteremia, suggesting that echocardiography is unnecessary in most children with SAB.

Nerve Injury Inhibits Oprd1 And Cnr1 Transcription Through Rest In Primary Sensory Neurons, Ashok Subedi, Asieh Etemad, Aadhya Tiwari, Yuying Huang, Biji Chatterjee, Samantha M Mcleod, Yungang Lu, Diangelo Gonzalez, Krishna Ghosh, Mario Sirito, Sanjay K Singh, Elisa Ruiz, Sandra L Grimm, Cristian Coarfa, Hui-Lin Pan, Sadhan Majumder

Faculty, Staff and Students Publications

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of four opioid receptor genes (Oprm1, Oprd1, Oprl1 and Oprk1) and the cannabinoid CB1 receptor (Cnr1) gene in the DRG regulate nociception. In this study, we determined the role of REST in controlling their expression in the DRG induced by spared nerve injury (SNI). SNI induced chronic pain hypersensitivity in wild-type mice and was accompanied by increased levels of Rest transcript and …

Transport Of Β-Amyloid From Brain To Eye Causes Retinal Degeneration In Alzheimer’S Disease, Qiuchen Cao, Shige Yang, Xiaowei Wang, Huaiqing Sun, Weijie Chen, Yuliang Wang, Junying Gao, Yanchi Wu, Qiuhua Yang, Xue Chen, Songtao Yuan, Ming Xiao, Maiken Nedergaard, Yuqing Huo, Qinghuai Liu

Faculty, Staff and Students Publications

The eye is closely connected to the brain, providing a unique window to detect pathological changes in the brain. In this study, we discovered β-amyloid (Aβ) deposits along the ocular glymphatic system in patients with Alzheimer's disease (AD) and 5×FAD transgenic mouse model. Interestingly, Aβ from the brain can flow into the eyes along the optic nerve through cerebrospinal fluid (CSF), causing retinal degeneration. Aβ is mainly observed in the optic nerve sheath, the neural axon, and the perivascular space, which might represent the critical steps of the Aβ transportation from the brain to the eyes. Aquaporin-4 facilitates the influx …

Data-Driven Cutoff Selection For The Patient Health Questionnaire-9 Depression Screening Tool, Brooke Levis, Parash Mani Bhandari, Dipika Neupane, Suiqiong Fan, Ying Sun, Chen He, Yin Wu, Ankur Krishnan, Zelalem Negeri, Mahrukh Imran, Danielle B Rice, Kira E Riehm, Marleine Azar, Alexander W Levis, Jill Boruff, Pim Cuijpers, Simon Gilbody, John P A Ioannidis, Lorie A Kloda, Scott B Patten, Roy C Ziegelstein, Daphna Harel, Yemisi Takwoingi, Sarah Markham, Sultan H Alamri, Dagmar Amtmann, Bruce Arroll, Liat Ayalon, Hamid R Baradaran, Anna Beraldi, Charles N Bernstein, Arvin Bhana, Charles H Bombardier, Ryna Imma Buji, Peter Butterworth, Gregory Carter, Marcos H Chagas, Juliana C N Chan, Lai Fong Chan, Dixon Chibanda, Kerrie Clover, Aaron Conway, Yeates Conwell, Federico M Daray, Janneke M De Man-Van Ginkel, Jesse R Fann, Felix H Fischer, Sally Field, Jane R W Fisher, Daniel S S Fung, Bizu Gelaye, Leila Gholizadeh, Felicity Goodyear-Smith, Eric P Green, Catherine G Greeno, Brian J Hall, Liisa Hantsoo, Martin Härter, Leanne Hides, Stevan E Hobfoll, Simone Honikman, Thomas Hyphantis, Masatoshi Inagaki, Maria Iglesias-Gonzalez, Hong Jin Jeon, Nathalie Jetté, Mohammad E Khamseh, Kim M Kiely, Brandon A Kohrt, Yunxin Kwan, Maria Asunción Lara, Holly F Levin-Aspenson, Shen-Ing Liu, Manote Lotrakul, Sonia R Loureiro, Bernd Löwe, Nagendra P Luitel, Crick Lund, Ruth Ann Marrie, Laura Marsh, Brian P Marx, Anthony Mcguire, Sherina Mohd Sidik, Tiago N Munhoz, Kumiko Muramatsu, Juliet E M Nakku, Laura Navarrete, Flávia L Osório, Brian W Pence, Philippe Persoons, Inge Petersen, Angelo Picardi, Stephanie L Pugh, Terence J Quinn, Elmars Rancans, Sujit D Rathod, Katrin Reuter, Alasdair G Rooney, Iná S Santos, Miranda T Schram, Juwita Shaaban, Eileen H Shinn, Abbey Sidebottom, Adam Simning, Lena Spangenberg, Lesley Stafford, Sharon C Sung, Keiko Suzuki, Pei Lin Lynnette Tan, Martin Taylor-Rowan, Thach D Tran, Alyna Turner, Christina M Van Der Feltz-Cornelis, Thandi Van Heyningen, Paul A Vöhringer, Lynne I Wagner, Jian Li Wang, David Watson, Jennifer White, Mary A Whooley, Kirsty Winkley, Karen Wynter, Mitsuhiko Yamada, Qing Zhi Zeng, Yuying Zhang, Brett D Thombs, Andrea Benedetti, Depression Screening Data (Depressd) Phq Group

Faculty, Staff and Students Publications

IMPORTANCE: Test accuracy studies often use small datasets to simultaneously select an optimal cutoff score that maximizes test accuracy and generate accuracy estimates.

OBJECTIVE: To evaluate the degree to which using data-driven methods to simultaneously select an optimal Patient Health Questionnaire-9 (PHQ-9) cutoff score and estimate accuracy yields (1) optimal cutoff scores that differ from the population-level optimal cutoff score and (2) biased accuracy estimates.

DESIGN, SETTING, AND PARTICIPANTS: This study used cross-sectional data from an existing individual participant data meta-analysis (IPDMA) database on PHQ-9 screening accuracy to represent a hypothetical population. Studies in the IPDMA database compared participant PHQ-9 …

Post-Artesunate Delayed Hemolysis In Pediatric Malaria Patients In The United States, Sesh A Sundararaman, Karen L Hanze Villavicencio, Brianne Roper, Ziyi Wang, Amy K F Davis, Jonathan A Mayhew, Michelle L Wang, Nina L Tang, Vijaya L Soma, Gail F Shust, Margaret E Feeney, Indi Trehan, Jill E Weatherhead, Chandy C John, Jeffrey S Gerber, Audrey R Odom John

Faculty, Staff and Students Publications

Post-artesunate delayed hemolysis (PADH) occurred in 6 of 24 children treated with artesunate for severe malaria in the United States; however, severe hemolysis requiring hospitalization or transfusion was rare. In children in the United States treated with artesunate, counseling, and symptom monitoring may be preferred to weekly laboratory surveillance for PADH.

Protein Consumption And Risk Of Cvd Among Us Adults: The Multi-Ethnic Study Of Atherosclerosis (Mesa), Ji Yun Tark, Ruosha Li, Bing Yu, Alexis C Wood, Nikhil S Padhye, Marcia C De Oliveira Otto

Faculty, Staff and Students Publications

BACKGROUND: Although some randomized trials have reported beneficial effects of protein intake on cardiometabolic risk factors, evidence from prospective studies have not supported a strong link between protein intake and cardiovascular disease (CVD) risk. It is also unclear whether diversity in protein intake plays a role in CVD risk.

OBJECTIVE: We investigated prospective associations of (1) protein intake, overall and by food source and (2) diversity of protein sources with risk of CVD, coronary heart disease (CHD), and stroke.

METHODS: In a multi-ethnic cohort of 5879 U.S. adults (45-84 years), who were free of CVD at baseline, protein intake was …

Act With Cf: A Randomized Trial Of Acceptance And Commitment Therapy Vs Supportive Psychotherapy For Adults With Cystic Fibrosis, C. Virginia O'Hayer, Patrick J. Smith, Christopher F. Drescher, Heather Bruschwein, Chelsi N. Nurse, Hallie M. Kushner, Krista Ingle, Michael J. Stephen, Jeffrey B. Hoag

Department of Psychiatry and Human Behavior Faculty Papers

PURPOSE: Psychological distress, including anxiety and depression, is common among adults with CF, associating with poor quality of life, lung function, and healthcare utilization. This 3-year, multi-site, telehealth-delivered randomized trial sought to determine whether Acceptance and Commitment Therapy (ACT with CF) is superior to supportive psychotherapy (SP), in improving psychological functioning for adults with CF.

METHODS: One hundred twenty-four adults with CF and elevated anxiety and/or depressive symptoms were recruited coincident with the first COVID lockdown, from Thomas Jefferson University Hospitals, University of Virginia, Augusta University, Duke University Medical Center, and social media. Participants were randomized to 6 weeks of …

Roflumilast Cream, 015%, For Atopic Dermatitis In Adults And Children: Integument-1 And Integument-2 Randomized Clinical Trials, Eric L Simpson, Lawrence F Eichenfield, Javier Alonso-Llamazares, Zoe D Draelos, Laura K Ferris, Seth B Forman, Melinda Gooderham, Mercedes E Gonzalez, Adelaide A Hebert, Leon H Kircik, Mark Lomaga, Angela Moore, Kim A Papp, Vimal H Prajapati, Diane Hanna, Scott Snyder, David Krupa, Patrick Burnett, Erin Almaraz, Robert C Higham, David H Chu, David R Berk

Faculty, Staff and Student Publications

Importance: Safe, effective, and well-tolerated topical treatment options available for long-term use in patients with atopic dermatitis (AD) are limited and associated with low adherence rates.

Objective: To evaluate efficacy and safety of once-daily roflumilast cream, 0.15%, vs vehicle cream in patients with AD.

Design, setting, and participants: Two phase 3, randomized, double-blind, vehicle-controlled trials (Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis 1 and 2 [INTEGUMENT-1 and INTEGUMENT-2]), included patients from sites in the US, Canada, and Poland. Participants were 6 years or older with mild to moderate AD based on Validated Global Assessment for Atopic …

Vagus Nerve Stimulation Recruits The Central Cholinergic System To Enhance Perceptual Learning, Kathleen A Martin, Eleni S Papadoyannis, Jennifer K Schiavo, Saba Shokat Fadaei, Habon A Issa, Soomin C Song, Sofia Orrey Valencia, Nesibe Z Temiz, Matthew J Mcginley, David A Mccormick, Robert C Froemke

Duncan NRI Faculty and Staff Publications

Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically …

Mean Arterial Pressure (Map) Augmentation In Traumatic Spinal Cord Injuries: Early Hyperperfusion Treatment Influences Neurologic Outcomes., Aimee K Lariccia, Kimberly Sperwer, Michael L Lieber, M Chance Spalding

Trauma and Acute Care Articles

Context: Hyperperfusion therapy, mean arterial blood pressure (MAP) > 85 mmHg, is a recommended treatment of blunt traumatic spinal cord injury (SCI). We hypothesized the first 24 h of MAP augmentation would be most influential on neurological outcomes.Design: This retrospective study from a level 1 urban trauma center dating 1/2017 to 12/2019 included all blunt traumatic spinal cord injured patients receiving hyperperfusion therapy. Patients were grouped as "No improvement" vs "Improvement" measured by change in American Spinal Injury Association (ASIA) score during their hospitalization. MAP values for the first 12, first 24 and last 72 h were compared between the …

Systemic Effects Of Anti-Vegf Intravitreal Injection In Patients With Age-Related Macular Degeneration: A Multi-Institutional Real-World Study, Tzu-Yi Lin, Yi-Ting Hsieh, Sunir J. Garg, Lee-Jen Chen, Kuan-Jen Chen, Wei-Chi Wu, Chi-Chun Lai, Yih-Shiou Hwang, Eugene Yu-Chuan Kang

Wills Eye Hospital Papers

PURPOSE: In individuals aged >50 years, age-related macular degeneration (AMD) is the leading cause of irreversible blindness. Intravitreal injections of antivascular endothelial growth factor (VEGF) agents (bevacizumab, ranibizumab, and aflibercept) show good efficacy and similar incidences of systemic adverse events (SAEs). However, comparative studies between agents are limited. Our study aimed to compare the real-world SAE risks of bevacizumab, ranibizumab, and aflibercept users.

METHODS: This retrospective cohort study identified new bevacizumab, ranibizumab, and aflibercept users in a multi-institutional database in Taiwan between 2014 and 2019. Inverse probability of treatment weights (IPTW) with propensity scores was conducted to achieve homogeneity among …

Outcomes And Genetic Dynamics Of Acute Myeloid Leukemia At First Relapse, Alex Bataller, Hagop Kantarjian, Alexandre Bazinet, Tapan Kadia, Naval Daver, Courtney D Dinardo, Gautam Borthakur, Sanam Loghavi, Keyur Patel, Guilin Tang, Koji Sasaki, Nicholas J Short, Musa Yilmaz, Ghayas C Issa, Yesid Alvarado, Guillermo Montalban-Bravo, Abhishek Maiti, Hussein A Abbas, Koichi Takahashi, Sherry Pierce, Elias Jabbour, Guillermo Garcia-Manero, Farhad Ravandi

Faculty, Staff and Student Publications

Patients with relapsed acute myeloid leukemia (AML) experience dismal outcomes. We performed a comprehensive analysis of patients with relapsed AML to determine the genetic dynamics and factors predicting survival. We analyzed 875 patients with newly diagnosed AML who received intensive treatment or low-intensity treatment. Of these patients, 197 subsequently relapsed. Data were available for 164 of these patients, with a median time from complete remission/complete remission with incomplete blood count recovery to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation. At relapse, mutations in genes involved in pathway signaling tended …

Fetal Sex Effects On Maternal Health Can Now Be Tested Via Randomization: A First-In-Class Illustration In Cows On Glucoregulatory Outcomes, Aridany Suarez-Trujillo, Colby J Vorland, Griffin T Nicholls, Daniella E Chusyd, Chelsie Parker, Lilian Golzarri-Arroyo, Sophia Swann, Bethany J Funnell, Kara R Stewart, David B Allison

Children’s Nutrition Research Center Staff Publications

Background: The maternal-offspring relationship, such as whether fetal sex influences maternal health, is essential to explore to advance prenatal and maternal health. While associations exist between fetal sex and maternal health outcomes, it is unclear whether these reflect a causal relationship.

Objective: To demonstrate that fetal sex can be randomly assigned to test the causal effect of fetal sex on maternal outcomes.

Methods: Holstein dairy cows were stratified and randomized using sealed opaque envelopes to be artificially inseminated with either X- or Y-sorted bull semen until 40 cows became pregnant. Monthly body weight measurements were recorded, and an intravenous glucose …

First Interim Results From Fine-Real: A Prospective, Non-Interventional, Phase 4 Study Providing Insights Into The Use And Safety Of Finerenone In A Routine Clinical Settingfirst Interim Results From Fine-Real: A Prospective, Non-Interventional, Phase 4 Study Providing Insights Into The Use And Safety Of Finerenone In A Routine Clinical Setting, Susanne B Nicholas, Ricardo Correa-Rotter, Nihar R Desai, Lixin Guo, Sankar D Navaneethan, Kevin M Pantalone, Christoph Wanner, Stefanie Hamacher, Samuel T Fatoba, Andrea Horvat-Broecker, Antonio Garreta-Rufas, Alain Gay, Martin Merz, David C Wheeler

Center for Medical Ethics and Health Policy Staff Publications

Background: Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). The FINE-REAL study (NCT05348733) aims to evaluate the characteristics and treatment patterns of participants treated with finerenone in clinical practice.

Methods: FINE-REAL is a prospective, single-arm, non-interventional study of patients initiated on finerenone as part of their routine care in accordance with country-approved labels. The study, initiated in June 2022, is expected to be completed by January 2028. The cutoff for this pre-specified interim analysis was June 13, 2023.

Results: Participants were …

Trends In The Use Of Biologic Disease-Modifying Antirheumatic Drugs In Patients With Rheumatoid Arthritis And Recently Diagnosed Colorectal, Lung, Or Prostate Cancer, Maria E Suarez-Almazor, Juan I Ruiz, Xiudong Lei, Chi-Fang Wu, Hui Zhao, Suja S Rajan, Sharon H Giordano

Faculty, Staff and Student Publications

INTRODUCTION: Biologic disease-modifying antirheumatic drugs (bDMARD) are often discontinued when a patient with rheumatoid arthritis (RA) is diagnosed with cancer. Our aim was to determine trends in bDMARD utilization in patients with RA and recently diagnosed cancer.

METHOD: We examined two national claims databases to identify adults with RA and recently diagnosed colorectal, lung, or prostate cancer (Optum's de-identified Clinformatics® Data Mart Database 2008-2022, and Surveillance, Epidemiology, and End Results Program (SEER) Medicare-linked 2008-2017). We determined time trends in bDMARD and tumor necrosis factor inhibitor (TNFi) prescriptions during the first 3 years after cancer with Cochram-Armitage tests and multivariable logistic …

Association Between Risk Of Alzheimer’S Disease And Related Dementias And Angiotensin Receptor Ⅱ Blockers Treatment For Individuals With Hypertension In High-Volume Claims Data, Sori Kim Lundin, Xinyue Hu, Jingna Feng, Karl Kristian Lundin, Lu Li, Yong Chen, Paul Ernest Schulz, Cui Tao

Faculty, Staff and Student Publications

Background: Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive.

Methods: Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses.

Findings: From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM …

History Of Incarceration And Dental Care Use Among Older Adults In The United States, Alexander Testa, Dylan B Jackson, Carmen Gutierrez, Chantal Fahmy, Vahed Maroufy, Rafael Samper-Ternent, Ana C Neumann

Faculty, Staff and Student Publications

INTRODUCTION: Dental care is a critical component of healthy aging; however, emerging evidence suggests that having been previously incarcerated is a risk factor for not using dental care services. This study investigates the relationship between prior incarceration and dental care among older adults and assesses whether wealth and dental insurance explain this relationship.

METHODS: Data are from the Health and Retirement Study, a nationally representative sample of community-dwelling older adults in the United States, collected in 2012 and 2014. Multivariable logistic regression is used to assess the relationship between a history of incarceration and dental care. Mediation analyses were conducted …

Incorporating External Controls In The Design Of Randomized Clinical Trials: A Case Study In Solid Tumors, Emily M Damone, Jiawen Zhu, Herbert Pang, Xiao Li, Yinqi Zhao, Evan Kwiatkowski, Lisa A Carey, Joseph G Ibrahim

Faculty, Staff and Student Publications

BACKGROUND: The use of historical external control data in clinical trials has grown in interest and needs when considering the design of future trials. Hybrid control designs can be more efficient to achieve the same power with fewer patients and limited resources. The literature is sparse on appropriate statistical methods which can account for the differences between historical external controls and the control patients in a study. In this article, we illustrate the analysis framework of a clinical trial if a hybrid control design was used after determining an RCT may not be feasible.

METHODS: We utilize two previously completed …

A Novel Statistical Framework For Meta-Analysis Of Total Mediation Effect With High-Dimensional Omics Mediators In Large-Scale Genomic Consortia, Zhichao Xu, Peng Wei

Faculty, Staff and Student Publications

Meta-analysis is used to aggregate the effects of interest across multiple studies, while its methodology is largely underexplored in mediation analysis, particularly in estimating the total mediation effect of high-dimensional omics mediators. Large-scale genomic consortia, such as the Trans-Omics for Precision Medicine (TOPMed) program, comprise multiple cohorts with diverse technologies to elucidate the genetic architecture and biological mechanisms underlying complex human traits and diseases. Leveraging the recent established asymptotic standard error of the R-squared (R2)-based mediation effect estimation for high-dimensional omics mediators, we have developed a novel meta-analysis framework requiring only summary statistics and allowing inter-study heterogeneity. Whereas the proposed …

A Phase I Dose Escalation Study Of The Lrp5 Antagonist Bi 905681 In Patients With Advanced And Metastatic Solid Tumors, D. R. Spigel, J. S. Wang, L. Pronk, B. Muskens, M. Teufel, Babar Bashir, H. Burris

Department of Medical Oncology Faculty Papers

BACKGROUND: The Wnt pathway is involved in proliferation and tissue homeostasis. Aberrant activation promotes cancer cell proliferation and survival. Inhibition of the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) coreceptors that regulate Wnt signaling could prevent cancer cell proliferation. BI 905681 is a novel LRP5 antagonist that has demonstrated potent in vivo antitumor activity.

PATIENTS AND METHODS: This was a phase I, dose escalation study (NCT04147247) evaluating BI 905681 in patients with advanced solid tumors over two dosing schedules (schedule A: every 3 weeks, 3-week cycles and schedule B: every 2 weeks, 4-week cycles). The primary endpoint was the maximum tolerated …

Impact Of Racial, Ethnic, And Socioeconomic Disparities On Presentation And Survival Of Hcc: A Multicenter Study, Nicole E Rich, Patricia D Jones, Hong Zhu, Tanushree Prasad, Amy Hughes, Sandi Pruitt, Caitlin C Murphy, Karim Seif-El-Dahan, Darine Daher, Gloria Figueroa, Stephanie Castaneda, Lisa Quirk, Michael Gonzales, Osiris Carranza, Samantha Bourque, Nargis Baset, Adam C Yopp, Amit G Singal

Faculty, Staff and Student Publications

BACKGROUND: Racial and ethnic disparities have been reported for HCC prognosis, although few studies fully account for clinically important factors and social determinants of health, including neighborhood socioeconomic status.

METHODS: We conducted a retrospective multicenter cohort study of patients newly diagnosed with HCC from January 2010 through August 2018 at 4 large health systems in the United States. We used multivariable logistic regression and cause-specific Cox proportional hazard models to identify factors associated with early-stage HCC presentation and overall survival.

RESULTS: Of 2263 patients with HCC (37.6% non-Hispanic White, 23.5% non-Hispanic Black, 32.6% Hispanic, and 6.4% Asian/other), 42.0% of patients …

Seasons Of Kawasaki Disease During The Covid-19 Pandemic., Todd T. Nowlen, Ashraf S. Harahsheh, Geetha Raghuveer, Simon Lee, Anji T. Yetman, Nagib Dahdah, Michael A. Portman, Supriya S. Jain, Michael Khoury, Selemet Tierney, Cedric Manlhiot, Pedrom Farid, Brian W. Mccrindle

Manuscripts, Articles, Book Chapters and Other Papers

The incidence of Kawasaki Disease has a peak in the winter months with a trough in late summer/early fall. Environmental/exposure factors have been associated with a time-varying incidence. These factors were altered during the COVID-19 pandemic. The study was performed through the International Kawasaki Disease Registry. Data from patients diagnosed with acute Kawasaki Disease and Multiple Inflammatory Syndrome-Children were obtained. Guideline case definitions were used to confirm site diagnosis. Enrollment was from 1/2020 to 7/2023. The number of patients was plotted over time. The patients/month were tabulated for the anticipated peak Kawasaki Disease season (December-April) and non-peak season (May-November). Data …

A Site-Wise Reliability Analysis Of The Abcd Diffusion Fractional Anisotropy And Cortical Thickness: Impact Of Scanner Platforms, Yezhi Pan, L Elliot Hong, Ashley Acheson, Paul M Thompson, Neda Jahanshad, Alyssa H Zhu, Jiaao Yu, Chixiang Chen, Tianzhou Ma, Ho-Ling Liu, Jelle Veraart, Els Fieremans, Nicole R Karcher, Peter Kochunov, Shuo Chen

Faculty, Staff and Student Publications

The Adolescent Brain and Cognitive Development (ABCD) project is the largest study of adolescent brain development. ABCD longitudinally tracks 11,868 participants aged 9-10 years from 21 sites using standardized protocols for multi-site MRI data collection and analysis. While the multi-site and multi-scanner study design enhances the robustness and generalizability of analysis results, it may also introduce nonbiological variances including scanner-related variations, subject motion, and deviations from protocols. ABCD imaging data were collected biennially within a period of ongoing maturation in cortical thickness and integrity of cerebral white matter. These changes can bias the classical test-retest methodologies, such as intraclass correlation …

A Rigorous Multi-Laboratory Study Of Known Pdac Biomarkers Identifies Increased Sensitivity And Specificity Over Ca19-9 Alone, Brian Haab, Lu Qian, Ben Staal, Maneesh Jain, Johannes Fahrmann, Christine Worthington, Denise Prosser, Liudmila Velokokhatnaya, Camden Lopez, Runlong Tang, Mark W Hurd, Gopalakrishnan Natarajan, Sushil Kumar, Lynette Smith, Sam Hanash, Surinder K Batra, Anirban Maitra, Anna Lokshin, Ying Huang, Randall E Brand

Faculty, Staff and Student Publications

A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the …

Epigenomic And Transcriptomic Profiling Of Solitary Fibrous Tumors Identifies Site-Specific Patterns And Candidate Genes Regulated By Dna Methylation, Hannah C Beird, Jeffrey M Cloutier, Nalan Gokgoz, Christopher Eeles, Anthony M Griffin, Davis R Ingram, Khalida M Wani, Rossana Lazcano Segura, Luca Cohen, Carl Ho, Jay S Wunder, Irene L Andrulis, P Andrew Futreal, Benjamin Haibe-Kains, Alexander J Lazar, Wei-Lien Wang, Joanna Przybyl, Elizabeth G Demicco

Faculty, Staff and Student Publications

A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and …

Intra-Tumoral And Peripheral Blood Tigit And Pd-1 As Immune Biomarkers In Nodular Lymphocyte Predominant Hodgkin Lymphoma, Jay Gunawardana, Soi C Law, Muhammed B Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I Leahy, Paul G Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N Lee, Emily Jude, Eliza A Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W D Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R Green, Francisco Vega, Maher K Gandhi

Faculty, Staff and Student Publications

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or …

Building Resilience: A Specialty Clinic Tailored To Older Adults At Risk For Violence And Abuse, Melba A Hernandez-Tejada, Deborah M Little, Madeline J Bruce, Sarly Butte, Jason Burnett, Leila Wood, Ron Acierno

Faculty, Staff and Student Publications

Objective: Both structural (e.g., ageism) and personal (e.g., stigma) barriers hinder older adults' access to and engagement with mental health care. These barriers are particularly problematic for those vulnerable to interpersonal violence and abuse (e.g., due to social isolation). This study presents a quality improvement program aimed at older adults who have experienced significant stressful events, particularly elder mistreatment, within a larger trauma specialty clinic. Leveraging home-based telemedicine, the clinic provides evidence-based psychotherapy tailored to the needs of older adults.

Methods: From 2021 through 2023, the authors retrospectively examined treatment initiation, engagement, completion, and clinical outcomes among 231 older adults …

Genomic Alterations In Dna Mismatch Repair Genes Across Different Cancer Types, Vijaykumar R Holla, Michael P Kahle, Sun-Hee Kim, Arash Ronaghy, Richard K Yang, Keyur P Patel, Mark J Routbort, Michael J Overman, Ecaterina E Dumbrava, Kenna R Mills Shaw, Daniel D Karp, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Purpose: PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

Methods: From January 2016 to December 2021, 15,701 …