Life Sciences Commons^™

A Scaled Proteomic Discovery Study For Prostate Cancer Diagnostic Markers Using Proteograph, Matthew E K Chang, Jane Lange, Jessie May Cartier, Travis W Moore, Sophia M Soriano, Brenna Albracht, Michael Krawitzky, Harendra Guturu, Amir Alavi, Alexey Stukalov, Xiaoyuan Zhou, Eltaher M Elgierari, Jessica Chu, Ryan Benz, Juan C Cuevas, Shadi Ferdosi, Daniel Hornburg, Omid Farokhzad, Asim Siddiqui, Serafim Batzoglou, Robin J Leach, Michael A Liss, Ryan P Kopp, Mark R Flory

Faculty, Staff and Student Publications

There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate …

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 …

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 …

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 …

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 …

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.

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 …

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 …

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 …

Cancer Incidence After Diagnosis Of Abdominal Aortic Aneurysm-Brief Report, Lingfeng Luo, Allen M Haas, Caitlin F Bell, Richard A Baylis, Shaunak S Adkar, Changhao Fu, Ivan Angelov, Sharon H Giordano, Derek Klarin, Nicholas J Leeper, Kevin T Nead

Faculty, Staff and Student Publications

Background: Epidemiological and mechanistic data support a potential causal link between cardiovascular disease (CVD) and cancer. Abdominal aortic aneurysms (AAAs) represent a common form of CVD with at least partially distinct genetic and biologic pathogenesis from other forms of CVD. The risk of cancer and how this risk differs compared with other forms of CVD, is unknown among AAA patients. We conducted a retrospective cohort study using the IBM MarketScan Research Database to test whether individuals with AAA have a higher cancer risk independent of traditional shared risk factors.

Methods: All individuals ≥18 years of age with ≥36 months of …

Breast Cancer (Bc) And Severe Covid-19 (C-19) Outcomes: A Matched Analysis, Marija Sullivan, Xiudong Lei, Sharon H Giordano, Mariana Chavez-Macgregor

Faculty, Staff and Student Publications

Purpose: Patients with cancer receiving anticancer treatment have a higher risk of severe COVID-19 (C-19) outcomes. We examine the association between breast cancer (BC), recent treatment (systemic therapy, surgery, radiation), and C-19 outcomes.

Methods: Retrospective matched cohort study using the Optum® de-identified C-19 Electronic Health Record dataset (2007-2022). Patients with C-19 were categorized into: no cancer, BC with recent treatment, and BC without recent treatment and matched based on age, C-19 diagnosis date, and comorbidity score. We evaluated 30-day mortality, mechanical ventilation, intensive care unit (ICU) stay, and hospitalization. A composite outcome including all outcomes was analyzed. Multivariable logistic regression …

Sequencing Of Kaposi’S Sarcoma Herpesvirus (Kshv) Genomes From Persons Of Diverse Ethnicities And Provenances With Kshv-Associated Diseases Demonstrate Multiple Infections, Novel Polymorphisms, And Low Intra-Host Variance, Vickie A Marshall, Elena M Cornejo Castro, Charles A Goodman, Nazzarena Labo, Isabella Liu, Nicholas C Fisher, Kyle N Moore, Ananthakrishnan Nair, Taina Immonen, Brandon F Keele, Mark N Polizzotto, Thomas S Uldrick, Yunxiang Mu, Tanuja Saswat, Laurie T Krug, Kevin M Mcbride, Kathryn Lurain, Ramya Ramaswami, Robert Yarchoan, Denise Whitby

Faculty, Staff and Student Publications

Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. …

Datopotamab Deruxtecan In Advanced Or Metastatic Hr+/Her2- And Triple-Negative Breast Cancer: Results From The Phase I Tropion-Pantumor01 Study, Aditya Bardia, Ian E Krop, Takahiro Kogawa, Dejan Juric, Anthony W Tolcher, Erika P Hamilton, Toru Mukohara, Aaron Lisberg, Toshio Shimizu, Alexander I Spira, Junji Tsurutani, Senthil Damodaran, Kyriakos P Papadopoulos, Jonathan Greenberg, Fumiaki Kobayashi, Hong Zebger-Gong, Rie Wong, Yui Kawasaki, Tadakatsu Nakamura, Funda Meric-Bernstam

Faculty, Staff and Student Publications

PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker.

PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Mutation Order In Acute Myeloid Leukemia Identifies Uncommon Patterns Of Evolution And Illuminates Phenotypic Heterogeneity, Matthew Schwede, Katharina Jahn, Jack Kuipers, Linde A Miles, Robert L Bowman, Troy Robinson, Ken Furudate, Hidetaka Uryu, Tomoyuki Tanaka, Yuya Sasaki, Asiri Ediriwickrema, Brooks Benard, Andrew J Gentles, Ross Levine, Niko Beerenwinkel, Koichi Takahashi, Ravindra Majeti

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) has a poor prognosis and a heterogeneous mutation landscape. Although common mutations are well-studied, little research has characterized how the sequence of mutations relates to clinical features. Using published, single-cell DNA sequencing data from three institutions, we compared clonal evolution patterns in AML to patient characteristics, disease phenotype, and outcomes. Mutation trees, which represent the order of select mutations, were created for 207 patients from targeted panel sequencing data using 1 639 162 cells, 823 mutations, and 275 samples. In 224 distinct orderings of mutated genes, mutations related to DNA methylation typically preceded those related to …

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …

A Modular Trial Of Androgen Signaling Inhibitor Combinations Testing A Risk-Adapted Strategy In Patients With Metastatic Castration-Resistant Prostate Cancer, Ana M Aparicio, Rebecca S S Tidwell, Shalini S Yadav, Jiun-Sheng Chen, Miao Zhang, Jingjing Liu, Shuai Guo, Patrick G Pilié, Yao Yu, Xingzhi Song, Haswanth Vundavilli, Sonali Jindal, Keyi Zhu, Paul V Viscuse, Justin M Lebenthal, Andrew W Hahn, Rama Soundararajan, Paul G Corn, Amado Zurita-Saavedra, Sumit K Subudhi, Jianhua Zhang, Wenyi Wang, Chad Huff, Patricia Troncoso, James P Allison, Padmanee Sharma, Christopher J Logothetis

Faculty, Staff and Student Publications

Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers.

Patients and methods: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and < 5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies.

Results: Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2-68.2], 41.4 (95% CI, 33.3-49.9), and 18.7 (95% CI, 14.3-26.3) months in modules 2A (n = 64), 2B (n = 64), and …

Exploring The Landscape Of Somatic Asxl2 Mutations In Myeloid Neoplasms: Frequency And Clinical Implications, Tareq Abuasab, Gautam Borthakur, Rashmi Kanagal-Shamanna, Lucia Masarova, Keyur Patel, Koichi Takahashi, Prithviraj Bose, John Villarreal, Sherry Pierce, Tapan Kadia, Guillermo Garcia-Manero, Nicholas J Short, Courtney Dinardo, Naval Daver, Farhad Ravandi, Hagop Kantarjian, Srdan Verstovsek, Musa Yilmaz

Faculty, Staff and Student Publications

No abstract provided.

Health-Related Quality Of Life In Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma Treated With Daratumumab, Lenalidomide, Bortezomib, And Dexamethasone: Patient-Reported Outcomes From Griffin, Rebecca Silbermann, Jacob Laubach, Jonathan L Kaufman, Douglas W Sborov, Brandi Reeves, Cesar Rodriguez, Ajai Chari, Luciano J Costa, Larry D Anderson, Nitya Nathwani, Nina Shah, Naresh Bumma, Sarah A Holstein, Caitlin Costello, Andrzej Jakubowiak, Robert Z Orlowski, Kenneth H Shain, Andrew J Cowan, Katharine S Gries, Huiling Pei, Annelore Cortoos, Sharmila Patel, Thomas S Lin, Peter M Voorhees, Saad Z Usmani, Paul G Richardson

Faculty, Staff and Student Publications

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of …

Impact Of Apolipoprotein E Genotype On Neurocognitive Function In Patients With Brain Metastases: An Analysis Of Nrg Oncology's Rtog 0614, Jeffrey S Wefel, Snehal Deshmukh, Paul D Brown, David R Grosshans, Erik P Sulman, Jane H Cerhan, Minesh P Mehta, Deepak Khuntia, Wenyin Shi, Mark V Mishra, John H Suh, Nadia N Laack, Yuhchyau Chen, Amarinthia Amy Curtis, Joanna M Laba, Ahmed Elsayed, Anu Thakrar, Stephanie L Pugh, Deborah W Bruner

Faculty, Staff and Student Publications

Purpose: Whole-brain radiation therapy (WBRT) is a common treatment for brain metastases and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer disease and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset time or extent of NCF impairment in patients with brain metastases treated with WBRT.

Methods and materials: NRG/Radiation Therapy Oncology Group 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- memantine), performed …

Mitochondrial Health, Physical Functioning, And Daily Affect: Bioenergetic Mechanisms Of Dementia Caregiver Well-Being, E Lydia Wu-Chung, Luis D Medina, Jensine Paoletti-Hatcher, Vincent Lai, Jennifer M Stinson, Itee Mahant, Paul E Schulz, Cobi J Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Objective: Chronic stress adversely affects mental and physical well-being. However, health outcomes vary among people experiencing the same stressor. Individual differences in physical and emotional well-being may depend on mitochondrial biology, as energy production is crucial for stress regulation. This study investigated whether mitochondrial respiratory capacity corresponds to individual differences in dementia spousal caregivers' mental and physical health.

Methods: Spousal caregivers of individuals with Alzheimer's disease and related dementias ( N = 102, mean age = 71, 78% female, 83% White) provided peripheral blood samples and completed self-report questionnaires on quality of life, caregiver burden, and a 7-day affect scale. …

Tumor-Immune Signatures Of Treatment Resistance To Brentuximab Vedotin With Ipilimumab And/Or Nivolumab In Hodgkin Lymphoma, Edgar Gonzalez-Kozlova, Hsin-Hui Huang, Opeyemi A Jagede, Kevin Tuballes, Diane M Del Valle, Geoffrey Kelly, Manishkumar Patel, Hui Xie, Jocelyn Harris, Kimberly Argueta, Kai Nie, Vanessa Barcessat, Radim Moravec, Jennifer Altreuter, Dzifa Y Duose, Brad S Kahl, Stephen M Ansell, Joyce Yu, Ethan Cerami, James R Lindsay, Ignacio I Wistuba, Seunghee Kim-Schulze, Catherine S Diefenbach, Sacha Gnjatic

Faculty, Staff and Student Publications

To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed a …

Reliable Detection Of Generalized Convulsive Seizures Using An Off-The-Shelf Digital Watch: A Multisite Phase 2 Study, Yash Shashank Vakilna, Xiaojin Li, Jaison S Hampson, Yan Huang, John C Mosher, Yuri Dabaghian, Xi Luo, Blanca Talavera, Sandipan Pati, Masel Todd, Ryan Hays, Charles Akos Szabo, Guo-Qiang Zhang, Samden D Lhatoo

Faculty, Staff and Student Publications

Objective: The aim of this study was to develop a machine learning algorithm using an off-the-shelf digital watch, the Samsung watch (SM-R800), and evaluate its effectiveness for the detection of generalized convulsive seizures (GCS) in persons with epilepsy.

Methods: This multisite epilepsy monitoring unit (EMU) phase 2 study included 36 adult patients. Each patient wore a Samsung watch that contained accelerometer, gyroscope, and photoplethysmographic sensors. Sixty-eight time and frequency domain features were extracted from the sensor data and were used to train a random forest algorithm. A testing framework was developed that would better reflect the EMU setting, consisting of …

Response-Adapted Ultra-Low-Dose 4 Gy Radiation As Definitive Therapy Of Gastric Malt Lymphoma: A Single-Centre, Pilot Trial, Jillian R Gunther, Jie Xu, Manoop S Bhutani, Paolo Strati, Penny Q Fang, Susan Y Wu, Bouthaina S Dabaja, Wenli Dong, Priya R Bhosale, Christopher R Flowers, Ranjit Nair, Luis Malpica Castillo, Luis Fayad, Swaminathan P Iyer, Simrit Parmer, Michael Wang, Hun Ju Lee, Felipe Samaniego, Jason Westin, Sairah Ahmed, Chijioke C Nze, Preetesh Jain, Sattva S Neelapu, Maria A Rodriguez, Dai Chihara, Loretta J Nastoupil, Chelsea C Pinnix

Faculty, Staff and Student Publications

Background: Given the favourable prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, treatment-related toxicity should be minimised. We aimed to evaluate the efficacy of 4 Gy radiotherapy given in a response-adapted approach.

Methods: We conducted a single-centre, single-arm, prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose radiotherapy. Eligible patients were 18 years or older and had newly diagnosed or relapsed Helicobacter pylori-negative gastric MALT lymphoma, with stage I-IV disease. Given the expected low toxicity profile of treatment, performance status was not an exclusion criterion. Patients received external beam photon-based radiotherapy for a total …