Biomedical Informatics Commons^™

Fruquintinib In Less Pretreated Patients: Multivariate Profile-Matching Analysis Of Fresco-2 To Fresco, Arvind Dasari, Cathy Eng, Sara Lonardi, Rocio Garcia-Carbonero, Toshiki Masuishi, Chiara Cremolini, François Ghiringhelli, Joleen Hubbard, Tanios Bekaii-Saab, Jeremy Jones, Rui-Hua Xu, Lin Shen, Jianming Xu, Yuxian Bai, Yanhong Deng, Ying Yuan, Wei Wei, Jianchang Lin, Lucy Chen, Zhao Yang, William R Schelman, Shukui Qin, Jin Li

Faculty, Staff and Student Publications

Background: In the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) studies, fruquintinib vs placebo, plus best supportive care, significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). These studies were conducted in temporally and geographically diverse populations that received distinct prior therapies; FRESCO patients were less pretreated than FRESCO-2 patients. This analysis assessed the efficacy and safety of fruquintinib in a less pretreated global population than the FRESCO-2 intention-to-treat (ITT) population.

Methods: In FRESCO and FRESCO-2, patients were randomized 2:1 to receive oral fruquintinib 5 mg or matched placebo. Profile matching was undertaken …

Lewy Body Dementia Promotion By Air Pollutants, Xiaodi Zhang, Haiqing Liu, Xiao Wu, Longgang Jia, Kundlik Gadhave, Lena Wang, Kevin Zhang, Hanyu Li, Rong Chen, Ramhari Kumbhar, Ning Wang, Chantelle E Terrillion, Bong Gu Kang, Bin Bai, Minhan Park, Ma Cristine Faye Denna, Shu Zhang, Wenqiang Zheng, Denghui Ye, Xiaoli Rong, Liu Yang, Lili Niu, Han Seok Ko, Weiyi Peng, Lingtao Jin, Mingyao Ying, Liana S Rosenthal, David W Nauen, Alex Pantelyat, Mahima Kaur, Kezia Irene, Liuhua Shi, Rahel Feleke, Sonia García-Ruiz, Mina Ryten, Valina L Dawson, Francesca Dominici, Rodney J Weber, Xuan Zhang, Pengfei Liu, Ted M Dawson, Shizhong Han, Xiaobo Mao

Faculty, Staff and Student Publications

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. Here we showed in a cohort of 56.5 million individuals across the U.S. that PM2.5 exposure raises LBD risk. Mechanistically, we found PM2.5 exposure led to brain atrophy in wild-type mice, an effect not seen in α-synuclein (αSyn)-deficient mice. PM2.5 exposure generated a highly pathogenic αSyn strain, PM-PFF, with enhanced proteinase K-resistance and neurotoxicity, resembling αSyn LBD strains. PM2.5 samples from China, the U.S., and Europe consistently induced proteinase-resistant αSyn strains and in vivo pathology. Transcriptomic analyses revealed shared responses between PM2.5-exposed mice and …

Detection Of Cancers Three Years Prior To Diagnosis Using Plasma Cell-Free Dna, Yuxuan Wang, Corinne E Joshu, Samuel D Curtis, Christopher Douville, Vernon A Burk, Meng Ru, Maria Popoli, Janine Ptak, Lisa Dobbyn, Natalie Silliman, Josef Coresh, Eric Boerwinkle, Anna Prizment, Chetan Bettegowda, Kenneth W Kinzler, Nickolas Papadopoulos, Elizabeth A Platz, Bert Vogelstein

Faculty, Staff and Student Publications

To explore how early can cancers be detected prior to clinical signs or symptoms, we assessed prospectively collected serial plasma samples from the Atherosclerosis Risk in Communities (ARIC) study, including 26 participants diagnosed with cancer and 26 matched controls. At the index time point, eight of these 52 participants scored positively with a multicancer early detection (MCED) test. All eight participants were diagnosed with cancer within 4 months after blood collection. In six of these 8 participants, we were able to assess an earlier plasma sample collected 3.1 to 3.5 years prior to clinical diagnosis. In four of these six …

Mucinous Cystic Neoplasms Of The Pancreas And Liver Share A Similar Dna Methylation Profile With Mucinous Ovarian Tumors, Zoe Leoni, Teodor G Calina, Tobias Janik, Elena Grafenhorst, Eliane T Taube, Christopher Cm Neumann, Baoqing Chen, Elena I Braicu, Jalid Sehouli, Thomas Malinka, Wenzel Schöning, Johann Pratschke, George A Calin, David S Klimstra, Jamal K Benhamida, Irene Esposito, Markus Möbs, David Horst, Simon Schallenberg, David Capper, Mihnea P Dragomir

Faculty, Staff and Student Publications

The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 …

Trop2 Expression In Salivary Gland Adenoidcystic Carcinoma (Acc) According To Histologic Subtype: Therapeutic Implications, Juliana Mota Siqueira, Yoshitsugu Mitani, Mario L Marques-Piubelli, Camilla Oliveira Hoff, Flavia Bonini, Luana Guimaraes De Sousa, Mutsumi Mitani, Giovanna Lopes Carvalho, Fabio Daumas Nunes, Leandro Luongo Matos, Shiaw-Yih Lin, Michael T Spiotto, Ehab Y Hanna, Daniel J Mcgrail, Adel K El-Naggar, Renata Ferrarotto

Faculty, Staff and Student Publications

Background: Adenoid cystic carcinoma (ACC) is a common salivary gland carcinoma with high recurrence and distant metastasis rates. Currently, there is no standard systemic treatment available. TROP2 is a transmembrane glycoprotein involved in the oncogenesis of several tumors that can be therapeutically targeted by a TROP2-antibody-drug conjugate (ADC). We aimed to characterize TROP2 expression in ACC and assess TROP2 as a potential therapeutic target.

Methods: TROP2 immunohistochemistry was performed in a tissue microarray including 165 ACC of salivary gland. The tumors were grouped according to the histological pattern as non-solid, solid + non-solid, or solid. TROP2 protein expression in ACC …

Auricular Point Acupressure For Older Adults With Chronic Low Back Pain: A Randomized Controlled Trial, Jennifer Kawi, Chao Hsing Yeh, Nada Lukkahatai, Hulin Wu, Natalia E Morone, Ronald Glick, Elizabeth A Schlenk, Claudia Campbell, Johannes Thrul, Xinran Huang, Hongyu Wang, Hejingzi Monica Jia, Paul Christo, Constance Johnson

Faculty, Staff and Student Publications

Objective: Efficacious modalities are limited in chronic low back pain (cLBP). We determined the efficacy of auricular point acupressure (APA) in older adults with cLBP.

Design: 3-arm randomized controlled trial.

Setting: Baltimore, Maryland.

Participants: Participants, ≥60 years with cLBP, were randomized (1:1:1) to APA with ear points targeted to cLBP (T-APA, n = 92), points nontargeted to cLBP (NT-APA, n = 91), or waitlist education control (n = 89), and followed up to 6 months (6M). Participants in the APA groups received 4 weekly APA sessions; the education control group received 4 weekly educational sessions.

Intervention: APA.

Main outcomes and …

Leveraging Existing Cohort Studies Of Mexican Women To Better Understand Hispanic Health And Cancer Risk, Dalia Stern, Liliana Gomez-Flores-Ramos, Britton Trabert, V Wendy Setiawan, Loïc Le Marchand, Henry Gomez, Paul A Scheet, Humberto Parada, Amber Pirzada, Martin Lajous, Leslie V Farland

Faculty, Staff and Student Publications

Background: Hispanics have been historically underrepresented in epidemiologic cancer research. Existing cohort studies focused on recruiting Hispanic participants have been relatively small, making studying cancer outcomes challenging. Therefore, we aimed to compare the distribution of cancer risk factors among Hispanic women of Mexican heritage (HWMH) participating in existing cohorts to explore the possibility of future data pooling efforts.

Methods: We used baseline data of HWMH from three US-based studies, the Mexican American Cohort (MAC; n = 19,797; 2001-2017), the Multiethnic Cohort (MEC; n = 18,007; 1993-1996), and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n = 4,022; 2008-2011), and …

Baseline Α-Synuclein Seeding Activity And Disease Progression In Sporadic And Genetic Parkinson’S Disease In The Ppmi Cohort, Jackson G Schumacher, Xinyuan Zhang, Eric A Macklin, Jian Wang, Armin Bayati, Johannes M Dijkstra, Hirohisa Watanabe, Michael A Schwarzschild, Marianna Cortese, Xuehong Zhang, Xiqun Chen

Faculty, Staff and Student Publications

Background: α-Synuclein (α-syn) seed amplification assays (SAAs) have shown remarkable potential in diagnosing Parkinson's disease (PD). Using data from the Parkinson's Progression Markers Initiative (PPMI) cohort, we aimed to test whether baseline α-syn seeding activity and α-syn SAA kinetic parameters are associated with disease progression in sporadic PD, LRRK2-associated PD (LRRK2 PD), and GBA-associated PD (GBA PD).

Methods: We analysed 7 years of motor, non-motor, and cognitive assessments and 5 years of dopamine transporter imaging along with baseline α-syn SAA results from 564 PPMI participants (n = 332 sporadic PD, 162 LRRK2 PD, and 70 GBA PD) using linear mixed-effects …

Isatuximab Plus Bortezomib, Lenalidomide, And Dexamethasone For Transplant-Ineligible Newly Diagnosed Multiple Myeloma Patients: A Frailty Subgroup Analysis Of The Imroz Trial, Salomon Manier, Meletios-Athanasios Dimopoulos, Xavier P Leleu, Philippe Moreau, Michele Cavo, Hartmut Goldschmidt, Robert Z Orlowski, Muriel Tron, Christina Tekle, Marie-France Brégeault, Andrea T Shafer, Meral Beksac, Thierry Facon

Faculty, Staff and Student Publications

Patients with multiple myeloma (MM) meeting frailty criteria have worse outcomes than those identified as non-frail. Here, we present a post hoc subgroup analysis of IMROZ, a global, phase III, open-label study investigating isatuximab (Isa) with bortezomib, lenalidomide, and dexamethasone (VRd) followed by Isa-Rd (N=265) versus VRd followed by Rd (N=181) in newly diagnosed transplant-ineligible MM (Ti NDMM) patients using the simplified International Myeloma Working Group (sIMWG) frailty score. Although patients aged >80 years were excluded, there was no exclusion for patients meeting frailty criteria. All patients received standard VRd/Rd dosing; Isa-VRd patients received intravenous Isa (cycle 1, 10 mg/kg …

Predicting Clinical Success Of Ct-Based Functional Drained Liver Volume Assessment In Malignant Biliary Obstruction, Ethan Y Lin, Bruno C Odisio, Koustav Pal, Iwan Paolucci, Ryan P Kempen, Nicolas Cardenas, Paige Reed, Ketan Y Shah, Ahmed Awad, Rahul A Sheth, David Fuentes, Alda Tam

Faculty, Staff and Student Publications

Purpose

To compare the predictive accuracy of subjective versus objective assessment of three-dimensional functional drained liver volume (fDLV) for clinical success after percutaneous transhepatic biliary drainage (PTBD).

Materials and Methods

This retrospective study included patients with malignant biliary obstruction and hyperbilirubinemia who underwent de novo PTBD between January 2016 and February 2017. Clinical success was defined as achieving total bilirubin level less than 1.8 mg/dL (30.8 μmol/L) within 30 days after PTBD. Seven interventional radiologists independently categorized subjective fDLV into four groups: less than 30%, 30%–50%, 51%–75%, and greater than 75% of the total liver volume. Objective fDLV was calculated …

Risk Of Second Primary Lung Cancer Among Cancer Survivors Stratified By The Site Of First Primary Cancer And The Lung Cancer Screening Eligibility Status, Sara Nofal, Edwin J Ostrin, Jianjun Zhang, Jia Wu, Paul Scheet, Mara B Antonoff, John V Heymach, Iakovos Toumazis

Faculty, Staff and Student Publications

Personal history of cancer is an independent risk factor for developing lung cancer. However, it is not considered in the current US lung cancer screening (LCS) guidelines. In this study, we assessed the risk of developing lung cancer among cancer survivors across 24 different sites of first primary cancer stratified by their LCS eligibility status. Using data from the Patient History Database at the University of Texas MD Anderson Cancer Center, we calculated and compared the cumulative incidence of second primary lung cancer, the overall and the LCS eligibility status-specific, stratified by the site of first primary cancer among cancer …

Heightened Risk: Childhood Trauma And Anticipatory Grief Exacerbate The Impact Of Loneliness On Depressive Symptoms And Lps-Stimulated Cytokines In Dementia Caregivers, Kelly N Brice, Jensine Paoletti-Hatcher, E Lydia Wu-Chung, Vincent D Lai, Daniel L Argueta, Michelle A Chen, Itee Mahant, Bryan T Denny, Charles Green, Luis D Medina, Paul Schulz, Jennifer Stinson, Samantha K Henry, Cobi Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Dementia spousal caregivers are at a disproportionate risk for adverse mental and physical health outcomes. Loneliness is associated with depressive symptoms and proinflammatory cytokine production among caregivers. Additionally, childhood trauma, anticipatory grief, and poor sleep quality are all associated with enhanced stress reactivity. This study used a cross-sectional design to investigate whether loneliness is associated with proinflammatory cytokine production and depressive symptoms in caregivers, and whether these relationships are strongest among caregivers who report high levels of childhood trauma, high amounts of anticipatory grief, or poor sleep quality. A sample of 111 dementia spousal caregivers provided blood samples and completed …

Risk Of Major Depression In Partners Of People With Alzheimer's Disease: A National Cohort Study, Casey Crump, Jingkai Wei, Barbara G Vickrey, Alexis C Edwards, Paul E Schulz, Weiva Sieh, Jan Sundquist, Kristina Sundquist

Faculty, Staff and Student Publications

Background: Alzheimer's disease (AD) may cause significant psychosocial distress not only in the patient but also their partner. However, long-term risks of major depression in partners of AD patients are largely unknown.

Methods: A national cohort study was conducted of all 145 289 partners of people diagnosed with all-cause dementia, including 57 113 partners of people diagnosed with AD, in Sweden during 1998-2017, and 1 300 561 population-based controls. Cox regression was used to compute hazard ratios (HRs) for subsequent risk of major depression identified from nationwide outpatient and inpatient diagnoses through 2018, adjusting for sociodemographic factors and prior mental …

Outcomes Of Patients With Newly Diagnosed Acute Myeloid Leukemia With Flt3-Tyrosine Kinase Domain Mutations: Prognostic Implications Of Npm1 Co-Mutation, Sankalp Arora, Wei-Ying Jen, Musa Yilmaz, Indraneel Deshmukh, Jayastu Senapati, Sanam Loghavi, Ghayas C Issa, Nicholas J Short, Tapan M Kadia, Courtney D Dinardo, Gautam Borthakur, Joseph Jabbour, Naveen Pemmaraju, Michael Andreeff, Koichi Takahashi, Kapil Bhalla, Uday Popat, Elizabeth J Shpall, Betul Oran, Hussein A Abbas, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Naval Daver

Faculty, Staff and Student Publications

Background: The prognostic impact of Fms-like tyrosine kinase 3 (FLT3)-tyrosine kinase domain (TKD) mutation in patients with acute myeloid leukemia (AML) is not well defined. The authors described outcomes of one of the largest cohorts of patients with FLT3-TKD mutated (FLT3-TKDmut) AML to date.

Methods: This retrospective study included patients with newly diagnosed AML who received frontline treatment at The University of Texas MD Anderson Cancer Center from January 2012 to March 2024 divided into two cohorts: FLT3-TKDmut AML and nucleophosmin-mutated (NPM1mut)/FLT3-TKD wild-type (FLT3-TKDwt) AML. Patients with FLT3 internal tandem duplication mutations were excluded.

Results: In total, 2922 patients were …

Lipidomic And Proteomic Insights From Extracellular Vesicles In The Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes, Chioma M Okeoma, Wasifa Naushad, Bryson C Okeoma, Carlos Gartner, Yulica Santos-Ortega, Calvin Vary, Savio Lima-Bastos, Victor Corasolla Carregari, Martin R Larsen, Alessio Noghero, Consuelo Walss-Bass, Rodrigo Grassi-Oliveira

Faculty, Staff and Student Publications

Substance use disorder (SUD) significantly increases the risk of neurotoxicity, inflammation, oxidative stress, and impaired neuroplasticity. The activation of inflammatory pathways by substances may lead to reactive astrogliosis and chronic neuroinflammation, potentially mediated by the release of extracellular particles (EPs), such as extracellular condensates (ECs) and extracellular vesicles (EVs). These particles, which reflect the physiological, pathophysiological, and metabolic states of their cells of origin, might carry molecular signatures indicative of SUD. In particular, our study investigated neuroinflammatory signatures in SUD patients by isolating EVs from the dorsolateral prefrontal cortex (dlPFC) Brodmann's area 9 (BA9) from postmortem subjects. We isolated BA9-derived …

Randomised, Placebo-Controlled Trial Of Oral Hymecromone In Adults With Pulmonary Hypertension, Kathryn Czepiel, Nadine Nagy, Tamera Panjalingam, Anissa Kalinowski, Adam R Frymoyer, Harry Karmouty-Quintana, Bo Gu, Haley Hedlin, Gernot Kaber, Sylvie Dobrota Lai, Joelle I Rosser, Paul L Bollyky, Vinicio De Jesus Perez, Roham T Zamanian

Faculty, Staff and Student Publications

Background: Pulmonary hypertension (PH) is a progressive cardiopulmonary condition associated with increased morbidity and mortality. The extracellular matrix component hyaluronan (HA) is linked to vascular remodelling and interstitial fibrosis in PH. We hypothesised that inhibition of HA synthesis with hymecromone could serve as a reverse-remodelling therapy in PH.

Methods: We performed a proof-of-concept phase IIa randomised, double-blind, placebo-controlled study in adults with pulmonary arterial hypertension and PH associated with interstitial lung disease (PH-ILD). Patients were randomised to a 5:3 ratio and stratified by PH group to receive oral hymecromone or placebo two times per day over 24 weeks. The primary …

Clinical, Tumor, And Product Features Associated With Outcomes After Axicabtagene Ciloleucel Therapy In Follicular Lymphoma, Soumya Poddar, Jiali Yan, Gayatri Tiwari, Darawan Rinchai, Justin Budka, Wangshu Zhang, Weixin Peng, Shruti Salunkhe, Madison Davis, Qinghua Song, Sara Beygi, Harry Miao, Mike Mattie, Rhine S Shen, Caron A Jacobson, Davide Bedognetti, Simone Filosto, Sattva S Neelapu

Faculty, Staff and Student Publications

Background: Axicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B cell lymphomas in the ZUMA-5 trial.

Methods:Here, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 patients with follicular lymphoma (FL).

Results: In univariate and multivariate analyses, pretreatment inflammatory markers, including TNF-α and IL-12p40, as well as total metabolic tumor volume (TMTV), associated with disease progression. Conversely, T-naive–like product phenotype associated with improved outcome, particularly in patients with high TMTV. These covariates improved risk stratification when combined with the …

Contemporary Outcomes Of Octa-Nonagenarians With Newly Diagnosed Acute Myeloid Leukemia, Jayastu Senapati, Hagop M Kantarjian, Tapan M Kadia, Jeannot Kekedjian, Gautam Borthakur, Naval Daver, Courtney D Dinardo, Elias Jabbour, Prithviraj Bose, Nicholas J Short, Musa Yilmaz, Nitin Jain, Naveen Pemmaraju, Hussein A Abbas, Ghayas C Issa, Abhishek Maiti, Guillermo Montalban Bravo, Indraneel Deshmukh, Elizabeth Shpall, Partow Kebriaei, Uday Popat, Sanam Loghavi, Beenu Thakral, Guilin Tang, Fadi G Haddad, Yesid Alvarado, Guillermo Garcia Manero, Farhad Ravandi

Faculty, Staff and Student Publications

Background: Octa-nonagenarians with acute myeloid leukemia (AML) represent a high-risk group due to frequently poor performance status, adverse genomics (e.g., TP53 mutations, complex karyotype), a high incidence of secondary AML, and inability to undergo an allogeneic stem cell transplantation. Evaluating their outcomes with modern treatment approaches is important.

Methods: This retrospective study analyzed outcomes of patients ≥80 years old with newly diagnosed AML treated at our center from 2013-2023.

Results: A total of 289 patients (median age, 83 years; range, 80-95 years) were included. Venetoclax containing low-intensity therapy was administered to 107 patients (37.0%). AML subtypes included de novo (123, …

Multidimensional Analysis Of B7 Homolog 3 Rna Expression In Small Cell Lung Cancer Molecular Subtypes, Carl M Gay, Taofeek K Owonikoko, Lauren A Byers, Noura J Choudhury, Sajid Ahmed, Zachary Cain, Xiaozhong Qian, Matthew Brentnall, Simon Heeke, Ming Poi, Sharon Wu, Charles M Rudin

Faculty, Staff and Student Publications

Purpose: B7 homolog 3 (B7-H3) is a promising target for antibody-drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.

Experimental design: Tumor RNA expression and mutational burden for 1,721 patients with SCLC were derived from a real-world database (Caris Life Sciences). A predominant molecular subtype was assigned based on RNA expression using a gene-ratio classifier. PD-L1 expression was assessed by IHC (antibody 22C3; positive cutoff: tumor …

Csf-Exosomal Mirnas And Delayed Cerebral Ischemia: Insights Into Pathophysiology But No Definitive Biomarkers, Chathathayil M Shafeeque, Devin W Mcbride, Yuanqing Yan, Hussein A Zeineddine, John P Hagen, H Alex Choi, Jude P Savarraj, Ari Dienel, Spiros L Blackburn, Peeyush Kumar Thankamani

Faculty, Staff and Student Publications

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is notoriously known for its high mortality and morbidity. Approximately one-third of the patients who survive aneurysm rupture are reported to develop delayed cerebral ischemia (DCI), which contributes to a poor clinical outcome. Currently, there are no biomarkers for identifying which aSAH patients are at risk of developing DCI. We aimed to determine the feasibility of cerebrospinal fluid (CSF) exosomal microRNAs (miRNAs) for predicting DCI post-aSAH.

Methods: aSAH patients were prospectively enrolled, and CSF samples were collected at two time points (< 24 h and 72 h post-aSAH) from individuals undergoing external ventricular drainage. Exosomal miRNAs were isolated from the CSF for analysis. In the initial group of patients (discovery cohort), an exploratory analysis was conducted using a CSF panel containing 84 miRNAs, assessed by quantitative real-time PCR (RT-qPCR). Based on this analysis, 27 miRNAs were selected for further evaluation in a second group of patients (validation cohort). Among these, 10 miRNAs had previously been reported in SAH-related CSF studies, supporting their relevance for continued investigation.

Results: In this study, RT-qPCR analysis of 84 miRNAs in CSF samples from …

Assessing The Muc5b Promoter Variant In A Large Cohort Of Systemic Sclerosis-Associated Interstitial Lung Disease, Carlos Rosa-Baez, Carlos Rangel-Pelaez, Inmaculada Rodriguez-Martin, Martin Kerick, Alfredo Guillen-Del-Castillo, Carmen P Simeon-Aznar, José Luis Callejas, Alexandre E Voskuyl, Alexander Kreuter, Oliver Distler, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Jeska K De Vries-Bouwstra, Ariane L Herrick, Yannick Allanore, Lorenzo Beretta, Maureen D Mayes, Christopher P Denton, Shervin Assassi, Javier Martin, Marialbert Acosta-Herrera

Faculty, Staff and Student Publications

Objective: The common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.

Methods: Samples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their …

Pd-1 Inhibition For Relapse After Allogeneic Transplantation In Acute Myeloid Leukemia And Myelodysplastic Syndrome, John M Magenau, David G Frame, Mary Riwes, John Maciejewski, Sarah Anand, Attaphol Pawarode, Anamarija M Perry, Marcus Geer, Thomas Braun, Monalisa Ghosh, Pavan Reddy

Faculty, Staff and Students Publications

Relapse of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains the primary source of mortality after allogeneic hematopoietic stem cell transplantation (HCT). Targeting programmed death-1 (PD-1) for reversing T-cell exhaustion and restoring the graft-versus-leukemia (GVL) effect may have logistical advantages over donor lymphocyte infusion. In a prospective phase 1B clinical trial, pembrolizumab was administered every 3 weeks to 16 patients with AML (n = 12) and MDS (n = 4) in relapse after HCT to assess graft-versus-host disease (GVHD), clinical response, and survival. The median time to relapse after HCT was 5.5 months and the median pretreatment bone marrow …

Frontline Acalabrutinib, Lenalidomide And Rituximab For Advanced Stage Follicular Lymphoma With High Tumor Burden: Phase Ii Trial, Paolo Strati, Lei Feng, Jason R Westin, Ranjit Nair, Luis E Fayad, Maria A Rodriguez, Dai Chihara, Luis Malpica, Jared Henderson, Mariana Gallardo, Marissa Rivera, Iris Wang, Anastasiia Bolshakova, Anastasia Radko, David Kurtz, Stefan K Alig, Christopher R Flowers, Ash A Alizadeh, Sattva S Neelapu

Faculty, Staff and Student Publications

This phase II trial aims to determine the efficacy and safety of frontline acalabrutinib, lenalidomide and rituximab for patients with advanced stage follicular lymphoma (FL) and high tumor burden. The primary endpoint was best complete response (CR) rate; the secondary endpoints were overall response rate (ORR), duration of response measured as CR at 30 months (CR30), progression of disease at 24 months (POD24) rate, progression-free survival (PFS), overall survival and safety. Twenty-four patients with previously untreated FL were included in this phase 2 single arm study (NCT04404088). The most common grade 3-4 adverse events were neutropenia (58%) and …

Histologic And Immune Characterization Of Cutaneous Immune-Related Adverse Events Induced By Immune Checkpoint Inhibitors, Omar Pacha, Anisha B Patel, Jonathan L Curry, Cara L Haymaker, Nejla Ozirmak Lermi, Dzifa Yawa Duose, Ken Chen, Joud Hajjar, Aung Naing

Faculty, Staff and Student Publications

Background: Although immune checkpoint inhibitors (ICIs) are efficacious, they often cause immune-related adverse events (irAEs), most commonly cutaneous irAEs (CirAEs). The mechanisms underlying CirAEs remain unclear.

Methods: Attempting to better understand their mechanisms and histology we conducted a prospective study of 15 patients with advanced cancers treated with ICIs who developed grade 2 or higher CirAEs. Clinical and histologic characterization of biopsy specimens of CirAEs was performed. Histologic analysis of patient biopsy specimens were subdivided by epidermal reaction patterns that included spongiotic, lichenoid, and interface dermatitis patterns. A targeted RNA expression assay was used to identify immune markers in CirAE …

Exploring Factors Affecting The Adoption And Use Of Digital Health Technologies Among Older Adults With Cancer: A Qualitative Study, Misun Hwang, Youmin Cho, Katie Gahn, Heidi Mason, Milisa Manojlovich, Yang Gong, Yun Jiang

Faculty, Staff and Student Publications

Purpose: Although digital health technologies (DHTs) are promising to improve health outcomes in older adults with cancer, the low adoption and limited use remain significant gaps in their effective digital health care. Little is known about their concerns about adopting and using DHTs in routine life, particularly in the continued use phase. This study aims to explore factors affecting the initial adoption and continued use of DHTs among older adults with cancer.

Methods: A secondary analysis of qualitative data was conducted based on interviews with 21 older adults (≥ 65 years) with breast, prostate, lung, or colorectal cancer. The transcripts …

Integrating Ctdna Analysis And Radiomics For Dynamic Risk Assessment In Localized Lung Cancer, Everett J Moding, Mohammad Shahrokh Esfahani, Cheng Jin, Angela B Hui, Barzin Y Nabet, Yufei Liu, Jacob J Chabon, Michael S Binkley, David M Kurtz, Emily G Hamilton, Aadel A Chaudhuri, Chih Long Liu, Zhe Li, Rene F Bonilla, Alice L Jiang, Brianna C Lau, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J Ramchandran, Sukhmani K Padda, Joel W Neal, Heather A Wakelee, Michael F Gensheimer, Billy W Loo, Ruijiang Li, Steven H Lin, Ash A Alizadeh, Maximilian Diehn

Faculty, Staff and Student Publications

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. Circulating tumor DNA (ctDNA) minimal residual disease after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. Here, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration …

Depletion Of Effector Regulatory T Cells Associates With Major Response To Induction Dual Immune Checkpoint Blockade, Xianli Jiang, Nils-Petter Rudqvist, Bo Jiang, Shengbin Ye, Shan He, Qingnan Liang, Jinzhuang Dou, Michelle D Williams, Joe Dan Dunn, Jason M Johnson, Keiko Akagi, Weihong Xiao, Shaoheng Liang, Satvik Elayavalli, Baohua Sun, Edwin R Parra, Renata Ferrarotto, Adam S Garden, Clifton David Fuller, Jay Reddy, Neil D Gross, Miriam N Lango, Cheuk Hong Leung, Suyu Liu, Diane D Liu, Meng Li, J Jack Lee, Michael A Curran, Jack Phan, Ken Chen, Maura L Gillison

Faculty, Staff and Student Publications

In a phase II trial, patients with local-regionally advanced human papillomavirus-positive oropharyngeal carcinoma (n = 35) received ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Coprimary endpoints included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histopathologic response rate. Single-cell profiling revealed responders had higher baseline intratumoral CD8+ T cells with a tumor-reactive, tissue-resident memory (TRM) phenotype and a treatment-related decrease in effector regulatory T (eTreg) cells. The eTreg decrease correlated with CD8+ T-cell clonotype transitioning from TRM to effector memory and IFNG+ effector cells. …

Transcriptomic Analysis Of Localized High-Risk Prostate Cancer Improves Prognostication And Identifies Benefit From Adding Docetaxel To Definitive Radiotherapy With Androgen Suppression In The Nrg Oncology/Rtog 0521 Phase 3 Trial, Ryan M Phillips, James A Proudfoot, Elai Davicioni, Yang Liu, Daniel E Spratt, Jeff M Simko, Robert B Den, Alan Pollack, Seth A Rosenthal, A Oliver Sartor, Christopher J Sweeney, Gerhardt Attard, Leslie Longoria, Samir Patel, Michael W Straza, Jason A Efstathiou, Amit B Shah, Karen E Hoffman, Joseph P Rodgers, Howard M Sandler, Felix Y Feng, Phuoc T Tran

Faculty, Staff and Student Publications

Background and objective: NRG/RTOG 0521 randomized men with high-risk localized prostate cancer (PC) to androgen suppression (AS) and definitive radiotherapy (RT) ± docetaxel-based chemotherapy (CT). The overall survival (OS) benefit with CT initially reported was lost on longer follow-up. The Decipher genomic classifier (GC) measures multiple transcripts relevant to docetaxel action. Basal/luminal differentiation portends differential response to AS and CT for high-risk localized and metastatic hormone-sensitive PC. We validated the Decipher GC in pretreatment biopsy samples for risk stratification and examined basal-luminal subtyping to predict docetaxel response.

Methods: Decipher GC scores and basal-luminal cellular subtypes were generated for specimens from …

Efficacy And Safety Of Oral Decitabine/Cedazuridine In The Chronic Myelomonocytic Leukaemia Subpopulations From Phase 2 And 3 Studies, Michael R Savona, Olatoyosi Odenike, Gail J Roboz, Harshad Amin, Amy E Dezern, Elizabeth A Griffiths, Kim-Hien Dao, Amer M Zeidan, Bhavana Bhatnagar, Rena Buckstein, Brian Leber, Mary-Margaret Keating, Somedeb Ball, Aram Oganesian, Yuri Sano, Harold N Keer, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

DNA methyltransferase inhibitors (DNMTis) are commonly used in treating chronic myelomonocytic leukaemia (CMML); however, data from prospective studies of DNMTis in CMML are limited. The present analysis evaluated the efficacy, safety and pharmacodynamics of the oral DNMTi decitabine/cedazuridine in the subset of patients with CMML from the phase 2 and 3 trials, which led to the approval of this agent for myelodysplastic syndromes and CMML in the United States and Canada. Potential prognostic factors also were analysed. In all, 34 patients with CMML were screened and 33 were treated. Most patients (76% [n = 25]) had myelodysplastic type-CMML and 77% …

Bayesian Counterfactual Machine Learning Individualizes Radiation Modality Selection To Mitigate Immunosuppression, Duo Yu, Michael J Kane, Yiqing Chen, Steven H Lin, Radhe Mohan, Brian P Hobbs

Faculty, Staff and Student Publications

Purpose: Lymphocytes play critical roles in cancer immunity and tumor surveillance. Radiation-induced lymphopenia (RIL) is a common side effect observed in patients with cancer undergoing chemoradiation therapy (CRT), leading to impaired immunity and worse clinical outcomes. Although proton beam therapy (PBT) has been suggested to reduce RIL risk compared with intensity-modulated radiation therapy (IMRT), this study used Bayesian counterfactual machine learning to identify distinct patient profiles and inform personalized radiation modality choice.

Methods: A novel Bayesian causal inferential technique is introduced and applied to a matched retrospective cohort of 510 patients with esophageal cancer undergoing CRT to identify patient profiles …