Medicine and Health Sciences Commons^™

Divergent Structures Of Mammalian And Gammaherpesvirus Uracil Dna Glycosylases Confer Distinct Dna Binding And Substrate Activity, Yunxiang Mu, Monika A Zelazowska, Zaowen Chen, Joshua B Plummer, Qiwen Dong, Laurie T Krug, Kevin M Mcbride

Faculty, Staff and Student Publications

Uracil DNA glycosylase (UNG) removes mutagenic uracil base from DNA to initiate base excision repair (BER). The result is an abasic site (AP site) that is further processed by the high-fidelity BER pathway to complete repair and maintain genome integrity. The gammaherpesviruses (GHVs), human Kaposi sarcoma herpesvirus (KSHV), Epstein-Barr virus (EBV), and murine gammaherpesvirus 68 (MHV68) encode functional UNGs that have a role in viral genome replication. Mammalian and GHVs UNG share overall structure and sequence similarity except for a divergent amino-terminal domain and a leucine loop motif in the DNA binding domain that varies in sequence and length. To …

Effect Of Sotagliflozin On Early Mortality And Heart Failure-Related Events: A Post Hoc Analysis Of Soloist-Whf, Bertram Pitt, Deepak L Bhatt, Michael Szarek, Christopher P Cannon, Lawrence A Leiter, Darren K Mcguire, Julia B Lewis, Matthew C Riddle, Adriaan A Voors, Marco Metra, Lars H Lund, Michel Komajda, Jeffrey M Testani, Christopher S Wilcox, Piotr Ponikowski, Renato D Lopes, Justin A Ezekowitz, Franklin Sun, Michael J Davies, Subodh Verma, Mikhail N Kosiborod, Ph Gabriel Steg, Soloist-Whf Investigators

Faculty, Staff and Student Publications

Background: Approximately 25% of patients admitted to hospitals for worsening heart failure (WHF) are readmitted within 30 days.

Objectives: The authors conducted a post hoc analysis of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post-WHF) trial to evaluate the efficacy of sotagliflozin versus placebo to decrease mortality and HF-related events among patients who began study treatment on or before discharge from their index hospitalization.

Methods: The main endpoint of interest was cardiovascular death or HF-related event (HF hospitalization or urgent care visit) occurring within 90 and 30 days after discharge for the index …

Life-Threatening Hemoptysis In Patients With Metastatic Kidney Cancer, Viral M Patel, Roy Elias, Annapoorani Asokan, Akanksha Sharma, Alana Christie, Ivan Pedrosa, Hsienchang Chiu, Scott Reznik, Raquibul Hannan, Robert Timmerman, James Brugarolas

Faculty, Staff and Student Publications

Hemoptysis is a complication of intrathoracic tumors, both primary and metastatic, and the risk may be increased by procedural interventions as well as Stereotactic Ablative Radiation (SAbR). The risk of hemoptysis with SAbR for lung cancer is well characterized, but there is a paucity of data about intrathoracic metastases. Here, we sought to evaluate the incidence of life-threatening/fatal hemoptysis (LTH) in patients with renal cell carcinoma (RCC) chest metastases with a focus on SAbR. We systematically evaluated patients with RCC at UT Southwestern Medical Center (UTSW) Kidney Cancer Program (KCP) from July 2005 to March 2020. We queried Kidney Cancer …

Open Innovation: The Key To Advancing Brain Health, Harris A Eyre, Jason Searfoss, Malcolm Hopwood, Michael Berk, Shuo Chen, Jeffrey Cummings, Francois Veron, Vicki Zikopoulou, Agustin Ibanez, Kacie Kelly, Jair C Soares, Erin Smith, Barnabas J Gilbert

Faculty, Staff and Student Publications

With the exponential growth in investment attention to brain health-solutions spanning brain wellness to mental health to neurological disorders-tech giants, payers, and biotechnology companies have been making forays into this field to identify technology solutions and pharmaceutical amplifiers. So far, their investments have had mixed results. The concept of open innovation (OI) was first coined by Henry Chesbrough to describe the paradigm by which enterprises allow free flow of ideas, products, and services from the outside to the inside and vice versa in order to remain competitive, particularly in rapidly evolving fields where there is abundant, relevant knowledge outside the …

Epinephrine-Induced Effects On Cerebral Microcirculation And Oxygenation Dynamics Using Multimodal Monitoring And Functional Photoacoustic Microscopy, Dong Zhang, Wei Wang, Xiaoyi Zhu, Ran Li, Wei Liu, Maomao Chen, Tri Vu, Laiming Jiang, Qifa Zhou, Cody L Evans, Dennis A Turner, Huaxin Sheng, Jerrold H Levy, Jianwen Luo, Wei Yang, Junjie Yao, Ulrike Hoffmann

Faculty, Staff and Student Publications

Background: The administration of epinephrine after severe refractory hypotension, shock, or cardiac arrest restores systemic blood flow and major vessel perfusion but may worsen cerebral microvascular perfusion and oxygen delivery through vasoconstriction. The authors hypothesized that epinephrine induces significant microvascular constriction in the brain, with increased severity after repetitive dosing and in the aged brain, eventually leading to tissue hypoxia.

Methods: The authors investigated the effects of intravenous epinephrine administration in healthy young and aged C57Bl/6 mice on cerebral microvascular blood flow and oxygen delivery using multimodal in vivo imaging, including functional photoacoustic microscopy, brain tissue oxygen sensing, and follow-up …

Image-Based Quantification Of Histological Features As A Function Of Spatial Location Using The Tissue Positioning System, Ruichen Rong, Yonglong Wei, Lin Li, Tao Wang, Hao Zhu, Guanghua Xiao, Yunguan Wang

Faculty, Staff and Student Publications

Background: Tissues such as the liver lobule, kidney nephron, and intestinal gland exhibit intricate patterns of zonated gene expression corresponding to distinct cell types and functions. To quantitatively understand zonation, it is important to measure cellular or genetic features as a function of position along a zonal axis. While it is possible to manually count, characterize, and locate features in relation to the zonal axis, it is labor-intensive and difficult to do manually while maintaining precision and accuracy.

Methods: We addressed this challenge by developing a deep-learning-based quantification method called the "Tissue Positioning System" (TPS), which can automatically analyze zonation …

Tumor Thickness In Mesothelioma Predicts Differential Response To Neoadjuvant Therapy And Survival, Nicolas Zhou, Cynthia S Bell, Hope A Feldman, Cara L Haymaker, Wayne L Hofstetter, Anne S Tsao, Reza J Mehran, David C Rice, Boris Sepesi

Faculty, Staff and Student Publications

Objective: Neoadjuvant systemic therapy in resectable malignant pleural mesothelioma remains controversial and demonstrates variable responses. We sought to evaluate tumor thickness as a predictor of response to neoadjuvant therapy and as a prognostic marker for overall survival.

Methods: Data from patients who underwent neoadjuvant therapy followed by cytoreductive surgery from 2002 to 2019 were reviewed. Baseline and postneoadjuvant therapy tumor thickness were measured on computed tomography. Radiological tumor response was categorized as progressive disease (≥20% increase), partial response (≥30% decrease), or stable disease (in between). Tumor response outcomes were modeled using logistic regression and multinomial regression models. Overall survival was …

Mesothelin-Targeting T Cell Receptor Fusion Construct Cell Therapy In Refractory Solid Tumors: Phase 1/2 Trial Interim Results, Raffit Hassan, Marcus Butler, Roisin E O'Cearbhaill, David Y Oh, Melissa Johnson, Kevin Zikaras, Munisha Smalley, Michael Ross, Janos L Tanyi, Azam Ghafoor, Nirali N Shah, Babak Saboury, Liang Cao, Alfonso Quintás-Cardama, David Hong

Faculty, Staff and Student Publications

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of …

Pathologist-Initiated Reflex Testing For Biomarkers In Non-Small-Cell Lung Cancer: Expert Consensus On The Rationale And Considerations For Implementation, J R Gosney, L Paz-Ares, P Jänne, K M Kerr, N B Leighl, M D Lozano, U Malapelle, T Mok, B S Sheffield, A Tufman, I I Wistuba, S Peters

Faculty, Staff and Student Publications

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

A Splicing Transcriptome-Wide Association Study Identifies Novel Altered Splicing For Alzheimer’S Disease Susceptibility, Yanfa Sun, Ye Eun Bae, Jingjing Zhu, Zichen Zhang, Hua Zhong, Jie Yu, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles in etiology of AD remain largely elusive. We performed a comprehensive splicing transcriptome-wide association study (spTWAS) using intronic excision expression genetic prediction models of 12 brain tissues developed through three modelling strategies, to identify candidate susceptibility splicing introns for AD risk. A total of 111,326 (46,828 proxy) cases and 677,663 controls of European ancestry were studied. We identified 343 associations of 233 splicing introns (143 genes) with AD risk after Bonferroni correction (0.05/136,884 = 3.65 × …

Mitotic Rate In Primary Cutaneous Melanoma: Cell Division Matters, Jeffrey E Gershenwald

Faculty, Staff and Student Publications

No abstract provided.

Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib In Previously Untreated Egfr-Mutated Metastatic Non-Small-Cell Lung Cancer (Relay): Exploratory Analysis Of Next-Generation Sequencing Results, E B Garon, M Reck, K Nishio, J V Heymach, M Nishio, S Novello, L Paz-Ares, S Popat, S Ponce Aix, H Graham, B D Butts, C Visseren-Grul, K Nakagawa

Faculty, Staff and Student Publications

Background: Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes.

Patients and methods: Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and …

Poziotinib In Treatment-Naive Nsclc Harboring Her2 Exon 20 Mutations: Zenith20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4), Robin Cornelissen, Arsela Prelaj, Sophie Sun, Christina Baik, Mirjana Wollner, Eric B Haura, Hirva Mamdani, Jonathan W Riess, Federico Cappuzzo, Marina C Garassino, John V Heymach, Mark A Socinski, Szu-Yun Leu, Gajanan Bhat, Francois Lebel, Xiuning Le, Zenith20-4 Investigators

Faculty, Staff and Student Publications

Introduction: ERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions.

Methods: ZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end …

Definitive Liver Radiotherapy For Intrahepatic Cholangiocarcinoma With Extrahepatic Metastases, Brian De, Rituraj Upadhyay, Kaiping Liao, Tiffany Kumala, Christopher Shi, Grace Dodoo, Joseph Abi Jaoude, Kelsey L Corrigan, Gohar S Manzar, Kathryn E Marqueen, Vincent Bernard, Sunyoung S Lee, Kanwal P S Raghav, Jean-Nicolas Vauthey, Ching-Wei D Tzeng, Hop S Tran Cao, Grace Lee, Jennifer Y Wo, Theodore S Hong, Christopher H Crane, Bruce D Minsky, Grace L Smith, Emma B Holliday, Cullen M Taniguchi, Albert C Koong, Prajnan Das, Milind Javle, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

INTRODUCTION: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT.

METHODS: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by …

Smooth Muscle Α-Actin Missense Variant Promotes Atherosclerosis Through Modulation Of Intracellular Cholesterol In Smooth Muscle Cells, Kaveeta Kaw, Abhijnan Chattopadhyay, Pujun Guan, Jiyuan Chen, Suravi Majumder, Xue-Yan Duan, Shuangtao Ma, Chen Zhang, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

AIMS: The variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery disease in individuals without cardiovascular risk factors. This study investigated how this variant drives increased atherosclerosis.

METHODS AND RESULTS: Apoe-/- mice with and without the variant were fed a high-fat diet for 12 weeks, followed by evaluation of atherosclerotic plaque formation and single-cell transcriptomics analysis. SMCs explanted from Acta2R149C/+ and wildtype (WT) ascending aortas were used to investigate atherosclerosis-associated SMC phenotypic modulation. Hyperlipidemic Acta2R149C/+Apoe-/- mice have a 2.5-fold increase in atherosclerotic plaque burden compared to Apoe-/- mice …

Deficits In Consummatory Reward Relate To Severity Of Cocaine Use, Margaret C Wardle, Jennifer K Hoots, Krista Miloslavich, Cecilia Nunez, Constanza De Dios, Christopher Holden, Aneet Ahluwahlia, Charles E Green, Scott D Lane, Joy M Schmitz

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Identifying modifiable neuropsychological factors associated with more severe CUD could improve CUD treatment. Impairments in processing of non-drug rewards may be one such factor. This study assessed the relationship between reward functioning and cocaine use severity using multi-modal measures of three distinct reward functions: consummatory reward (pleasure or "liking"); motivational reward ("wanting") and reward learning.

METHODS: Fifty-three adults with at least moderate CUD completed self-report and behavioral measures of consummatory reward, motivational reward and reward learning, and a composite cocaine use severity measure including quantity, frequency and life impacts of cocaine use. We conducted parallel Frequentist and …

Efficacy And Mortality Of Rotating Sheaths Versus Laser Sheaths For Transvenous Lead Extraction: A Meta-Analysis, Sun Yong Lee, Isabel E Allen, Celso Diaz, Xiaofan Guo, Cara Pellegrini, Ramin Beygui, Ricardo Cardona-Guarache, Gregory M Marcus, Byron K Lee

Faculty, Staff and Student Publications

Background: Rotating and laser sheaths are both routinely used in transvenous lead extraction (TLE) which can lead to catastrophic complications including death. The efficacy and risk of each approach are uncertain. To perform a meta-analysis to compare success and mortality rates associated with rotating and laser sheaths.

Methods: We searched electronic academic databases for case series of consecutive patients and randomized controlled trials published 1998-2017 describing the use of rotating and laser sheaths for TLE. Among 48 studies identified, rotating sheaths included 1,094 patients with 1,955 leads in 14 studies, and laser sheaths included 7,775 patients with 12,339 leads in …

Heterozygous Midnolin Knockout Attenuates Severity Of Nonalcoholic Fatty Liver Disease In Mice Fed A Western-Style Diet High In Fat, Cholesterol, And Fructose, Soo-Mi Kweon, Jose Irimia-Dominguez, Gayeoun Kim, Patrick T Fueger, Kinji Asahina, Keith K Lai, Daniela S Allende, Quincy R Lai, Chih-Hong Lou, Walter M Tsark, Ju Dong Yang, Dominic S Ng, Ju-Seog Lee, Patrick Tso, Wendong Huang, Keane K Y Lai

Faculty, Staff and Student Publications

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first …

Vincristine Enhances The Efficacy Of Mek Inhibitors In Preclinical Models Of Kras-Mutant Colorectal Cancer, Susmita Ghosh, Fan Fan, Reid T Powell, Jason Roszik, Yong Sung Park, Clifford Stephan, Manu Sebastian, Lin Tan, Alexey V Sorokin, Philip L Lorenzi, Scott Kopetz, Lee M Ellis, Rajat Bhattacharya

Faculty, Staff and Student Publications

Mutations in KRAS are found in more than 50% of tumors from patients with metastatic colorectal cancer (mCRC). However, direct targeting of most KRAS mutations is difficult; even the recently developed KRASG12C inhibitors failed to show significant benefit in patients with mCRC. Single agents targeting mitogen-activated protein kinase kinase (MEK), a downstream mediator of RAS, have also been ineffective in colorectal cancer. To identify drugs that can enhance the efficacy of MEK inhibitors, we performed unbiased high-throughput screening using colorectal cancer spheroids. We used trametinib as the anchor drug and examined combinations of trametinib with the NCI-approved Oncology Library version …

Development And Validation Of An Automated Image-Based Deep Learning Platform For Sarcopenia Assessment In Head And Neck Cancer, Zezhong Ye, Anurag Saraf, Yashwanth Ravipati, Frank Hoebers, Paul J Catalano, Yining Zha, Anna Zapaishchykova, Jirapat Likitlersuang, Christian Guthier, Roy B Tishler, Jonathan D Schoenfeld, Danielle N Margalit, Robert I Haddad, Raymond H Mak, Mohamed Naser, Kareem A Wahid, Jaakko Sahlsten, Joel Jaskari, Kimmo Kaski, Antti A Mäkitie, Clifton D Fuller, Hugo J W L Aerts, Benjamin H Kann

Faculty, Staff and Student Publications

Importance: Sarcopenia is an established prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC); the quantification of sarcopenia assessed by imaging is typically achieved through the skeletal muscle index (SMI), which can be derived from cervical skeletal muscle segmentation and cross-sectional area. However, manual muscle segmentation is labor intensive, prone to interobserver variability, and impractical for large-scale clinical use.

Objective: To develop and externally validate a fully automated image-based deep learning platform for cervical vertebral muscle segmentation and SMI calculation and evaluate associations with survival and treatment toxicity outcomes.

Design, setting, and participants: For this prognostic study, …

Myelodysplastic Syndromes: 2023 Update On Diagnosis, Risk-Stratification, And Management, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Disease overview: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy.

Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, and molecular genetics is usually complementary and may help refine diagnosis. A new WHO classification of MDS was proposed in 2022. Under this classification, …

Pitfalls In Machine Learning-Based Assessment Of Tumor-Infiltrating Lymphocytes In Breast Cancer: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Jeppe Thagaard, Glenn Broeckx, David B Page, Chowdhury Arif Jahangir, Sara Verbandt, Zuzana Kos, Rajarsi Gupta, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Mohamed Amgad, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Eva Balslev, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Anders B Dahl, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Johan Doré Hansen, Sarah N Dudgeon, Thomas Ebstrup, Mahmoud Elghazawy, Claudio Fernandez-Martín, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Søren Hauberg, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Roslind, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Ely Scott, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Susan Fineberg, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Reena Md Zin, Sylvia Adams, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. …

Spatial Analyses Of Immune Cell Infiltration In Cancer: Current Methods And Future Directions: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, David B Page, Glenn Broeckx, Chowdhury Arif Jahangir, Sara Verbandt, Rajarsi R Gupta, Jeppe Thagaard, Reena Khiroya, Zuzana Kos, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Scott Ely, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Alexandros Hardas, Steven N Hart, Johan Hartman, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Sylvia Adams, John Mark Seaverns Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical …

Generative Pre-Trained Transformers (Gpt) And Space Health: A Potential Frontier In Astronaut Health During Exploration Missions, Ethan Waisberg, Joshua Ong, Mouayad Masalkhi, Nasif Zaman, Sharif Amit Kamran, Prithul Sarker, Andrew G Lee, Alireza Tavakkoli

Faculty, Staff and Student Publications

In anticipation of space exploration where astronauts are traveling away from Earth, and for longer durations with an increasing communication lag, artificial intelligence (AI) frameworks such as large language learning models (LLMs) that can be trained on Earth can provide real-time answers. This emerging technology may be helpful for acute medical emergencies, particularly in austere and distant space environments. In this manuscript, we provide an overview of generative pre-trained transformer (GPT) technology, a rapidly emerging AI technology, and implications, considerations, and limitations of such technology for space health.

Predictive Model Of Liver Toxicity To Aid The Personalized Selection Of Proton Versus Photon Therapy In Hepatocellular Carcinoma, Ibrahim Chamseddine, Yejin Kim, Brian De, Issam El Naqa, Dan G Duda, John A Wolfgang, Jennifer Pursley, Jennifer Y Wo, Theodore S Hong, Harald Paganetti, Eugene J Koay, Clemens Grassberger

Faculty, Staff and Student Publications

Purpose: Our objective was to develop an externally validated model for predicting liver toxicity after radiation therapy in patients with hepatocellular carcinoma (HCC) that can integrate both photon and proton dose distributions with patient-specific characteristics.

Methods and materials: Training data consisted of all patients with HCC treated between 2008 and 2019 at our institution (n = 117, 60%/40% photon/proton). We developed a shallow convolutional neural network (CNN) to predict posttreatment liver dysfunction from the differential dose-volume histogram (DVH) and baseline liver metrics. To reduce bias and improve robustness, we used ensemble learning (CNNE). After a preregistered study analysis plan, we …

Ultrasensitive Ngs Mrd Assessment In Ph+ All: Prognostic Impact And Correlation With Rt-Pcr For Bcr::Abl1, Nicholas J Short, Elias Jabbour, Walid Macaron, Farhad Ravandi, Nitin Jain, Rashmi Kanagal-Shamanna, Keyur P Patel, Sanam Loghavi, Fadi G Haddad, Musa Yilmaz, Ghayas C Issa, Partow Kebriaei, Steven M Kornblau, Sarah Pelletier, Wilmer Flores, Jairo Matthews, Rebecca Garris, Hagop Kantarjian

Faculty, Staff and Student Publications

Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10-6 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were …

A Spatiotemporal Notch Interaction Map From Plasma Membrane To Nucleus, Alexandre P Martin, Gary A Bradshaw, Robyn J Eisert, Emily D Egan, Lena Tveriakhina, Julia M Rogers, Andrew N Dates, Gustavo Scanavachi, Jon C Aster, Tom Kirchhausen, Marian Kalocsay, Stephen C Blacklow

Faculty, Staff and Student Publications

Notch signaling relies on ligand-induced proteolysis of the transmembrane receptor Notch to liberate a nuclear effector that drives cell fate decisions. Upon ligand binding, sequential cleavage of Notch by the transmembrane protease ADAM10 and the intracellular protease γ-secretase releases the Notch intracellular domain (NICD), which translocates to the nucleus and forms a complex that induces target gene transcription. To map the location and timing of the individual steps required for the proteolysis and movement of Notch from the plasma membrane to the nucleus, we used proximity labeling with quantitative, multiplexed mass spectrometry to monitor the interaction partners of endogenous NOTCH2 …

Retrospective Analysis Of Retroperitoneal-Abdominal-Pelvic Ganglioneuromas: An International Study By The Transatlantic Australasian Retroperitoneal Sarcoma Working Group (Tarpswg), Sangkyu Noh, Carolyn Nessim, Emily Z Keung, Christina L Roland, Dirk Strauss, Gausihi Sivarajah, Marco Fiore, Davide Biasoni, Stefano Piero Bernardo Cioffi, Winta Mehtsun, Ferdinando Carlo Maria Cananzi, Federico Sicoli, Vittorio Quagliuolo, Jun Chen, Chenghua Luo, Rebecca A Gladdy, Carol Swallow, Wendy Johnston, Samuel J Ford, Caroline Evenden, Fabio Tirotta, Max Almond, Laura Nguyen, Piotr Rutkowski, Maria Krotewicz, Elisabetta Pennacchioli, Kenneth Cardona, Adriana Gamboa, Daphne Hompes, Marleen Renard, Attila Kollár, Christoph O Ryser, Nikolaos Vassos, Chandrajit P Raut, Mark Fairweather, Dagmar Adamkova Krakorova, Sergio Quildrian, Andraz Perhavec, Eran Nizri, Jeffrey M Farma, Stephanie H Greco, Bruno Vincenzi, José Antonio González Lopez, Mireia Solans Solerdecoll, Shintaro Iwata, Suguru Fukushima, Teresa Kim, Francesco Tolomeo, Hayden Snow, Ynez Howlett-Jansen, Dimitri Tzanis, Maxim Nikulin, Alessandro Gronchi, Jason K Sicklick, Transatlantic Australasian Retroperitoneal Sarcoma Working Group

Faculty, Staff and Student Publications

OBJECTIVE: The Transatlantic Australasian Retroperitoneal Sarcoma Working Group conducted a retrospective study on the disease course and clinical management of ganglioneuromas.

BACKGROUND: Ganglioneuromas are rare tumors derived from neural crest cells. Data on these tumors remain limited to case reports and single-institution case series.

METHODS: Patients of all ages with pathologically confirmed primary retroperitoneal, intra-abdominal, and pelvic ganglioneuromas between January 1, 2000, and January 1, 2020, were included. We examined demographic, clinicopathologic, and radiologic characteristics, as well as clinical management.

RESULTS: Overall, 328 patients from 29 institutions were included. The median age at diagnosis was 37 years with 59.1% of …

Quality-Adjusted Survival In Women With Gynecologic Malignancies Receiving Imrt After Surgery: A Patient Reported Outcome Study Of Nrg Oncology’S Rtog 1203, Andre Konski, Snehal Deshmukh, Ann H Klopp, Anamaria R Yeung, Shannon N Westin, J Spencer Thompson, Desiree E Doncals, Guilherme H C Cantuaria, David P D'Souza, Amy Chang, Vijayananda Kundapur, Dasarahally S Mohan, Michael L Haas, Yong Bae Kim, Catherine L Ferguson, Stephanie L Pugh, Lisa A Kachnic, Deborah W Bruner

Faculty, Staff and Student Publications

INTRODUCTION: NRG/RTOG 1203 compared 3-D conformal radiotherapy (3D CRT) to intensity-modulated radiotherapy (IMRT) in patients with endometrial or cervical cancer requiring post-operative radiotherapy after hysterectomy. The purpose of this study was to report the first quality-adjusted survival analysis comparing the two treatments.

METHODS: NRG/RTOG 1203 randomized patients having undergone hysterectomy to either 3DCRT or IMRT. Stratification factors included RT dose, chemotherapy, and disease site. The EQ-5D, both index and visual analog scale (VAS), were obtained at baseline, 5 weeks after the start of RT, 4-6 weeks post RT and 1 and 3-years post RT. EQ-5D index and VAS scores along …

Ddx41 Mutations In Patients With Non-Myeloid Hematologic Neoplasms, Fatima Zahra Jelloul, Mark J Routbort, Courtney D Dinardo, Carlos E Bueso-Ramos, Rashmi Kanagal-Shamanna, Beenu Thakral, Zhuang Zuo, C Cameron Yin, Sanam Loghavi, Chi Young Ok, Sa A Wang, Zhenya Tang, M James You, Keyur P Patel, L Jeffrey Medeiros, Andrés E Quesada

Faculty, Staff and Student Publications

No abstract provided.