Biomedical Informatics Commons^™

Multi-Antigen Intranasal Vaccine Protects Against Challenge With Sarbecoviruses And Prevents Transmission In Hamsters, Ankita Leekha, Arash Saeedi, K M Samiur Rahman Sefat, Monish Kumar, Melisa Martinez-Paniagua, Adrian Damian, Rohan Kulkarni, Kate Reichel, Ali Rezvan, Shalaleh Masoumi, Xinli Liu, Laurence J N Cooper, Manu Sebastian, Courtney M Sands, Vallabh E Das, Nimesh B Patel, Brett Hurst, Navin Varadarajan

Faculty, Staff and Student Publications

Immunization programs against SARS-CoV-2 with commercial intramuscular vaccines prevent disease but are less efficient in preventing infections. Mucosal vaccines can provide improved protection against transmission, ideally for different variants of concern (VOCs) and related sarbecoviruses. Here, we report a multi-antigen, intranasal vaccine, NanoSTING-SN (NanoSTING-Spike-Nucleocapsid), eliminates virus replication in both the lungs and the nostrils upon challenge with the pathogenic SARS-CoV-2 Delta VOC. We further demonstrate that NanoSTING-SN prevents transmission of the SARS-CoV-2 Omicron VOC (BA.5) to vaccine-naïve hamsters. To evaluate protection against other sarbecoviruses, we immunized mice with NanoSTING-SN. We showed that immunization affords protection against SARS-CoV, leading to protection …

Impact Of Patient Demographics And Neighborhood Socioeconomic Variables On Clinical Trial Participation Patterns For Nhl, Chijioke Nze, Clark R Andersen, Amy A Ayers, Jason Westin, Michael Wang, Swaminathan Iyer, Sairah Ahmed, Chelsea Pinnix, Francisco Vega, Lynne Nguyen, Lorna Mcneill, Loretta J Nastoupil, Kehe Zhang, Cici X Bauer, Christopher R Flowers

Faculty, Staff and Student Publications

Prior studies have demonstrated that certain populations including older patients, racial/ethnic minority groups, and women are underrepresented in clinical trials. We performed a retrospective analysis of patients with non-Hodgkin lymphoma (NHL) seen at MD Anderson Cancer Center (MDACC) to investigate the association between trial participation, race/ethnicity, travel distance, and neighborhood socioeconomic status (nSES). Using patient addresses, we ascertained nSES variables on educational attainment, income, poverty, racial composition, and housing at the census tract (CT) level. We also performed geospatial analysis to determine the geographic distribution of clinical trial participants and distance from patient residence to MDACC. We examined 3146 consecutive …

First-In-Human Dose Escalation Trial To Evaluate The Clinical Safety And Efficacy Of An Anti-Magea1 Autologous Tcr-Transgenic T Cell Therapy In Relapsed And Refractory Solid Tumors, Martin Wermke, Tobias A W Holderried, Jason John Luke, Van K Morris, Winfried H Alsdorf, Katrin Wetzko, Borje S Andersson, Ignacio I Wistuba, Edwin R Parra, Mohammad B Hossain, Sandra Grund-Gröschke, Katrin Aslan, Arun Satelli, Anantha Marisetty, Swapna Satam, Mamta Kalra, Jens Hukelmann, M Alper Kursunel, Karine Pozo, Andreas Acs, Linus Backert, Melissa Baumeister, Sebastian Bunk, Claudia Wagner, Oliver Schoor, Ali S Mohamed, Andrea Mayer-Mokler, Norbert Hilf, Delfi Krishna, Steffen Walter, Apostolia M Tsimberidou, Cedrik M Britten

Faculty, Staff and Student Publications

RATIONALE OF THE TRIAL: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.

TRIAL DESIGN: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of …

Low Skeletal Muscle Mass Is Associated With Inferior Preoperative And Postoperative Shoulder Function In Elderly Rotator Cuff Tear Patients, Yang Yang, Binbin Zheng, Xiaofang Lin, Mengqin Zhang, Yongzhi Ye, Haixiao Chen, Xiaobo Zhou

Faculty, Staff and Student Publications

BACKGROUND: The age-related loss of skeletal muscle mass is an important characteristic of sarcopenia, an increasingly recognized condition with systemic implications. However, its association with shoulder function in elderly patients with rotator cuff tears (RCT) remains unknown. This study aimed to investigate the relationship between low skeletal muscle mass and shoulder function in elderly RCT patients.

METHODS: A retrospective analysis was conducted on RCT patients who underwent chest computed tomography (CT) scans for clinical evaluation. Preoperative CT scan images of the chest were used to calculate the cross-sectional area (CSA) of thoracic muscle at the T4 level. The medical records …

Safety And Effectiveness Of Using Disposable Ultrasonic Shears To Coagulate 5–7 Mm Blood Vessels: Protocol For A Prospective, Multicenter, Randomized, Parallel Controlled, Non-Inferiority Clinical Trial, Xipeng Wang, Chengqiang Li, Junqiang Fan, Jian Hu, Mingsong Wang, Hecheng Li

Faculty, Staff and Student Publications

BACKGROUND: The ultrasonic scalpel is widely used during surgery. It is safe and effective to close the pulmonary artery branch vessels of 7 mm or below with an ultrasonic energy device as reported. However, there have been no multicenter randomized clinical trial to assess the safety and effectiveness of using ultrasonic scalpel to coagulate 5-7 mm blood vessels in thoracic surgery.

METHODS: This is a prospective, multicenter, randomized, parallel controlled, non-inferiority clinical trial. A total of 144 eligible patients planning to undergo lung or esophageal surgery will be randomly allocated to the experimental group and the control group. The investigational …

Exploration Of A Potential Door Endpoint For Hospital-Acquired Bacterial Pneumonia And Ventilator-Associated Bacterial Pneumonia Using Six Registrational Trials For Antibacterial Drugs, Tori Kinamon, Ursula Waack, Mark Needles, Daniel Rubin, Deborah Collyar, Sarah B Doernberg, Scott R Evans, Toshimitsu Hamasaki, Thomas L Holland, Jessica Howard-Anderson, Henry Chambers, Vance G Fowler, Sumati Nambiar, Peter Kim, Helen W Boucher, Ramya Gopinath

Faculty, Staff and Student Publications

BACKGROUND: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).

METHODS: Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that …

Targeted Sequencing For Hereditary Breast And Ovarian Cancer In Brca1/2-Negative Families Reveals Complex Genetic Architecture And Phenocopies, Jocelyn N Plowman, Evanjalina J Matoy, Lavanya V Uppala, Samantha B Draves, Cynthia J Watson, Bridget A Sefranek, Mark L Stacey, Samuel P Anderson, Michael A Belshan, Elizabeth E Blue, Chad D Huff, Yusi Fu, Holly A F Stessman

Faculty, Staff and Student Publications

Approximately 20% of breast cancer cases are attributed to increased family risk, yet variation in BRCA1/2 can only explain 20%-25% of cases. Historically, only single gene or single variant testing were common in at-risk family members, and further sequencing studies were rarely offered after negative results. In this study, we applied an efficient and inexpensive targeted sequencing approach to provide molecular diagnoses in 245 human samples representing 134 BRCA mutation-negative (BRCAX) hereditary breast and ovarian cancer (HBOC) families recruited from 1973 to 2019 by Dr. Henry Lynch. Sequencing identified 391 variants, which were functionally annotated and ranked based on their …

Morphotype-Specific Calcium Signaling In Human Microglia, Sofia Nevelchuk, Bianca Brawek, Niklas Schwarz, Ariel Valiente-Gabioud, Thomas V Wuttke, Yury Kovalchuk, Henner Koch, Anke Höllig, Frederik Steiner, Katherine Figarella, Oliver Griesbeck, Olga Garaschuk

Faculty, Staff and Student Publications

Background: Key functions of Ca2+ signaling in rodent microglia include monitoring the brain state as well as the surrounding neuronal activity and sensing the danger or damage in their vicinity. Microglial Ca2+ dyshomeostasis is a disease hallmark in many mouse models of neurological disorders but the Ca2+ signal properties of human microglia remain unknown.

Methods: We developed a novel genetically-encoded ratiometric Ca2+ indicator, targeting microglial cells in the freshly resected human tissue, organotypically cultured tissue slices and analyzed in situ ongoing Ca2+ signaling of decades-old microglia dwelling in their native microenvironment.

Results: The data revealed marked compartmentalization of Ca2+ signals, …

Epigenome-Wide Association Study Of Lung Cancer Among Never Smokers In Two Prospective Cohorts In Shanghai, China, Mohammad L Rahman, Charles E Breeze, Xiao-Ou Shu, Jason Y Y Wong, Batel Blechter, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas A Bell, Wei Zheng, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted.

METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse …

Hiv/Aids-Associated Knowledge And Attitudes Towards Treating Disadvantaged Communities Among Pre-Community-Based Dental Education Dental Students In The Us, Aditi Tomar, Hannah Balcezak, Shirley Lewis Miranda, Marie C Latortue, Richa Chinchkhandi, Lisa Wigfall

Faculty, Staff and Student Publications

This study examines HIV/AIDS-associated knowledge and attitudes towards treating disadvantaged communities among predoctoral dental students in U.S. dental schools who have not yet commenced their Community-Based Dental Education (CBDE) training. It also compares the difference in the knowledge and attitudes between students with reported community engagement with PLWHA and those without. Our study comprised 89 predoctoral dental students within their D1-D3 years of dental school who had not yet initiated their Community-Based Dental Education (referred to as pre-CBDE dental students). Their responses were collected via an online survey. The participants were 68% females, 94% heterosexual, and with a mean age …

Clinical And Genomic Landscape Of Ras Mutations In Gynecologic Cancers, Ji Son, Yingao Zhang, Heather Lin, Oriol Mirallas, Pablo Alvarez Ballesteros, Mirella Nardo, Natalie Clark, R Tyler Hillman, Erick Campbell, Vijaykumar Holla, Amber M Johnson, Amadeo B Biter, Ying Yuan, Lauren P Cobb, David M Gershenson, Amir A Jazaeri, Karen H Lu, Pamela T Soliman, Shannon N Westin, Elizabeth D Euscher, Barrett C Lawson, Richard K Yang, Funda Meric-Bernstam, David S Hong

Faculty, Staff and Student Publications

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications.

Experimental design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model.

Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and …

Intratumoral Microbiome Of Adenoid Cystic Carcinomas And Comparison With Other Head And Neck Cancers, Tatiana V Karpinets, Yoshitsugu Mitani, Chia-Chi Chang, Xiaogang Wu, Xingzhi Song, Ivonne I Flores, Lauren K Mcdaniel, Yasmine M Hoballah, Fabiana J Veguilla, Renata Ferrarotto, Lauren E Colbert, Nadim J Ajami, Robert R Jenq, Jianhua Zhang, Andrew P Futreal, Adel K El-Naggar

Faculty, Staff and Student Publications

Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the …

Multiparametric Mri-Based Radiomic Models For Early Prediction Of Response To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Rania M Mohamed, Bikash Panthi, Beatriz E Adrada, Medine Boge, Rosalind P Candelaria, Huiqin Chen, Mary S Guirguis, Kelly K Hunt, Lei Huo, Ken-Pin Hwang, Anil Korkut, Jennifer K Litton, Tanya W Moseley, Sanaz Pashapoor, Miral M Patel, Brandy Reed, Marion E Scoggins, Jong Bum Son, Alastair Thompson, Debu Tripathy, Vicente Valero, Peng Wei, Jason White, Gary J Whitman, Zhan Xu, Wei Yang, Clinton Yam, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) > 0.7. The top-performing model combined 35 radiomic features of relative difference between …

Patient-Reported Quality Of Life At Diagnosis In Adolescent And Young Adults With Cancer, Goldy C George, Clark Andersen, Xiaohui Tang, Elizabeth Rodriguez, Midhat Jafry, Maria C Swartz, Sairah Ahmed, Carlos H Barcenas, J Andrew Livingston, Michael E Roth, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: The overall landscape of health-related quality of life (HRQoL) has not been thoroughly investigated in adolescents and young adults (AYAs) with cancer. Data are also lacking on how well HRQoL at the time of cancer diagnosis can prognosticate long-term survival in AYA survivors.

Patients and methods: We included 3,497 survivors of AYA cancer (age 15-39 years at diagnosis) who completed the Short-Form 12 Health Survey (SF-12) HRQoL questionnaire at diagnosis. Physical component summary (PCS) and mental component summary (MCS) scores were generated, with scores < 50 representing poor HRQoL. Differences in HRQoL by patient characteristics and tumor type were investigated using violin plots and t tests/analysis of variance. The effect of HRQoL on overall survival was assessed using Kaplan-Meier plots and Cox proportional hazards models.

Results: Overall mean PCS and MCS scores in this racially/ethnically diverse cohort (64% White, 19% …

Monoallelic De Novo Ajap1 Loss-Of-Function Variants Disrupt Trans-Synaptic Control Of Neurotransmitter Release, Simon Früh, Sami Boudkkazi, Peter Koppensteiner, Vita Sereikaite, Li-Yuan Chen, Diego Fernandez-Fernandez, Pascal D Rem, Daniel Ulrich, Jochen Schwenk, Ziyang Chen, Elodie Le Monnier, Thorsten Fritzius, Sabrina M Innocenti, Valérie Besseyrias, Luca Trovò, Michal Stawarski, Emanuela Argilli, Elliott H Sherr, Bregje Van Bon, Erik-Jan Kamsteeg, Maria Iascone, Alba Pilotta, Maria R Cutrì, Mahshid S Azamian, Andrés Hernández-García, Seema R Lalani, Jill A Rosenfeld, Xiaonan Zhao, Tiphanie P Vogel, Herda Ona, Daryl A Scott, Peter Scheiffele, Kristian Strømgaard, Mehdi Tafti, Martin Gassmann, Bernd Fakler, Ryuichi Shigemoto, Bernhard Bettler

Faculty, Staff and Students Publications

Adherens junction–associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed …

Chronic Eosinophilic Leukemia With A Novel Jak1 Mutation Responds Well To The Jak1/2 Inhibitor Ruxolitinib, Qing Wei, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

Psmd11 Loss-Of-Function Variants Correlate With A Neurobehavioral Phenotype, Obesity, And Increased Interferon Response, Wallid Deb, Cory Rosenfelt, Virginie Vignard, Jonas Johannes Papendorf, Sophie Möller, Martin Wendlandt, Maja Studencka-Turski, Benjamin Cogné, Thomas Besnard, Léa Ruffier, Bérénice Toutain, Léa Poirier, Silvestre Cuinat, Amy Kritzer, Amy Crunk, Janette Dimonda, Jaime Vengoechea, Sandra Mercier, Lotte Kleinendorst, Mieke M Van Haelst, Linda Zuurbier, Telma Sulem, Hildigunnur Katrínardóttir, Rún Friðriksdóttir, Patrick Sulem, Kari Stefansson, Berglind Jonsdottir, Shimriet Zeidler, Margje Sinnema, Alexander P A Stegmann, Natali Naveh, Cara M Skraban, Christopher Gray, Jill R Murrell, Sedat Isikay, Davut Pehlivan, Daniel G Calame, Jennifer E Posey, Mathilde Nizon, Kirsty Mcwalter, James R Lupski, Bertrand Isidor, François V Bolduc, Stéphane Bézieau, Elke Krüger, Sébastien Küry, Frédéric Ebstein

Faculty, Staff and Students Publications

Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be …

Tsg-6+ Cancer-Associated Fibroblasts Modulate Myeloid Cell Responses And Impair Anti-Tumor Response To Immune Checkpoint Therapy In Pancreatic Cancer, Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra, Padmanee Sharma

Faculty, Staff and Student Publications

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. …

Radiation Therapy With Or Without Cisplatin For Local Recurrences Of Endometrial Cancer: Results From An Nrg Oncology/Gog Prospective Randomized Multicenter Clinical Trial, Ann H Klopp, Danielle Enserro, Matthew Powell, Marcus Randall, Julian C Schink, Robert S Mannel, Laura Holman, David Bender, Christina L Kushnir, Floor Backes, Susan L Zweizig, Steven Waggoner, Kristin A Bradley, Lana Desouza Lawrence, Parviz Hanjani, Christopher J Darus, William Small, Higinia R Cardenes, Jonathan M Feddock, David S Miller

Faculty, Staff and Student Publications

Purpose: Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy.

Materials and methods: Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS.

Results: The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to …

The Cns Relapse In T-Cell Lymphoma Index Predicts Cns Relapse In Patients With T- And Nk-Cell Lymphomas, Rahul S Bhansali, Fredrik Ellin, Thomas Relander, Miao Cao, Wenrui Li, Qi Long, Nivetha Ganesan, Robert Stuver, Steven M Horwitz, Kitsada Wudhikarn, Steven R Hwang, N Nora Bennani, Julio Chavez, Lubomir Sokol, Hayder Saeed, Frank Duan, Pierluigi Porcu, Priyanka Pullarkat, Neha Mehta-Shah, Jasmine M Zain, Miguel Ruiz, Jonathan E Brammer, Rishab Prakash, Swaminathan P Iyer, Adam J Olszewski, Ajay Major, Peter A Riedell, Sonali M Smith, Caroline Goldin, Bradley Haverkos, Bei Hu, Tony Z Zhuang, Pamela B Allen, Wael Toama, Murali Janakiram, Taylor R Brooks, Deepa Jagadeesh, Nisha Hariharan, Aaron M Goodman, Gabrielle Hartman, Paola Ghione, Fatima Fayyaz, Joanna M Rhodes, Elise A Chong, James N Gerson, Daniel J Landsburg, Sunita D Nasta, Stephen J Schuster, Jakub Svoboda, Mats Jerkeman, Stefan K Barta

Faculty, Staff and Student Publications

Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. …

Daratumumab In Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma: Final Analysis Of Clinically Relevant Subgroups In Griffin, Ajai Chari, Jonathan L Kaufman, Jacob Laubach, Douglas W Sborov, Brandi Reeves, Cesar Rodriguez, Rebecca Silbermann, Luciano J Costa, Larry D Anderson, Nitya Nathwani, Nina Shah, Naresh Bumma, Sarah A Holstein, Caitlin Costello, Andrzej Jakubowiak, Tanya M Wildes, Robert Z Orlowski, Kenneth H Shain, Andrew J Cowan, Huiling Pei, Annelore Cortoos, Sharmila Patel, Thomas S Lin, Peter M Voorhees, Saad Z Usmani, Paul G Richardson

Faculty, Staff and Student Publications

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease–negativity (10−5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a …

Self-Explainable Graph Neural Network For Alzheimer Disease And Related Dementias Risk Prediction: Algorithm Development And Validation Study, Xinyue Hu, Zenan Sun, Yi Nian, Yichen Wang, Yifang Dang, Fang Li, Jingna Feng, Evan Yu, Cui Tao

Faculty, Staff and Student Publications

Background: Alzheimer disease and related dementias (ADRD) rank as the sixth leading cause of death in the United States, underlining the importance of accurate ADRD risk prediction. While recent advancements in ADRD risk prediction have primarily relied on imaging analysis, not all patients undergo medical imaging before an ADRD diagnosis. Merging machine learning with claims data can reveal additional risk factors and uncover interconnections among diverse medical codes.

Objective: The study aims to use graph neural networks (GNNs) with claim data for ADRD risk prediction. Addressing the lack of human-interpretable reasons behind these predictions, we introduce an innovative, self-explainable method …

Efficacy, Safety, And Tolerability Of Tivozanib In Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma, Andrew C Johns, Matthew T Campbell, Mamie Gao, Andrew W Hahn, Zita Lim, Emily Wang, Jianjun Gao, Amishi Y Shah, Pavlos Msaouel, Nizar M Tannir

Faculty, Staff and Student Publications

BACKGROUND: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC).

METHODS: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) for …

Reverse Phase Proteomic Array Profiling Of Asparagine Synthetase Expression In Newly Diagnosed Acute Myeloid Leukemia, Nisha Narayanan, Jennifer Marvin-Peek, Mohamad K Abouelnaaj, Dhabya Majid, Bofei Wang, Brandon D Brown, Yihua Qiu, Steven M Kornblau, Hussein A Abbas

Faculty, Staff and Student Publications

Asparaginase-based therapy is a cornerstone in acute lymphoblastic leukemia (ALL) treatment, capitalizing on the methylation status of the asparagine synthetase (ASNS) gene, which renders ALL cells reliant on extracellular asparagine. Contrastingly, ASNS expression in acute myeloid leukemia (AML) has not been thoroughly investigated, despite studies suggesting that AML with chromosome 7/7q deletions might have reduced ASNS levels. Here, we leverage reverse phase protein arrays to measure ASNS expression in 810 AML patients and assess its impact on outcomes. We find that AML with inv(16) has the lowest overall ASNS expression. While AML with deletion 7/7q had ASNS levels slightly lower …

Ai Driven Analysis Of Mri To Measure Health And Disease Progression In Fshd, Lara Riem, Olivia Ducharme, Matthew Cousins, Xue Feng, Allison Kenney, Jacob Morris, Stephen J Tapscott, Rabi Tawil, Jeff Statland, Dennis Shaw, Leo Wang, Michaela Walker, Leann Lewis, Michael A Jacobs, Doris G Leung, Seth D Friedman, Silvia S Blemker

Faculty, Staff and Student Publications

Facioscapulohumeral muscular dystrophy (FSHD) affects roughly 1 in 7500 individuals. While at the population level there is a general pattern of affected muscles, there is substantial heterogeneity in muscle expression across- and within-patients. There can also be substantial variation in the pattern of fat and water signal intensity within a single muscle. While quantifying individual muscles across their full length using magnetic resonance imaging (MRI) represents the optimal approach to follow disease progression and evaluate therapeutic response, the ability to automate this process has been limited. The goal of this work was to develop and optimize an artificial intelligence-based image …

Hur Controls Glutaminase Rna Metabolism, Douglas Adamoski, Larissa M Dos Reis, Ana Carolina Paschoalini Mafra, Felipe Corrêa-Da-Silva, Pedro Manoel Mendes De Moraes-Vieira, Ioana Berindan-Neagoe, George A Calin, Sandra Martha Gomes Dias

Faculty, Staff and Student Publications

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and …

Genomic Determinants Of Response And Resistance To Inotuzumab Ozogamicin In B-Cell All, Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S Garris, Lewis F Nasr, Richard W Kriwacki, Kathryn G Roberts, Marina Konopleva, Elias J Jabbour, Charles G Mullighan

Faculty, Staff and Student Publications

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO …

Post-Immunotherapy Ctla-4 Ig Treatment Improves Antitumor Efficacy, Stephen Mok, Didem Ağaç Çobanoğlu, Huey Liu, James J Mancuso, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether …

Loss Of The Dna Repair Gene Rnase H2 Identifies A Unique Subset Of Ddr-Deficient Leiomyosarcomas, Michael S Nakazawa, Ian M Silverman, Victoria Rimkunas, Artur Veloso, Dominik Glodzik, Adrienne Johnson, Toshiro K Ohsumi, Shreyaskumar R Patel, Anthony P Conley, Christina L Roland, Pamela T Soliman, Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Rossana Lazcano, Dawon Song, Khalida M Wani, Alexander J Lazar, Timothy A Yap, Wei-Lien Wang, J Andrew Livingston

Faculty, Staff and Student Publications

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In …

Effect Of Medicaid Expansion On Cancer Treatment And Survival Among Medicaid Beneficiaries And The Uninsured, Kristin M Primm, Hui Zhao, Naomi N Adjei, Charlotte C Sun, Alen Haas, Larissa A Meyer, Shine Chang

Faculty, Staff and Student Publications

BACKGROUND: The Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.

METHODS: Medicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences …