Biomedical Informatics Commons^™

Epigenomic And Transcriptomic Profiling Of Solitary Fibrous Tumors Identifies Site-Specific Patterns And Candidate Genes Regulated By Dna Methylation, Hannah C Beird, Jeffrey M Cloutier, Nalan Gokgoz, Christopher Eeles, Anthony M Griffin, Davis R Ingram, Khalida M Wani, Rossana Lazcano Segura, Luca Cohen, Carl Ho, Jay S Wunder, Irene L Andrulis, P Andrew Futreal, Benjamin Haibe-Kains, Alexander J Lazar, Wei-Lien Wang, Joanna Przybyl, Elizabeth G Demicco

Faculty, Staff and Student Publications

A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and …

Intra-Tumoral And Peripheral Blood Tigit And Pd-1 As Immune Biomarkers In Nodular Lymphocyte Predominant Hodgkin Lymphoma, Jay Gunawardana, Soi C Law, Muhammed B Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I Leahy, Paul G Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N Lee, Emily Jude, Eliza A Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W D Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R Green, Francisco Vega, Maher K Gandhi

Faculty, Staff and Student Publications

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or …

Genetic Regulation Of Human Brain Proteome Reveals Proteins Implicated In Psychiatric Disorders, Jie Luo, Ling Li, Mingming Niu, Dehui Kong, Yi Jiang, Suresh Poudel, Annie W Shieh, Lijun Cheng, Gina Giase, Kay Grennan, Kevin P White, Chao Chen, Sidney H Wang, Dalila Pinto, Yue Wang, Chunyu Liu, Junmin Peng, Xusheng Wang

Faculty, Staff and Student Publications

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate < 5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

Corpus Callosum Structure And Auditory Interhemispheric Transfer In Spina Bifida Myelomeningocele, Kailyn A Bradley, Jenifer J Juranek, H Julia Hannay, Paul T Cirino, Larry A Kramer, Jack M Fletcher

Faculty, Staff and Student Publications

Objective: Maldevelopment of the posterior corpus callosum is common in spina bifida myelomeningocele (SBM) due to hydrocephalus-related hypoplasia and congenital partial hypogenesis. This study examined the relations of macro- and microstructural integrity of the interhemispheric temporal tract in SBM and auditory interhemispheric transfer using consonant-vowel dichotic listening.

Method: We collected T₁-weighted and diffusion tensor imaging data from 46 individuals with SBM and 15 typically developing individuals. Probabilistic tractography was used to isolate the interhemispheric white matter connecting auditory processing regions in both hemispheres. Interhemispheric transfer was assessed with a dichotic listening task.

Results: Although the typically developing group and …

Genomic Alterations In Dna Mismatch Repair Genes Across Different Cancer Types, Vijaykumar R Holla, Michael P Kahle, Sun-Hee Kim, Arash Ronaghy, Richard K Yang, Keyur P Patel, Mark J Routbort, Michael J Overman, Ecaterina E Dumbrava, Kenna R Mills Shaw, Daniel D Karp, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Purpose: PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

Methods: From January 2016 to December 2021, 15,701 …

Self-Management Intervention Improves Patient Adherence To Swallowing Exercises During Radiation For Head And Neck Cancer, Eileen H Shinn, Adam S Garden, Minxing Chen, Karen Basen-Engquist, Bryan Fellman, Kate Hutcheson, William H Morrison, Susan Peterson, Liang Li

Faculty, Staff and Student Publications

Background: While preventive swallowing exercises reduce the risk of radiation-associated dysphagia in patients with head and neck cancer, strategies are needed to improve patient adherence.

Methods: Before radiation, all participants were taught preventive swallowing exercises and randomized to either an adherence intervention or enhanced usual care. During radiation, all participants met twice with a speech pathologist for swallowing assessment and reinforcement of exercises. Intervention participants met weekly with a counselor in-person or by phone. At 6-week post-radiation follow-up, all participants completed a follow-up assessment of self-reported adherence, which was then corroborated with medical record documentation.

Results: Newly diagnosed pharyngeal and …

Secondary Acquisition Of The Philadelphia Chromosome In Acute Lymphoblastic Leukemia, Qiudan Shen, Elias J Jabbour, Guilin Tang, Hong Fang, Wei Wang, Nicholas J Short, M James You, L Jeffrey Medeiros, Shimin Hu

Faculty, Staff and Student Publications

No abstract provided.

Efficacy Of Trastuzumab Deruxtecan In Her2-Expressing Solid Tumors By Enrollment Her2 Ihc Status: Post Hoc Analysis Of Destiny-Pantumor02, Ana Oaknin, Jung-Yun Lee, Vicky Makker, Do-Youn Oh, Susana Banerjee, Antonio González-Martín, Kyung Hae Jung, Iwona Ługowska, Luis Manso, Aránzazu Manzano, Bohuslav Melichar, Salvatore Siena, Daniil Stroyakovskiy, Anitra Fielding, Soham Puvvada, Ann Smith, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Introduction: DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n = 202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results …

Intraoperative Methadone Administration For Total Mastectomy: A Single Center Retrospective Study, Juan P Cata, Yusuf Zaidi, Juan Jose Guerra-Londono, Evan D Kharasch, Matthew Piotrowski, Spencer Kee, Nicolas A Cortes-Mejia, Jose Miguel Gloria-Escobar, Peter F Thall, Ruitao Lin

Faculty, Staff and Student Publications

Background: Breast cancer is the most frequent type of cancer and the second leading cause of cancer-related mortality in women. Mastectomies remain a key component of the treatment of non-metastatic breast cancer, and strategies to treat acute postoperative pain, a complication affecting nearly all patients undergoing surgery, continues to be an important clinical challenge. This study aimed to determine the impact of intraoperative methadone administration compared to conventional short-acting opioids on pain-related perioperative outcomes in women undergoing a mastectomy.

Methods: This single-center retrospective study included adult women undergoing total mastectomy. The primary outcome of this study was postoperative pain intensity …

Decitabine, Venetoclax, And Ponatinib For Advanced Phase Chronic Myeloid Leukaemia And Philadelphia Chromosome-Positive Acute Myeloid Leukaemia: A Single-Arm, Single-Centre Phase 2 Trial, Nicholas J Short, Daniel Nguyen, Elias Jabbour, Jayastu Senapati, Zhihong Zeng, Ghayas C Issa, Hussein Abbas, Cedric Nasnas, Wei Qiao, Xuelin Huang, Gautam Borthakur, Kelly Chien, Fadi G Haddad, Naveen Pemmaraju, Omer S Karrar, Danielle Nguyen, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

BACKGROUND: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, …

Surgical Predictors Of Clinical Outcome 6 Years After Revision Acl Reconstruction, Rick W Wright, Laura J Huston, Amanda K Haas, Jacquelyn S Pennings, Christina R Allen, Daniel E Cooper, Thomas M Deberardino, Warren R Dunn, Brett Brick A Lantz, Kurt P Spindler, Michael J Stuart, Annunziato Ned Amendola, Christopher C Annunziata, Robert A Arciero, Bernard R Bach, Champ L Baker, Arthur R Bartolozzi, Keith M Baumgarten, Jeffrey H Berg, Geoffrey A Bernas, Stephen F Brockmeier, Robert H Brophy, Charles A Bush-Joseph, J Brad Butler, James L Carey, James E Carpenter, Brian J Cole, Jonathan M Cooper, Charles L Cox, R Alexander Creighton, Tal S David, David C Flanigan, Robert W Frederick, Theodore J Ganley, Charles J Gatt, Steven R Gecha, James Robert Giffin, Sharon L Hame, Jo A Hannafin, Christopher D Harner, Norman Lindsay Harris, Keith S Hechtman, Elliott B Hershman, Rudolf G Hoellrich, David C Johnson, Timothy S Johnson, Morgan H Jones, Christopher C Kaeding, Ganesh V Kamath, Thomas E Klootwyk, Bruce A Levy, C Benjamin Ma, G Peter Maiers, Robert G Marx, Matthew J Matava, Gregory M Mathien, David R Mcallister, Eric C Mccarty, Robert G Mccormack, Bruce S Miller, Carl W Nissen, Daniel F O'Neill, Brett D Owens, Richard D Parker, Mark L Purnell, Arun J Ramappa, Michael A Rauh, Arthur C Rettig, Jon K Sekiya, Kevin G Shea, Orrin H Sherman, James R Slauterbeck, Matthew V Smith, Jeffrey T Spang, Steven J Svoboda, Timothy N Taft, Joachim J Tenuta, Edwin M Tingstad, Armando F Vidal, Darius G Viskontas, Richard A White, James S Williams, Michelle L Wolcott, Brian R Wolf, James J York

Faculty, Staff and Student Publications

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown.

Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient's outcome at 6-year follow-up.

Study design: Cohort study; Level of evidence, 2.

Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) …

Results Of A Randomized Phase Ii Trial Of Paclitaxel And Carboplatin Versus Bleomycin, Etoposide And Cisplatin For Newly Diagnosed And Recurrent Chemonaive Stromal Ovarian Tumors: An Nrg Oncology/Gynecologic Oncology Group Study14, Jubilee Brown, Austin Miller, Laura L Holman, Floor Backes, Christa Nagel, David Bender, David S Miller, Matthew A Powell, Shannon N Westin, Albert Bonebrake, Carolyn Y Muller, Angeles Alvarez Secord, Erin Crane, John Schorge, William P Tew, Anil K Sood, Michael A Bookman, Carol Aghajanian, David M Gershenson

Faculty, Staff and Student Publications

Objectives: To assess the efficacy and toxicity of paclitaxel and carboplatin (PC) compared to bleomycin, etoposide, and cisplatin (BEP) for treatment of newly diagnosed Stage IIA-IV or recurrent chemotherapy-naive ovarian sex cord-stromal tumors (SCST).

Methods: This phase II noninferiority trial randomly assigned patients to receive PC (6 cycles P 175 mg/m2 and C AUC = 6 IV every 3 weeks), or BEP (4 cycles B 20 units/m2 IV push day 1, E 75 mg/m2 IV days 1-5, and cisplatin 20 mg/m2 IV days 1-5 every 3 weeks). The primary endpoint was progression- free survival (PFS). This trial is registered with …

Pharmacogenomic Insights In Psychiatric Care: Uncovering Novel Actionability, Allele-Specific Cyp2d6 Copy Number Variation, And Phenoconversion In 15,000 Patients, Jai N Patel, Sarah A Morris, Raul Torres, Brooke Rhead, Chris Vlangos, Daniel J Mueller, Lisa C Brown, Hailey Lefkofsky, Muneer Ali, Francisco M De La Vega, Kathleen C Barnes, Anthony Zoghbi, Joseph D Stanton, Marcus A Badgeley

Faculty, Staff and Students Publications

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and …

Evaluation Of Chronic Pancreatitis Prognosis Score In An American Cohort, Soo Kyung Park, Darwin L Conwell, Phil A Hart, Shuang Li, Kimberly Stello, Evan L Fogel, William E Fisher, Christopher E Forsmark, Stephen J Pandol, Walter G Park, Mark Topazian, Jose Serrano, Santhi Swaroop Vege, Stephen K Van Den Eeden, Liang Li, Dhiraj Yadav, Jami L Saloman

Faculty, Staff and Student Publications

Introduction: Chronic Pancreatitis Prognosis Score (COPPS) was developed to discriminate disease severity and predict risk for future hospitalizations. In this cohort study, we evaluated if COPPS predicts the likelihood of hospitalization(s) in an American cohort.

Methods: The Chronic Pancreatitis, Diabetes, and Pancreatic Cancer consortium provided data and serum from subjects with chronic pancreatitis (N = 279). COPPS was calculated with baseline data and stratified by severity (low, moderate, and high). Primary endpoints included number and duration of hospitalizations during 12-month follow-up.

Results: The mean ± SD COPPS was 8.4 ± 1.6. COPPS correlated with all primary outcomes: hospitalizations for any …

Optimal Infused Cd34+ Cell Dose In Multiple Myeloma Patients Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation, Oren Pasvolsky, Curtis Marcoux, Denái R Milton, Babar Pal, Mark R Tanner, Qaiser Bashir, Samer Srour, Jaehyun Lee, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Yosra Aljawai, Partow Kebriaei, Melody R Becnel, Hans C Lee, Krina K Patel, Sheeba K Thomas, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Autologous transplantation remains the standard of care for eligible multiple myeloma (MM) patients, yet optimal CD34+ cell dose remains unclear. We conducted a retrospective study on MM patients undergoing upfront transplant between 2005 and 2021 and divided them into low (≤2.5 × 106 cells/kg) and high (>2.5 × 106 cells/kg) CD34+ dose groups. We included 2479 patients, 95 in the low CD34+ group and 2384 in the high CD34+ group. Patients in the low CD34+ group were older (63.2 vs 61.1 years, p = 0.013), more often had R-ISS III (19% vs 9%, p = 0.014), received plerixafor (60% …

A Qualitative Analysis Of A Primary Care Medical-Legal Partnership: Impact, Barriers, And Facilitators, Winston Liaw, Christine Bakos-Block, Thomas F Northrup, Angela L Stotts, Abigail Hernandez, Lisandra Finzetto, Pelumi Oloyede, Bruno Moscoso Rodriguez, Skye Johnson, Lauren Gilbert, Jessica Dobbins, Lechauncy Woodard, Thomas Murphy

Faculty, Staff and Student Publications

Background: Certain health-related risk factors require legal interventions. Medical-legal partnerships (MLPs) are collaborations between clinics and lawyers that address these health-harming legal needs (HHLNs) and have been shown to improve health and reduce utilization.

Objective: The objective of this study is to explore the impact, barriers, and facilitators of MLP implementation in primary care clinics.

Methods: A qualitative design using a semistructured interview assessed the perceived impact, barriers, and facilitators of an MLP, among clinicians, clinic and MLP staff, and clinic patients. Open AI software (otter.ai) was used to transcribe interviews, and NVivo was used to code the data. Braun …

Optical Genome Mapping For Detection Of Bcr::Abl1-Another Tool In Our Toolbox, Zhenya Tang, Wei Wang, Gokce A Toruner, Shimin Hu, Hong Fang, Jie Xu, M James You, L Jeffrey Medeiros, Joseph D Khoury, Guilin Tang

Faculty, Staff and Student Publications

Background:BCR::ABL1 fusion is mostly derived from a reciprocal translocation t(9;22)(q34.1;q11.2) and is rarely caused by insertion. Various methods have been used for the detection of t(9;22)/BCR::ABL1, such as G-banded chromosomal analysis, fluorescence in situ hybridization (FISH), quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and optical genome mapping (OGM). Understanding the strengths and limitations of each method is essential for the selection of appropriate method(s) of disease diagnosis and/or during the follow-up.

Methods: We compared the results of OGM, chromosomal analysis, FISH, and/or RT-PCR in 12 cases with BCR::ABL1.

Results:BCR:ABL1 was detected by FISH and RT-PCR …

Micrornas Are Enriched At Covid-19 Genomic Risk Regions, And Their Blood Levels Correlate With The Covid-19 Prognosis Of Cancer Patients Infected By Sars-Cov-2, Simone Anfossi, Faezeh Darbaniyan, Joseph Quinlan, Steliana Calin, Masayoshi Shimizu, Meng Chen, Paola Rausseo, Michael Winters, Elena Bogatenkova, Kim-Anh Do, Ivan Martinez, Ziyi Li, Loredana Antal, Tudor Rares Olariu, Ignacio Wistuba, George A Calin

Faculty, Staff and Student Publications

Background: Cancer patients are more susceptible to an aggressive course of COVID-19. Developing biomarkers identifying cancer patients at high risk of COVID-19-related death could help determine who needs early clinical intervention. The miRNAs hosted in the genomic regions associated with the risk of aggressive COVID-19 could represent potential biomarkers for clinical outcomes.

Patients and methods: Plasma samples were collected at The University of Texas MD Anderson Cancer Center from cancer patients (N = 128) affected by COVID-19. Serum samples were collected from vaccinated healthy individuals (n = 23) at the Municipal Clinical Emergency Teaching Hospital in Timisoara, Romania. An in …

Influence Of Tp53 Gene Mutations And Their Allelic Status In Myelodysplastic Syndromes With Isolated 5q Deletion, Maria Julia Montoro, Laura Palomo, Claudia Haferlach, Pamela Acha, Onyee Chan, Víctor Navarro, Yasuo Kubota, Felicitas Isabel Schulz, Manja Meggendorfer, Robert Briski, Najla Al Ali, Blanca Xicoy, Félix López-Cadenas, Francesc Bosch, Teresa González, Lea Naomi Eder, Andrés Jerez, Yu-Hung Wang, Alessia Campagna, Valeria Santini, Teresa Bernal Del Castillo, Esperanza Such, Hwei-Fang Tien, Nicolás Diaz Varela, Uwe Platzbecker, Detlef Haase, María Díez-Campelo, Matteo Della Porta, Guillermo Garcia-Manero, Daniel H Wiseman, Ulrich Germing, Jaroslaw P Maciejewski, Rami S Komrokji, Francesc Sole, Torsten Haferlach, David Valcárcel

Faculty, Staff and Student Publications

Mutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the impact of TP53 gene mutations and their allelic state in patients with MDS-del(5q). To that end, a comprehensive analysis of TP53 abnormalities, examining both TP53 mutations and allelic imbalances, in 682 patients diagnosed with MDS-del(5q) was conducted. Twenty-four percent of TP53-mutated patients exhibited multihit alterations, whereas the remaining patients displayed monoallelic …

Bridging Big Data In The Enigma Consortium To Combine Non-Equivalent Cognitive Measures, Eamonn Kennedy, Shashank Vadlamani, Hannah M Lindsey, Pui-Wa Lei, Mary Jo-Pugh, Paul M Thompson, David F Tate, Frank G Hillary, Emily L Dennis, Elisabeth A Wilde, Enigma Clinical Endpoints Working Group Collaborators

Faculty, Staff and Student Publications

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample size. These efforts unveil new questions about how to integrate data across distinct sources and instruments. The goal of this study was to link scores across common auditory verbal learning tasks (AVLTs). This international secondary analysis aggregated multisite raw data for AVLTs across 53 studies totaling 10,505 individuals. Using the ComBat-GAM algorithm, we isolated and removed the component of memory scores associated with site effects while preserving instrumental effects. After adjustment, a continuous item response theory model used multiple memory items of varying …

A Phase Ib/Ii Randomized Clinical Trial Of Oleclumab With Or Without Durvalumab Plus Chemotherapy In Patients With Metastatic Pancreatic Ductal Adenocarcinoma, Andrew L Coveler, Matthew J Reilley, Mark Zalupski, Teresa Macarulla, Christos Fountzilas, Mariano Ponz-Sarvisé, Adnan Nagrial, Nataliya V Uboha, Sophia Frentzas, Michael Overman, Anne Noonan, Wells A Messersmith, Nick Pavlakis, Niharika B Mettu, Ina Bisha, Ying Wang, Paul Smith, Elina Murtomaki, Agata A Bielska, Veronique Bragulat, Zachary A Cooper, Rakesh Kumar, David R Spigel

Faculty, Staff and Student Publications

Purpose: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option.

Patients and methods: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm …

Npm1-Mutated Myeloid Neoplasms Are A Unique Entity Not Defined By Bone Marrow Blast Percentage, Georgina Gener-Ricos, Alex Bataller, Juan Jose Rodriguez-Sevilla, Kelly S Chien, Andres E Quesada, Emmanuel Almanza-Huante, Danielle Hammond, Koji Sasaki, Courtney Dinardo, Tapan Kadia, Naval Daver, Gautam Borthakur, Ghayas C Issa, Nicholas J Short, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo

Faculty, Staff and Student Publications

Introduction: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with < 20% bone marrow (BM) blasts (NPM1mut MNs< 20) are uncommon, and their classification remains inconsistent.

Methods: The clinicopathologic features of 54 patients with NPM1mut MNs < 20 were evaluated and compared with wild-type NPM1 MNs < 20 and NPM1mut MNs≥20, respectively.

Results: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs < 20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age < 60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for < 10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs < 20 had marrow blast progression to ≥20%.

Conclusions: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.

Evaluating Debio 1347 In Patients With Fgfr Fusion-Positive Advanced Solid Tumors From The Fuze Multicenter, Open-Label, Phase Ii Basket Trial, Petros Grivas, Elena Garralda, Funda Meric-Bernstam, Ingo K Mellinghoff, Lipika Goyal, James J Harding, E Claire Dees, Rastislav Bahleda, Nilofer S Azad, Asha Karippot, Razelle Kurzrock, Josep Tabernero, Juha Kononen, Matthew C H Ng, Rutika Mehta, Nataliya V Uboha, Frédéric Bigot, Valentina Boni, Samantha E Bowyer, Valeriy Breder, Andrés Cervantes, Nancy Chan, James M Cleary, Mallika Dhawan, Rikke L Eefsen, James Ewing, Donna M Graham, Tormod K Guren, Jin Won Kim, Krassimir Koynov, Do-Youn Oh, Rebecca Redman, Chia-Jui Yen, David Spetzler, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Rafik Ait-Sarkouh, Claudio Zanna, Abdallah Ennaji, Anna Pokorska-Bocci, Keith T Flaherty

Faculty, Staff and Student Publications

Purpose: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion.

Patients and methods: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of …

First-In-Human Clinical Outcomes With Ng-350a, An Anti-Cd40 Expressing Tumor-Selective Vector Designed To Remodel Immunosuppressive Tumor Microenvironments, Aung Naing, Danny Khalil, Oliver Rosen, D Ross Camidge, Tom Lillie, Rui-Ru Ji, Andrea Stacey, Matthew Thomas, Lee Rosen

Faculty, Staff and Student Publications

Background: Tumor-selective oncolytic viral vectors are promising anticancer therapeutics; however, challenges with dosing and potency in advanced/metastatic cancers have limited efficacy and usage. NG-350A is a next-generation blood-stable adenoviral vector engineered to express an agonist anti-cluster of differentiation (CD)40 antibody without affecting tumor-selectivity and oncolytic potency.

Methods: Intravenous and intratumoral (IT) administration of NG-350A was assessed in a phase Ia/Ib study in patients with metastatic/advanced epithelial tumors (NCT03852511). Dose-escalation was performed separately for intravenous (four dose levels available, each with infusions on Days 1, 3 and 5 of a 57-day treatment period) and IT (single injection on D1 …

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 …

Larp1 Haploinsufficiency Is Associated With An Autosomal Dominant Neurodevelopmental Disorder, James Chettle, Raymond J Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R Curtis Rogers, Barbara R Dupont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M Wentzensen, Blake Vuocolo, Seema R Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J Sanders, Sarah P Blagden

Faculty, Staff and Students Publications

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and …

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 …

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 …

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.