Biomedical Informatics Commons^™

International Multicenter Retrospective Study From The Ultra-Rare Sarcoma Working Group On Low-Grade Fibromyxoid Sarcoma, Sclerosing Epithelioid Fibrosarcoma, And Hybrid Forms: Outcome Of Primary Localized Disease, Claudia Giani, Abdulazeez Salawu, Silva Ljevar, Ryan A Denu, Andrea Napolitano, Emanuela Palmerini, Elizabeth A Connolly, Koichi Ogura, Daniel D Wong, Roberto Scanferla, Evan Rosenbaum, Jyoti Bajpai, Zola Chia-Chen Li, Susie Bae, Lorenzo D'Ambrosio, Steve Bialick, Andrew J Wagner, Alexander T J Lee, Hanna Koseła-Paterczyk, Giacomo G Baldi, Antonella Brunello, Yeh Chen Lee, Herbert H Loong, Sosipatros Boikos, Fernando Campos, Carlo M Cicala, Robert G Maki, Nadia Hindi, Costanza Figura, Shahd S Almohsen, Sheyaskumar Patel, Robin L Jones, Toni Ibrahim, Rooshdiya Karim, Akira Kawai, Richard Carey-Smith, Richard Boyle, Silvia M Taverna, Alexander J Lazar, Elizabeth G Demicco, Judith V M G Bovee, Angelo P Dei Tos, Christopher Fletcher, Daniel Baumhoer, Marta Sbaraglia, Inga-Marie Schaefer, Rosalba Miceli, Alessandro Gronchi, Silvia Stacchiotti

Faculty, Staff and Student Publications

The aim of the study was to report the outcome of primary localized low-grade fibromyxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), and hybrid LGFMS/SEF (H-LGFMS/SEF). Patients with primary localized LGFMS, SEF, or H-LGFMS/SEF, surgically treated with curative intent from January 2000 to September 2022, were enrolled from 14 countries and 27 institutions. Pathologic inclusion criteria were predefined by expert pathologists. The primary endpoint was overall survival (OS). Secondary endpoints were crude cumulative incidence (CCI) of local recurrence (LR), CCI of distant metastases (DM), and post-metastases OS (p-OS). Two hundred ninety-four patients (239 LGFMS, 32 SEF, and 23 H-LGFMS/SEF) were identified. …

Accumulated Seizure Burden Predicts Neurodevelopmental Outcome At 36 Months Of Age In Patients With Tuberous Sclerosis Complex, S Katie Z Ihnen, Samuel Alperin, Jamie K Capal, Alexander L Cohen, Jurriaan M Peters, E Martina Bebin, Hope A Northrup, Mustafa Sahin, Darcy A Krueger

Faculty, Staff and Student Publications

Objective: Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear.

Methods: Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 TSC patients followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of …

Comprehensive Genomic Analysis Reveals Molecular Heterogeneity In Pediatric Alk-Positive Anaplastic Large Cell Lymphoma, Timothy I Shaw, Stanley Pounds, Xueyuan Cao, Jing Ma, Gustavo Palacios, John Mason, Sherrie Perkins, Gang Wu, Yiping Fan, Jian Wang, Xin Zhou, Alyssa Obermayer, Marsha C Kinney, Jacqueline Kraveka, Thomas Gross, John Sandlund, Jinghui Zhang, Charles Mullighan, Megan S Lim, Vasiliki Leventaki

Faculty, Staff and Student Publications

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL (ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription …

Improved Survival And Decreased Cancer Deaths In Young Adults With Cancer After Passage Of The Affordable Care Act Dependent Coverage Expansion, Michael Roth, Clark R Andersen, Amy Berkman, Stuart Siegel, Branko Cuglievan, J Andrew Livingston, Michelle Hildebrandt, Jaime Estrada, Archie Bleyer

Faculty, Staff and Student Publications

Background: The Patient Protection and Affordable Care Act (ACA) allowed Americans aged 19-25 years to remain on their parents' health insurance plans until age 26 years (the Dependent Care Expansion [DCE]). Have those with cancer diagnoses benefited?

Methods: The ACE DCE 7-year age range of 19-25 years was compared for changes in cancer survival and mortality before and after enactment of the ACA with groups that were younger and older (in 7-year age spans: ages 12-18 and 26-32 years, respectively). Cancer death data for the entire United States were obtained from the Centers for Disease Control and Prevention, and relative …

Prevalence Of Carotid Ultrasound Screening In Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study, Yolanda Bryce, Jillian A Whitton, Kayla L Stratton, Wendy M Leisenring, Eric J Chow, Gregory Armstrong, Brent Weil, Bryan Dieffenbach, Rebecca M Howell, Kevin C Oeffinger, Paul C Nathan, Emily S Tonorezos

Faculty, Staff and Student Publications

Introduction: Many childhood cancer survivors are at risk for cardiovascular disease and stroke. The North American Children's Oncology Group long-term follow-up guidelines recommend carotid ultrasound in cancer survivors 10 years after neck radiation therapy (RT) ≥40 Gy. The use of carotid ultrasound in this population has not been described.

Methods: Survivors of childhood cancer diagnosed 1970-1999 (N = 8693) and siblings (N = 1989) enrolled in the Childhood Cancer Survivor Study were asked if they had ever had a carotid ultrasound. Prevalence of carotid ultrasound was evaluated. Prevalence ratios (PR) and 95% confidence intervals (CIs) were evaluated in multivariate Poisson …

High-Grade B-Cell Lymphoma Not Otherwise Specified, With Diffuse Large B-Cell Lymphoma Gene Expression Signatures: Genomic Analysis And Potential Therapeutics, Waseem Lone, Alyssa Bouska, Tyler A Herek, Catalina Amador, Joo Song, Alexander M Xu, Dylan Jochum, Issa Ismail Issa, Dennis D Weisenburger, Xuan Zhang, Sharath Kumar Bhagavathi, Tayla B Heavican-Foral, Sunandini Sharma, Ab Rauf Shah, Abdul Rouf Mir, Aisha Ahmad Alkhinji, Dalia El-Gamal, Bhavana J Dave, Keenan Hartert, Jiayu Yu, Mallick Saumyaranjan, Timothy C Greiner, Julie Vose, Timothy W Mckeithan, Kai Fu, Michael Green, Chengfeng Bi, Akil Merchant, Wing C Chan, Javeed Iqbal

Faculty, Staff and Student Publications

High-grade B-cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort (n = 55) in adults (n = 45) and in children (n = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with de novo DLBCL (n = 85) and BL (n = 52). …

Ntrk Fusion-Positive Thyroid Carcinoma: From Diagnosis To Targeted Therapy, Vicente R Marczyk, Sasan Fazeli, Ramona Dadu, Naifa L Busaidy, Priyanka Iyer, Mimi I Hu, Steven I Sherman, Sarah Hamidi, Sayed Mohsen Hosseini, Michelle D Williams, Salmaan Ahmed, Mark J Routbort, Raja Luthra, Sinchita Roy-Chowdhuri, Francis Anthony San Lucas, Keyur P Patel, David S Hong, Mark Zafereo, Jennifer R Wang, Anastasios Maniakas, Steven G Waguespack, Maria E Cabanillas

Faculty, Staff and Student Publications

Purpose: Neurotrophic tropomyosin receptor kinase (NTRK) fusions may act as an oncogenic driver in thyroid carcinomas. Given their low frequency, clinical, pathological, and molecular data on these patients and their responses to targeted therapies are limited.

Methods: This is an observational retrospective study conducted at a single high-volume cancer center in the United States. Data were retrospectively collected from medical records.

Results: We included 65 patients (37 adult, 28 pediatric) with an NTRK fusion-positive thyroid carcinoma (24 NTRK1, 41 NTRK3), of which 54 were papillary thyroid carcinomas (PTC), four poorly differentiated thyroid carcinomas (PDTC), and seven …

Structural Variant Allelic Heterogeneity In Mecp2 Duplication Syndrome Provides Insight Into Clinical Severity And Variability Of Disease Expression, Davut Pehlivan, Jesse D Bengtsson, Sameer S Bajikar, Christopher M Grochowski, Ming Yin Lun, Mira Gandhi, Angad Jolly, Alexander J Trostle, Holly K Harris, Bernhard Suter, Sukru Aras, Melissa B Ramocki, Haowei Du, Michele G Mehaffey, Kyunghee Park, Ellen Wilkey, Cemal Karakas, Jesper J Eisfeldt, Maria Pettersson, Lynn Liu, Marwan S Shinawi, Virginia E Kimonis, Wojciech Wiszniewski, Kyle Mckenzie, Timo Roser, Angela M Vianna-Morgante, Alberto S Cornier, Ahmed Abdelmoity, James P Hwang, Shalini N Jhangiani, Donna M Muzny, Tadahiro Mitani, Kazuhiro Muramatsu, Shin Nabatame, Daniel G Glaze, Jawid M Fatih, Richard A Gibbs, Zhandong Liu, Anna Lindstrand, Fritz J Sedlazeck, James R Lupski, Huda Y Zoghbi, Claudia M B Carvalho

Faculty, Staff and Students Publications

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive …

Clonal Landscape And Clinical Outcomes Of Telomere Biology Disorders: Somatic Rescue And Cancer Mutations, Fernanda Gutierrez-Rodrigues, Emma M Groarke, Natthakan Thongon, Juan Jose Rodriguez-Sevilla, Luiz Fernando B Catto, Marena R Niewisch, Ruba Shalhoub, Lisa J Mcreynolds, Diego V Clé, Bhavisha A Patel, Xiaoyang Ma, Dalton Hironaka, Flávia S Donaires, Nina Spitofsky, Barbara A Santana, Tsung-Po Lai, Lemlem Alemu, Sachiko Kajigaya, Ivana Darden, Weiyin Zhou, Paul V Browne, Subrata Paul, Justin Lack, David J Young, Courtney D Dinardo, Abraham Aviv, Feiyang Ma, Michel Michels De Oliveira, Ana Paula De Azambuja, Cynthia E Dunbar, Malgorzata Olszewska, Emmanuel Olivier, Eirini P Papapetrou, Neelam Giri, Blanche P Alter, Carmem Bonfim, Colin O Wu, Guillermo Garcia-Manero, Sharon A Savage, Neal S Young, Simona Colla, Rodrigo T Calado

Faculty, Staff and Student Publications

Telomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, …

The Study Of The Epidemiology Of Pediatric Hypertension Registry (Superhero): Rationale And Methods, Andrew M South, Victoria C Giammattei, Kiri W Bagley, Christine Y Bakhoum, William H Beasley, Morgan B Bily, Shupti Biswas, Aaron M Bridges, Rushelle L Byfield, Jessica Fallon Campbell, Rahul Chanchlani, Ashton Chen, Lucy D'Agostino Mcgowan, Stephen M Downs, Gina M Fergeson, Jason H Greenberg, Taylor A Hill-Horowitz, Elizabeth T Jensen, Mahmoud Kallash, Margret Kamel, Stefan G Kiessling, David M Kline, John R Laisure, Gang Liu, Jackson Londeree, Caroline B Lucas, Sai Sudha Mannemuddhu, Kuo-Rei Mao, Jason M Misurac, Margaret O Murphy, James T Nugent, Elizabeth A Onugha, Ashna Pudupakkam, Kathy M Redmond, Sandeep Riar, Christine B Sethna, Sahar Siddiqui, Ashley L Thumann, Stephen R Uss, Carol L Vincent, Irina V Viviano, Michael J Walsh, Blanche D White, Robert P Woroniecki, Michael Wu, Ikuyo Yamaguchi, Emily Yun, Donald J Weaver

Faculty, Staff and Students Publications

Despite increasing prevalence of hypertension in youth and high adult cardiovascular mortality rates, the long-term consequences of youth-onset hypertension remain unknown. This is due to limitations of prior research, such as small sample sizes, reliance on manual record review, and limited analytic methods, that did not address major biases. The Study of the Epidemiology of Pediatric Hypertension (SUPERHERO) is a multisite, retrospective registry of youth evaluated by subspecialists for hypertension disorders. Sites obtain harmonized electronic health record data using standardized biomedical informatics scripts validated with randomized manual record review. Inclusion criteria are index visit for International Classification of Diseases, 10th …

Prevalence, Diagnostic Features, And Medical Outcomes Of Females With Turner Syndrome With A Trisomy X Cell Line (45, X/47, Xxx): Results From The Insights Registry, Natalia Klamut, Samantha Bothwell, Alexandra E Carl, Vaneeta Bamba, Jennifer R Law, Wendy J Brickman, Karen O Klein, Roopa Kanakatti Shankar, Catherina T Pinnaro, Patricia Y Fechner, Siddharth K Prakash, Iris Gutmark-Little, Susan Howell, Nicole Tartaglia, Marybel Good, Kelly C Ranallo, Shanlee M Davis

Faculty, Staff and Student Publications

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS-related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly …

High Activity Of The New Myeloablative Regimen Of Gemcitabine/Clofarabine/Busulfan For Allogeneic Transplant For Aggressive Lymphomas, Jeremy Ramdial, Ruitao Lin, Peter F Thall, Benigno C Valdez, Chitra Hosing, Samer Srour, Uday Popat, Muzaffar Qazilbash, Amin Alousi, Melissa Barnett, Alison Gulbis, Terri Lynn Shigle, Elizabeth J Shpall, Borje S Andersson, Yago Nieto

Faculty, Staff and Student Publications

Refractory aggressive lymphomas can be treated with allo-SCT, pursuing a graft-vs-lymphoma effect. While reduced intensity conditioning is safe, tumors often progress rapidly, indicating the need for more active conditioning regimens. The preclinical synergy we saw between gemcitabine (Gem), clofarabine (Clo) and busulfan (Bu) against lymphoma cell lines led us to study Gem/Clo/Bu clinically. Eligibility: age 12-65, refractory aggressive B-NHL, T-NHL or Hodgkin, with a matched donor. Infusional Gem was dose-escalated on days (d) -6 and -4 (475-975 mg/m2/day), followed by Clo (40 mg/m2/day) and Bu (target AUC, 4000 μMol min/day) (d -6 to -3). CD20+ tumors received rituximab. GVHD prophylaxis …

Mtor Maintains Endothelial Cell Integrity To Limit Lung Vascular Injury, Michelle Warren Millar, Rauf A Najar, Spencer A Slavin, Mohammad Shadab, Imran Tahir, Zahra Mahamed, Xin Lin, Jun-Ichi Abe, Terry W Wright, David A Dean, Fabeha Fazal, Arshad Rahman

Faculty, Staff and Student Publications

The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify mechanistic target of rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis …

Keratinocyte Carcinomas In Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study, Christina Boull, Yan Chen, Cindy Im, Alan Geller, Yadav Sapkota, James E Bates, Rebecca Howell, Michael A Arnold, Miriam Conces, Louis S Constine, Leslie Robison, Yutaka Yasui, Gregory T Armstrong, Joseph P Neglia, Lucie M Turcotte

Faculty, Staff and Student Publications

Background: Childhood cancer survivors (CCS) are at increased risk for keratinocyte carcinomas (KC) however, the long-term incidence of single and multiple KC is not well established.

Objective: Identify risk factors and quantify KC cumulative incidence and multiple-incidence burden in CCS.

Methods: KC were identified among Childhood Cancer Survivor Study participants, a cohort of 5-year cancer survivors diagnosed < 21 years of age between 1970 and 1999 in North America. Cumulative incidence was estimated and multivariable models assessed relative rates of KC associated with survivor and treatment characteristics.

Results: Among 25,658 participants, 1446 developed 5363 KC (93.5% basal cell carcinoma, 6.7% squamous cell carcinoma; mean age 37.0 years (range 7.3-67.4), mean latency 25.7 years; 95.3% White and 88.4% with radiotherapy). Mean lesion count was 3.7 with 26.1% experiencing ≥4. Radiotherapy imparted …

The Emerging Field Of Viroimmunotherapy For Pediatric Brain Tumors, Marc Garcia-Moure, Virginia Laspidea, Sumit Gupta, Andrew G Gillard, Soumen Khatua, Akhila Parthasarathy, Jiasen He, Frederick F Lang, Juan Fueyo, Marta M Alonso, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the …

A Site-Wise Reliability Analysis Of The Abcd Diffusion Fractional Anisotropy And Cortical Thickness: Impact Of Scanner Platforms, Yezhi Pan, L Elliot Hong, Ashley Acheson, Paul M Thompson, Neda Jahanshad, Alyssa H Zhu, Jiaao Yu, Chixiang Chen, Tianzhou Ma, Ho-Ling Liu, Jelle Veraart, Els Fieremans, Nicole R Karcher, Peter Kochunov, Shuo Chen

Faculty, Staff and Student Publications

The Adolescent Brain and Cognitive Development (ABCD) project is the largest study of adolescent brain development. ABCD longitudinally tracks 11,868 participants aged 9-10 years from 21 sites using standardized protocols for multi-site MRI data collection and analysis. While the multi-site and multi-scanner study design enhances the robustness and generalizability of analysis results, it may also introduce nonbiological variances including scanner-related variations, subject motion, and deviations from protocols. ABCD imaging data were collected biennially within a period of ongoing maturation in cortical thickness and integrity of cerebral white matter. These changes can bias the classical test-retest methodologies, such as intraclass correlation …

Single-Cell Integration Reveals Metaplasia In Inflammatory Gut Diseases, Amanda J Oliver, Ni Huang, Raquel Bartolome-Casado, Ruoyan Li, Simon Koplev, Hogne R Nilsen, Madelyn Moy, Batuhan Cakir, Krzysztof Polanski, Victoria Gudiño, Elisa Melón-Ardanaz, Dinithi Sumanaweera, Daniel Dimitrov, Lisa Marie Milchsack, Michael E B Fitzpatrick, Nicholas M Provine, Jacqueline M Boccacino, Emma Dann, Alexander V Predeus, Ken To, Martin Prete, Jonathan A Chapman, Andrea C Masi, Emily Stephenson, Justin Engelbert, Sebastian Lobentanzer, Shani Perera, Laura Richardson, Rakeshlal Kapuge, Anna Wilbrey-Clark, Claudia I Semprich, Sophie Ellams, Catherine Tudor, Philomeena Joseph, Alba Garrido-Trigo, Ana M Corraliza, Thomas R W Oliver, C Elizabeth Hook, Kylie R James, Krishnaa T Mahbubani, Kourosh Saeb-Parsy, Matthias Zilbauer, Julio Saez-Rodriguez, Marte Lie Høivik, Espen S Bækkevold, Christopher J Stewart, Janet E Berrington, Kerstin B Meyer, Paul Klenerman, Azucena Salas, Muzlifah Haniffa, Frode L Jahnsen, Rasa Elmentaite, Sarah A Teichmann

Faculty, Staff and Student Publications

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease3. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning …

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

Faculty, Staff and Student Publications

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

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

Results: Although the typically developing group and …

Identification Of Single-Cell Blasts In Pediatric Acute Myeloid Leukemia Using An Autoencoder, Alice Driessen, Susanne Unger, An-Phi Nguyen, Rhonda E Ries, Soheil Meshinchi, Stefanie Kreutmair, Chiara Alberti, Pavel Sumazin, Richard Aplenc, Michele S Redell, Burkhard Becher, María Rodríguez Martínez

Faculty, Staff and Students Publications

Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell …

Loss-Of-Function In Rbbp5 Results In A Syndromic Neurodevelopmental Disorder Associated With Microcephaly, Yue Huang, Kristy L Jay, Alden Yen-Wen Huang, Jijun Wan, Sharayu V Jangam, Odelia Chorin, Annick Rothschild, Ortal Barel, Milena Mariani, Maria Iascone, Han Xue, Undiagnosed Diseases Network, Jing Huang, Cyril Mignot, Boris Keren, Virginie Saillour, Annelise Y Mah-Som, Stephanie Sacharow, Farrah Rajabi, Carrie Costin, Shinya Yamamoto, Oguz Kanca, Hugo J Bellen, Jill A Rosenfeld, Christina G S Palmer, Stanley F Nelson, Michael F Wangler, Julian A Martinez-Agosto

Faculty, Staff and Students Publications

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.

RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the …

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

Faculty, Staff and Student Publications

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

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

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

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

Faculty, Staff and Students Publications

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

Impact Of Age On Pharmacogenomics And Treatment Outcomes Of B-Cell Acute Lymphoblastic Leukemia, Satoshi Yoshimura, Zhenhua Li, Yoshihiro Gocho, Wenjian Yang, Kristine R Crews, Shawn H R Lee, Kathryn G Roberts, Charles G Mullighan, Mary V Relling, Jiyang Yu, Allen E J Yeoh, Mignon L Loh, Caner Saygin, Mark R Litzow, Sima Jeha, Seth E Karol, Hiroto Inaba, Ching-Hon Pui, Marina Konopleva, Nitin Jain, Wendy Stock, Elisabeth Paietta, Elias Jabbour, Steven M Kornblau, William E Evans, Jun J Yang

Faculty, Staff and Student Publications

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations …

Biologic And Clinical Analysis Of Childhood Gamma Delta T-All Identifies Lmo2/Stag2 Rearrangements As Extremely High Risk, Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A De Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan

Faculty, Staff and Student Publications

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in …

The Cochlear Dose And The Age At Radiotherapy Predict Severe Hearing Loss After Passive Scattering Proton Therapy And Cisplatin In Children With Medulloblastoma, Mohammad H Abu-Arja, Austin L Brown, Jack M Su, M Fatih Okcu, Holly B Lindsay, Susan L Mcgovern, Mary Frances Mcaleer, David R Grosshans, Murali M Chintagumpala, Arnold C Paulino

Faculty, Staff and Student Publications

Background: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin.

Methods: We identified patients aged 3-21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI).

Results: Seventy-nine patients …

Decoding Complex Inherited Phenotypes In Rare Disorders: The Decipherd Initiative For Rare Undiagnosed Diseases In Chile, M Cecilia Poli, Boris Rebolledo-Jaramillo, Catalina Lagos, Joan Orellana, Gabriela Moreno, Luz M Martín, Gonzalo Encina, Daniela Böhme, Víctor Faundes, M Jesús Zavala, Trinidad Hasbún, Sara Fischer, Florencia Brito, Diego Araya, Manuel Lira, Javiera De La Cruz, Camila Astudillo, Guillermo Lay-Son, Carolina Cares, Mariana Aracena, Esteban San Martin, Zeynep Coban-Akdemir, Jennifer E Posey, James R Lupski, Gabriela M Repetto

Faculty, Staff and Students Publications

Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the "diagnostic odyssey" for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international …

Impact Of Race And Ethnicity On Outcomes After Umbilical Cord Blood Transplantation, Karen Ballen, Tao Wang, Naya He, Jennifer M Knight, Sanghee Hong, Haydar Frangoul, Leo F Verdonck, Amir Steinberg, Miguel A Diaz, C Fred Lemaistre, Sherif M Badawy, Jeffrey J Pu, Hasan Hashem, Bipin Savani, Akshay Sharma, Hillard M Lazarus, Muhammad Bilal Abid, Jason Tay, Hemalatha G Rangarajan, Tamila Kindwall-Keller, Cesar O Freytes, Amer Beitinjaneh, Lena E Winestone, Usama Gergis, Nosha Farhadfar, Neel S Bhatt, Raquel M Schears, David Gómez-Almaguer, Mahmoud Aljurf, Vaibhav Agrawal, Yachiyo Kuwatsuka, Sachiko Seo, David I Marks, Leslie Lehmann, William A Wood, Shahrukh Hashmi, Wael Saber

Faculty, Staff and Student Publications

Background: Umbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients.

Objective: To compare outcomes by social determinants of health.

Study design: We designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, …

Late Subsequent Leukemia After Childhood Cancer: A Report From The Childhood Cancer Survivor Study (Ccss), Taumoha Ghosh, Geehong Hyun, Rikeenkumar Dhaduk, Miriam Conces, Michael A Arnold, Rebecca M Howell, Tara O Henderson, Aaron Mcdonald, Leslie L Robison, Yutaka Yasui, Kirsten K Ness, Gregory T Armstrong, Joseph P Neglia, Lucie M Turcotte

Faculty, Staff and Student Publications

Background: Subsequent short-latency leukemias are well-described among survivors of childhood cancer. However, late (5-14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort.

Methods: Subsequent leukemias, among 25,656 five-year survivors, were self-reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures.

Results: Seventy-seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 …

Menin Inhibitors In Pediatric Acute Leukemia: A Comprehensive Review And Recommendations To Accelerate Progress In Collaboration With Adult Leukemia And The International Community, Branko Cuglievan, Hagop Kantarjian, Jeffrey E Rubnitz, Todd M Cooper, C Michel Zwaan, Jessica A Pollard, Courtney D Dinardo, Tapan M Kadia, Erin Guest, Nicholas J Short, David Mccall, Naval Daver, Cesar Nunez, Fadi G Haddad, Miriam Garcia, Kapil N Bhalla, Abhishek Maiti, Samanta Catueno, Warren Fiskus, Bing Z Carter, Amber Gibson, Michael Roth, Sajad Khazal, Priti Tewari, Hussein A Abbas, Wallace Bourgeois, Michael Andreeff, Neerav N Shukla, Danh D Truong, Jeremy Connors, Joseph A Ludwig, Janine Stutterheim, Elisabeth Salzer, Kristian L Juul-Dam, Koji Sasaki, Kris M Mahadeo, Sarah K Tasian, Gautam Borthakur, Samantha Dickson, Nitin Jain, Elias Jabbour, Soheil Meshinchi, Guillermo Garcia-Manero, Farhad Ravandi, Eytan M Stein, E Anders Kolb, Ghayas C Issa

Faculty, Staff and Student Publications

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell …

Hospital Acquired Venous Thromboembolism In Children With Sickle Cell Disease, Shreya Agarwal, Kayla L Foster, Shaniqua J Anum, Mary C Shapiro, Hyojeong Han, Michael E Scheurer, Gladstone Airewele, Sarah E Sartain

Faculty, Staff and Students Publications

Sickle cell disease (SCD) is well recognized as a hypercoagulablestate, however, it remains unclear whether a subgroup of children with SCD at higher risk of venous thromboembolic event (VTE) during hospitalization may benefit from thromboprophylaxis. Our objectives were to describe the clinical characteristics, outcomes and recurrence of hospital acquired VTE in patients with SCD younger than 21 years. This was a single center retrospective study. Data regarding demographics, reason for admission, location of VTE, risk factors like central venous catheter (CVC), intensive care unit (ICU) admission among others were extracted from electronic medical records over a 10-year study period (2011-2021). …