Medical Genetics Commons^™

Patient, Physician, And Assessor Blinding In Phase Iii Randomized Trials In Oncology: A Meta-Epidemiological Analysis, Gabrielle Brown, Pavlos Msaouel, Avital M Miller, Ramez Kouzy, Timothy A Lin, Joseph Abi Jaoude, Ethan B Ludmir, Alexander D Sherry

Faculty, Staff and Student Publications

Background: Blinding mitigates bias in randomized trials and may be especially crucial for surrogate endpoints, such as progression-free survival (PFS). Here, we characterize utilization of and factors associated with blinding in Phase III oncology trials with PFS primary endpoints.

Methods: Two-arm, superiority-design trials investigating systemic therapy were identified in May 2024 from ClinicalTrials.gov with no date limitation. Trials were required to have a PFS primary endpoint. The study outcomes were the presence of double-blind designs and blinded independent central review (BICR) for the primary endpoint. Ninety-five percent credible intervals for binary outcomes were estimated from beta distributions, and multivariable logistic …

Single-Cell Proteomic Analysis Reveals Multiple Myeloma Heterogeneity And The Dynamics Of The Tumor Immune Microenvironment In Precursor And Advanced States, Mohamed Kamal, Stephanie N Shishido, Jeremy Mason, Krina Patel, Elisabet E Manasanch, Robert Z Orlowski, Peter Kuhn

Faculty, Staff and Student Publications

Multiple myeloma (MM) is an aggressive hematologic malignancy arising from plasma cell (PC) proliferation in the bone marrow, progressing from its precursor states MGUS and SMM. Despite therapeutic advances, MM remains incurable, underscoring the need for better risk stratification and early detection. Tumor heterogeneity and dynamic immune microenvironment changes drive progression, yet bulk analyses overlook rare subpopulations critical to disease evolution and resistance. This study employed multiplexed targeted proteomics to characterize bone marrow aspirates (BMA) from 22 patients to observe the change in the distribution of PCs and tumor immune microenvironment (TiME) cells across MM disease states and controls. Bone …

Acquired Resistance In Cancer: Towards Targeted Therapeutic Strategies, Alice Soragni, Erik S Knudsen, Thomas N O'Connor, Cristina E Tognon, Jeffrey W Tyner, Beatrice Gini, Donghwa Kim, Trever G Bivona, Xingxing Zang, Agnieszka K Witkiewicz, David W Goodrich, Dadi Jiang, Seth T Gammon, Christopher D Willey, Paul C Boutros, Vlad C Sandulache, Abdullah A Osman, Jeffrey N Myers, Kamiya Mehla, Pankaj K Singh, Keith S Chan, Hongbo Gao, Himangi Marathe

Faculty, Staff and Student Publications

Development of acquired therapeutic resistance limits the efficacy of cancer treatments and accounts for therapeutic failure in most patients. How resistance arises, varies across cancer types and differs depending on therapeutic modalities is incompletely understood. Novel strategies that address and overcome the various and complex resistance mechanisms necessitate a deep understanding of the underlying dynamics. We are at a crucial time when innovative technologies applied to patient-relevant tumour models have the potential to bridge the gap between fundamental research into mechanisms and timing of acquired resistance and clinical applications that translate these findings into actionable strategies to extend therapy efficacy. …

Provider Attitudes And Perspectives On Rehabilitation For Pediatric Cancer Patients, Maria C Swartz, Eduardo Gonzalez Villarreal, Keri Schadler, Donna Kelly, Alakh P Rajan, Clark Andersen, Shiming Zhang, Stephanie J Wells, Amy Heaton, Karen M Moody

Faculty, Staff and Student Publications

PurposeTwenty percent of childhood cancer survivors experience physical function impairments, and ∼75% develop a chronic health condition. Physical and occupational therapists (PT/OTs) can mitigate these late effects, yet few children receive cancer rehabilitation (CR). This research aimed to identify provider attitudes and perspectives towards CR services for children across inpatient and outpatient settings at a cancer center.MethodsThree cardiac rehabilitation instruments were adapted to evaluate knowledge, attitudes, and perceptions regarding CR delivery. Descriptive statistics were used to summarize participant survey results.ResultsTwenty administrators, 20 physicians/advanced practice providers (APPs), and 20 PT/OTs completed surveys. All disciplines strongly agreed on the value of CR …

Author Correction: The Long-Term Effects Of Chemotherapy On Normal Blood Cells, Emily Mitchell, My H Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I Hsu, Nina Friesgaard Øbro, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E Machado, E Joanna Baxter, George Follows, Daniel J Hodson, Ultan Mcdermott, Gary J Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A Goodell, David Kent, Elisa Laurenti, Peter J Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R Stratton

Faculty, Staff and Student Publications

No abstract provided.

The Significance Of Detecting An Unusual Myeloblast Immunophenotype In A Presumptive Clinical Diagnosis Of Myelodysplastic Syndromes, Fnu Sameeta, Wei Wang, Fatima Zahra Jelloul, Okechukwu V Nwogbo, Beenu Thakral, Jie Xu, Shaoying Li, Chi Young Ok, Guilin Tang, Fuli Jia, L Jeffrey Medeiros, Sanam Loghavi, Jeffrey L Jorgensen, Sa A Wang

Faculty, Staff and Student Publications

Context.—: Blasts in myelodysplastic syndromes (MDSs) typically have a primitive myeloid immunophenotype (CD34+CD117+CD13+CD33+HLA-DR+). On rare occasions, blasts were found to be CD34 negative or minimally expressed in a presumptive MDS.

Objective.—: To investigate the occurrence of these cases, and to examine any unique molecular genetic features, and clinical relevance.

Design.—: More than 2000 flow cytometry immunophenotyping tests for MDS performed during a 5-year period were retrospectively reviewed. Chronic myelomonocytic leukemia and overt acute myeloid leukemia (AML) (≥20% blasts) were excluded.

Results.—: Approximately 800 cases had abnormal myeloblasts consistent with myeloid neoplasms; 96% of cases showed a typical primitive phenotype, but …

Bard: A Seamless Two-Stage Dose Optimization Design Integrating Backfill And Adaptive Randomization, Yixuan Zhao, Rachael Liu, Jianchang Lin, Ying Yuan

Faculty, Staff and Student Publications

One common approach for dose optimization is a two-stage design, which initially conducts dose escalation to identify the maximum tolerated dose, followed by a randomization stage where patients are assigned to two or more doses to further assess and compare their risk-benefit profiles to identify the optimal dose. A limitation of this approach is its requirement for a relatively large sample size. To address this challenge, we propose a seamless two-stage design, BARD (Backfill and Adaptive Randomization for Dose Optimization), which incorporates two key features to reduce sample size and shorten trial duration. The first feature is the integration of …

Characterization Of The Germline Pathogenic Mutational Landscape And Oncologic Outcomes Among 877 Patients With Invasive Lobular Carcinoma, Victoria D Huynh, Jason Mouabbi, Henry M Kuerer, Kerollos Nashat Wanis, Hiam M Abdel-Salam, Angelica M Gutierrez, Helen M Johnson, Anthony Lucci, Kelly K Hunt, Banu K Arun

Faculty, Staff and Student Publications

Purpose: There is a paucity of literature on germline pathogenic variants (gPVs) in patients with invasive lobular carcinoma (ILC). This study characterizes the landscape and compares clinicopathologic variables and treatment outcomes between those with and without gPVs.

Methods: A prospectively maintained institutional database was used to identify all patients diagnosed with nonmetastatic ILC who had germline genetic testing. Clinicopathologic characteristics and time to recurrence, contralateral cancer, and death were compared for patients with and without gPVs. Conditional hazard ratios, computed by Cox proportional hazards models, described associations between clinicopathologic factors, including gPV status, and cancer events.

Results: Of 4398 patients …

Computed Tomography Radiomics-Based Cross-Sectional Detection Of Mandibular Osteoradionecrosis In Head And Neck Cancer Survivors, Serageldin Kamel, Laia Humbert-Vidan, Zaphanlene Kaffey, Sarah Mirbahaeddin, Abdulrahman Abusaif, David T A Fuentes, Kareem Wahid, Cem Dede, Mohamed A Naser, Renjie He, Ahmed W Moawad, Khaled M Elsayes, Melissa M Chen, Adegbenga O Otun, Jillian Rigert, Mark S Chambers, Andrew Hope, Erin Watson, Kristy K Brock, Katherine Hutcheson, Lisanne Van Dijk, Amy C Moreno, Stephen Y Lai, Clifton D Fuller, Abdallah S R Mohamed, Md Anderson Head And Neck Cancer Symptom Working Group

Faculty, Staff and Student Publications

Purpose: This study aims to identify radiomic features from contrast-enhanced CT (CECT) scans that differentiate osteoradionecrosis (ORN) from normal mandibular bone in head and neck cancer (HNC) patients treated with radiotherapy (RT).

Materials and methods: CECT images from 150 patients with confirmed ORN diagnosis (2008-2018) at MD Anderson Cancer Center (MDACC) were analyzed (80 % train, 20 % test). Radiomic features were extracted using PyRadiomics from manually segmented ORN regions and automated contralateral healthy mandible regions. Correlation analysis (r > 0.95) reduced features for model training. A random Forest (RF) classifier with Recursive Feature Elimination identified discriminative features. Explainability was assessed …

Management Of Aromatase Inhibitor-Associated Bone Loss (Aibl) In Women With Hormone-Sensitive Breast Cancer: An Updated Joint Position Statement Of The Iof, Cabs, Ects, Ieg, Esceo, Ims, And Siog, Peyman Hadji, Matty Aapro, Nasser Al-Dagri, Majed Alokail, Emmanuel Biver, Jean-Jacques Body, Maria Luisa Brandi, Janet Brown, Cyrille Confavreux, Bernard Cortet, Matthew Drake, Peter Ebeling, Erik Fink Eriksen, Ghada El-Hajj Fuleihan, Theresa A Guise, Nick C Harvey, Andreas Kurth, Bente Langdahl, Willem Lems, Radmila Matijevic, Eugene Mccloskey, Rossella Nappi, Santiago Palacios, Georg Pfeiler, Jean-Yves Reginster, René Rizzoli, Daniele Santini, Sansin Tuzun, Catherine Van Poznak, Tobias De Villiers, M Carola Zillikens, Robert Coleman

Faculty, Staff and Student Publications

Background: Women with hormone-responsive breast cancer who receive adjuvant endocrine treatment with aromatase inhibitors (AI) are known to be at higher fracture risk due to a marked increase in bone resorption. In 2017, several interdisciplinary cancer and bone societies involved in the management of women with AI-associated bone loss (AIBL) published a joint position statement comprising evidence-based recommendations and a practical management algorithm for the assessment of fracture risk and optimal treatment of this patient population.

Patients and methods: In order to provide updated recommendations that reflect recent advances in the assessment and management of AIBL since publication of the …

Tert Promoter Mutations And Survival Outcomes In Adult-Type Granulosa Cell Tumors, Allison L Brodsky, Alejandra Flores Legarreta, Bryan M Fellman, Deanna Glassman, Jeffrey How, Veena Vuttaradhi, Anil K Sood, Lois Michelle Ramondetta, David Gershenson, R Tyler Hillman

Faculty, Staff and Student Publications

Objectives: To evaluate survival outcomes among patients with adult-type granulosa cell tumors who have telomerase reverse transcriptase (TERT) promoter mutations.

Methods: This is a retrospective cohort study using the MD Anderson Rare Gynecologic Malignancy Registry. Patients with adult granulosa cell tumors who underwent molecular testing for TERT promoter and FOXL2 c.C402G mutations were included. We used descriptive statistics to compare demographic and clinical variables and estimated progression-free and overall survival with Kaplan-Meier curves. Cox proportional hazards regression and log-rank tests were employed for comparisons, with multivariable analyses adjusting for various factors.

Results: Among 70 patients, 28 (40%) had TERT+ tumors. …

Ppp2r1a Mutations Portend Improved Survival After Cancer Immunotherapy, Yibo Dai, Anne Knisely, Mitsutake Yano, Minghao Dang, Emily M Hinchcliff, Sanghoon Lee, Annalyn Welp, Manoj Chelvanambi, Matthew Lastrapes, Heng Liu, Zhe Yuan, Chen Wang, Hao Nie, Stephanie Jean, Luis J Montaner, Jiakai Hou, Ami Patel, Shrina Patel, Bryan Fellman, Ying Yuan, Baohua Sun, Renganayaki Krishna Pandurengan, Edwin Roger Parra Cuentas, Joseph Celestino, Yan Liu, Jinsong Liu, R Tyler Hillman, Shannon N Westin, Anil K Sood, Pamela T Soliman, Aaron Shafer, Larissa A Meyer, David M Gershenson, David Vining, Dhakshinamoorthy Ganeshan, Karen Lu, Jennifer A Wargo, Weiyi Peng, Rugang Zhang, Linghua Wang, Amir A Jazaeri

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes1-5. Here we studied ICB response in a cohort of patients with ovarian clear cell carcinoma-a cancer type that poses considerable clinical challenges and lacks effective therapies6-8. We observed significantly prolonged overall survival and progression-free survival in patients with tumours with PPP2R1A mutations. Importantly, our findings were validated in additional ICB-treated patient cohorts across multiple cancer types. Translational analyses from tumour biopsies demonstrated enhanced IFNγ signalling, and the presence of tertiary lymphoid structures at the baseline, …

Molecular Determinants Of Sotorasib Clinical Efficacy In Krasg12c-Mutated Non-Small-Cell Lung Cancer, Ferdinandos Skoulidis, Bob T Li, Adrianus Johannes De Langen, David S Hong, Herve Lena, Juergen Wolf, Grace K Dy, Alessandra Curioni Fontecedro, Pascale Tomasini, Vamsidhar Velcheti, Anthonie J Van Der Wekken, Christophe Dooms, Luis Paz-Ares Rodriguez, Giannis Mountzios, Adrian Sacher, Ernest Nadal, Sebastien Couraud, Sang-We Kim, Kenneth O'Byrne, Danilo Rocco, Ryo Toyozawa, Izabela Chmielewska, Colin R Lindsay, Antreas Hindoyan, Lata Mukundan, Tomasz Wilmanski, Abraham Anderson, Christine Ardito-Abraham, Amrita Pati, Anita Reddy, Bhakti Mehta, Martin Schuler

Faculty, Staff and Student Publications

Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRASG12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest …

Large-Scale Genome-Wide Analyses Of Stuttering, Hannah G Polikowsky, Alyssa C Scartozzi, Douglas M Shaw, Dillon G Pruett, Hung-Hsin Chen, Lauren E Petty, Alexander S Petty, Emily J Lowther, Shu-Hsien Cho, Yao Yu, Sahar Mozaffari, Christy L Avery, Kathleen Mullan Harris, Reyna L Gordon, Janet M Beilby, Kathryn Z Viljoen, Robin M Jones, Chad D Huff, Heather M Highland, Shelly Jo Kraft, Jennifer E Below

Faculty, Staff and Student Publications

Developmental stuttering is a highly heritable, common speech condition characterized by prolongations, blocks and repetitions of speech. Although stuttering is highly heritable and enriched within families, the genetic architecture is largely understudied. We reasoned that there are both shared and distinct genetic variants impacting stuttering risk within sex and ancestry groups. To test this idea, we performed eight primary genome-wide association analyses of self-reported stuttering that were stratified by sex and ancestry, as well as secondary meta-analyses of more than one million individuals (99,776 cases and 1,023,243 controls), identifying 57 unique loci. We validated the genetic risk of self-reported stuttering …

Clinical And Dosimetric Considerations For Yttrium-90 Glass Microspheres Radioembolization Of Intrahepatic Cholangiocarcinoma, Metastatic Colorectal Carcinoma, And Metastatic Neuroendocrine Carcinoma: Recommendations From An International Multidisciplinary Working Group, Marnix Lam, Riad Salem, Beau Toskich, S Cheenu Kappadath, Carlo Chiesa, Kirk Fowers, Paul Haste, Joseph M Herman, Edward Kim, Thomas Leung, Siddharth A Padia, Bruno Sangro, Daniel Y Sze, Etienne Garin

Faculty, Staff and Student Publications

Purpose: The TheraSphere Global Steering Committee reconvened to review clinical data and address knowledge gaps related to treatment and dosimetry in non-HCC indications using Yttrium-90 (90Y) glass microspheres.

Methods: A PubMed search was performed. References were reviewed and adjudicated by the Delphi method. Recommendations were graded according to the degree of recommendation and strength of consensus. Dosimetry focused on a mean dose approach, i.e., aiming for an average dose over either single or multicompartment volumes of interests. Committee discussion and consensus focused on optimal patient selection, disease presentation, liver function, tumour type, tumour vascularity, and curative/palliative treatment intent for intrahepatic …

Genetic Study Of Von Willebrand Factor Antigen Levels ≤ 50 Iu/Dl Identifies Variants Associated With Increased Risk Of Vwd And Bleeding, Rachel K. Friedman, Adam S. Heath, Jennifer E. Huffman, James T. Baker, Natalie R. Hasbani, Sarah A. Gagliano Taliun, Ming-Huei Chen, Tom Howard, Joanne E. Curran, John Blangero

School of Medicine Publications

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤50 IU/dL) in the general population is underexplored.

Methods: To identify genetic variants influencing VWF:Ag levels ≤50 IU/dL, we performed a genome-wide association study in 926 cases with VWF:Ag levels ≤50 IU/dL and 12,846 controls from 7 studies from the TOPMed program. We then examined whether genome-wide significant findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1,286,069 controls, and with …

Nature-Inspired Metaheuristics For Optimizing Dose-Finding And Computationally Challenging Clinical Trial Designs, Weng Kee Wong, Yevgen Ryeznik, Oleksandr Sverdlov, Ping-Yang Chen, Xinying Fang, Ray-Bing Chen, Shouhao Zhou, J Jack Lee

Faculty, Staff and Student Publications

Metaheuristics are commonly used in computer science and engineering to solve optimization problems, but their potential applications in clinical trial design have remained largely unexplored. This article provides a brief overview of metaheuristics and reviews their limited use in clinical trial settings. We focus on nature-inspired metaheuristics and apply one of its exemplary algorithms, the particle swarm optimization (PSO) algorithm, to find phase I/II designs that jointly consider toxicity and efficacy. As a specific application, we demonstrate the utility of PSO in designing optimal dose-finding studies to estimate the optimal biological dose (OBD) for a continuation-ratio model with four parameters …

Optimization Of Mhealth Behavioral Interventions For Patients With Chronic Lymphocytic Leukemia: The Health4cll Study, Che Young Lee, Max J Gordon, Melissa M Markofski, Emily C Lavoy, Susan K Peterson, Liang Li, Sara Fares, Miranda Baum, Margaret Pace, Danielle Walsh, Alessandra Ferrajoli, Karen Basen-Engquist

Faculty, Staff and Student Publications

Purpose: This pilot study of a diet and physical activity intervention (HEALTH4CLL) was conducted to reduce fatigue and improve physical function (PF) in patients with chronic lymphocytic leukemia (CLL).

Methods: The HEALTH4CLL study used a randomized factorial design based on the multiphase optimization strategy (MOST). Patients received diet, exercise, and body weight management instructional materials plus a Fitbit and were randomized to undergo one of 16 combinations of 4 evidence-based mHealth intervention strategies over 16 weeks. Patients' fatigue, PF, health-related quality of life, behavior changes, and program satisfaction and retention were assessed. Paired t-tests were used to examine changes in …

Nanotechnology For Immuno-Oncology, Adam J Grippin, Daeyong Lee, Eileen E Parkes, Wen Jiang, Betty Y S Kim

Faculty, Staff and Student Publications

Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.

White Matter Abnormalities And Cognition In Aging And Alzheimer Disease, Christopher Peter, Aditi Sathe, Niranjana Shashikumar, Kimberly R Pechman, Abigail W Workmeister, T Bryan Jackson, Yuankai Huo, Shubhabrata Mukherjee, Jesse Mez, Logan C Dumitrescu, Katherine A Gifford, Corey J Bolton, Leslie S Gaynor, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Duygu Tosun-Turgut, Mohamad Habes, Di Wang, Arthur W Toga, Paul M Thompson, Panpan Zhang, Kurt G Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Barbara B Bendlin, Sterling C Johnson, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Paul K Crane, Michael L Cuccaro, Timothy J Hohman, Derek B Archer, Dimitrios Zaras, Yisu Yang, Alaina Durant, Praitayini Kanakaraj, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Seo-Eun Choi, Brandon Klinedinst, Michael L Lee, Phoebe Scollard, Emily H Trittschuh, Elizabeth A Sanders

Faculty, Staff and Student Publications

Importance: There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD).

Objective: To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment.

Design setting and participants: This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite z scores, demographic and clinical data, were …