Digital Commons Network^™

Sars-Cov-2 Viral Load In The Nasopharynx At Time Of First Infection Among Unvaccinated Individuals, Leigh H Fisher, Jia Jin Kee, Albert Liu, Claudia M Espinosa, April K Randhawa, James Ludwig, Craig A Magaret, Samuel T Robinson, Peter B Gilbert, Ollivier Hyrien, James G Kublin, Nadine Rouphael, Ann R Falsey, Magdalena E Sobieszczyk, Hana M El Sahly, Beatriz Grinsztejn, Glenda E Gray, Karen L Kotloff, Cynthia L Gay, Brett Leav, Ian Hirsch, Frank Struyf, Lisa M Dunkle, Kathleen M Neuzil, Lawrence Corey, Yunda Huang, Paul A Goepfert, Stephen R Walsh, Lindsey R Baden, Holly Janes, Covid-19 Prevention Network (Covpn)

Faculty, Staff and Student Publications

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity.

Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease.

Design, setting, and participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline …

Synthetic Cationic Helical Polypeptides For The Stimulation Of Antitumour Innate Immune Pathways In Antigen-Presenting Cells, Daeyong Lee, Kristin Huntoon, Yifan Wang, Minjeong Kang, Yifei Lu, Seong Dong Jeong, Todd M Link, Thomas D Gallup, Yaqing Qie, Xuefeng Li, Shiyan Dong, Benjamin R Schrank, Adam J Grippin, Abin Antony, Jonghoon Ha, Mengyu Chang, Yi An, Liang Wang, Dadi Jiang, Jing Li, Albert C Koong, John A Tainer, Wen Jiang, Betty Y S Kim

Faculty, Staff and Student Publications

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) …

Revisiting Feeding Tube Utilization In Oropharynx Cancer: 6-Year Prospective Registry Analysis, Brady J Anderson, Amy C Moreno, Yun Qing, J Jack Lee, Faye M Johnson, Miriam N Lango, Carly E A Barbon, Lavanya Tripuraneni, Ariana Sahli, Vicki Piper, Neil Gross, Clifton D Fuller, Stephen Y Lai, Jeffrey N Myers, Katherine A Hutcheson

Faculty, Staff and Student Publications

OBJECTIVE: Patients treated for oropharyngeal cancer (OPC) have historically demonstrated high feeding tube rates for decreased oral intake and malnutrition. We re-examined feeding tube practices in these patients.

STUDY DESIGN: Retrospective analysis of prospective cohort from 2015 to 2021.

SETTING: Single-institution NCI-Designated Comprehensive Cancer Center.

METHODS: With IRB approval, patients with new oropharyngeal squamous cell cancer or (unknown primary with neck metastasis) were enrolled. Baseline swallowing was assessed via videofluoroscopy and Performance Status Scale for Head and Neck Cancer (PSSHN). G-tubes or nasogastric tubes (NGT) were placed for weight loss before, during, or after treatment. Prophylactic NGT were placed during …

Clinical And Prognostic Differences In Oropharyngeal Squamous Cell Carcinoma In Usa And Denmark, Two Hpv High-Prevalence Areas, Amanda-Louise Fenger Carlander, Simone Kloch Bendtsen, Jacob H Rasmussen, Kathrine Kronberg Jakobsen, Martin Garset-Zamani, Christian Grønhøj, Jeppe Friborg, Katherine Hutcheson, Faye M Johnson, Clifton D Fuller, Amy C Moreno, Toyin Babarinde, Neil D Gross, Jeffrey N Myers, Christian Von Buchwald

Faculty, Staff and Student Publications

BACKGROUND: Uncertainty persists regarding clinical and treatment variations crucial to consider when comparing high human papillomavirus (HPV)-prevalence oropharyngeal squamous cell carcinoma (OPSCC) cohorts for accurate patient stratification and replicability of clinical trials across different geographical areas.

METHODS: OPSCC patients were included from The University of Texas MD Anderson Cancer Center (UTMDACC), USA and from The University Hospital of Copenhagen, Denmark from 2015-2020, (n = 2484). Outcomes were 3-year overall survival (OS) and recurrence-free interval (RFI). Subgroup analyses were made for low-risk OPSCC patients (T1-2N0M0) and high-risk patients (UICC8 III-IV).

RESULTS: There were significantly more HPV-positive (88.2 % vs. 63.1 %), …

High-Grade Pleomorphic Sarcomas Treated With Immune Checkpoint Blockade: The Md Anderson Cancer Center Experience, Lewis F Nasr, Marianne Zoghbi, Rossana Lazcano, Michael Nakazawa, Andrew J Bishop, Ahsan Farooqi, Devarati Mitra, Beverly Ashleigh Guadagnolo, Robert Benjamin, Shreyaskumar Patel, Vinod Ravi, Dejka M Araujo, Andrew Livingston, Maria A Zarzour, Anthony P Conley, Ravin Ratan, Neeta Somaiah, Alexander J Lazar, Christina Roland, Emily Z Keung, Elise F Nassif Haddad

Faculty, Staff and Student Publications

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available.

PURPOSE: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution.

METHODS: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in …

Coronary Stenosis And Cardiogenic Shock Secondary To Aortitis Following Aortic Root Support Procedure, Alexander Carpenter, Stephanie Connaire, Nitin Chandra Mohan, Stephanie L Curtis, Serban C Stoica, Massimo Caputo, Julian W Strange

Faculty, Staff and Student Publications

A woman with recent personalized external aortic root support implant presented in cardiogenic shock with bilateral coronary ostial occlusion and aortic inflammation requiring emergency coronary angioplasty. Subsequent computed tomography with positron emission tomography scanning demonstrated aortitis with extensive inflammation adjacent to the personalized external aortic root support mesh, the first report of this important complication.

De Novo Detection Of Somatic Mutations In High-Throughput Single-Cell Profiling Data Sets, Francesc Muyas, Carolin M Sauer, Jose Espejo Valle-Inclán, Ruoyan Li, Raheleh Rahbari, Thomas J Mitchell, Sahand Hormoz, Isidro Cortés-Ciriano

Faculty, Staff and Student Publications

Characterization of somatic mutations at single-cell resolution is essential to study cancer evolution, clonal mosaicism and cell plasticity. Here, we describe SComatic, an algorithm designed for the detection of somatic mutations in single-cell transcriptomic and ATAC-seq (assay for transposase-accessible chromatin sequence) data sets directly without requiring matched bulk or single-cell DNA sequencing data. SComatic distinguishes somatic mutations from polymorphisms, RNA-editing events and artefacts using filters and statistical tests parameterized on non-neoplastic samples. Using >2.6 million single cells from 688 single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) data sets spanning cancer and non-neoplastic samples, we show that SComatic detects mutations in …

Cross-Vendor Multiparametric Mapping Of The Human Brain Using 3d-Qalas: A Multicenter And Multivendor Study, Shohei Fujita, Borjan Gagoski, Ken-Pin Hwang, Akifumi Hagiwara, Marcel Warntjes, Issei Fukunaga, Wataru Uchida, Yuya Saito, Towa Sekine, Rina Tachibana, Tomoya Muroi, Toshiya Akatsu, Akihiro Kasahara, Ryo Sato, Tsuyoshi Ueyama, Christina Andica, Koji Kamagata, Shiori Amemiya, Hidemasa Takao, Yasunobu Hoshino, Yuji Tomizawa, Kazumasa Yokoyama, Berkin Bilgic, Nobutaka Hattori, Osamu Abe, Shigeki Aoki

Faculty, Staff and Student Publications

Purpose: To evaluate a vendor-agnostic multiparametric mapping scheme based on 3D quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) for whole-brain T1, T2, and proton density (PD) mapping.

Methods: This prospective, multi-institutional study was conducted between September 2021 and February 2022 using five different 3T systems from four prominent MRI vendors. The accuracy of this technique was evaluated using a standardized MRI system phantom. Intra-scanner repeatability and inter-vendor reproducibility of T1, T2, and PD values were evaluated in 10 healthy volunteers (6 men; mean age ± SD, 28.0 ± 5.6 y) who underwent scan-rescan sessions …

Mapping Genotypes To Chromatin Accessibility Profiles In Single Cells, Franco Izzo, Robert M Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Tamara Prieto, Elliot O Eton, Theo Botella, Andrew J Dunbar, Robert L Bowman, Jesus Sotelo, Catherine Potenski, Eleni P Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, Joann Arandela, Ramya Raviram, Daniel C Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M Ghobrial, Joseph M Scandura, Bridget Marcellino, Ross L Levine, Dan A Landau

Faculty, Staff and Student Publications

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. …

Stabilization Of Interdomain Interactions In G Protein Α Subunits As A Determinant Of Gαi Subtype Signaling Specificity, Tyler J Lefevre, Wenyuan Wei, Elizaveta Mukhaleva, Sai Pranathi Meda Venkata, Naincy R Chandan, Saji Abraham, Yong Li, Carmen W Dessauer, Nagarajan Vaidehi, Alan V Smrcka

Faculty, Staff and Student Publications

Highly homologous members of the Gαi family, Gαi1-3, have distinct tissue distributions and physiological functions, yet their biochemical and functional properties are very similar. We recently identified PDZ-RhoGEF (PRG) as a novel Gαi1 effector that is poorly activated by Gαi2. In a proteomic proximity labeling screen we observed a strong preference for Gαi1 relative to Gαi2 with respect to engagement of a broad range of potential targets. We investigated the mechanistic basis for this selectivity using PRG as a representative target. Substitution of either the helical domain (HD) from Gαi1 into Gαi2 or substitution of a single amino acid, A230 …

Genome-Wide Association Analyses Of Breast Cancer In Women Of African Ancestry Identify New Susceptibility Loci And Improve Risk Prediction, Guochong Jia, Jie Ping, Xingyi Guo, Yaohua Yang, Ran Tao, Bingshan Li, Stefan Ambs, Mollie E Barnard, Yu Chen, Montserrat Garcia-Closas, Jian Gu, Jennifer J Hu, Dezheng Huo, Esther M John, Christopher I Li, James L Li, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Tuya Pal, Michael F Press, Maureen Sanderson, Dale P Sandler, Xiao-Ou Shu, Melissa A Troester, Song Yao, Prisca O Adejumo, Thomas Ahearn, Abenaa M Brewster, Anselm J M Hennis, Timothy Makumbi, Paul Ndom, Katie M O'Brien, Andrew F Olshan, Mojisola M Oluwasanu, Sonya Reid, Ebonee N Butler, Maosheng Huang, Atara Ntekim, Huijun Qian, Haoyu Zhang, Christine B Ambrosone, Qiuyin Cai, Jirong Long, Julie R Palmer, Christopher A Haiman, Wei Zheng

Faculty, Staff and Student Publications

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Stat3 Protects Hematopoietic Stem Cells By Preventing Activation Of A Deleterious Autocrine Type-I Interferon Response, Bhakti Patel, Yifan Zhou, Rachel L Babcock, Feiyang Ma, M Anna Zal, Dhiraj Kumar, Yusra B Medik, Laura M Kahn, Josué E Pineda, Elizabeth M Park, Sarah M Schneider, Ximing Tang, Maria Gabriela Raso, Collene R Jeter, Tomasz Zal, Karen Clise-Dwyer, Khandan Keyomarsi, Filippo G Giancotti, Simona Colla, Stephanie S Watowich

Faculty, Staff and Student Publications

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, …

Chelation Enables Selectivity Control In Enantioconvergent Suzuki-Miyaura Cross-Couplings On Acyclic Allylic Systems, Violeta Stojalnikova, Stephen J Webster, Ke Liu, Stephen P Fletcher

Faculty, Staff and Student Publications

Asymmetric Suzuki-Miyaura cross-couplings with aryl boronic acids and allylic electrophiles are a powerful method to convert racemic mixtures into enantioenriched products. Currently, enantioconvergent allylic arylations are limited to substrates that are symmetrical about the allylic unit, and the absence of strategies to control regio-, E/Z- and enantioselectivity in acyclic allylic systems is a major restriction. Here, using a system capable of either conjugate addition or allylic arylation, we have discovered the structural features and experimental conditions that allow an acyclic system to undergo chemo- and regioselective, enantioconvergent allylic Suzuki-Miyaura-type arylation. A wide variety of boronic acid coupling partners can be …

Prevalence And Associations Of Dural Arteriovenous Fistulae In Cerebral Venous Thrombosis: Analysis Of Action-Cvt, Aaron Shoskes, Liqi Shu, Thanh N Nguyen, Mohamad Abdalkader, James Giles, Jordan Amar, James E Siegler, Nils Henninger, Marwa Elnazeir, Sami Al Kasab, Piers Klein, Mirjam R Heldner, Kateryna Antonenko, Marios Psychogios, David S Liebeskind, Thalia Field, Ava Liberman, Charles Esenwa, Alexis Simpkins, Grace Li, Jennifer Frontera, Lindsey Kuohn, Aaron Rothstein, Ossama Khazaal, Yasmin Aziz, Eva Mistry, Pooja Khatri, Setareh Salehi Omran, Adeel S Zubair, Richa Sharma, Robert M Starke, Jacques J Morcos, Jose G Romano, Shadi Yaghi, Negar Asdaghi

Faculty, Staff and Student Publications

No abstract provided.

Hypertensive Disorders Of Pregnancy And Long-Term Maternal Cardiovascular And Metabolic Biomarkers, Ashley N Battarbee, Lisa Mele, Mark B Landon, Michael W Varner, Brian M Casey, Uma M Reddy, Ronald J Wapner, Dwight J Rouse, John M Thorp, Edward K Chien, George Saade, Alan M Peaceman, Sean C Blackwell

Faculty, Staff and Student Publications

Objective: This study aimed to measure the association between hypertensive disorders of pregnancy (HDP) and long-term maternal metabolic and cardiovascular biomarkers.

Study design: Follow-up study of patients who completed glucose tolerance testing 5 to 10 years after enrollment in a mild gestational diabetes mellitus (GDM) treatment trial or concurrent non-GDM cohort. Maternal serum insulin concentrations and cardiovascular markers VCAM-1, VEGF, CD40L, GDF-15, and ST-2 were measured, and insulinogenic index (IGI, pancreatic β-cell function) and 1/ homeostatic model assessment (insulin resistance) were calculated. Biomarkers were compared by presence of HDP (gestational hypertension or preeclampsia) during pregnancy. Multivariable linear regression estimated the …

Is Routine Use Of External Spinal Orthoses Necessary After Operative Stabilization Of Cervical Spine Injuries?, Derek Moody, James Showery, Ran Lador, Isaac Hernandez, Mark L Prasarn

Faculty, Staff and Student Publications

Study design: Retrospective Review.

Objective: The purpose of this study is to evaluate the efficacy of postoperative cervical orthoses to prevent fixation failure and loss of reduction after operative treatment of cervical spine fractures.

Summary of background data: While cervical orthoses are most times tolerated in trauma patients, it is not clear that postoperative bracing is effective at reducing the rate of fixation failure or nonunion in this patient population. Cervical collars may delay rehabilitation, increase the risk of dysphagia and aspiration, and can contribute to skin breakdown.

Methods: All patients who underwent operative stabilization for cervical spine injuries at …

Dynamics Of Karyotype Evolution, Elena Kuzmin, Toby M Baker, Peter Van Loo, Leon Glass

Faculty, Staff and Student Publications

In the evolution of species, the karyotype changes with a timescale of tens to hundreds of thousand years. In the development of cancer, the karyotype often is modified in cancerous cells over the lifetime of an individual. Characterizing these changes and understanding the mechanisms leading to them has been of interest in a broad range of disciplines including evolution, cytogenetics, and cancer genetics. A central issue relates to the relative roles of random vs deterministic mechanisms in shaping the changes. Although it is possible that all changes result from random events followed by selection, many results point to other non-random …

Pet Imaging Of Metabolism, Perfusion, And Hypoxia: Fdg And Beyond, Austin R Pantel, Seong-Woo Bae, Elizabeth J Li, Sophia R O'Brien, H Charles Manning

Faculty, Staff and Student Publications

Imaging glucose metabolism with [18F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and …

Benefit Of Axicabtagene Ciloleucel Versus Chemoimmunotherapy In Older Patients And/Or Patients With Poor Ecog Performance Status With Relapsed Or Refractory Large B-Cell Lymphoma After 2 Or More Lines Of Prior Therapy, Matthew A Lunning, Hai-Lin Wang, Zhen-Huan Hu, Frederick L Locke, Tanya Siddiqi, Caron A Jacobson, Sairah Ahmed, David B Miklos, Yi Lin, Brian T Hill, Armin Ghobadi, Sattva S Neelapu, Jason Westin, Chrisopher Dieyi, Polly Field, Harry Miao, Shilpa A Shahani, Anik Patel, Clare Spooner, Christine Fu, David Muramoto, Hairong Xu, Marcelo C Pasquini

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients …

On The Optimal Diagnosis And The Evolving Role Of Pimavanserin In Parkinson's Disease Psychosis, Fernando L Pagan, Paul E Schulz, Yasar Torres-Yaghi, Gregory M Pontone

Faculty, Staff and Student Publications

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, …

First-Line Ibrutinib Treatment In Patients With Chronic Lymphocytic Leukemia Is Associated With Overall Survival Rates Similar To Those Of An Age-Matched General Population: A Pooled Post Hoc Analysis, Paolo Ghia, Carolyn Owen, John N Allan, Jacqueline C Barrientos, Paul M Barr, Chunxue Shi, Anita Szoke, Christopher Abbazio, Gabriel S Krigsfeld, Jan A Burger

Faculty, Staff and Student Publications

No abstract provided.

Artificial Intelligence-Powered Assessment Of Pathologic Response To Neoadjuvant Atezolizumab In Patients With Nsclc: Results From The Lcmc3 Study, Sanja Dacic, William D Travis, Jennifer M Giltnane, Filip Kos, John Abel, Stephanie Hilz, Junya Fujimoto, Lynette Sholl, Jon Ritter, Farah Khalil, Yi Liu, Amaro Taylor-Weiner, Murray Resnick, Hui Yu, Fred R Hirsch, Paul A Bunn, David P Carbone, Valerie Rusch, David J Kwiatkowski, Bruce E Johnson, Jay M Lee, Stephanie R Hennek, Ilan Wapinski, Alan Nicholas, Ann Johnson, Katja Schulze, Mark G Kris, Ignacio I Wistuba

Faculty, Staff and Student Publications

Introduction: Pathologic response (PathR) by histopathologic assessment of resected specimens may be an early clinical end point associated with long-term outcomes with neoadjuvant therapy. Digital pathology may improve the efficiency and precision of PathR assessment. LCMC3 (NCT02927301) evaluated neoadjuvant atezolizumab in patients with resectable NSCLC and reported a 20% major PathR rate.

Methods: We determined PathR in primary tumor resection specimens using guidelines-based visual techniques and developed a convolutional neural network model using the same criteria to digitally measure the percent viable tumor on whole-slide images. Concordance was evaluated between visual determination of percent viable tumor (n = …

Discovering Genetic Biomarkers For Targeted Cancer Therapeutics With Explainable Artificial Intelligence, Debaditya Chakraborty, Elizabeth Gutierrez-Chakraborty, Cristian Rodriguez-Aguayo, Hakan Başağaoğlu, Gabriel Lopez-Berestein, Paola Amero

Faculty, Staff and Student Publications

No abstract provided.

Survival Outcomes Of Patients With Her2/Neu-Positive Breast Cancer With Germline Brca Mutations, Fatma Nihan Akkoc Mustafayev, Mihir Amitabh Shukla, Amanda Lanier, Denái R Milton, Angelica M Gutierrez, Stephen K Gruschkus, John E Lewis, Rashmi K Murthy, Banu K Arun

Faculty, Staff and Student Publications

Background: Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations.

Methods: This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were …

A Novel Sik2 Inhibitor Sic-19 Exhibits Synthetic Lethality With Parp Inhibitors In Ovarian Cancer, Fang Wang, Xuejiao Yu, Jun Qian, Yumin Cao, Shunli Dong, Shenghua Zhan, Zhen Lu, Robert C Bast, Qingxia Song, Youguo Chen, Yi Zhang, Jinhua Zhou

Faculty, Staff and Student Publications

Purpose: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer.

Methods: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, …

Safety And Tolerability Of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy, Jasmijn M Westerhoff, Lois A Daamen, John P Christodouleas, Erwin L A Blezer, Ananya Choudhury, Rosalyne L Westley, Beth A Erickson, Clifton D Fuller, Shaista Hafeez, Uulke A Van Der Heide, Martijn P W Intven, Anna M Kirby, Susan Lalondrelle, Bruce D Minsky, Stella Mook, Marlies E Nowee, Corrie A M Marijnen, Kristina M Orrling, Arjun Sahgal, Christopher J Schultz, Corinne Faivre-Finn, Robbert J H A Tersteeg, Alison C Tree, Chia-Lin Tseng, Tine Schytte, Dustin M Silk, Dave Eggert, Marco Luzzara, Jochem R N Van Der Voort Van Zyp, Helena M Verkooijen, William A Hall

Faculty, Staff and Student Publications

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy.

Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach).

Design, setting, and participants: This cohort study included adults with solid tumors treated with a …

Intrabiliary Metastasis Of Colorectal Mucinous Adenocarcinoma Mimicking Choledocholithiasis 18 Years After The Primary Tumor, Sumaya Abdul Ghaffar, David Pfau, Nikhil Madhuripan, Robert Christopher Harmon, Antonio Galvao Neto, Ana Luiza Gleisner

Faculty, Staff and Student Publications

This case report presents a 62-year-old male who had previously undergone curative colectomy and neoadjuvant chemotherapy in 2005 for colorectal cancer. He presented with jaundice, which was initially attributed to choledocholithiasis. After cholecystectomy and repeat ERCPs, hyperbilirubinemia persisted. There was persistent dilation of the right posterior duct on imaging, concerning for biliary stricture, possibly due to cholangiocarcinoma or intraductal papillary neoplasm. During a right posterior hepatectomy, a peripheral liver lesion was found in association with the dilated bile duct. On frozen evaluation, the lesion was found to be invasive adenocarcinoma. The final pathology was compatible with a metastatic mucinous adenocarcinoma …

Pulmonary Endobronchial Hamartoma Presenting With Post-Obstructive Pneumonia, Diane S Habib, Pushan Jani, Bihong Zhao, Elakiya Anjali Jayaraman, Ramesh Kesavan

Faculty, Staff and Student Publications

Pulmonary hamartomas (PH) are rare but are the most common benign tumors found in the lungs. They are slow-growing and are usually found incidentally on chest imaging during the sixth decade of life. Approximately 10% of pulmonary hamartomas are endobronchial. Rarely, pulmonary hamartomas can cause a spectrum of pulmonary symptoms depending on their size and location. We present a case of endobronchial hamartoma causing airway obstruction and recurrent post-obstructive pneumonia.

Igwas: Image-Based Genome-Wide Association Of Self-Supervised Deep Phenotyping Of Retina Fundus Images, Ziqian Xie, Tao Zhang, Sangbae Kim, Jiaxiong Lu, Wanheng Zhang, Cheng-Hui Lin, Man-Ru Wu, Alexander Davis, Roomasa Channa, Luca Giancardo, Han Chen, Sui Wang, Rui Chen, Degui Zhi

Faculty, Staff and Student Publications

Existing imaging genetics studies have been mostly limited in scope by using imaging-derived phenotypes defined by human experts. Here, leveraging new breakthroughs in self-supervised deep representation learning, we propose a new approach, image-based genome-wide association study (iGWAS), for identifying genetic factors associated with phenotypes discovered from medical images using contrastive learning. Using retinal fundus photos, our model extracts a 128-dimensional vector representing features of the retina as phenotypes. After training the model on 40,000 images from the EyePACS dataset, we generated phenotypes from 130,329 images of 65,629 British White participants in the UK Biobank. We conducted GWAS on these phenotypes …

Proton Therapy Mediates Dose Reductions To Brain Structures Associated With Cognition In Children With Medulloblastoma, Julianna Sienna, Lisa S Kahalley, Donald Mabbott, David Grosshans, Anna Theresa Santiago, Arnold Dela Cruz Paulino, Thomas E Merchant, Gohar S Manzar, Hitesh Dama, David C Hodgson, Murali Chintagumpala, Mehmet Fatih Okcu, William E Whitehead, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Uri Tabori, Julie M Bennett, Anirban Das, Tim Craig, Derek S Tsang

Faculty, Staff and Student Publications

Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy.

Methods and materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores.

Results: The mean dose and dose to …