Medical Genetics Commons^™

Targeting Multiple Receptor Tyrosine Kinases With Sitravatinib: A Phase 1b Study In Advanced Renal Cell Carcinoma And Castrate-Resistant Prostate Cancer, Shubham Pant, Byoung Chul Cho, Christos E Kyriakopoulos, Alexander Spira, Nizar Tannir, Theresa L Werner, Xiaohong Yan, Saskia Neuteboom, Richard Chao, Sanjay Goel

Faculty, Staff and Student Publications

Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also …

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 …

Autonomic Dysfunction Among Adult Survivors Of Childhood Cancer In The St Jude Lifetime Cohort Study, John D Groarke, Kirsten K Ness, Rikeenkumar Dhaduk, Juan C Plana, Jean Bernard Durand, Russell V Luepker, Vijaya M Joshi, Matthew Ehrhardt, Daniel A Mulrooney, Stephanie B Dixon, Anju Nohria, Daniel M Green, Rebecca M Howell, Deo Kumar Srivastava, John L Jefferies, Leslie L Robison, Melissa M Hudson, Gregory T Armstrong

Faculty, Staff and Student Publications

Background: The burden and functional significance of autonomic dysfunction among survivors of childhood cancer is unknown.

Objectives: We evaluated the prevalence, risk factors, and functional relevance of autonomic dysfunction in survivors.

Methods: We conducted a cross-sectional prospective evaluation of 1,041 adult survivors of childhood cancer treated with anthracyclines (31.1%), chest-directed radiation (13.5%), both (19.5%), or neither (35.9%), and 286 community control subjects enrolled in the SJLIFE (St Jude Lifetime Cohort Study). Four measures of autonomic dysfunction were evaluated: elevated resting heart rate, decreased heart rate reserve, decreased systolic blood pressure response to exercise, and delayed heart rate recovery. Logistic regression …

A Brave New Framework For Glioma Drug Development, Kelly M Hotchkiss, Philipp Karschnia, Karisa C Schreck, Marjolein Geurts, Timothy F Cloughesy, Jason Huse, Elizabeth S Duke, Justin Lathia, David M Ashley, Edjah K Nduom, Georgina Long, Kirit Singh, Anthony Chalmers, Manmeet S Ahluwalia, Amy Heimberger, Stephen Bagley, Tomoki Todo, Roel Verhaak, Patrick D Kelly, Shawn Hervey-Jumper, John De Groot, Anoop Patel, Peter Fecci, Ian Parney, Victoria Wykes, Colin Watts, Terry C Burns, Nader Sanai, Matthias Preusser, Joerg Christian Tonn, Katharine J Drummond, Michael Platten, Sunit Das, Kirk Tanner, Michael A Vogelbaum, Michael Weller, James R Whittle, Mitchel S Berger, Mustafa Khasraw

Faculty, Staff and Student Publications

Patients with brain tumours are motivated to participate in clinical trials involving repeat tissue sampling. Normalising the use of neoadjuvant and staged surgical trials necessitates collaboration among patients, regulatory agencies, and researchers. Initial and repetitive tissue sampling plays a crucial role in enhancing our understanding of resistance mechanisms and vulnerabilities in brain tumour therapy. Standardising biopsy techniques and ensuring technical uniformity across institutions are vital for effective interinstitutional collaboration. Although liquid biopsy technologies hold promise, they are not yet ready to replace tissue analysis. Clear communication about the risks and benefits of biopsies is essential, particularly regarding potential postoperative deficits. …

A Molecular Switch From Tumor Suppressor To Oncogene In Er+Ve Breast Cancer: Role Of Androgen Receptor, Jak-Stat, And Lineage Plasticity, Sarah Asemota, Wendy Effah, Jeremiah Holt, Daniel Johnson, Linnea Cripe, Suriyan Ponnusamy, Thirumagal Thiyagarajan, Yekta Khosrosereshki, Dong-Jin Hwang, Yali He, Brandy Grimes, Martin D Fleming, Frances E Pritchard, Ashley Hendrix, Meiyun Fan, Abhinav Jain, Hyo Young Choi, Liza Makowski, D Neil Hayes, Duane D Miller, Lawrence M Pfeffer, Balaji Santhanam, Ramesh Narayanan

Faculty, Staff and Student Publications

Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable growth inhibition. Due to the lack of tumor suppressor agonists, this hypothesis and the mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor offering a promising avenue for this investigation. Spatial genomics suggests that the molecular portrait of AR-expressing BC cells in …

Diffusion Tensor Imaging For Characterizing Changes In Triple-Negative Breast Cancer During Neoadjuvant Systemic Therapy, Benjamin C Musall, David E Rauch, Rania M M Mohamed, Bikash Panthi, Medine Boge, Rosalind P Candelaria, Huiqin Chen, Mary S Guirguis, Kelly K Hunt, Lei Huo, Ken-Pin Hwang, Anil Korkut, Jennifer K Litton, Tanya W Moseley, Sanaz Pashapoor, Miral M Patel, Brandy J Reed, Marion E Scoggins, Jong Bum Son, Debu Tripathy, Vicente Valero, Peng Wei, Jason B White, Gary J Whitman, Zhan Xu, Wei T Yang, Clinton Yam, Beatriz E Adrada, Jingfei Ma

Faculty, Staff and Student Publications

Background: Assessment of treatment response in triple-negative breast cancer (TNBC) may guide individualized care for improved patient outcomes. Diffusion tensor imaging (DTI) measures tissue anisotropy and could be useful for characterizing changes in the tumors and adjacent fibroglandular tissue (FGT) of TNBC patients undergoing neoadjuvant systemic treatment (NAST).

Purpose: To evaluate the potential of DTI parameters for prediction of treatment response in TNBC patients undergoing NAST.

Study type: Prospective.

Population: Eighty-six women (average age: 51 ± 11 years) with biopsy-proven clinical stage I-III TNBC who underwent NAST followed by definitive surgery. 47% of patients (40/86) had pathologic complete response (pCR). …

Social Determinants Of Health And Surgical Desirability Of Outcome Ranking In Older Veterans, Michael A Jacobs, Yubo Gao, Susanne Schmidt, Paula K Shireman, Michael Mader, Carly A Duncan, Leslie R M Hausmann, Karyn B Stitzenberg, Lillian S Kao, Mary Vaughan Sarrazin, Daniel E Hall

Faculty, Staff and Student Publications

Importance: Evaluating how social determinants of health (SDOH) influence veteran outcomes is crucial, particularly for quality improvement.

Objective: To measure associations between SDOH, care fragmentation, and surgical outcomes using a Desirability of Outcome Ranking (DOOR).

Design, setting, and participants: This was a cohort study of US veterans using data from the Veterans Affairs (VA) Surgical Quality Improvement Program (VASQIP; 2013-2019) limited to patients aged 65 years or older with inpatient stays between 2 and 30 days, merged with multiple data sources, including Medicare. Race and ethnicity data were retrieved from VASQIP, Medicare and Medicaid beneficiary summary files, the Veterans Health …

Tailoring Neoadjuvant Systemic Therapy In Breast Cancer: “The Advent Of A Personalized Approach”-The Breast-Gynecological And Immuno-Oncology International Cancer Conference (Bgicc) Consensus And Recommendations, Hesham Elghazaly, Hamdy A Azim, Hope S Rugo, David Cameron, Sandra M Swain, Giuseppe Curigliano, Nadia Harbeck, Debu Tripathy, Banu Arun, Matti Aapro, Martine Piccart, Fatima Cardoso, Joseph Gligorov, Hagar Elghazawy, Nagi S El Saghir, Frederique Penault-Llorca, Edith A Perez, Philip Poortmans, Hany Abdelaziz, Heba M El-Zawahry, Loay Kassem, Mohamed Sabry, Giuseppe Viale, Sana Al-Sukhun, Neven Gado, Jessica W T Leung, Lobna Ezz Elarab, Maria João Cardoso, Khaled Abdel Karim, Meteb Foheidi, Merit M Elmaadawy, Pierfranco Conte, Ashraf S M Selim, Alaa Kandil, Rasha M Kamal, Ruslan M Paltuev, Valentina Guarneri, Omalkhair Abulkhair, Omar Zakaria, Mehra Golshan, Roberto Orecchia, Manal Elmahdy, Ahmed M Abdel-Aziz, Nermean Bahie Eldin

Faculty, Staff and Student Publications

Background: The management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus.

Methods: During the 14th Breast-Gynecological and Immuno-Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this …

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, …

Artificial Intelligence Applications In Oral Cancer And Oral Dysplasia, Chi T Viet, Michael Zhang, Neeraja Dharmaraj, Grace Y Li, Alexander T Pearson, Victoria A Manon, Anupama Grandhi, Ke Xu, Bradley E Aouizerat, Simon Young

Faculty, Staff and Student Publications

Oral squamous cell carcinoma (OSCC) is a highly unpredictable disease with devastating mortality rates that have not changed over the past decades, in the face of advancements in treatments and biomarkers, which have improved survival for other cancers. Delays in diagnosis are frequent, leading to more disfiguring treatments and poor outcomes for patients. The clinical challenge lies in identifying those patients at the highest risk of developing OSCC. Oral epithelial dysplasia (OED) is a precursor of OSCC with highly variable behavior across patients. There is no reliable clinical, pathological, histological, or molecular biomarker to determine individual risk in OED patients. …

Vessel-Targeted Compensation Of Deformable Motion In Interventional Cone-Beam Ct, Alexander Lu, Heyuan Huang, Yicheng Hu, Wojciech Zbijewski, Mathias Unberath, Jeffrey H Siewerdsen, Clifford R Weiss, Alejandro Sisniega

Faculty, Staff and Student Publications

The present standard of care for unresectable liver cancer is transarterial chemoembolization (TACE), which involves using chemotherapeutic particles to selectively embolize the arteries supplying hepatic tumors. Accurate volumetric identification of intricate fine vascularity is crucial for selective embolization. Three-dimensional imaging, particularly cone-beam CT (CBCT), aids in visualization and targeting of small vessels in such highly variable anatomy, but long image acquisition time results in intra-scan patient motion, which distorts vascular structures and tissue boundaries. To improve clarity of vascular anatomy and intra-procedural utility, this work proposes a targeted motion estimation and compensation framework that removes the need for any prior …

Structures And Compositional Dynamics Of Mediator In Transcription Regulation, Tao Li, Ti-Chun Chao, Kuang-Lei Tsai

Faculty, Staff and Student Publications

The eukaryotic Mediator, comprising a large Core (cMED) and a dissociable CDK8 kinase module (CKM), functions as a critical coregulator during RNA polymerase II (RNAPII) transcription. cMED recruits RNAPII and facilitates the assembly of the pre-initiation complex (PIC) at promoters. In contrast, CKM prevents RNAPII binding to cMED while simultaneously exerting positive or negative influence on gene transcription through its kinase function. Recent structural studies on cMED and CKM have revealed their intricate architectures and subunit interactions. Here, we explore these structures, providing a comprehensive insight into Mediator (cMED-CKM) architecture and its potential mechanism in regulating RNAPII transcription. Additionally, we …

A Commissioning Protocol For Portal Imaging-Based Radiotherapy In Vivo Dosimetry Systems, Marco Esposito, Riccardo Baldoni, Evy Bossuyt, Sara Bresciani, Catharine H Clark, Matthew Jones, Stephen Kry, Joseph Perry, Jeroen Van De Kamer, Dirk Verellen, Nuria Jornet

Faculty, Staff and Student Publications

Background and purpose: With the availability of commercial electronic portal imaging detector-based in vivo dosimetry (EPID-based IVD) solutions, many radiotherapy departments are adopting this technology. However, comprehensive commissioning guidance is lacking. This study aims to provide a protocol for testing the accuracy and sensitivity of EPID-based IVD systems.

Material and methods: The protocol was tested across four institutions using two different systems. Accuracy was evaluated with homogeneous slab phantoms using different square regular fields, and clinical plans in a CIRS lung phantom. Multiple forward and back-projected algorithm implementations were assessed for different energies. Sensitivity analysis in the lung phantom examined …

Inulin-Gel-Based Oral Immunotherapy Remodels The Small Intestinal Microbiome And Suppresses Food Allergy, Kai Han, Fang Xie, Olamide Animasahun, Minal Nenwani, Sho Kitamoto, Yeji Kim, May Thazin Phoo, Jin Xu, Fulei Wuchu, Kehinde Omoloja, Abhinav Achreja, Srinadh Choppara, Zhaoheng Li, Wang Gong, Young Seok Cho, Hannah Dobson, Jinsung Ahn, Xingwu Zhou, Xuehui Huang, Xinran An, Alexander Kim, Yao Xu, Qi Wu, Soo-Hong Lee, Jessica J O'Konek, Yuying Xie, Yu Leo Lei, Nobuhiko Kamada, Deepak Nagrath, James J Moon

Faculty, Staff and Student Publications

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells …

Fast Model Calibration For Predicting The Response Of Breast Cancer To Chemotherapy Using Proper Orthogonal Decomposition, Chase Christenson, Chengyue Wu, David A Hormuth, Casey E Stowers, Megan Lamonica, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Constructing digital twins for predictive tumor treatment response models can have a high computational demand that presents a practical barrier for their clinical adoption. In this work, we demonstrate that proper orthogonal decomposition, by which a low-dimensional representation of the full model is constructed, can be used to dramatically reduce the computational time required to calibrate a partial differential equation model to magnetic resonance imaging (MRI) data for rapid predictions of tumor growth and response to chemotherapy. In the proposed formulation, the reduction basis is based on each patient's own MRI data and controls the overall size of the "reduced …

Subsyndromes And Symptom Clusters: Multilevel Factor Analysis Of Behavioral And Psychological Symptoms Of Dementia With Intensive Longitudinal Data, Carolyn E Z Pickering, Vicki Winstead, Mustafa Yildiz, Danny Wang, Maria Yefimova, Andrew M Pickering

Faculty, Staff and Student Publications

Introduction: Behavioral and psychological symptoms in dementia (BPSD) are dynamic phenomena with a high amount of intraindividual variability. We applied a multilevel framework to identify subsyndromes (between-person factors) that represent clinically relevant profiles of BPSD and identify symptom clusters (within-person factors) that represent contextually driven daily symptom experiences.

Methods: This study used an intensive longitudinal design in which 68 co-residing family caregivers to persons living with dementia were recruited to proxy report on their care recipient's daily symptom experiences of 23 different BPSD for eight consecutive days (n = 443 diaries). A multilevel exploratory/confirmatory factor analysis was used to account …

Challenges And Opportunities For Early Phase Clinical Trials Of Novel Drug-Radiotherapy Combinations: Recommendations From Nrg Oncology, The American Society For Radiation Oncology (Astro), The American College Of Radiology (Acr), The Sarah Cannon Research Institute, And The American College Of Radiation Oncology (Acro), Zachary S Zumsteg, Siddharth Sheth, Salma K Jabbour, Krishnan R Patel, Randall J Kimple, Terence M Williams, Meng Xu-Welliver, Pedro A Torres-Saavedra, Arta M Monjazeb, Jyoti Mayadev, Steven E Finkelstein, John M Buatti, Sandip P Patel, Steven H Lin

Faculty, Staff and Student Publications

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.

Mhc Hammer Reveals Genetic And Non-Genetic Hla Disruption In Cancer Evolution, Clare Puttick, Thomas P Jones, Michelle M Leung, Felipe Galvez-Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Oriol Pich, Carlos Martinez-Ruiz, Robert Bentham, Krijn K Dijkstra, James R M Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A Quezada, Tracerx Consortium, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% …

Development Of An Engineered Extracellular Vesicles-Based Vaccine Platform For Combined Delivery Of Mrna And Protein To Induce Functional Immunity, Xin Luo, Kathleen M Mcandrews, Kent A Arian, Sami J Morse, Viktoria Boeker, Shreyasee V Kumbhar, Yingying Hu, Krishnan K Mahadevan, Kaira A Church, Sriram Chitta, Nicolas T Ryujin, Janine Hensel, Jianli Dai, Dara P Dowlatshahi, Hikaru Sugimoto, Michelle L Kirtley, Valerie S Lebleu, Shabnam Shalapour, Joe H Simmons, Raghu Kalluri

Faculty, Staff and Student Publications

mRNA incorporated in lipid nanoparticles (LNPs) became a new class of vaccine modality for induction of immunity against COVID-19 and ushered in a new era in vaccine development. Here, we report a novel, easy-to-execute, and cost effective engineered extracellular vesicles (EVs)-based combined mRNA and protein vaccine platform (EVX-M+P vaccine) and explore its utility in proof-of-concept immunity studies in the settings of cancer and infectious disease. As a first example, we engineered EVs, natural nanoparticle carriers shed by all cells, to contain ovalbumin mRNA and protein (EVOvaM+P vaccine) to serve as cancer vaccine against ovalbumin-expressing melanoma tumors. EVOvaM+P administration to mice …

High Throughput And Rapid Isolation Of Extracellular Vesicles And Exosomes With Purity Using Size Exclusion Liquid Chromatography, Kshipra S Kapoor, Kristen Harris, Kent A Arian, Lihua Ma, Beatriz Schueng Zancanela, Kaira A Church, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) have emerged as potential biomarkers for diagnosing a range of diseases without invasive procedures. Extracellular vesicles also offer advantages compared to synthetic vesicles for delivery of various drugs; however, limitations in segregating EVs from other particles and soluble proteins have led to inconsistent EV retrieval rates with low levels of purity. Here, we report a new high-yield (88.47 %) and rapid (< 20 min) EV isolation method termed size exclusion - fast protein liquid chromatography (SE-FPLC). We show SE-FPLC can effectively isolate EVs from multiple sources including EVs derived from human and mouse cells and serum samples. The results indicate that SE-FPLC can successfully remove highly abundant protein contaminants such as albumin and lipoprotein complexes, which can represent a major hurdle in large scale isolation of EVs. The high-yield nature of SE-FPLC allows for easy industrial scaling up of EV production for various clinical utilities. SE-FPLC also enables analysis of small volumes of blood for use in point-of-care diagnostics in the clinic. Collectively, SE-FPLC offers many advantages over current EV isolation methods and offers rapid clinical translation.

Drug-Resistant Epilepsy In Tuberous Sclerosis Complex Is Associated With Tsc2 Genotype: More Findings From The Preventing Epilepsy Using Vigatrin (Prevent) Trial, Laura S Farach, Melissa A Richard, Aynara C Wulsin, Elizabeth M Bebin, Darcy A Krueger, Mustafa Sahin, Brenda E Porter, Tarrant O Mcpherson, Jurriaan M Peters, Sarah O'Kelley, Katherine S Taub, Rajsekar Rajaraman, Stephanie C Randle, William M Mcclintock, Mary Kay Koenig, Michael D Frost, Klaus Werner, Danielle A Nolan, Michael Wong, Gary Cutter, Hope Northrup, Kit Sing Au

Faculty, Staff and Student Publications

Background: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE.

Methods: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to …

Asxl1/Tet2 Genotype-Based Risk Stratification Outperforms Asxl1 Mutational Impact And Is Independent Of Mutant Variant Allele Fractions In Chronic Myelomonocytic Leukemia, Clifford M Csizmar, Mark Gurney, Rashmi Kanagal-Shamanna, Kelly Chien, Danielle Hammond, Terra L Lasho, Christy M Finke, Christopher Dean, Anuya Natu, Abhishek A Mangaonkar, Aref Al-Kali, Naseema Gangat, Ayalew Tefferi, Hassan Alkhateeb, Guillermo Garcia-Manero, Rami S Komrokji, Najla A Ali, Eric Padron, Guillermo Montalban-Bravo, Mrinal M Patnaik

Faculty, Staff and Student Publications

No abstract provided.

Prognostic Scores For Ursodeoxycholic Acid-Treated Patients Predict Graft Loss And Mortality In Recurrent Primary Biliary Cholangitis After Liver Transplantation, Aldo J Montano-Loza, Ellina Lytvyak, Gideon Hirschfield, Bettina E Hansen, Maryam Ebadi, Thierry Berney, Christian Toso, Giulia Magini, Alejandra Villamil, Frederik Nevens, Natalie Van Den Ende, Albert Pares, Pablo Ruiz, Débora Terrabuio, Palak J Trivedi, Nadir Abbas, Maria Francesca Donato, Lei Yu, Charles Landis, Jérôme Dumortier, Jessica Katharine Dyson, Adriaan J Van Der Meer, Rozanne De Veer, Mark Pedersen, Marlyn Mayo, Michael P Manns, Richard Taubert, Theresa Kirchner, Luca S Belli, Chiara Mazzarelli, Guido Stirnimann, Annarosa Floreani, Nora Cazzagon, Francesco Paolo Russo, Patrizia Burra, Udi Zigmound, Inbal Houri, Marco Carbone, Giacomo Mulinacci, Stefano Fagiuoli, Daniel Stephan Pratt, Alan Bonder, Thomas D Schiano, Brandy Haydel, Ansgar Lohse, Christoph Schramm, Darius Rüther, Stefania Casu, Xavier Verhelst, Benedetta Terziroli Beretta-Piccoli, Mercedes Robles, Andrew L Mason, Christophe Corpechot, Global Pbc Study Group

Faculty, Staff and Student Publications

Background & aims: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC.

Methods: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC …

The Role Of Aldh1a1 In Glioblastoma Proliferation And Invasion, Yu-Kai Huang, Tzu-Ming Wang, Chi-Yu Chen, Chia-Yang Li, Shu-Chi Wang, Khushboo Irshad, Yuan Pan, Kun-Che Chang

Faculty, Staff and Student Publications

High-grade gliomas, including glioblastoma multiforme (GBM), continue to be a leading aggressive brain tumor in adults, marked by its rapid growth and invasive nature. Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), an enzyme, plays a significant role in tumor progression, yet its function in high-grade gliomas is still poorly investigated. In this study, we evaluated ALDH1A1 levels in clinical samples of GBM. We also assessed the prognostic significance of ALDH1A1 expression in GBM and LGG (low grade glioma) patients using TCGA (The Cancer Genome Atlas) database analysis. The MTT and transwell assays were utilized to examine cell growth and the …

Does Time To Initiation Of Adjuvant Radiotherapy Affect Reconstruction Outcomes After Endoscopic Resection Of Skull Base Malignancies?, Franco Rubino, Bledi Brahimaj, Ehab Y Hanna, Shirley Y Su, Jack Phan, David R Grosshans, Franco Demonte, Shaan M Raza

Faculty, Staff and Student Publications

No abstract provided.

Astrocyte-Induced Cdk5 Expedites Breast Cancer Brain Metastasis By Suppressing Mhc-I Expression To Evade Immune Recognition, Arseniy E Yuzhalin, Frank J Lowery, Yohei Saito, Xiangliang Yuan, Jun Yao, Yimin Duan, Jingzhen Ding, Sunil Acharya, Chenyu Zhang, Abigail Fajardo, Hao-Nien Chen, Yongkun Wei, Yutong Sun, Lin Zhang, Yi Xiao, Ping Li, Philip L Lorenzi, Jason T Huse, Huihui Fan, Zhongming Zhao, Mien-Chie Hung, Dihua Yu

Faculty, Staff and Student Publications

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to …

The Qiba Profile For Diffusion-Weighted Mri: Apparent Diffusion Coefficient As A Quantitative Imaging Biomarker, Michael A Boss, Dariya Malyarenko, Savannah Partridge, Nancy Obuchowski, Amita Shukla-Dave, Jessica M Winfield, Clifton D Fuller, Kevin Miller, Virendra Mishra, Michael Ohliger, Lisa J Wilmes, Raj Attariwala, Trevor Andrews, Nandita M Desouza, Daniel J Margolis, Thomas L Chenevert

Faculty, Staff and Student Publications

The apparent diffusion coefficient (ADC) provides a quantitative measure of water mobility that can be used to probe alterations in tissue microstructure due to disease or treatment. Establishment of the accepted level of variance in ADC measurements for each clinical application is critical for its successful implementation. The Diffusion-Weighted Imaging Biomarker Committee of the Quantitative Imaging Biomarkers Alliance (QIBA) has recently advanced the ADC Profile from the consensus to clinically feasible stage for the brain, liver, prostate, and breast. This profile distills multiple studies on ADC repeatability and describes detailed procedures to achieve stated performance claims on an observed ADC …

Genomic Biomarkers To Predict Response To Atezolizumab Plus Bevacizumab Immunotherapy In Hepatocellular Carcinoma: Insights From The Imbrave150 Trial, Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee

Faculty, Staff and Student Publications

Background/aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.

Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full …

Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly

Faculty, Staff and Student Publications

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer …

Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly

Faculty, Staff and Student Publications

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer …