Medical Specialties Commons^™

Metabolic Clearance Rate Of Insulin Across The Glucose Tolerance Spectrum By Race And Ethnicity In Youth With Obesity, Wonhee Cho, Fida Bacha, Hala Tfayli, Sojung Lee, Sara F Michaliszyn, Joon Young Kim, Silva Arslanian

Children’s Nutrition Research Center Staff Publications

Objective: Despite β-cell failure in youth with dysglycemia (i.e., impaired glucose tolerance [IGT] and type 2 diabetes), fasting insulin (FI) concentrations are elevated. Herein, we examined the following: 1) metabolic clearance rate of insulin (MCRI) in youth with obesity and normal glucose tolerance (NGT) versus those with IGT versus those with type 2 diabetes; 2) racial and ethnic differences in insulin dynamics; and 3) metabolic/adiposity correlates of MCRI.

Methods: A total of 206 youth underwent assessment of fasting glucose, FI, MCRI and peripheral insulin sensitivity (PIS), first-phase insulin secretion, disposition index, body composition, and abdominal adiposity.

Results: In type 2 …

Inhibition Of Srebp-1c Rescues Hepatic Cyp7b1 Expression And Bile Acid Synthesis In Malnourished Mice, Xiaoyang Wan, Krishnakant G Soni, Jong Min Choi, Sun Yun Jung, Margaret E Conner, Geoffrey A Preidis

Faculty, Staff and Students Publications

Malnutrition decreases intestinal bile acids, resulting in inefficient nutrient absorption and impaired catch-up growth. Mechanisms by which bile acid depletion occurs in malnutrition are unknown. Using a mouse model of early-life malnutrition, we explored bile acid homeostasis, focusing on transcriptional repression of CYP7B1, a rate-limiting enzyme in the alternative pathway of bile acid biosynthesis, by SREBP-1c, a master regulator of lipid metabolism. Mice were maintained on a low-protein low-fat or isocaloric control chow until eight weeks of age when livers were harvested for proteome profiling, western blot, RT-qPCR, and chromatin immunoprecipitation. Cultured hepatocytes and mice were treated with the SREBP-1c …

A Phase 2 Trial Of Short-Term Intravenous N-Acetylcysteine In Biliary Atresia After Kasai Portoenterostomy, Sanjiv Harpavat, Kristin A Borovsky, Michael E Scheurer, Laurel Cavallo, Franca E Erhiawarie, Sanjeev Vasudevan, Adam M Vogel, Dana Cerminara, Elizabeth M Tessier, Kalyani R Patel, Sridevi Devaraj, Benjamin L Shneider

Center for Medical Ethics and Health Policy Staff Publications

Background: For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow.

Methods: This was a phase 2 study following the two-stage "minimax" trial design. Participants received IV NAC (150 mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) ≤10 μmol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel …

First-In-Human Phase 1 Study Of Khk2455 Monotherapy And In Combination With Mogamulizumab In Patients With Advanced Solid Tumors, Timothy A Yap, Olivier Rixe, Capucine Baldini, Ursa Brown-Glaberman, Sergey Efuni, David S Hong, Christophe Massard, Jameel Muzaffar, Andreea Varga, Emrullah Yilmaz, Yuta Ikawa, Lisa H Shiue, Yi Liu, Matthew W Hruska, Henry Zhao, Akihiro Tokunaga, Solmaz Sahebjam

Faculty, Staff and Student Publications

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long-acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first-in-human, two-part, multicenter, open-label, phase 1, dose-escalation, cohort-expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment-refractory advanced solid tumors. …

The Loss Of Opa1 Accelerates Intervertebral Disc Degeneration And Osteoarthritis In Aged Mice, Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige Boneski, Hiromi Sesaki, Ruteja Barve, John Collins, Makarand Risbud

Department of Orthopaedic Surgery Faculty Papers

Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and

Validation Of Established Thyroid Ultrasound Volume Norms In A Chernobyl Cohort, Lydia B. Zablotska, Robert J. Mcconnell, Aleksandr V. Rozhko, Patrick O'Kane, Vasilina Yauseyenka, Mark P. Little, Victor Minenko, Vladimir Drozdovitch, Tamara Moskvicheva, Maureen Hatch, Tamara Yeudachkova, Kiyohiko Mabuchi, Elizabeth K. Cahoon

Department of Radiology Faculty Papers

OBJECTIVE: To establish thyroid ultrasound volume norms appropriate for studies of diffuse goiter in a cohort of children and adolescents from an iodine-deficient population exposed to 131I by the Chernobyl fallout.

METHODS: A cohort of 11,970 Belarusians aged ≤18 years at the time of the 1986 Chernobyl accident with individual thyroid radiation dose estimates was screened 10-18 years later. From these, a low-dose subset of 2,392 with no thyroid diseases was selected to construct age- and sex-specific normative values for thyroid ultrasound volume, compared to Belarusian Ministry of Health (MOH) norms and existing WHO and European standards.

RESULTS: Cohort-specific values …

Renal G Protein-Coupled Estrogen Receptor 1 Regulates The Epithelial Sodium Channel Promoting Natriuresis To A Greater Extent In Females, Victoria L Nasci, Jean C Bopassa, Elena Mironova, Megan Rhoads, Ravneet Singh, Dennis P Buehler, David M Pollock, Oleh M Pochynyuk, James D Stockand, Eman Y Gohar

Faculty, Staff and Student Publications

Hypertension prevalence is lower in women than men. Enhanced renal sodium (Na+) handling in females has been implicated in sex-differences in hypertension. Epithelial Na+ channel (ENaC) is a key contributor to Na+ homeostasis and is regulated by estrogen. Recent evidence suggests G protein-coupled estrogen receptor 1 (GPER1) evokes a female-specific natriuresis that involves endothelin-1 (ET-1). ET-1 has been shown to downregulate ENaC activity, but whether GPER1 regulates ENaC to modulate natriuresis is unknown. We tested the hypothesis that renal GPER1 functionally interacts with ENaC to promote natriuresis in a sex-specific manner. RNAscope confirmed co-expression of GPER1 and ENaC in rat …

What Is The Expected Clearance Of Methotrexate? A Therapeutic Drug Monitoring Reference Guide For High-Dose Methotrexate Use In Pediatric Malignancies., Zachary L. Taylor, Tamara P. Miller, Sarah G. Board, Ethan Poweleit, Ashley Chavana, Allison Weisnicht, Austin L. Brown, Melanie B. Bernhardt, Eric S. Schafer, Maureen M. O'Brien, Sharon M. Castellino, Laura Ramsey

Manuscripts, Articles, Book Chapters and Other Papers

High-dose methotrexate dosage and infusion durations differ across treatment protocols for pediatric leukemia, lymphoma, and osteosarcoma. Supportive care interventions are dependent on a patient's elimination of methotrexate (MTX). Therefore, it is important to establish the expected MTX elimination across protocols. Using modeling and simulation of real-world data, we determined the expected MTX concentrations at common time points from the start of infusion (24, 36, 42, 48, 60, and 72 hours) and the time that each patient would reach a typical discharge threshold (0.4, 0.2, 0.15, and 0.10 µM). These data provide a reference for MTX concentrations for common pediatric protocols.

Daily Physical Activity And Cardiorespiratory Fitness In Adults With Down Syndrome With And Without Congenital Heart Disease., Julianne G. Clina, David A. White, Joseph R. Sherman, Jessica C. Danon, Daniel Forsha, Brian C. Helsel, Richard A. Washburn, Joseph E. Donnelly, Lauren T. Ptomey

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Individuals with Down syndrome (DS) typically exhibit lower cardiorespiratory fitness and reduced moderate-to-vigorous physical activity (MVPA) compared to persons without disability. Approximately 50-55 % of individuals with DS have congenital heart disease (CHD), which is associated with cardiopulmonary deficiencies and reduced MVPA participation in non-DS populations. It is unknown if CHD related comorbidities compound with DS associated deficits in physical activity and fitness.

OBJECTIVE: To compare physical activity, cardiorespiratory fitness, and cardiovascular function, of persons with DS with and without CHD.

METHODS: Baseline data were used from a 12-month randomized controlled physical activity intervention of adults with DS. Participants …

Utility Of The Us Preventive Services Task Force For Preeclampsia Risk Assessment And Aspirin Prophylaxis, Thomas F Mcelrath, Arun Jeyabalan, Arkady Khodursky, Alison B Moe, Manfred Lee, Maneesh Jain, Laura Goetzl, Elizabeth F Sutton, Pamela M Simmons, George R Saade, Antonio Saad, Luis D Pacheco, Esther Park-Hwang, Antonina I Frolova, Ebony B Carter, Ai-Ris Y Collier, Daniel G Kiefer, Vincenzo Berghella, Rupsa C Boelig, Michal A Elovitz, Cynthia Gyamfi-Bannerman, Joseph R Biggio, Kara Rood, William A Grobman, Carrie Haverty, Morten Rasmussen

Faculty, Staff and Student Publications

Importance: The US Preventive Services Task Force (USPSTF) guidelines on preeclampsia risk assessment and aspirin prophylaxis (AP) have not been evaluated for clinical utility.

Objective: To evaluate which characteristics in the USPSTF guidelines identify risk status and the association of preeclampsia risk with AP recommendations.

Design, setting, and participants: This observational cohort study enrolled from July 2020 to March 2023 with data analysis performed from October to December 2024. Enrollment occurred at 11 centers throughout the US or via direct-to-participant recruitment. Pregnant participants aged 18 years or older with a singleton pregnancy less than 22 weeks' gestation were selected via …

Gut Virome Profile In New Onset Treatment Naïve Saudi Children With Ulcerative Colitis, Mohammad El Mouzan, Tor C Savidge, Ahmed Al Sarkhy, Shyam Badu, Badr Alsaleem, Mohammad Al Mofarreh, Abdullah Almasood, Asaad Assiri

Faculty, Staff and Students Publications

Background: Gut microbiome imbalance is well established in ulcerative colitis (UC) in Western populations. Significantly less is known about the gut virome and whether geography impacts the UC-associated microbiome. The aim of this study was to characterize gut bacteriophage changes, as well as to identify phage-bacterial associations that can serve as potential biomarkers of UC.

Methods: Twenty children with UC and 20 healthy controls were enrolled in the study. Inclusion criteria included newly diagnosed treatment-naïve children with UC with no antibiotic exposure for at least six months prior to sample collection. Deoxyribonucleic acid (DNA) was extracted from stool and rectal …

Involved But Not Essential: Cognitive Activity In Periventricular Nodules And Neuropsychological Outcomes Following Their Ablation, Yosefa A Modiano, Oscar Woolnough, Ryan M Mccormack, Kathryn Snyder, Ellery Wheeler, Samden D Lhatoo, Nuria Lacuey, Sandipan Pati, Katherine Harris, Jay Gavvala, Jessica A Johnson, Nitin Tandon

Faculty, Staff and Student Publications

Objective: Periventricular nodular heterotopia (PVNH) is a malformation of cortical development with high rates of epilepsy. The extent to which nodules participate in normal cerebral functions in addition to pathological processes is unclear. The authors assessed the functional utility (i.e., cognitive impacts) of surgically ablated epileptogenic PVNH tissue via comprehensive neuropsychological testing.

Methods: The sample included 32 patients with PVNH who underwent presurgical neuropsychological evaluation and a subsample of 16 patients who underwent MR-guided laser interstitial thermal therapy (MRgLITT) of nodules, with postsurgical neuropsychological testing. In 11 patients in whom intracranial recordings were performed, reading and naming tasks were tested …

Ovarian Cancer Risk And Survival According To Tumor Sex Hormone Receptor Expression: An Ovarian Cancer Association Consortium And Ovarian Tumor Tissue Analysis Consortium Pooled Analysis, Zhuxuan Fu, Lauren Borho, Sarah E Taylor, Linda E Kelemen, Anna Defazio, Penelope M Webb, Martin Köbel, Nicola S Meagher, Renhua Na, Antonis C Antoniou, Alison H Brand, Catherine J Kennedy, Nikilyn Nevins, Paul D P Pharoah, Yurii B Shvetsov, Stacey J Winham, Jennifer Alsop, Matthias W Beckmann, Adelyn Bolithon, Jessica Boros, David D L Bowtell, James D Brenton, Michael E Carney, Anita Chudecka-Głaz, Linda S Cook, Cezary Cybulski, Peter A Fasching, Sian Fereday, Renée T Fortner, María J García, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Arndt Hartmann, Brenda Y Hernandez, Estrid Høgdall, David G Huntsman, Allan Jensen, Mercedes Jimenez-Linan, Janine M Joseph, Beth Y Karlan, Ewa Kaznowska, Susanne K Kjaer, Tomasz Kluz, Jennifer M Koziak, Jenny Lester, Teri A Longacre, Maria Lycke, Valerie Mcguire, Kirsten B Moysich, Rachel A Murphy, Sandra Orsulic, Susan J Ramus, Cristina Rodríguez-Antona, Joseph H Rothstein, Spinder Samra, Weiva Sieh, Helen Steed, Karin Sundfeldt, Aline Talhouk, Jan Uciński, Chen Wang, Nicolas Wentzensen, Alice S Whittemore, Lynne R Wilkens, Thomas Songer, Maria Mori Brooks, Lu Tang, Francesmary Modugno

Faculty, Staff and Student Publications

Objective: Many epithelial ovarian cancer (EOC) risk factors relate to sex hormones. The association between these factors and the expression of androgen receptor (AR), estrogen receptor-α (ER), and progesterone receptor (PR) in tumors is unknown.

Method: We linked epidemiologic, AR/ER/PR tumor expression, and survival data from 19 studies in the Ovarian Cancer Association Consortium (OCAC; 4762 cases, 20,888 controls) and the Ovarian Tumor Tissue Analysis (OTTA) consortium (5737 cases). We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) between hormonally-linked factors and tumor AR/ER/PR expression using polytomous logistic regression. We assessed survival by AR/ER/PR tumor expression overall and …

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

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes …

Βiv Spectrin Abundancy, Cellular Distribution And Sensitivity To Akt/Gsk3 Regulation In Schizophrenia, Jessica Di Re, Michela Marini, Syed Ibrar Hussain, Aditya K Singh, Akshaya Venkatesh, Musaad A Alshammari, Tahani K Alshammari, Abdul-Rizaq Ali Hamoud, Ali Sajid Imami, Zahra Haghighijoo, Nickolas Fularcyzk, Laura Stertz, Derek Hawes, Angela Mosebarger, Jordan Jernigan, Claire Chaljub, Ralda Nehme, Consuelo Walss-Bass, Anton Schulmann, Marquis P Vawter, Robert Mccullumsmith, Robert D Damoiseaux, Agenor Limon, Demetrio Labate, Michael F Wells, Fernanda Laezza

Faculty, Staff and Student Publications

Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that βIV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between βIV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA …

Targeting Cdk2 And Other Novel Cell Cycle Targets For Breast Cancer Therapy, Mei-Kuang Chen, Linjie Luo, Nicole Massoumi, Khandan Keyomarsi

Faculty, Staff and Student Publications

Introduction: The dysregulation of cyclin-dependent kinases (CDKs) is a key driver of cancer progression, making them attractive therapeutic targets. In CDK4/6 inhibitor (CDK4/6i)-resistant breast cancer, targeting CDK2 offers a promising approach. CDK2 is frequently hyperactivated due to cyclin E1 overexpression or retinoblastoma protein loss, acting as a mechanism that sustains proliferation despite CDK4/6 inhibition. CDK2 inhibitors (CDK2i) show strong anti-tumor activity, particularly in combination with CDK4/6i or immune checkpoint inhibitors.

Areas covered: This review explores the biological roles of CDK2 and its regulatory mechanisms. The review highlights the latest advancements in CDK2i, their mechanisms of action, and their potential in …

Long-Term Cytoreduction Outcomes With Or Without Heated Intraperitoneal Chemotherapy For Colorectal Peritoneal Metastases, Michael G White, Paula Marincola Smith, Neal Bhutiani, Beth Helmink, Norman Galbraith, Scott Kopetz, Michael Overman, Paul Mansfield, Keith Fournier, Abhineet Uppal

Faculty, Staff and Student Publications

Background: Patients with peritoneal metastases from colorectal adenocarcinoma (CRC) benefit from cytoreductive surgery (CRS). However, the role of heated intraperitoneal chemotherapy (HIPEC) remains unclear. We studied associations between HIPEC, peritoneal disease-free survival (PDFS), and overall survival (OS) in patients with CRC undergoing CRS.

Study design: All patients with CRC undergoing CRS between 2008 and 2023 were retrospectively identified at our center. Patient clinicodemographic factors were determined by chart review. OS and PDFS were evaluated using the Kaplan-Meier method. Associations between clinical factors and survival were determined using Cox proportional hazard models.

Results: A total of 147 patients were identified with …

Pathologist-Read Vs Ai-Driven Assessment Of Tumor-Infiltrating Lymphocytes In Melanoma, Thazin N Aung, Matthew Liu, David Su, Saba Shafi, Ceren Boyaci, Sanna Steen, Nikolaos Tsiknakis, Joan Martinez Vidal, Nigel Maher, Goran Micevic, Samuel X Tan, Matthew D Vesely, Saeed Nourmohammadi, Yalai Bai, Dijana Djureinovic, Pok Fai Wong, Katherine Bates, Nay N N Chan, Niki Gavirelatou, Mengni He, Sneha Burela, Robert Barna, Martina Bosic, Konstantin Bräutigam, Irineu Illabochaca, Zhou Chenhao, Joao Gama, Bianca Kreis, Reka Mohacsi, Nir Pillar, Joao Pinto, Christos Poulios, Maria Angeliki Toli, Evangelos Tzoras, Yadriel Bracero, Francesca Bosisio, Gábor Cserni, Alis Dema, Francesco Fortarezza, Mercedes Solorzano Gonzalez, Irene Gullo, Francisco Javier Queipo Gutiérrez, Ezgi Hacihasanoglu, Viktor Jovic, Bianca Lazar, Maria Olinca, Christina Neppl, Rui Caetano Oliveira, Federica Pezzuto, Daniel Gomes Pinto, Vanda Plotar, Ovidiu Pop, Tilman Rau, Kristijan Skok, Wenwen Sun, Ezgi Dicle Serbes, Wiebke Solass, Olga Stanowska, Marcell Szasz, Krzysztof Szymonski, Franziska Thimm, Danielle Vignati, Alon Vigdorovits, Victor Prieto, Tobias Sinnberg, James Wilmott, Shawn Cowper, Jonathan Warrell, Yvonne Saenger, Johan Hartman, Jasmine Plummer, Iman Osman, David L Rimm, Balazs Acs

Faculty, Staff and Student Publications

Importance: Tumor-infiltrating lymphocytes (TILs) are a provocative biomarker in melanoma, influencing diagnosis, prognosis, and immunotherapy outcomes; however, traditional pathologist-read TIL assessment on hematoxylin and eosin-stained slides is prone to interobserver variability, leading to inconsistent clinical decisions. Therefore, development of newer TIL scoring approaches that produce more reliable and consistent readouts is important.

Objective: To evaluate the analytical and clinical validity of a machine learning algorithm for TIL quantification in melanoma compared with traditional pathologist-read methods.

Design, setting, and participants: This multioperator, global, multi-institutional prognostic study compared TIL scoring reproducibility between traditional pathologist-read methods and an artificial intelligence (AI)-driven approach. The …

Adtnorm: Robust Integration Of Single-Cell Protein Measurement Across Cite-Seq Datasets, Ye Zheng, Daniel P Caron, Ju Yeong Kim, Seong-Hwan Jun, Yuan Tian, Florian Mair, Kenneth D Stuart, Peter A Sims, Raphael Gottardo

Faculty, Staff and Student Publications

Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) enables paired measurement of surface protein and mRNA expression in single cells using antibodies conjugated to oligonucleotide tags. Due to the high copy number of surface protein molecules, sequencing antibody-derived tags (ADTs) allows for robust protein detection, improving cell-type identification. However, variability in antibody staining leads to batch effects in the ADT expression, obscuring biological variation, reducing interpretability, and obstructing cross-study analyses. Here, we present ADTnorm, a normalization and integration method designed explicitly for ADT abundance. Benchmarking against 14 existing scaling and normalization methods, we show that ADTnorm accurately aligns populations …

Mutation Dynamics From Diagnosis To Relapse In Acute Myeloid Leukemia With Chromosomal 7 Deletions, Eitan Kugler, Enes Dasdemir, Alex Bataller, Bofei Wang, Courtney D Dinardo, Naval Daver, Musa Yilmaz, Nicholas J Short, Gautam Borthakur, Tapan M Kadia, Koji Sasaki, Danielle Hammond, Alexandre Bazinet, Ehsan Irajizad, Beenu Thakral, Sherry Pierce, Patrick Reville, Farhad Ravandi, Hussein A Abbas

Faculty, Staff and Student Publications

Monosomy 7 and 7q deletions (-7/del(7q)) are the most common adverse cytogenetic event in acute myeloid leukemia (AML), linked to high relapse rates. We analyzed 115 AML patients with -7/del(7q) who achieved remission after induction therapy to characterize the mutational landscape from diagnosis to relapse. Median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months) or complex karyotype (12.4 vs. 8.6 months). TP53 mutations were most frequent (67% of cases at diagnosis) and persisted in 97% of patients at relapse. At time of relapse, patients with TP53 mutations had fewer co-occurring …

Blood Bacterial Dna Signatures In A Prospective Cohort Of Patients With Masld Cirrhosis, Suet-Ying Kwan, Lillian I Dolapchiev, Caren I Sanchez, Tiffany L Calderone, Jessica I Sanchez, Megha B Bhongade, Ahmed El Sabagh, Darrel W Cleere, Nakul Gupta, Prasun K Jalal, David W Victor, Laura Beretta

Faculty, Staff and Student Publications

Background: Predictive biomarkers are needed to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), at high risk for HCC. Our study aimed to determine whether the detection of circulating bacterial DNA could be associated with HCC development in MASLD patients with liver cirrhosis.

Methods: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance for HCC by contrast-enhanced magnetic resonance imaging. In a nested cohort study, we performed 16S rRNA sequencing of cell-free DNA extracted from 343 longitudinal plasma samples collected from 151 MASLD patients with cirrhosis. Among the 151 patients, 25 developed HCC during follow-up.

Results: …

Long-Term Transfusion Independence With Luspatercept Versus Epoetin Alfa In Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes In The Commands Trial, Guillermo Garcia-Manero, Valeria Santini, Amer M Zeidan, Rami S Komrokji, Veronika Pozharskaya, Shelonitda Rose, Karen Keeperman, Yinzhi Lai, Sameer Kalsekar, Barkha Aggarwal, Dimana Miteva, David Valcárcel, Pierre Fenaux, Jake Shortt, Matteo Giovanni Della Porta, Uwe Platzbecker

Faculty, Staff and Student Publications

Introduction: The efficacy of erythropoiesis-stimulating agents (ESAs) for transfusion-dependent (TD) anemia in lower-risk myelodysplastic syndromes (LR-MDS) is limited. Luspatercept achieved significantly greater rates of red blood cell (RBC) transfusion independence (TI) versus epoetin alfa (an ESA) in the phase 3 COMMANDS trial. This analysis assessed long-term RBC-TI, cumulative response, and safety with luspatercept in COMMANDS.

Methods: Eligible patients aged ≥ 18 years, with ESA-naive, RBC TD LR-MDS were randomized 1:1 to receive luspatercept (1.0 mg/kg, titration to 1.75 mg/kg permitted) or epoetin alfa (450 IU/kg, titration to 1050 IU/kg). Disease assessment was carried out at week 24 (day 169) and …

Clonal Evolution Of Hematopoietic Stem Cells After Autologous Stem Cell Transplantation, Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Linda Zhang, Jennifer Padilla, Li Zhao, Joanne I Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney Dinardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Daisuke Nakada, Gheath Al-Atrash, Jeffery Molldrem, P Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi

Faculty, Staff and Student Publications

The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated …

Hyalinization-Based Pathologic Response And Immune Infiltration Following Neoadjuvant Radiotherapy With Or Without Immune-Checkpoint Blockade In Localized Undifferentiated Pleomorphic Sarcoma, R S Traweek, M Zoghbi, R Lazcano, B M Cope, A J Bishop, A Farooqi, D Mitra, A K Yoder, B A Guadagnolo, D R Ingram, K Wani, D Shamsutdinova, A J Lazar, W-L Wang, C P Scally, E Z Keung, K E Torres, K K Hunt, R Ratan, J A Livingston, M S Nakazawa, D M Araujo, S Patel, V Ravi, A P Conley, M A Zarzour, N Somaiah, C L Roland, E F Nassif Haddad

Faculty, Staff and Student Publications

BACKGROUND: Standard-of-care treatment of localized undifferentiated pleomorphic sarcoma (UPS) involves preoperative radiotherapy (RT) and surgery. Combination of RT with immune-checkpoint blockade (ICB) represents a promising new strategy.

METHODS: Our primary objective was to assess survival outcomes and pathologically documented response in patients receiving RT with or without ICB or chemotherapy.

RESULTS: In a retrospective cohort of 68 patients with primary or locally recurrent UPS who received neoadjuvant RT with or without ICB, the ICB group had greater tumor hyalinization than the non-ICB group (89% compared with 30%, P = 0.018). In the non-ICB group, 19/37 patients (51%) achieved hyalinization-based pathologic …

Dynamic Contrast-Enhanced Mri Processing Comparison For Distinguishing True Progression From Pseudoprogression In High-Grade Glioma, Ahmad Amer, Shehbaz Ansari, Apollo Krayyem, Suprateek Kundu, Swapnil Khose, Halyna Pokhylevych, Susana Calle, Chirag B Patel, Zixi Yang, Ho-Ling Anthony Liu, Jason M Johnson

Faculty, Staff and Student Publications

Background: Treatment-related changes may occur due to radiation and temozolomide in glioblastoma and can mimic tumor progression on conventional MRI. DCE-MRI enables quantification of the extent of blood-brain barrier (BBB) disruption, providing information about areas of suspicious postcontrast T1 enhancement. We compared DCE-MRI processing methods for distinguishing true disease progression from pseudoprogression in high-grade gliomas (HGGs).

Methods: We identified 110 patients with HGG treated with surgery and chemoradiation who underwent DCE-MRI to further interrogate areas of new/increasing enhancement. All patients had confirmatory surgery/biopsy with pathology-confirmed progression or pseudoprogression. Scans were performed at 3T and analyzed using nordicICE. The MCA, SSS, …

Kap1 Promotes Gastric Adenocarcinoma Progression By Activating Hippo/Yap1 Signaling Via Binding To Hnrnpab, Shumei Song, Yibo Fan, Gengyi Zou, Longfei Huo, Janani Kumar, Yuan Li, Ruiping Wang, Enyu Dai, Jiankang Jin, Ailing W Scott, Shan Shao, Melissa Pool Pizzi, Jody V Vykoukal, Hiroyuki Katayama, Samir Hanash, George A Calin, Xing Zhang, Min Gyu Lee, Zhenning Wang, Yuan-Hung Lo, Qiong Gan, Rebecca E Waters, Feng Yin, Linghua Wang, Xiaodong Cheng, Jaffer A Ajani, Shilpa S Dhar

Faculty, Staff and Student Publications

Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter …

Risk Of Early Death After Acute Leukemia Diagnosis Among Adolescents And Young Adults, Amy M Berkman, Clark R Andersen, Vidya Puthenpura, Nicholas J Short, Kelly Merriman, Mahesh Swaminathan, Branko Cuglievan, David Mccall, Courtney Dinardo, Cesar Nunez, Nitin Jain, Tapan Kadia, Ghayas Issa, Amber Gibson, Miriam B Garcia, J Andrew Livingston, Susan Parsons, Michelle A T Hildebrandt, Michael E Roth

Faculty, Staff and Student Publications

Background: Advances in care have led to improvements in survival for adolescents and young adults (AYAs) diagnosed with cancer; however, the risk of early death remains high for certain cancers, particularly acute leukemias. Risk factors for early death in AYAs diagnosed with acute leukemia have not been well studied.

Methods: The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death (within 2 months of diagnosis) in AYAs diagnosed with acute leukemia (n = 16 153). Early death proportion, by year, for AYAs diagnosed between 2006 and 2020 was described. Associations between incidence of early death …

A Follow-Up Study On The Novel Use Of Contrast-Enhanced Susceptibility-Weighted Imaging For Extremity Desmoid Fibromatosis Response Assessment, Raul F Valenzuela, Elvis Duran-Sierra, Mathew Antony, Behrang Amini, Sam Lo, Keila E Torres, Ken-Pin Hwang, Jingfei Ma, R Jasson Stafford, Ravin Ratan, John E Madewell, Dejka Araujo, William A Murphy, Colleen M Costelloe

Faculty, Staff and Student Publications

Desmoid tumors are rare mesenchymal neoplasms characterized by a clonal proliferation of fibroblasts and myofibroblasts. Using the novel contrast-enhanced susceptibility-weighted imaging (CE-SWI) for characterizing desmoid tumors can enhance the separation between fibrous T2-hypointense and cellular T1-enhancing components. We aim to evaluate the effectiveness of the CE-SWI signal, volumetric, and radiomics-derived features in assessing desmoid treatment response. This IRB-approved study included 17 single-lesion extremity desmoid fibromatosis patients who underwent standard-of-care MRI, including CE-SWI, from March 2021 to February 2024. Measurements of maximum diameter, volume, and the modified Choi (m-Choi: tumor/muscle T2 ratio) were computed based on CE-SWI and T2-STIR volumetric tumor …

Autologous T Cell Therapy For Prame, Martin Wermke, Dejka M Araujo, Manik Chatterjee, Apostolia M Tsimberidou, Tobias A W Holderried, Amir A Jazaeri, Ran Reshef, Carsten Bokemeyer, Winfried Alsdorf, Katrin Wetzko, Peter Brossart, Katrin Aslan, Linus Backert, Sebastian Bunk, Jens Fritsche, Swapna Gulde, Silvana Hengler, Norbert Hilf, Mohammad B Hossain, Jens Hukelmann, Mamta Kalra, Delfi Krishna, M Alper Kursunel, Dominik Maurer, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Karine Pozo, Arun Satelli, Marilena Letizia, Heiko Schuster, Oliver Schoor, Claudia Wagner, Hans-Georg Rammensee, Carsten Reinhardt, Harpreet Singh-Jasuja, Steffen Walter, Toni Weinschenk, Jason J Luke, Cedrik M Britten

Faculty, Staff and Student Publications

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose …

Outcomes And Toxicity Following 3 Or More Definitive Courses Of Thoracic Radiation Therapy For Non-Small Cell Lung Cancer, Abigael Odwuor, Percy Lee, Joe Y Chang, Saumil Gandhi, Zhongxing Liao, Steven H Lin, Aileen Chen, Quynh-Nhu Nguyen, Michael S O'Reilly, Stephen G Chun, Julianna Bronk, David Qian, Matthew S Ning

Faculty, Staff and Student Publications

Purpose: Salvage re-irradiation is increasingly utilized to manage non-small cell lung cancer (NSCLC) locoregional recurrence or new lung primaries in previously treated areas. There is sparse information on efficacy and toxicity profile. We report a large experience of patients treated with multiple courses of definitive radiation for new and recurrent NSCLC.

Methods and materials: Medical records of patients who underwent ≥ 3 definitive thoracic radiation therapy (RT) courses for new or recurrent NSCLC at our cancer center from 2012 through 2021 were retrospectively reviewed following institutional review board approval. Toxicity was graded per Common Terminology Criteria for Adverse Events (CTCAE) …