Biomedical Informatics Commons^™

A Phase 1/2 Study Of Ds-1594 Menin Inhibitor In Relapsed/Refractory Acute Leukemias, Jayastu Senapati, Marina Konopleva, Ghayas C Issa, Elias Jabbour, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Indraneel Deshmukh, Joie Alvarez, Sanam Loghavi, Guilin Tang, Hussein A Abbas, Michael Andreeff, Kapil Bhalla, Narasimha M Midde, Nabil Said, Amy Noyalis, Derek E Mires, Jing Ning, Lianchun Xiao, Farhad Ravandi, Guillermo Garcia-Manero, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and …

Predicting The Response Of Triple Negative Breast Cancer To Neoadjuvant Systemic Therapy Via Biology-Based Modeling And Habitat Analysis, Casey E Stowers, Chengyue Wu, Clinton Yam, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Despite being the standard-of-care treatment, neoadjuvant therapy (NAT) attains a complete response only in approximately half of the patients with triple negative breast cancer. Thus, methods to predict and optimize patient response to NAT are needed. Previously, we employed patient-specific MRI data to calibrate a biology-based mathematical model that describes cell movement, proliferation, and death due to drug at the tumor level and cell proliferation at an image voxel level. We now extend our approach by using MRI data to group voxels into "habitats" whereby tumor cells of a habitat share the same proliferation. With this approach, we now calibrate …

An Analysis Of Diagnostic Metabolomic Profiles Associated With Hepatotoxicity During Childhood All Induction Therapy, Emily J Mason, Anna M Crain, Michael E Scheurer, Philip J Lupo, Karen R Rabin, Olga A Taylor, Marley Roberts, John P Woodhouse, Ashley Chavana, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, M Monica Gramatges, Joanna S Yi, Sandi L Pruitt, M Brooke Bernhardt, Hong Zhu, Steven D Mittelman, Van Huynh, Etan Orgel, Jeremy M Schraw, Austin L Brown

Faculty, Staff and Students Publications

Hepatotoxicity is a well-documented complication of induction chemotherapy for acute lymphoblastic leukemia (ALL), but our understanding of its biological mechanisms is limited. We identified 314 patients with ALL (aged 1-19 years) treated at Texas Children’s Hospital (2008-2019) with diagnostic bone marrow plasma available for metabolomic profiling: 234 for discovery and 80 for replication. Hepatotoxicity during induction was defined as follows: (1) transaminitis: grade ≥3 aspartate aminotransferase or alanine aminotransferase or (2) conjugated hyperbilirubinemia: conjugated bilirubin (c.bili) >3 mg/dL. Untargeted profiling detected 519 metabolites. Adjusted odds ratios (aORs) for each metabolite were calculated with logistic regression, accounting for sex, age, body …

Stiefel Md Anderson Oropharynx Cancer (Mda-Opc) Cohort: A Single-Institution, Prospective Longitudinal Outcomes Study, Amy Moreno, Ariana J Sahli, Faye Johnson, Xiaowen Sun, Carly Barbon, Waree Rinsurongkawong, Wenye Song, Flavie M Luciani, Han Liang, Jun Li, Wei Liu, J Jack Lee, S J Frank, Stephen Lai, Clifton Fuller, Katherine Hutcheson

Faculty, Staff and Student Publications

Purpose: The MD Anderson Oropharynx Cancer (MDA-OPC) cohort is a unique single-institution, prospective longitudinal cancer cohort. The cohort aims to enhance the therapeutic index of OPC management by supporting data needs for independent investigators to conduct rigorous observational studies examining exposures and factors associated with acute and late toxicities, cancer progression, recurrence, new malignancies and quality of life in OPC survivors.

Participants: A total of 1811 patients with OPC with a minimum follow-up of 6 months have been consented to our prospective registry between 18 March 2015 and 29 December 2023. Clinical and treatment (Tx) data are available on all …

Analysis Of A Deeply-Phenotyped Familial Hypercholesterolemia Cohort From Mexico Shows A Role For Both Rare And Common Alleles Across Known Dyslipidemia Genes And Reveals Structural Variation In A Novel Locus, Nicholas Katsanis, Niki Mourtzi, Consuelo D Quinto-Cortés, Alexandro J Martagon, Alexander G Ioannidis, Francisco M De La Vega, Jeff Gulcher, Ming Ta Michael Lee, Mohammad A Faghihi, Arturo Lopez-Pineda, Sonia Moreno-Grau, Daniel Mas Montserrat, Míriam Barrabés, David Bonet, Pavel Salazar Fernandez, Jeff Wall, Babak Moatamed, Roopa Mehta, Gabriela A Galan-Ramirez, Rafael Zubirán, Daniel Elias-Lopez, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Carlos D Bustamante

Faculty, Staff and Student Publications

Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway: LDLR, APOB, and PCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in …

Five-Year Follow-Up Analysis Of Zuma-5: Axicabtagene Ciloleucel In Relapsed/Refractory Indolent Non-Hodgkin Lymphoma, Sattva S Neelapu, Julio C Chavez, Alison R Sehgal, Narendranath Epperla, Matthew L Ulrickson, Emmanuel Bachy, Pashna N Munshi, Carla Casulo, David G Maloney, Sven De Vos, Ran Reshef, Lori A Leslie, Olalekan O Oluwole, Ibrahim Yakoub-Agha, Rashmi Khanal, Joseph D Rosenblatt, Jacob Wulff, Rhine R Shen, Wangshu Zhang, Soumya Poddar, Harry Miao, Olga Nikolajeva, Caron A Jacobson

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Here, we report updated clinical outcomes from ZUMA-5 in 159 enrolled patients with R/R indolent non-Hodgkin lymphoma (iNHL; 127 with FL and 31 with marginal zone lymphoma) after a median follow-up of 64.6 months. Patients underwent leukapheresis and received lymphodepleting chemotherapy and axi-cel (2 × 106 CAR T cells/kg). The overall response rate was 90% (75% complete response rate). The median duration of response was 60.4 months, and the median progression-free survival (PFS) was 62.2 months; median time to next …

Using Machine Learning For Early Prediction Of In-Hospital Mortality During Icu Admission In Liver Cancer Patients, Zhuo Zheng, Jinhong Xia, Jiawei Luo, Lei Du, Xiaobo Zhou, Xiaoyan Yang, Yan Xia, Mengyao Liu, Shixin Huang

Faculty, Staff and Student Publications

Liver cancer has a high incidence and mortality rate globally, particularly in patients requiring intensive care unit (ICU) admission. Early prediction of in-hospital mortality for these patients is crucial, yet lacking reliable tools. This study aims to develop and evaluate machine learning (ML) models for predicting in-hospital mortality in critically ill liver cancer patients admitted to the ICU. This retrospective study used data from the MIMIC-III and MIMIC-IV databases, including 862 patients from MIMIC-III (training cohort) and 692 patients from MIMIC-IV (validation cohort). The study focused on patients diagnosed with liver cancer, identified by specific ICD codes. Four ML algorithms, …

Prognosis And Treatment Response Stratification According To Loss Of Proofreading (Lop), Giulia Maddalena, Fadl A Zeineddine, Saikat Chowdhury, Mohammad A Zeineddine, Abdelrahman M Yousef, Francesca Bergamo, Sara Lonardi, Timothy A Yap, Michael Geoffrey White, Michael J Overman, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Background: Only a subset of polymerase epsilon (POLE) mutations is associated with hypermutant phenotype; we hypothesized that only loss-of-proofreading (LOP) POLE mutations are associated with favorable immunotherapy response.

Methods: This retrospective cohort study included a pan-cancer cohort of 69,223 patients from cBioPortal and a cohort of patients with 41 POLE mutant metastatic colorectal (CRC) treated with immunotherapy at the MD Anderson Cancer Center between January 2017 and May 2023. We evaluated prognosis according to POLE mutation functionality.

Results: In the pan-cancer cBioPortal cohort (n=69,223) POLE was mutated in 2.8% (1,965) of tumors; of these, only 7.5% (n=148) had …

Identification Of Therapeutic Targets For Renal Medullary Carcinoma Via Integrated Genomic And Transcriptomic Profiling, Pavlos Msaouel, Nizar M Tannir, Funda Meric-Bernstam, Jennifer M King, Martin H Voss, Jessica P Cheng, Susan S Thomas, Zita D Lim, Menuka Karki, Rong He, Giannicola Genovese, Rahul A Sheth, Davis R Ingram, Diana Shamsutdinova, Khalida M Wani, Wei-Lien Wang, Alexander J Lazar, Dominique Knipper-Davis, Amber Berlinski, Tayla Soares, Danil Stupichev, Kirill Kryukov, Suren Davitavyan, Anna Novokreshchenova, Dmitry Lebedev, Stanislav Kurpe, Andrey Kravets, Dmitrii Belousov, Michael Hensley, Alexander Bagaev, Francesca Paradiso, Vladimir Kushnarev

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable …

First-Line Met Tyrosine Kinase Inhibitors Versus Immunotherapy ± Chemotherapy For Patients With Met Exon 14 Skipping Mutant Metastatic Nsclc, Federica Pecci, Hui Li, Alessandro Di Federico, Jia Wu, Hong Chen, Eleonora Gariazzo, Francesco Mantuano, Edoardo Garbo, Mihaela Aldea, Valentina Santo, Don Gibbons, Hai Tran, Francesco Paoloni, Guilherme Rossato De Almeida, Giulio Metro, Andrea De Giglio, Francesco Gelsomino, Xinan Wang, Marcello Tiseo, Julia Rotow, Andrea Ardizzoni, J Jack Lee, Mark M Awad, Alfredo Addeo, Lingzhi Hong, Marcelo V Negrao, Pasi A Jänne, John V Heymach, Jianjun Zhang, Biagio Ricciuti, Xiuning Le

Faculty, Staff and Student Publications

Purpose: First-line treatment options for MET exon 14 skipping-mutant metastatic non-small cell lung cancer vary because of differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI) ± chemotherapy.

Experimental design: Clinicopathologic data were collected from patients with metastatic MET exon 14 skipping-mutant non-small cell lung cancer treated with first-line MET TKI or ICI ± chemotherapy at five centers. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS) to first-line MET TKI versus ICI ± chemotherapy. Subgroup analyses by clinical and tumor characteristics …

Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle …

Investigating Prognostic Features In High-Grade Serous Ovarian Cancer Through Gene Regulatory Network Inference With Single-Cell Transcriptomic Profiles, Toshiyuki Itai, Yulin Dai, Wendao Liu, Dung-Fang Lee, Zhongming Zhao

Faculty, Staff and Student Publications

This study aimed to identify prognostic features in high-grade serous ovarian cancer (HGSOC) through the application of gene regulatory network (GRN) inference with single-cell RNA-sequencing (scRNA-seq) profiles. To achieve this goal, we developed a workflow comprising scRNA-seq analysis, metacell construction, GRN inference, and a binary classification task for prognosis prediction. We curated 118,173 cells from HGSOC patients in three conditions (Before-chemotherapy, After-chemotherapy, and control samples) from previous studies, and then constructed 1,211 metacells. GRN inference analysis revealed 312 regulons, each consisting of one transcription factor and its targeted features. For prognosis evaluation, we used bulk RNA-seq data covering 342 HGSOC …

Distinct Tumor-Associated Macrophage Signatures Shape The Immune Microenvironment And Patient Prognosis In Renal Cell Carcinoma, Youngsoo Han, Aidan Shen, Cheng-Chi Chao, Lucas Yeung, Aliesha Garrett, Jianming Zeng, Satoru Kawakita, Jesse Wang, Zhaohui Wang, Alireza Hassani, Xiling Shen, Chongming Jiang

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) accounts for 90% of adult renal cancer cases and is characterized by significant heterogeneity within its tumor microenvironment. This study tests the hypothesis that tumor-associated macrophages (TAMs) influence RCC progression and patient response to treatment by investigating the prognostic implications of TAM signatures. Utilizing independent single-cell RNA sequencing data from RCC patients, we developed eight distinct TAM signatures reflective of TAM presence. A LASSO Cox regression model was constructed to predict survival outcomes, evaluated using the TCGA dataset, and validated across independent RCC cohorts. Model performance was assessed through Kaplan-Meier survival plots, receiver operating characteristic (ROC) …

Distinguishing Syndromic And Nonsyndromic Cleft Palate Through Analysis Of Protein-Altering De Novo Variants In 818 Trios, Kelsey R Robinson, Sarah W Curtis, Justin E Paschall, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, David J Cutler, Michael P Epstein, Lord J J Gowans, Jacqueline T Hecht, Gary M Shaw, Lina Moreno Uribe, Jeffrey C Murray, Harrison Brand, Seth M Weinberg, Mary L Marazita, Kimberly F Doheny, Elizabeth J Leslie-Clarkson

Faculty, Staff and Student Publications

De novo variants (DNs) are sporadically occurring variants found in an offspring but absent in both parents. DNs most commonly arise in the germline and are not under selective pressure; therefore, they may be enriched for disease-causing alleles. In fact, DNs have been implicated in multiple rare genetic disorders. Cleft palate (CP) is a craniofacial congenital anomaly occurring in ∼1 in 1,700 live births. Genome-wide association studies have found fewer than a dozen CP-specific loci, while exome and targeted sequencing studies in family-based and case-control cohorts often lack statistical power to conclusively identify causal variants. We therefore hypothesized that CP …

Compadre: Combined Pedigree-Aware Distant Relatedness Estimation For Improved Pedigree Reconstruction, Grahame F Evans, James T Baker, Lauren E Petty, Alexander S Petty, Hannah G Polikowsky, Ryan J Bohlender, Hung-Hsin Chen, Che-Yu Chou, Kathryn Z Viljoen, Janet M Beilby, Shelly Jo Kraft, Wanying Zhu, Joshua M Landman, Autumn R Morrow, Dayi Bian, Alyssa C Scartozzi, Chad D Huff, Jennifer E Below

Faculty, Staff and Student Publications

Designing powerful and unbiased genomic studies requires accurate assessment of familial relatedness even when this information is not captured from participants. Characterization of pairwise degrees of relatedness from participants' genetic data enables reconstruction of pedigrees, and several pedigree reconstruction tools have emerged in the last decade. However, limitations of these tools include high computational burden in large datasets, reliance on external information, reduced accuracy in admixed populations, and most notably, an inability to accurately reconstruct pedigrees when only a subset of family members is represented in the genetic data. To improve pedigree reconstruction in large-scale data and in pedigrees with …

Prospective Phase Ii Clinical Trial Of Molecular Glioblastoma (Historical Grade 2 And 3 Idh Wildtype Gliomas) Preliminary Novel Exploratory Analyses: Treatment Intensification, Margin Reduction And Epigenetic Stratified Outcomes With Radiation Therapy And Chemotherapy, Debra Nana Yeboa, Benjamin T Whitfield, Ruitao Lin, Chinenye Lynette Ejezie, Todd A Swanson, Thomas H Beckham, Chenyang Wang, Brian De, Subha Perni, Martin C Tom, Jing Li, Susan L Mcgovern, Rebecca Harrison, Nazanin K Majd, Vinay K Puduvalli, Ashley E Aaroe, Monica Loghin, Barbara J O'Brien, Anuj D Patel, Chirag B Patel, Jeffrey S Wefel, Ceylan Altintas Taslicay, Maria Gule-Monroe, Arnold C Paulino, Mary Frances Mcaleer, David R Grosshans, Amol J Ghia, Wen Jiang, Caroline Chung, Moshe Maor, Cheng-Han Yang, Maria A Gubbiotti, Carlos Kamiya-Matsuoka, Leomar Y Ballester, Shiao-Pei Weathers, Jason T Huse

Faculty, Staff and Student Publications

Purpose: Molecular glioblastoma (molGBM) is a variant lacking the full histopathological profile of glioblastoma. We report a trial aimed at addressing the optimal management of this newly recognized rarer form of glioma.

Methods: In this phase II study, molGBM patients were treated with radiation to a dose of 60Gy to the gross tumor volume (GTV) only, and a single smaller margin potentially as low as 1cm to the clinical tumor volume (CTV). As the trial is ongoing, we report on important exploratory biomarker findings correlating with median overall survival (mOS). Analysis included Kaplan-Meier and univariable/multivariable cox proportional hazard models. Available …

Cofilin Inhibition Ameliorates Piezo2 And Ampa Dysfunction In A Mouse Model Of Angelman Syndrome, Luis O Romero, Manisha Bade, Elisa Carrillo, Sonia Paz-López, Syed A M Hasan, William James Antonisamy, Vasanthi Jayaraman, Zahoor A Shah, Valeria Vásquez, Julio F Cordero-Morales

Faculty, Staff and Student Publications

Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous (F-)actin, a decrease we also reported in dorsal root ganglia (DRG) neurons, along with impaired mechanosensitive ion channel activity. Currently, there are no pharmacological targets to prevent the decrease of F-actin in AS. Here, we utilize a first-in-class selective cofilin inhibitor (SZ-3) to restore PIEZO2 function in DRG neurons and glutamate-evoked currents in hippocampal neurons from AS mice. Using atomic force microscopy, we demonstrate that inhibiting cofilin, an actin-severing protein, with SZ-3 increases cellular stiffness by stabilizing the actin …

Pregnancy Outcomes In Women With Heritable Thoracic Aortic Disease: Data From The Eorp Esc Registry Of Pregnancy And Cardiac Disease (Ropac) Iii, Puck N J Peters, Johanna A Van Der Zande, Julie De Backer, Guillaume Jondeau, Osama Ahmad, Marjorie Richardson, Francesca M Comoglio, Heleen Van Der Zwaan, Siddharth K Prakash, Christina Christersson, Karishma P Ramlakhan, Roger Hall, Mark R Johnson, Jolien W Roos-Hesselink, Ropac Investigators

Faculty, Staff and Student Publications

Aims: The risk of pregnancy in women with heritable thoracic aortic disease (HTAD) is estimated to be high, but supporting data are scarce. The aim of this study is to prospectively investigate pregnancy outcomes to improve patient management and care.

Methods and results: The Registry of Pregnancy and Cardiac disease (ROPAC) III is a prospective global registry including pregnant women with known aortic pathology between 2018 and 2023. Cardiac, obstetric and fetal outcomes, beta-blocker use, and the impact of breastfeeding were investigated. Additionally, changes in aortic diameters were assessed. In total, 176 pregnancies in 170 women (mean age 32 years, …

Effects Of Combining Traditional East Asian And Conventional Western Medicine On Acute Stroke Outcomes, Dong-Seok Gwak, Jong-Sik Lee, Dawid Schellingerhout, Jinyong Chung, Hyerin Oh, Sang-Wuk Jeong, Ji Sung Lee, Hee-Joon Bae, Mikyung Kim, Dong-Jun Choi, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Traditional East Asian medicine (TM) is widely used in Korea and other East Asian countries. However, the effects of TM treatment on acute ischemic stroke (AIS) outcomes remain unclear, as previous studies lacked a sufficient sample size, a consecutive series design, or a prospective outcome capture approach. We aimed to investigate whether combining TM with conventional Western medicine (CM) treatments (C+TM) leads to better outcomes after AIS, relative to CM treatment alone.

Methods: We retrospectively analyzed 2157 consecutive patients with AIS from a prospectively collected registry (2011-2021) at our center and compared the CM and C+TM groups in terms …

Validation Of A Risk Score For Cancer-Associated Thrombosis Using Nationwide Ehr Data, Ang Li, Omid Jafari, Barbara D Lam, Jun Y Jiang, Rock Bum Kim, Shengling Ma, Emily Zhou, Joyce W Tiong, Elizabeth C Chiang, Justine Ryu, Christopher I Amos, Jennifer La, Nathanael R Fillmore

Faculty, Staff and Student Publications

Importance: Venous thromboembolism (VTE) is associated with increased mortality and morbidity in patients with cancer. Existing risk prediction models are typically validated within individual sites, a fragmented approach that limits clinical adoption.

Objective: To validate the electronic health record cancer-associated thrombosis (EHR-CAT) score compared with the benchmark Khorana score in a contemporary cohort of patients with cancer across the nation, before and after treatment, excluding those at high risk of bleeding.

Design, setting, and participants: This prognostic study included patients in a nationwide longitudinal EHR database from January 2018 to December 2023 with follow-up continuing to April 2025. Patients with …

Early Ctdna Dynamics Inform First-Line Therapy In Patients With Extensive-Stage Small Cell Lung Cancer, Carmela Ciardullo, Luis Tobalina, T Hedley Carr, Philip Szekeres, Silvija Kraljevic, Lauren Averett Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis despite initial treatment responses. This study evaluates ctDNA for monitoring disease and assessing the efficacy of first-line therapy in patients with extensive-stage SCLC (1L ES-SCLC).

Experimental design: In the TAZMAN trial, 31 patients with 1L ES-SCLC received standard treatment with durvalumab and etoposide plus carboplatin or cisplatin. We analyzed 228 plasma samples from 27 of 31 patients using a liquid biopsy approach to detect somatic mutations and copy-number aberrations, while also accounting for clonal hematopoiesis mutations.

Results: Baseline ctDNA analysis detected somatic alterations in 96.3% of …

Preclinical Fluorescence-Guided Imaging Leveraging Surrounding Sentinel Tumor Microenvironment Identifies High-Risk Premalignant Pancreatic Lesions, Shilpa Sharma, Xiaoxia Wen, Jianbo Wang, Beibei Huang, Denise A Hernandez, Cong-Dat Pham, Zhiwen Liu, Susanne Je-Han Lin, Aiko Yamaguchi, Dimitra K Georgiou, Ryan P Coll, H Charles Manning

Faculty, Staff and Student Publications

Purpose: Because surgery is the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often evade detection by palpation or white-light visualization, increasing the risk of recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment as a sentinel of local disease and, thus, enhance surgery outcomes.

Experimental design: Fluorescence-guided surgery was performed on genetically engineered mice [Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox (KSC)] at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein …

Genetic Contribution To Treatment-Related Dyslipidemia In Adult Survivors Of Childhood Cancer: Findings From The Ccss, Sjlife, And Dccss-Later Cohorts, Melissa Bolier, Vincent G Pluimakers, Linda Broer, Sebastian J C M M Neggers, Demi T C De Winter, Fan Wang, Jessica L Baedke, André G Uitterlinden, Kateryna Petrykey, Leontien C M Kremer, Jacqueline J Loonen, Marloes Louwerens, Heleen J Van Der Pal, E Lieke A M Feijen, Kevin C Oeffinger, Rebecca M Howell, Eric J Chow, Wendy M Leisenring, Maria Monica M Gramatges, Lindsay M Morton, Leslie L Robison, Melissa M Hudson, Kirsten K Ness, Yadav Sapkota, Gregory T Armstrong, Smita Bhatia, Yutaka Yasui, Marry M Van Den Heuvel-Eibrink

Faculty, Staff and Student Publications

Background: Dyslipidemia can occur as a long-term side effect of childhood cancer treatment. The difference in prevalence among children receiving comparable treatment suggests a role for genetic variation. We conducted the first genome-wide association study on dyslipidemia in a large childhood cancer survivor cohort, using three additional cohorts for replication.

Methods: Discovery analysis was performed in the original Childhood Cancer Survivor Study (CCSS) cohort (N = 4,332). Replication analyses were carried out in the CCSS expansion (N = 2,212), St. Jude Lifetime (N = 2,829), and Dutch Childhood Cancer Survivor Study (DCCSS-LATER) (N = 1,814) cohorts. In the CCSS cohorts, …

An Annotated Biobank Of Triple-Negative Breast Cancer Patient-Derived Xenografts Features Treatment-Naïve And Longitudinal Samples During Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Baameur Hancock, Sabrina L Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443), including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT treatment and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of the PDX models were capable of metastasizing …

Hand Swelling And Other Non-Raynaud Phenomenon Symptoms As The Initial Presentation Of Systemic Sclerosis: Prevalence And Clinical Associations In Two Us Cohorts, Iqtidar Hanif, Shervin Assassi, Maureen D Mayes, Zsuzsanna H Mcmahan, Meng Zhang, Julio Charles, John M Vanburen, Jessica S Alvey, Kimia Ghaffari, Elana J Bernstein, Flavia V Castelino, Lorinda Chung, Luke Evnin, Tracy M Frech, Jessica K Gordon, Faye N Hant, Laura K Hummers, Dinesh Khanna, Kimberly S Lakin, Dorota Lebiedz-Odrobina, Yiming Luo, Ashima Makol, Jerry A Molitor, Duncan F Moore, Carrie Richardson, Nora Sandorfi, Ami A Shah, Ankoor Shah, Victoria K Shanmugam, Virginia D Steen, Elizabeth R Volkmann, Carleigh Zahn, Brian Skaug

Faculty, Staff and Student Publications

Objective: Raynaud phenomenon (RP) is often the initial clinical manifestation of systemic sclerosis (SSc), but some patients develop other manifestations first. To help elucidate the diversity of SSc presentation in its early stages, we describe the initial clinical manifestations and antinuclear antibody (ANA) profiles of patients in two early SSc cohorts.

Methods: All patient data in the Genetics vs Environment in Scleroderma Outcomes Study (GENISOS) and Collaborative National Quality and Efficacy Registry (CONQUER) cohorts were reviewed. Both studies enrolled patients within five years of the first non-RP symptom.

Results: In GENISOS and CONQUER, respectively, 194 (44.2%) of 439 and 292 …

Microbial Signals In Primary And Metastatic Brain Tumors, Golnaz Morad, Ashish V Damania, Brenda Melendez, Bharat B Singh, Fabiana J Veguilla, Rebecca A Soto, Yasmine M Hoballah, Pranoti V Sahasrabhojane, Matthew C Wong, Mona M Ahmed, Rene N Rico, Kaitlyn N Lewis, Khalida Wani, Diana D Shamsutdinova, Rossana N Lazcano Segura, Davis R Ingram, Eric A Goethe, Abderrahman Day, Ivonne I Flores, Lauren K Mcdaniel, Manoj Chelvanambi, Sarah B Johnson, Florentia Dimitriou, Pravesh Gupta, Shivangi Oberai, M Anna Zal, Phoebe Doss, Mohamed A Jamal, Eiko Hayase, Chetna Wathoo, Lisa M Norberg, Stephanie L Jenkins, Sara Nass, Joy Gumin, Lihong Long, Jing Yang, Gina R Bradley, Mahesh Prasad Bekal, Antonio G Dono, Pavel S Pichardo-Rojas, Samuel W Andrewes, Leomar Y Ballester, Jillian S Losh, Jiyong Liang, Longfei Huo, Douglas C Nielsen, Brittany C Parker Kerrigan, Priscilla K Brastianos, Natalie Wall Fowlkes, Chia-Chi Chang, Robert R Jenq, Candelaria Gomez-Manzano, Jason T Huse, Michael A Davies, Alexander J Lazar, Krishna P Bhat, Nitin Tandon, Yoshua Esquenazi, Christine B Peterson, Vinay K Puduvalli, Frederick F Lang, Christopher D Johnston, Susan Bullman, Nadim J Ajami, Sherise D Ferguson, Jennifer A Wargo

Faculty, Staff and Student Publications

Gliomas and brain metastases are associated with poor prognosis, necessitating a deeper understanding of brain tumor biology and the development of effective therapeutic strategies. Although our group and others have demonstrated microbial presence in various tumors, recent controversies regarding cancer-type-specific intratumoral microbiota emphasize the importance of rigorous, orthogonal validation. This prospective, multi-institutional study included a total of 243 samples from 221 patients, comprising 168 glioma and brain metastases samples and 75 non-cancerous or tumor-adjacent tissues. Using stringent fluorescence in situ hybridization, immunohistochemistry and high-resolution spatial imaging, we detected intracellular bacterial 16S rRNA and lipopolysaccharides in both glioma and brain metastases …

Colorectal-Specific Radiation Dose And Chemotherapy Risk For Subsequent Colorectal Malignancies In Childhood Cancer Survivors: A Childhood Cancer Survivor Study (Ccss) Report, Constance A Owens, Ethan B Ludmir, Qi Liu, Weiyu Qiu, Aashish C Gupta, Susan A Smith, Bastien Rigaud, Kristy K Brock, James E Bates, Taylor G Meyers, Arnold C Paulino, Christine B Peterson, Stephen F Kry, Jop C Teepen, Cécile M Ronckers, Joseph P Neglia, Wendy M Leisenring, Kevin C Oeffinger, Paul C Nathan, Lucie M Turcotte, David C Hodgson, Melissa M Hudson, Leslie L Robison, Chaya S Moskowitz, Gregory T Armstrong, Tara O Henderson, Yutaka Yasui, Rebecca M Howell

Faculty, Staff and Student Publications

Purpose: Among childhood cancer survivors, we evaluated not previously explored relationships between colorectal subsequent malignant neoplasm (SMN) incidence and colorectum-specific radiation dose metrics currently used in radiation therapy (RT) planning and expanded upon previously reported chemotherapy associations.

Methods: The Childhood Cancer Survivor Study (CCSS) includes 5-year survivors of childhood cancer diagnosed between 1970 and 1999. RT was assessed as mean colorectal dose (MCD) and the percent volume (VX Gy) receiving ≥5, 10, 20, 30, and 40 Gy. Chemotherapy was assessed as cumulative doses for procarbazine and platinum agents, cyclophosphamide-equivalent doses for alkylating agents, and doxorubicin-equivalent doses for anthracyclines. Piecewise-exponential models …

Probabilistic Template Matching For Detecting Resting-State Functional Mri Language Network In Brain Tumor Patients, Jian Ming Teo, Vinodh A Kumar, Alexander M Khalaf, Kyle R Noll, Sherise D Ferguson, Chibawanye I Ene, Sujit S Prabhu, Max Wintermark, Ho-Ling Liu

Faculty, Staff and Student Publications

Background: Intersubject variation among patients with brain tumors complicates the template matching process for detecting the resting-state (rs) functional MRI (fMRI) language network when using independent component analysis (ICA).

Purpose: This study aimed to develop methods that use a probabilistic language atlas to incorporate intersubject variation in brain tumor patients into the template matching process.

Methods: This retrospective study included 79 patients with brain tumors (average age, 50 ± 15 years) who underwent presurgical task-based (tb)-fMRI and rs-fMRI at clinical 3T scanners. At varying template generation thresholds (τ), binary and probabilistic templates were obtained from the language atlas. A binary …

Sars-Cov-2 Mrna Vaccines Sensitize Tumours To Immune Checkpoint Blockade, Adam J Grippin, Christiano Marconi, Sage Copling, Nan Li, Chen Braun, Cole Woody, Elliana Young, Priti Gupta, Min Wang, Annette Wu, Seong Dong Jeong, Dhruvkumar Soni, Frances Weidert, Chao Xie, Eden Goldenberg, Andrew Kim, Chong Zhao, Anna Devries, Paul Castillo, Rishabh Lohray, Michael K Rooney, Benjamin R Schrank, Yifan Wang, Yifan Ma, Enoch Chang, Ramez Kouzy, Kyle Dyson, Jordan Jafarnia, Nina Nariman, Gregory Gladish, Jacob New, Ada Argueta, Diana Amaya, Nagheme Thomas, Andria Doty, Joe Chen, Nikhil Copling, Gabriel Alatrash, Julie Simon, Alicia Bea Davies, William Dennis, Richard Liang, Jeff Lewis, Xiong Wei, Waree Rinsurongkawong, Ara A Vaporciyan, Andrew Johns, D3code Team, Jack Lee, Ji-Hyun Lee, Ryan Sun, Padmanee Sharma, Hai Tran, Jianjun Zhang, Don L Gibbons, Jennifer Wargo, Betty Y S Kim, John V Heymach, Hector R Mendez-Gomez, Wen Jiang, Elias J Sayour, Steven H Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1–9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10–14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for …

Integration Of Genetic And Imaging Data For Alzheimer's Disease Diagnosis And Interpretation, Yanfei Wang, Qing Wang, Minghao Zhou, Jialu Liang, Lei You, Breton Asken, Xiaobo Zhou, Qianqian Song

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by complex interactions between genetic risk factors and structural brain changes. Traditional diagnostic approaches that rely on single-modality data, such as imaging or genomics alone, often fall short in both predictive accuracy and biological interpretability. To address these limitations, AlzCLIP, a novel contrastive learning framework that integrates single nucleotide polymorphism (SNP) profiles and MRI-derived imaging features into a unified embedding space is introduced. This joint representation captures disease-relevant interactions between genetic variation and brain structure, enabling both accurate diagnosis and mechanistic insight into AD. AlzCLIP is trained and evaluated on two …