Medical Specialties Commons^™

Ovarian Cancer Metastasis: Looking Beyond The Surface, Emine Bayraktar, Sisy Chen, Sara Corvigno, Jinsong Liu, Anil K Sood

Faculty, Staff and Student Publications

Historically, ovarian cancer (OC) was thought to metastasize by surface-to-surface spread, but recent developments have yielded a new understanding of the paths of metastatic spread. Given the histologic and molecular heterogeneity of OC, we will focus on high-grade serous carcinoma (HGSC). Here, we provide a critical and more holistic view of the evidence supporting various routes of metastasis, including peritoneal, hematogenous, lymphatic, and nerve-related. Understanding the underlying mechanisms is necessary to improve treatment strategies for this challenging disease.

Left Ventricular Diastolic Dysfunction With Elevated Filling Pressures Is Associated With Embolic Stroke Of Undetermined Source And Atrial Fibrillation, Zubair Bashir, Liqi Shu, Yuqian Guo, Edward W Chen, Shuyuan Wang, Eric D Goldstein, Maheen Rana, Narendra Kala, Xing Dai, Daniel Mandel, Shadi Yaghi, Phinnara Has, Mingxing Xie, Tao Wang, James Simmons, Christopher Song, Philip Haines

Faculty, Staff and Student Publications

Background/Objectives: Left ventricular diastolic dysfunction (LVDD) and elevated left ventricular filling pressure (LVFP) are strong predictors of clinical outcomes across various populations. However, their diagnostic utility in embolic stroke of undetermined source (ESUS) remains unclear. We hypothesized that LVDD with elevated LVFP (based on echocardiography) was more likely to be prevalent in ESUS compared to non-cardioembolic stroke (NCE) and to be associated with atrial fibrillation (AF) on follow-up monitoring.

Methods: This is a single-center retrospective study that included adult patients with a diagnosis of acute ischemic stroke between January 2016 and June 2017. LV function was assessed by …

Bi-Directional Allosteric Pathway In Nmda Receptor Activation And Modulation, Paula A Bender, Subhajit Chakraborty, Ryan J Durham, Vladimir Berka, Elisa Carrillo, Vasanthi Jayaraman

Faculty, Staff and Student Publications

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane …

Impact Of Age On Pharmacogenomics And Treatment Outcomes Of B-Cell Acute Lymphoblastic Leukemia, Satoshi Yoshimura, Zhenhua Li, Yoshihiro Gocho, Wenjian Yang, Kristine R Crews, Shawn H R Lee, Kathryn G Roberts, Charles G Mullighan, Mary V Relling, Jiyang Yu, Allen E J Yeoh, Mignon L Loh, Caner Saygin, Mark R Litzow, Sima Jeha, Seth E Karol, Hiroto Inaba, Ching-Hon Pui, Marina Konopleva, Nitin Jain, Wendy Stock, Elisabeth Paietta, Elias Jabbour, Steven M Kornblau, William E Evans, Jun J Yang

Faculty, Staff and Student Publications

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations …

Molecular And Clinical Features Of Pancreatic Acinar Cell Carcinoma: A Single-Institution Case Series, Ashwathy Balachandran Pillai, Mahmoud Yousef, Abdelrahman Yousef, Kristin D Alfaro-Munoz, Brandon G Smaglo, Jason Willis, Robert A Wolff, Shubham Pant, Mark W Hurd, Anirban Maitra, Huamin Wang, Matthew Harold G Katz, Laura R Prakash, Ching-Wei D Tzeng, Rebecca Snyder, Luca F Castelnovo, Anthony Chen, Andrey Kravets, Kseniia Kudriavtseva, Artem Tarasov, Kirill Kryukov, Haoqiang Ying, John Paul Shen, Dan Zhao

Faculty, Staff and Student Publications

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods: We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023-2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing …

Phase I/Ii Study Of Bms-986156 With Ipilimumab Or Nivolumab With Or Without Stereotactic Ablative Radiotherapy In Patients With Advanced Solid Malignancies, Joe Y Chang, Xinyan Xu, Girish S Shroff, Nathan I Comeaux, Wei Li, Jordi Rodon Ahnert, Daniel D Karp, Ecaterina E Dumbrava, Vivek Verma, Aileen Chen, James Welsh, David S Hong

Faculty, Staff and Student Publications

Background: BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043).

Methods: This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 …

Impact Of Cancer Therapy On Clonal Hematopoiesis Mutations And Subsequent Clinical Outcomes, Kevin T Nead, Taebeom Kim, Lijin Joo, Tina L Mcdowell, Justin W Wong, Irenaeus C C Chan, Elizabeth Brock, Jing Zhao, Ting Xu, Chad Tang, Chang-Lung Lee, Jun-Ichi Abe, Kelly L Bolton, Zhongxing Liao, Paul A Scheet, Steven H Lin

Faculty, Staff and Student Publications

Exposure to cancer therapies is associated with an increased risk of clonal hematopoiesis (CH). The objective of our study was to investigate the genesis and evolution of CH after cancer therapy. In this prospective study, we undertook error-corrected duplex DNA sequencing in blood samples collected before and at 2 time points after chemoradiation in patients with esophageal or lung cancer recruited from 2013 to 2018. We applied a customized workflow to identify the earliest changes in CH mutation count and clone size and determine their association with clinical outcomes. Our study included 29 patients (87 samples). Their median age was …

Flagellar Motility Is Mutagenic, Souvik Bhattacharyya, Shelby Lopez, Abhyudai Singh, Rasika M Harshey

Faculty, Staff and Student Publications

Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but also to promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ~10% of the entire energy budget of an

Rapid Hyperspectral Photothermal Mid-Infrared Spectroscopic Imaging From Sparse Data For Gynecologic Cancer Tissue Subtyping, Reza Reihanisaransari, Chalapathi Charan Gajjela, Xinyu Wu, Ragib Ishrak, Sara Corvigno, Yanping Zhong, Jinsong Liu, Anil K Sood, David Mayerich, Sebastian Berisha, Rohith Reddy

Faculty, Staff and Student Publications

Ovarian cancer detection has traditionally relied on a multistep process that includes biopsy, tissue staining, and morphological analysis by experienced pathologists. While widely practiced, this conventional approach suffers from several drawbacks: it is qualitative, time-intensive, and heavily dependent on the quality of staining. Mid-infrared (MIR) hyperspectral photothermal imaging is a label-free, biochemically quantitative technology that, when combined with machine learning algorithms, can eliminate the need for staining and provide quantitative results comparable to traditional histology. However, this technology is slow. This work presents a novel approach to MIR photothermal imaging that enhances its speed by an order of magnitude. This …

Fast, Variable Stiffness-Induced Braided Coiled Artificial Muscles, Xinghao Hu, Xiangyu Wang, Jian Wang, Guorong Zhang, Shaoli Fang, Fengrui Zhang, Ye Xiao, Guanggui Cheng, Ray H Baughman, Jianning Ding

Faculty, Staff and Student Publications

Biomimetic actuation technologies with high muscle strokes, cycle rates, and work capacities are necessary for robotic systems. We present a muscle type that operates based on changes in muscle stiffness caused by volume expansion. This muscle is created by coiling a mechanically strong braid, in which an elastomer hollow tube is adhesively attached inside. We show that the muscle reversibly contracts by 47.3% when driven by an oscillating input air pressure of 120 kilopascals at 10 Hz. It generates a maximum power density of 3.0 W/g and demonstrates a mechanical contractile efficiency of 74%. The muscle's low-pressure operation allowed for …

The Impact Of A Web-Based Prognostic Calculator On Prognostic Confidence In Outpatient Palliative Care, David Hui, John P Maxwell, Allison De La Rosa, Kristofer Jennings, Marieberta Vidal, Akhila Reddy, Ahsan Azhar, Rony Dev, Kimberson Tanco, Yvonne Heung, Marvin Delgado-Guay, Donna Zhukovsky, Joseph Arthur, Suresh Reddy, Sriram Yennu, Amy Ontai, Eduardo Bruera

Faculty, Staff and Student Publications

Purpose: Clinicians are often uncertain about their prognostic estimates, which may impede prognostic communication and clinical decision-making. We assessed the impact of a web-based prognostic calculator on physicians' prognostic confidence.

Methods: In this prospective study, palliative care physicians estimated the prognosis of patients with advanced cancer in an outpatient clinic using the temporal, surprise, and probabilistic approaches for 6 m, 3 m, 2 m, 1 m, 2 w, 1 w, and 3 d. They then reviewed information from www.predictsurvival.com , which calculated survival estimates from seven validated prognostic scores, including the Palliative Prognostic Score, Palliative Prognostic Index, and Palliative Performance …

Ct Strain Metrics Allow For Earlier Diagnosis Of Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplant, Husham Sharifi, Christopher D Bertini, Mansour Alkhunaizi, Maria Hernandez, Zayan Musa, Carlos Borges, Ihsan Turk, Lara Bashoura, Burton F Dickey, Guang-Shing Cheng, Gregory Yanik, Craig J Galban, Huawei Henry Guo, Myrna C B Godoy, Joseph M Reinhardt, Eric A Hoffman, Mario Castro, Gabriela Rondon, Amin M Alousi, Richard E Champlin, Elizabeth J Shpall, Ying Lu, Samuel Peterson, Keshav Datta, Mark R Nicolls, Joe Hsu, Ajay Sheshadri

Faculty, Staff and Student Publications

Bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is associated with substantial morbidity and mortality. Quantitative computed tomography (qCT) can help diagnose advanced BOS meeting National Institutes of Health (NIH) criteria (NIH-BOS) but has not been used to diagnose early, often asymptomatic BOS (early BOS), limiting the potential for early intervention and improved outcomes. Using pulmonary function tests (PFTs) to define NIH-BOS, early BOS, and mixed BOS (NIH-BOS with restrictive lung disease) in patients from 2 large cancer centers, we applied qCT to identify early BOS and distinguish between types of BOS. Patients with transient impairment or healthy lungs …

Atr Inhibition Radiosensitizes Cells Through Augmented Dna Damage And G2 Cell Cycle Arrest Abrogation, Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H Mcfadden, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells, which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 …

Immunologic Signatures Of Response And Resistance To Nivolumab With Ipilimumab In Advanced Metastatic Cancer, Apostolia M Tsimberidou, Farah A Alayli, Kwame Okrah, Alexandra Drakaki, Danny N Khalil, Shivaani Kummar, Saad A Khan, F Stephen Hodi, David Y Oh, Christopher R Cabanski, Shikha Gautam, Stefanie L Meier, Meelad Amouzgar, Shannon M Pfeiffer, Robin Kageyama, Enjun Yang, Marko Spasic, Michael T Tetzlaff, Wai Chin Foo, Travis J Hollmann, Yanyun Li, Matthew Adamow, Phillip Wong, Jonni S Moore, Sharlene Velichko, Richard O Chen, Dinesh Kumar, Samantha Bucktrout, Ramy Ibrahim, Ute Dugan, Lisa Salvador, Vanessa M Hubbard-Lucey, Jill O'Donnell-Tormey, Sandra Santulli-Marotto, Lisa H Butterfield, Diane M Da Silva, Justin Fairchild, Theresa M Lavallee, Lacey J Padrón, Padmanee Sharma

Faculty, Staff and Student Publications

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

An Iron-Rich Subset Of Macrophages Promotes Tumor Growth Through A Bach1-Ednrb Axis, Ian W Folkert, William A Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S Molina, Jason Shoush, Hesham Mohei, Li Zhai, Md Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J Lazar, Khalida Wani, William P Israel, Zhan Zhang, Venkata S Chaluvadi, Robert J Norgard, Ying Liu, Ashley M Fuller, Mai T Dang, Robert E Roses, Giorgos C Karakousis, John T Miura, Douglas L Fraker, T S Karin Eisinger-Mathason, M Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar

Faculty, Staff and Student Publications

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional …

Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity And Tumor-Immune Evolution In Refractory Mantle Cell Lymphoma, Shaojun Zhang, Vivian Changying Jiang, Guangchun Han, Dapeng Hao, Junwei Lian, Yang Liu, Qingsong Cai, Rongjia Zhang, Joseph Mcintosh, Ruiping Wang, Minghao Dang, Enyu Dai, Yuanxin Wang, David Santos, Maria Badillo, Angela Leeming, Zhihong Chen, Kimberly Hartig, John Bigcal, Jia Zhou, Rashmi Kanagal-Shamanna, Chi Young Ok, Hun Lee, Raphael E Steiner, Jianhua Zhang, Xingzhi Song, Ranjit Nair, Sairah Ahmed, Alma Rodriquez, Selvi Thirumurthi, Preetesh Jain, Nicolaus Wagner-Bartak, Holly Hill, Krystle Nomie, Christopher Flowers, Andrew Futreal, Linghua Wang, Michael Wang

Faculty, Staff and Student Publications

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and …

Author Correction: Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity And Tumor-Immune Evolution In Refractory Mantle Cell Lymphoma, Shaojun Zhang, Vivian Changying Jiang, Guangchun Han, Dapeng Hao, Junwei Lian, Yang Liu, Qingsong Cai, Rongjia Zhang, Joseph Mcintosh, Ruiping Wang, Minghao Dang, Enyu Dai, Yuanxin Wang, David Santos, Maria Badillo, Angela Leeming, Zhihong Chen, Kimberly Hartig, John Bigcal, Jia Zhou, Rashmi Kanagal-Shamanna, Chi Young Ok, Hun Lee, Raphael E Steiner, Jianhua Zhang, Xingzhi Song, Ranjit Nair, Sairah Ahmed, Alma Rodriquez, Selvi Thirumurthi, Preetesh Jain, Nicolaus Wagner-Bartak, Holly Hill, Krystle Nomie, Christopher Flowers, Andrew Futreal, Linghua Wang, Michael Wang

Faculty, Staff and Student Publications

No abstract provided.

Conserved Signaling Modules Regulate Filamentous Growth In Fungi: A Model For Eukaryotic Cell Differentiation, Matthew D Vandermeulen, Michael C Lorenz, Paul J Cullen

Faculty, Staff and Student Publications

Eukaryotic organisms are composed of different cell types with defined shapes and functions. Specific cell types are produced by the process of cell differentiation, which is regulated by signal transduction pathways. Signaling pathways regulate cell differentiation by sensing cues and controlling the expression of target genes whose products generate cell types with specific attributes. In studying how cells differentiate, fungi have proved valuable models because of their ease of genetic manipulation and striking cell morphologies. Many fungal species undergo filamentous growth-a specialized growth pattern where cells produce elongated tube-like projections. Filamentous growth promotes expansion into new environments, including invasion into …

Multiregional Transcriptomic Profiling Provides Improved Prognostic Insight In Localized Non-Small Cell Lung Cancer, Chenyang Li, Thinh T Nguyen, Jian-Rong Li, Xingzhi Song, Junya Fujimoto, Latasha Little, Curtis Gumb, Chi-Wan B Chow, Ignacio I Wistuba, Andrew P Futreal, Jianhua Zhang, Shawna M Hubert, John V Heymach, Jia Wu, Christopher I Amos, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with …

The History Of Chromosomal Instability In Genome-Doubled Tumors, Toby M Baker, Siqi Lai, Andrew R Lynch, Tom Lesluyes, Haixi Yan, Huw A Ogilvie, Annelien Verfaillie, Stefan Dentro, Amy L Bowes, Nischalan Pillay, Adrienne M Flanagan, Charles Swanton, Paul T Spellman, Maxime Tarabichi, Peter Van Loo

Faculty, Staff and Student Publications

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe Gain Route Identification and Timing In Cancer (GRITIC), a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains …

Biologic And Clinical Analysis Of Childhood Gamma Delta T-All Identifies Lmo2/Stag2 Rearrangements As Extremely High Risk, Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A De Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan

Faculty, Staff and Student Publications

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in …

Tissue-Agnostic Targeting Of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals And Future Directions, Mohamed A Gouda, Kyaw Z Thein, David S Hong

Faculty, Staff and Student Publications

NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition …

Cd28 Costimulation Augments Car Signaling In Nk Cells Via The Lck/Cd3Ζ/Zap70 Signaling Axis, Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, …

Multi-Ancestry Gwas Meta-Analyses Of Lung Cancer Reveal Susceptibility Loci And Elucidate Smoking-Independent Genetic Risk, Bryan R Gorman, Sun-Gou Ji, Michael Francis, Anoop K Sendamarai, Yunling Shi, Poornima Devineni, Uma Saxena, Elizabeth Partan, Andrea K Devito, Jinyoung Byun, Younghun Han, Xiangjun Xiao, Don D Sin, Wim Timens, Jennifer Moser, Sumitra Muralidhar, Rachel Ramoni, Rayjean J Hung, James D Mckay, Yohan Bossé, Ryan Sun, Christopher I Amos, Va Million Veteran Program, Saiju Pyarajan

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 …

Romi: A Randomized Two-Stage Basket Trial Design To Optimize Doses For Multiple Indications, Shuqi Wang, Peter F Thall, Kentaro Takeda, Ying Yuan

Faculty, Staff and Student Publications

Optimizing doses for multiple indications is challenging. The pooled approach of finding a single optimal biological dose (OBD) for all indications ignores that dose-response or dose-toxicity curves may differ between indications, resulting in varying OBDs. Conversely, indication-specific dose optimization often requires a large sample size. To address this challenge, we propose a Randomized two-stage basket trial design that Optimizes doses in Multiple Indications (ROMI). In stage 1, for each indication, response and toxicity are evaluated for a high dose, which may be a previously obtained maximum tolerated dose, with a rule that stops accrual to indications where the high dose …

Whole-Exome Sequencing Uncovers The Genetic Complexity Of Bicuspid Aortic Valve In Families With Early-Onset Complications, Sara Mansoorshahi, Anji T Yetman, Malenka M Bissell, Yuli Y Kim, Hector I Michelena, Julie De Backer, Laura Muiño Mosquera, Dawn S Hui, Anthony Caffarelli, Maria G Andreassi, Ilenia Foffa, Dongchuan Guo, Rodolfo Citro, Margot De Marco, Justin T Tretter, Shaine A Morris, Simon C Body, Jessica X Chong, Michael J Bamshad, Dianna M Milewicz, Siddharth K Prakash

Faculty, Staff and Student Publications

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate …

Likelihood Adaptively Incorporated External Aggregate Information With Uncertainty For Survival Data, Ziqi Chen, Yu Shen, Jing Qin, Jing Ning

Faculty, Staff and Student Publications

Population-based cancer registry databases are critical resources to bridge the information gap that results from a lack of sufficient statistical power from primary cohort data with small to moderate sample size. Although comprehensive data associated with tumor biomarkers often remain either unavailable or inconsistently measured in these registry databases, aggregate survival information sourced from these repositories has been well documented and publicly accessible. An appealing option is to integrate the aggregate survival information from the registry data with the primary cohort to enhance the evaluation of treatment impacts or prediction of survival outcomes across distinct tumor subtypes. Nevertheless, for rare …

The Biological Significance Of Tumor Grade, Age, Enhancement, And Extent Of Resection In Idh-Mutant Gliomas: How Should They Inform Treatment Decisions In The Era Of Idh Inhibitors?, Martin J Van Den Bent, Pim J French, Daniel Brat, Joerg C Tonn, Mehdi Touat, Benjamin M Ellingson, Robert J Young, Johan Pallud, Andreas Von Deimling, Felix Sahm, Dominique Figarella Branger, Raymond Y Huang, Michael Weller, Ingo K Mellinghoff, Tim F Cloughsey, Jason T Huse, Kenneth Aldape, Guido Reifenberger, Gilbert Youssef, Philipp Karschnia, Houtan Noushmehr, Katherine B Peters, Francois Ducray, Matthias Preusser, Patrick Y Wen

Faculty, Staff and Student Publications

The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with …

The Cochlear Dose And The Age At Radiotherapy Predict Severe Hearing Loss After Passive Scattering Proton Therapy And Cisplatin In Children With Medulloblastoma, Mohammad H Abu-Arja, Austin L Brown, Jack M Su, M Fatih Okcu, Holly B Lindsay, Susan L Mcgovern, Mary Frances Mcaleer, David R Grosshans, Murali M Chintagumpala, Arnold C Paulino

Faculty, Staff and Student Publications

Background: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin.

Methods: We identified patients aged 3-21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI).

Results: Seventy-nine patients …

Identification Of A Single-Dose, Low-Flip-Angle-Based Cbv Threshold For Fractional Tumor Burden Mapping In Recurrent Glioblastoma, Aliya Anil, Ashley M Stokes, John P Karis, Laura C Bell, Jennifer Eschbacher, Kristofer Jennings, Melissa A Prah, Leland S Hu, Jerrold L Boxerman, Kathleen M Schmainda, C Chad Quarles

Faculty, Staff and Student Publications

Background and purpose: DSC-MR imaging can be used to generate fractional tumor burden (FTB) maps via application of relative CBV thresholds to spatially differentiate glioblastoma recurrence from posttreatment radiation effects (PTRE). Image-localized histopathology was previously used to validate FTB maps derived from a reference DSC-MR imaging protocol by using preload, a moderate flip angle (MFA, 60°), and postprocessing leakage correction. Recently, a DSC-MR imaging protocol with a low flip angle (LFA, 30°) with no preload was shown to provide leakage-corrected relative CBV (rCBV) equivalent to the reference protocol. This study aimed to identify the rCBV thresholds for the LFA protocol …