Biomedical Informatics Commons^™

The Novel Phosphatase Nudt5 Is A Critical Regulator Of Triple-Negative Breast Cancer Growth, Jing Qian, Yanxia Ma, William M Tahaney, Cassandra L Moyer, Amanda Lanier, Jamal Hill, Darian Coleman, Negar Koupaei, Susan G Hilsenbeck, Michelle I Savage, Brent D G Page, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target …

Identification Of New Egfr Inhibitors By Structure-Based Virtual Screening And Biological Evaluation, Shuyi Wang, Xiaotian Xu, Chuxin Pan, Qian Guo, Qinlan Li, Shanhe Wan, Zhonghuang Li, Jiajie Zhang, Xiaoyun Wu

Faculty, Staff and Student Publications

Epidermal growth factor receptor (EGFR) inhibitors have been used in clinical for the treatment of non-small-cell lung cancer for years. However, the emergence of drug resistance continues to be a major problem. To identify potential inhibitors, molecular docking-based virtual screening was conducted on ChemDiv and Enamine commercial databases using the Glide program. After multi-step VS and visual inspection, a total of 23 compounds with novel and varied structures were selected, and the predicted ADMET properties were within the satisfactory range. Further molecular dynamics simulations revealed that the reprehensive compound ZINC49691377 formed a stable complex with the allosteric pocket of EGFR …

Impact Of Kras Mutations And Co-Mutations On Clinical Outcomes In Pancreatic Ductal Adenocarcinoma, Abdelrahman Yousef, Mahmoud Yousef, Saikat Chowdhury, Kawther Abdilleh, Mark Knafl, Paul Edelkamp, Kristin Alfaro-Munoz, Ray Chacko, Jennifer Peterson, Brandon G Smaglo, Robert A Wolff, Shubham Pant, Michael S Lee, Jason Willis, Michael Overman, Sudheer Doss, Lynn Matrisian, Mark W Hurd, Rebecca Snyder, Matthew H G Katz, Huamin Wang, Anirban Maitra, John Paul Shen, Dan Zhao

Faculty, Staff and Student Publications

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 patients with PDAC (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p < 0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRASG12R had a similar OS (median 34 months), while patients with KRASQ61 and KRASG12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2-3.0, p = 0.006] and 22 months [HR: 1.7, 95% CI 1.3-2.3, p < 0.001], respectively). There was enrichment of KRASG12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2-2.4, p = 0.001) and enrichment of KRASG12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05-2.99, p = 0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor® dataset, n = 408).

Gestational Diabetes Augments Group B Streptococcus Infection By Disrupting Maternal Immunity And The Vaginal Microbiota, Vicki Mercado-Evans, Marlyd E Mejia, Jacob J Zulk, Samantha Ottinger, Zainab A Hameed, Camille Serchejian, Madelynn G Marunde, Clare M Robertson, Mallory B Ballard, Simone H Ruano, Natalia Korotkova, Anthony R Flores, Kathleen A Pennington, Kathryn A Patras

Faculty, Staff and Student Publications

Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals differential GBS adaptation to the GDM reproductive tract, including a putative glycosyltransferase (yfhO), and altered host responses. GDM immune disruptions include reduced uterine natural killer cell activation, impaired recruitment to placentae, …

Targeting Alk Averts Ribonuclease 1-Induced Immunosuppression And Enhances Antitumor Immunity In Hepatocellular Carcinoma, Chunxiao Liu, Chenhao Zhou, Weiya Xia, Yifan Zhou, Yufan Qiu, Jialei Weng, Qiang Zhou, Wanyong Chen, Ying-Nai Wang, Heng-Huan Lee, Shao-Chun Wang, Ming Kuang, Dihua Yu, Ning Ren, Mien-Chie Hung

Faculty, Staff and Student Publications

Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a …

Acceptability Of Personalized Lung Cancer Screening Program Among Primary Care Providers, Paul J Resong, Jiangong Niu, Gabrielle F Duhon, Lewis E Foxhall, Sanjay Shete, Robert J Volk, Iakovos Toumazis

Faculty, Staff and Student Publications

Current lung cancer screening (LCS) guidelines rely on age and smoking history. Despite its benefit, only 5%-15% of eligible patients receive LCS. Personalized screening strategies select individuals based on their lung cancer risk and may increase LCS's effectiveness. We assess current LCS practices and the acceptability of personalized LCS among primary care providers (PCP) in Texas. We surveyed 32,983 Texas-based PCPs on an existing network (Protocol 2019-1257; PI: Dr. Shete) and 300 attendees of the 2022 Texas Academy of Family Physicians (TAFP) conference. We analyzed the responses by subgroups of interest. Using nonparametric bootstrap, we derived an enriched dataset to …

Efficacy And Safety Of Autologous Tumor-Infiltrating Lymphocytes In Recurrent Or Refractory Ovarian Cancer, Colorectal Cancer, And Pancreatic Ductal Adenocarcinoma, Rodabe Amaria, Anne Knisely, David Vining, Scott Kopetz, Michael J Overman, Milind Javle, Mara B Antonoff, Ching-Wei D Tzeng, Robert A Wolff, Shubham Pant, Kathryn Lito, Kelly Rangel, Bryan Fellman, Ying Yuan, Karen H Lu, Donastas Sakellariou-Thompson, Cara L Haymaker, Marie-Andrée Forget, Patrick Hwu, Chantale Bernatchez, Amir A Jazaeri

Faculty, Staff and Student Publications

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture.

METHODS: Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was …

Editing Of The Ethylene Biosynthesis Gene In Carnation Using Crispr-Cas9 Ribonucleoprotein Complex, Oluwaseun Suleimon Adedeji, Aung Htay Naing, Hyunhee Kang, Junping Xu, Mi Young Chung, Chang Kil Kim

Faculty, Staff and Student Publications

The study aimed to edit ethylene (ET) biosynthesis genes [1-aminocyclopropane-1-carboxylic acid (ACC) synthetase 1 (ACS1) and ACC oxidase 1 (ACO1)] in carnation using the CRISPR/Cas9 ribonucleoprotein (RNP) complex system. Initially, the conserved regions of the target genes (ACS1 and ACO1) were validated for the generation of different single guide RNAs (sgRNAs), followed by the use of an in vitro cleavage assay to confirm the ability of the sgRNAs to cleave the target genes specifically. The in vitro cleavage assay revealed that the sgRNAs were highly effective in cleaving their respective target regions. The complex of sgRNA: Cas9 was directly delivered …

Tumor-Specific Polycistronic Mirna Delivered By Engineered Exosomes For The Treatment Of Glioblastoma, Malcolm F Mcdonald, Anwar Hossain, Eric N Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang

Faculty, Staff and Student Publications

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

Methods: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to …

Targeting Prostate Tumor Low-Molecular Weight Tyrosine Phosphatase For Oxidation-Sensitizing Therapy, Stephanie M Stanford, Tiffany P Nguyen, Joseph Chang, Zixuan Zhao, G Lavender Hackman, Eugenio Santelli, Colton M Sanders, Madhusudhanarao Katiki, Eleonora Dondossola, Brooke L Brauer, Michael A Diaz, Yuan Zhan, Sterling H Ramsey, Philip A Watson, Banumathi Sankaran, Claudia Paindelli, Vanessa Parietti, Antonios G Mikos, Alessia Lodi, Aditya Bagrodia, Andrew Elliott, Rana R Mckay, Ramachandran Murali, Stefano Tiziani, Arminja N Kettenbach, Nunzio Bottini

Faculty, Staff and Student Publications

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor …

Chronic Wasting Disease: State Of The Science, Jason C Bartz, Rebeca Benavente, Byron Caughey, Sonja Christensen, Allen Herbst, Edward A Hoover, Candace K Mathiason, Debbie Mckenzie, Rodrigo Morales, Marc D Schwabenlander, Daniel P Walsh, The Nc North American Interdisciplinary Chronic Wasting Disease Research Consortium Members

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting cervid species, both free-ranging and captive populations. As the geographic range continues to expand and disease prevalence continues to increase, CWD will have an impact on cervid populations, local economies, and ecosystem health. Mitigation of this "wicked" disease will require input from many different stakeholders including hunters, landowners, research biologists, wildlife managers, and others, working together. The NC1209 (North American interdisciplinary chronic wasting disease research consortium) is composed of scientists from different disciplines involved with investigating and managing CWD. Leveraging this broad breadth of expertise, the Consortium has created a state-of-the-science …

Deep Learning-Based H-Score Quantification Of Immunohistochemistry-Stained Images, Zhuoyu Wen, Danni Luo, Shidan Wang, Ruichen Rong, Bret M Evers, Liwei Jia, Yisheng Fang, Elena V Daoud, Shengjie Yang, Zifan Gu, Emily N Arner, Cheryl M Lewis, Luisa M Solis Soto, Junya Fujimoto, Carmen Behrens, Ignacio I Wistuba, Donghan M Yang, Rolf A Brekken, Kathryn A O'Donnell, Yang Xie, Guanghua Xiao

Faculty, Staff and Student Publications

Immunohistochemistry (IHC) is a well-established and commonly used staining method for clinical diagnosis and biomedical research. In most IHC images, the target protein is conjugated with a specific antibody and stained using diaminobenzidine (DAB), resulting in a brown coloration, whereas hematoxylin serves as a blue counterstain for cell nuclei. The protein expression level is quantified through the H-score, calculated from DAB staining intensity within the target cell region. Traditionally, this process requires evaluation by 2 expert pathologists, which is both time consuming and subjective. To enhance the efficiency and accuracy of this process, we have developed an automatic algorithm for …

Immune Evasion, Infectivity, And Fusogenicity Of Sars-Cov-2 Ba286 And Flip Variants, Panke Qu, Kai Xu, Julia N Faraone, Negin Goodarzi, Yi-Min Zheng, Claire Carlin, Joseph S Bednash, Jeffrey C Horowitz, Rama K Mallampalli, Linda J Saif, Eugene M Oltz, Daniel Jones, Richard J Gumina, Shan-Lu Liu

Faculty, Staff and Student Publications

Evolution of SARS-CoV-2 requires the reassessment of current vaccine measures. Here, we characterized BA.2.86 and XBB-derived variant FLip by investigating their neutralization alongside D614G, BA.1, BA.2, BA.4/5, XBB.1.5, and EG.5.1 by sera from 3-dose-vaccinated and bivalent-vaccinated healthcare workers, XBB.1.5-wave-infected first responders, and monoclonal antibody (mAb) S309. We assessed the biology of the variant spikes by measuring viral infectivity and membrane fusogenicity. BA.2.86 is less immune evasive compared to FLip and other XBB variants, consistent with antigenic distances. Importantly, distinct from XBB variants, mAb S309 was unable to neutralize BA.2.86, likely due to a D339H mutation based on modeling. BA.2.86 had …

From Primary Myelofibrosis To Chronic Myeloid Leukemia, Bcr::Abl1+ B-Lymphoblastic Leukemia, And Back To Primary Myelofibrosis: An Illustration Of Dynamic Clonal Evolution, Devin Wang, Wataru Kamata, Fengxi Ye, M James You

Faculty, Staff and Student Publications

The simultaneous detection of BCR::ABL1 and JAK2 V617F was rarely reported and their clonal relationship and dynamic clonal shift were not characterized. Here, we described a unique case with the initial presentation as JAK2 V617F+ primary myelofibrosis, followed by the emergence of BCR::ABL1+ chronic myeloid leukemia. The patient then developed BCR::ABL1+ B-lymphoblastic leukemia. Treatment for B-lymphoblastic leukemia prompted a regression to the state of primary myelofibrosis. In light of these observations, we proposed a clonal evolution model for this case.

Sionx Coating Regulates Mesenchymal Stem Cell Antioxidant Capacity Via Nuclear Erythroid Factor 2 Activity Under Toxic Oxidative Stress Conditions, Neelam Ahuja, Kamal Awad, Su Yang, He Dong, Antonios Mikos, Pranesh Aswath, Simon Young, Marco Brotto, Venu Varanasi

Faculty, Staff and Student Publications

Healing in compromised and complicated bone defects is often prolonged and delayed due to the lack of bioactivity of the fixation device, secondary infections, and associated oxidative stress. Here, we propose amorphous silicon oxynitride (SiONx) as a coating for the fixation devices to improve both bioactivity and bacteriostatic activity and reduce oxidative stress. We aimed to study the effect of increasing the N/O ratio in the SiONx to fine-tune the cellular activity and the antioxidant effect via the NRF2 pathway under oxidative stress conditions. The in vitro studies involved using human mesenchymal stem cells (MSCs) to examine the effect of …

Metabolism, Fibrosis, And Apoptosis: The Effect Of Lipids And Their Derivatives On Keloid Formation, Chen-Yu Li, Ru-Xin Xie, Shi-Wei Zhang, Jiao Yun, Ai Zhong, Ying Cen, Jun-Jie Chen

Faculty, Staff and Student Publications

Keloids, pathological scars resulting from skin trauma, have traditionally posed significant clinical management challenges due to their persistence and high recurrence rates. Our research elucidates the pivotal roles of lipids and their derivatives in keloid development, driven by underlying mechanisms of abnormal cell proliferation, apoptosis, and extracellular matrix deposition. Key findings suggest that abnormalities in arachidonic acid (AA) synthesis and non-essential fatty acid synthesis are integral to keloid formation. Further, a complex interplay exists between lipid derivatives, notably butyric acid (BA), prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), and the regulation of hyperfibrosis. Additionally, combinations of docosahexaenoic acid (DHA) with BA …

Epigenetic Regulation In Cancer, Minzhi Gu, Bo Ren, Yuan Fang, Jie Ren, Xiaohong Liu, Xing Wang, Feihan Zhou, Ruiling Xiao, Xiyuan Luo, Lei You, Yupei Zhao

Faculty, Staff and Student Publications

Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as …

Identification Of A Novel Cg307 Sub-Clade In Third-Generation-Cephalosporin-Resistant, Selvalakshmi Selvaraj Anand, Chin-Ting Wu, Jordan Bremer, Micah Bhatti, Todd J Treangen, Awdhesh Kalia, Samuel A Shelburne, William C Shropshire

Faculty, Staff and Student Publications

Despite the notable clinical impact, recent molecular epidemiology regarding third-generation-cephalosporin-resistant (3GC-R) Klebsiella pneumoniae in the USA remains limited. We performed whole-genome sequencing of 3GC-R K. pneumoniae bacteraemia isolates collected from March 2016 to May 2022 at a tertiary care cancer centre in Houston, TX, USA, using Illumina and Oxford Nanopore Technologies platforms. A comprehensive comparative genomic analysis was performed to dissect population structure, transmission dynamics and pan-genomic signatures of our 3GC-R K. pneumoniae population. Of the 178 3GC-R K. pneumoniae bacteraemias that occurred during our study time frame, we were able to analyse 153 (86 %) bacteraemia isolates, 126 …

Neurologic Morbidity And Functional Independence In Adult Survivors Of Childhood Cancer, Stefanie C Vuotto, Mingjuan Wang, M Fatih Okcu, Daniel C Bowers, Nicole J Ullrich, Kirsten K Ness, Chenghong Li, Deo Kumar Srivastava, Rebecca M Howell, Todd M Gibson, Wendy M Leisenring, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

OBJECTIVE: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies.

METHODS: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal …

Aneuploidy And Complex Genomic Rearrangements In Cancer Evolution, Toby M Baker, Sara Waise, Maxime Tarabichi, Peter Van Loo

Faculty, Staff and Student Publications

Mutational processes that alter large genomic regions occur frequently in developing tumors. They range from simple copy number gains and losses to the shattering and reassembly of entire chromosomes. These catastrophic events, such as chromothripsis, chromoplexy and the formation of extrachromosomal DNA, affect the expression of many genes and therefore have a substantial effect on the fitness of the cells in which they arise. In this review, we cover large genomic alterations, the mechanisms that cause them and their effect on tumor development and evolution.

Transcription-Replication Interactions Reveal Bacterial Genome Regulation, Andrew W Pountain, Peien Jiang, Tianyou Yao, Ehsan Homaee, Yichao Guan, Kevin J C Mcdonald, Magdalena Podkowik, Bo Shopsin, Victor J Torres, Ido Golding, Itai Yanai

Faculty, Staff and Student Publications

Organisms determine the transcription rates of thousands of genes through a few modes of regulation that recur across the genome1. In bacteria, the relationship between the regulatory architecture of a gene and its expression is well understood for individual model gene circuits2,3. However, a broader perspective of these dynamics at the genome scale is lacking, in part because bacterial transcriptomics has hitherto captured only a static snapshot of expression averaged across millions of cells4. As a result, the full diversity of gene expression dynamics and their relation to regulatory architecture remains unknown. Here we present a novel genome-wide classification of …

Phase I Study Of Sapanisertib (Cb-228/Tak-228/Mln0128) In Combination With Ziv-Aflibercept In Patients With Advanced Solid Tumors, Niamh Coleman, Bettzy Stephen, Siqing Fu, Daniel Karp, Vivek Subbiah, Jordi Rodon Ahnert, Sarina A Piha-Paul, John Wright, Senait N Fessahaye, Fengying Ouyang, Bulent Yilmaz, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

BACKGROUND: Sapanisertib is a potent ATP-competitive, dual inhibitor of mTORC1/2. Ziv-aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF-1α inhibition in combination with anti-angiogenic therapy is a promising anti-tumor strategy. This Phase 1 dose-escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv-aflibercept in advanced solid tumors.

METHODS: Fifty-five patients with heavily pre-treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels.

RESULTS: Fifty-five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age …

Patient Interest In Exploring Nonsurgical Treatment Approaches For Early-Stage Breast Cancer: A Qualitative Study, Maya Guhan, Stacey M Crane, Lillian S Valerius, Denise De La Cruz, Benjamin D Smith, Wendy A Woodward, Melissa P Mitchell, Vicente Valero, Gaiane M Rauch, Savitri Krishnamurthy, Carla L Warnecke, Henry M Kuerer, Simona F Shaitelman

Faculty, Staff and Student Publications

Purpose: Advances in radiation therapy have enabled the ability to deliver ablative treatments, but there has been limited application of these treatments to early-stage breast cancers with a goal of omitting surgery. The purpose of this study was to explore patient interest in pursuing nonsurgical treatment approaches for their early-stage breast cancer.

Methods and materials: We conducted a qualitative study involving interviews with 21 patients with early-stage breast cancer who were eligible for participation in a phase 2 clinical trial offering omission of definitive surgery. Interviews were transcribed and an inductive, thematic analysis was performed by 3 independent reviewers to …

Absence Of Btk, Bcl2, And Plcg2 Mutations In Chronic Lymphocytic Leukemia Relapsing After First-Line Treatment With Fixed-Duration Ibrutinib Plus Venetoclax, Nitin Jain, Lisa J Croner, John N Allan, Tanya Siddiqi, Alessandra Tedeschi, Xavier C Badoux, Karl Eckert, Leo W K Cheung, Anwesha Mukherjee, James P Dean, Edith Szafer-Glusman, John F Seymour

Faculty, Staff and Student Publications

Purpose: Mutations in BTK, PLCG2, and BCL2 have been reported in patients with progressive disease (PD) on continuous single-agent BTK or BCL2 inhibitor treatment. We tested for these mutations in samples from patients with PD after completion of first-line treatment with fixed-duration ibrutinib plus venetoclax for chronic lymphocytic leukemia (CLL) in the phase II CAPTIVATE study.

Patients and methods: A total of 191 patients completed fixed-duration ibrutinib plus venetoclax (three cycles of ibrutinib then 12-13 cycles of ibrutinib plus venetoclax). Genomic risk features [del(11q), del(13q), del(17p), trisomy 12, complex karyotype, unmutated IGHV, TP53 mutated] and mutations in genes recurrently mutated …

Regression Analysis Of Multivariate Recurrent Event Data Allowing Time-Varying Dependence With Application To Stroke Registry Data, Wen Li, Mohammad H Rahbar, Sean I Savitz, Jing Zhang, Sori Kim Lundin, Amirali Tahanan, Jing Ning

Faculty, Staff and Student Publications

In multivariate recurrent event data, each patient may repeatedly experience more than one type of event. Analysis of such data gets further complicated by the time-varying dependence structure among different types of recurrent events. The available literature regarding the joint modeling of multivariate recurrent events assumes a constant dependency over time, which is strict and often violated in practice. To close the knowledge gap, we propose a class of flexible shared random effects models for multivariate recurrent event data that allow for time-varying dependence to adequately capture complex correlation structures among different types of recurrent events. We developed an expectation-maximization …

Increased Prevalence Of Clostridioides Difficile Infection Among Pediatric Oncology Patients: Risk Factors For Infection And Complications, Brianna R Murphy, Natalie J Dailey Garnes, Hyunsoo Hwang, Christine B Peterson, Kevin W Garey, Pablo Okhuysen

Faculty, Staff and Student Publications

Background: Pediatric oncology patients, who are typically immunosuppressed, exposed to medications associated with increased Clostridioides difficile infection (CDI) risk and hospitalized, are expected to be at substantial risk for infection and complications. Although certain C. difficile ribotypes have been associated with more severe infection in adults, such an association has not been described in children.

Methods: To characterize CDI epidemiology, including risk factors and complications among pediatric oncology patients, we retrospectively reviewed charts of patients 1-18 years old treated at a designated cancer center during 2000-2017. We used fluorescence-based polymerase chain reaction to identify ribotypes causing disease at our institution. …

Safety And Efficacy Of A New High-Dose Regimen Of Panobinostat, Gemcitabine, Busulfan, And Melphalan For 1st Or 2nd Salvage Asct For Refractory/Relapsed Or High-Risk Myeloma: Matched-Pair Comparisons With Concurrent Control Cohorts, Yago Nieto, Zixi Yang, Benigno C Valdez, Suprateek Kundu, Qaiser Bashir, Jeremy Ramdial, Samer Srour, Muzaffar Qazilbash

Faculty, Staff and Student Publications

Improvement of autologous stem-cell transplantation (ASCT) for myeloma is needed. Building on our prior work, we prospectively evaluated panobinostat and gemcitabine/busulfan/melphalan (GemBuMel) with ASCT in this population. Patients aged 18-65 years with relapsed/refractory or high-risk myeloma and adequate end-organ function were eligible. Treatment included panobinostat (20 mg/day, days -9 to -2) and GemBuMel (days -8 to -2). Patients were enrolled in 1st (ASCT-1) or 2nd ASCT (ASCT-2) cohorts. We compared their outcomes with all our other concurrent ASCT patients who met eligibility criteria but received melphalan or BuMel off study, matched for age, prior therapy lines, high-risk cytogenetics, and response …

Convergent Mapk Pathway Alterations Mediate Acquired Resistance To Fgfr Inhibitors In Fgfr2 Fusion-Positive Cholangiocarcinoma, Timothy P Diperi, Ming Zhao, Kurt W Evans, Kaushik Varadarajan, Tyler Moss, Stephen Scott, Michael P Kahle, Charnel C Byrnes, Huiqin Chen, Sunyoung S Lee, Abdel-Baset Halim, Hiroshi Hirai, Volker Wacheck, Lawrence N Kwong, Jordi Rodon, Milind Javle, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Background & aims: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA).

Methods: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance …

Phase 2 Study Of Inotuzumab Ozogamicin For Measurable Residual Disease In Acute Lymphoblastic Leukemia In Remission, Elias Jabbour, Fadi G Haddad, Nicholas J Short, Jayastu Senapati, Nitin Jain, Koji Sasaki, Jeffrey Jorgensen, Sa A Wang, Yesid Alvarado, Xuemei Wang, Courtney Dinardo, Lucia Masarova, Tapan Kadia, Rebecca S Garris, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10-4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) …

Shape Anisotropy-Governed High-Performance Nanomagnetosol For In Vivo Magnetic Particle Imaging Of Lungs, Saumya Nigam, Jeotikanta Mohapatra, Ashley V Makela, Hanaan Hayat, Jessi Mercedes Rodriguez, Aixia Sun, Elizabeth Kenyon, Nathan A Redman, Dana Spence, George Jabin, Bin Gu, Mohamed Ashry, Lorenzo F Sempere, Arijit Mitra, Jinxing Li, Jiahui Chen, Guo-Wei Wei, Steven Bolin, Brett Etchebarne, J Ping Liu, Christopher H Contag, Ping Wang

Faculty, Staff and Student Publications

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has shown extensive lung manifestations in vulnerable individuals, putting lung imaging and monitoring at the forefront of early detection and treatment. Magnetic particle imaging (MPI) is an imaging modality, which can bring excellent contrast, sensitivity, and signal-to-noise ratios to lung imaging for the development of new theranostic approaches for respiratory diseases. Advances in MPI tracers would offer additional improvements and increase the potential for clinical translation of MPI. Here, a high-performance nanotracer based on shape anisotropy of magnetic nanoparticles is developed and its use in MPI imaging …