Medicine and Health Sciences Commons^™

Unraveling The Genetic Architecture Of Congenital Vertebral Malformation With Reference To The Developing Spine, Sen Zhao, Hengqiang Zhao, Lina Zhao, Xi Cheng, Zhifa Zheng, Mengfan Wu, Wen Wen, Shengru Wang, Zixiang Zhou, Haibo Xie, Dengfeng Ruan, Qing Li, Xinquan Liu, Chengzhu Ou, Guozhuang Li, Zhengye Zhao, Guilin Chen, Yuchen Niu, Xiangjie Yin, Yuhong Hu, Xiaochen Zhang, Deciphering Disorders Involving Scoliosis And Comorbidities (Disco) Study, Pengfei Liu, Guixing Qiu, Wanlu Liu, Chengtian Zhao, Zhihong Wu, Jianguo Zhang, Nan Wu

Faculty, Staff and Students Publications

Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord …

Impact Of Individual Level Uncertainty Of Lung Cancer Polygenic Risk Score (Prs) On Risk Stratification, Xinan Wang, Ziwei Zhang, Yi Ding, Tony Chen, Lorelei Mucci, Demetrios Albanes, Maria Teresa Landi, Neil E Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angie Cox, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Rayjean J Hung, Christopher I Amos, Xihong Lin, David C Christiani

Faculty, Staff and Student Publications

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored.

METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the …

Efficacy Of Novel Agents Against Cellular Models Of Familial Platelet Disorder With Myeloid Malignancy (Fpd-Mm), Christopher P Mill, Warren C Fiskus, Courtney D Dinardo, Patrick Reville, John A Davis, Christine E Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and …

Evaluation Of A Tiered Opioid Prescription Algorithm In An Eras Pathway: Exploring Opportunities For Further Refinement, M Sol Basabe, Tina S Suki, Mark F Munsell, Maria D Iniesta, Juan E Garcia Lopez, Robert Tyler Hillman, Katherine Cain, Sarah Huepenbecker, Gabriel Mena, Jolyn S Taylor, Pedro T Ramirez, Larissa A Meyer

Faculty, Staff and Student Publications

Background: Opioid over-prescription is wasteful and contributes to the opioid crisis. We implemented a personalized tiered discharge opioid protocol and education on opioid disposal to minimize over-prescription.

Objective: To evaluate the intervention by investigating opioid use post-discharge for women undergoing abdomino-pelvic surgery, and patient adherence to opioid disposal education.

Methods: We analyzed post-discharge opioid consumption among 558 patients. Eligible patients included those who underwent elective gynecologic surgery, were not taking scheduled opioids pre-operatively, and received discharge opioids according to a tiered prescribing algorithm. A survey assessing discharge opioid consumption and disposal safety knowledge was distributed on post-discharge day 21. Over-prescription …

Author Correction: A Ck2 And Sumo-Dependent, Pml Nb-Involved Regulatory Mechanism Controlling Blm Ubiquitination And G-Quadruplex Resolution, Shichang Liu, Erin Atkinson, Adriana Paulucci-Holthauzen, Bin Wang

Faculty, Staff and Student Publications

No abstract provided.

Insights Of Clinical Significance From 109 695 Solid Tumor Tissue-Based Comprehensive Genomic Profiles, Andreas M Heilmann, Jonathan W Riess, Margaret Mclaughlin-Drubin, Richard S P Huang, Meghann Hjulstrom, James Creeden, Brian M Alexander, Rachel L Erlich

Faculty, Staff and Student Publications

BACKGROUND: FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles.

MATERIALS AND METHODS: Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, …

Tumor-Specific Polycistronic Mirna Delivered By Engineered Exosomes For The Treatment Of Glioblastoma, Malcolm F Mcdonald, Anwar Hossain, Eric N Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang

Faculty, Staff and Student Publications

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

Methods: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to …

Impact Of Neighborhood Disadvantage On Tumor Biology And Breast Cancer Survival, Neha Goel, Alexandra Hernandez, Deukwoo Kwon, Michael H Antoni, Steve Cole

Faculty, Staff and Student Publications

Objective: The aim of this study was to evaluate the association between neighborhood disadvantage and Oncotype DX score, a surrogate for tumor biology, among a national cohort.

Background: Women living in disadvantaged neighborhoods have shorter breast cancer (BC) survival, even after accounting for individual-level, tumor, and treatment characteristics. This suggests unaccounted social and biological mechanisms by which neighborhood disadvantage may impact BC survival.

Methods: This cross-sectional study included stage I and II, ER + /HER2 - BC patients with Oncotype DX score data from the National Cancer Database (NCDB) from 2004 to 2019. Multivariate regression models tested the association of …

Parental Age Effects And Rett Syndrome, Xiaolan Fang, Lauren M Baggett, Raymond C Caylor, Alan K Percy, Jeffrey L Neul, Jane B Lane, Daniel G Glaze, Tim A Benke, Eric D Marsh, Kathleen J Motil, Judy O Barrish, Fran E Annese, Steven A Skinner

Children’s Nutrition Research Center Staff Publications

Rett syndrome (RTT) is a progressive neurodevelopmental disorder, and pathogenic Methyl-CpG-binding Protein 2 (MECP2) variants are identified in >95% of individuals with typical RTT. Most of RTT-causing variants in MECP2 are de novo and usually on the paternally inherited X chromosome. While paternal age has been reported to be associated with increased risk of genetic disorders, it is unknown whether parental age contributes to the risk of the development of RTT. Clinical data including parental age, RTT diagnostic status, and clinical severity are collected from 1226 participants with RTT and confirmed MECP2 variants. Statistical analyses are performed using Student t-test, …

Patient Interest In Exploring Nonsurgical Treatment Approaches For Early-Stage Breast Cancer: A Qualitative Study, Maya Guhan, Stacey M Crane, Lillian S Valerius, Denise De La Cruz, Benjamin D Smith, Wendy A Woodward, Melissa P Mitchell, Vicente Valero, Gaiane M Rauch, Savitri Krishnamurthy, Carla L Warnecke, Henry M Kuerer, Simona F Shaitelman

Faculty, Staff and Student Publications

Purpose: Advances in radiation therapy have enabled the ability to deliver ablative treatments, but there has been limited application of these treatments to early-stage breast cancers with a goal of omitting surgery. The purpose of this study was to explore patient interest in pursuing nonsurgical treatment approaches for their early-stage breast cancer.

Methods and materials: We conducted a qualitative study involving interviews with 21 patients with early-stage breast cancer who were eligible for participation in a phase 2 clinical trial offering omission of definitive surgery. Interviews were transcribed and an inductive, thematic analysis was performed by 3 independent reviewers to …

Absence Of Btk, Bcl2, And Plcg2 Mutations In Chronic Lymphocytic Leukemia Relapsing After First-Line Treatment With Fixed-Duration Ibrutinib Plus Venetoclax, Nitin Jain, Lisa J Croner, John N Allan, Tanya Siddiqi, Alessandra Tedeschi, Xavier C Badoux, Karl Eckert, Leo W K Cheung, Anwesha Mukherjee, James P Dean, Edith Szafer-Glusman, John F Seymour

Faculty, Staff and Student Publications

Purpose: Mutations in BTK, PLCG2, and BCL2 have been reported in patients with progressive disease (PD) on continuous single-agent BTK or BCL2 inhibitor treatment. We tested for these mutations in samples from patients with PD after completion of first-line treatment with fixed-duration ibrutinib plus venetoclax for chronic lymphocytic leukemia (CLL) in the phase II CAPTIVATE study.

Patients and methods: A total of 191 patients completed fixed-duration ibrutinib plus venetoclax (three cycles of ibrutinib then 12-13 cycles of ibrutinib plus venetoclax). Genomic risk features [del(11q), del(13q), del(17p), trisomy 12, complex karyotype, unmutated IGHV, TP53 mutated] and mutations in genes recurrently mutated …

Regression Analysis Of Multivariate Recurrent Event Data Allowing Time-Varying Dependence With Application To Stroke Registry Data, Wen Li, Mohammad H Rahbar, Sean I Savitz, Jing Zhang, Sori Kim Lundin, Amirali Tahanan, Jing Ning

Faculty, Staff and Student Publications

In multivariate recurrent event data, each patient may repeatedly experience more than one type of event. Analysis of such data gets further complicated by the time-varying dependence structure among different types of recurrent events. The available literature regarding the joint modeling of multivariate recurrent events assumes a constant dependency over time, which is strict and often violated in practice. To close the knowledge gap, we propose a class of flexible shared random effects models for multivariate recurrent event data that allow for time-varying dependence to adequately capture complex correlation structures among different types of recurrent events. We developed an expectation-maximization …

Increased Prevalence Of Clostridioides Difficile Infection Among Pediatric Oncology Patients: Risk Factors For Infection And Complications, Brianna R Murphy, Natalie J Dailey Garnes, Hyunsoo Hwang, Christine B Peterson, Kevin W Garey, Pablo Okhuysen

Faculty, Staff and Student Publications

Background: Pediatric oncology patients, who are typically immunosuppressed, exposed to medications associated with increased Clostridioides difficile infection (CDI) risk and hospitalized, are expected to be at substantial risk for infection and complications. Although certain C. difficile ribotypes have been associated with more severe infection in adults, such an association has not been described in children.

Methods: To characterize CDI epidemiology, including risk factors and complications among pediatric oncology patients, we retrospectively reviewed charts of patients 1-18 years old treated at a designated cancer center during 2000-2017. We used fluorescence-based polymerase chain reaction to identify ribotypes causing disease at our institution. …

Safety And Efficacy Of A New High-Dose Regimen Of Panobinostat, Gemcitabine, Busulfan, And Melphalan For 1st Or 2nd Salvage Asct For Refractory/Relapsed Or High-Risk Myeloma: Matched-Pair Comparisons With Concurrent Control Cohorts, Yago Nieto, Zixi Yang, Benigno C Valdez, Suprateek Kundu, Qaiser Bashir, Jeremy Ramdial, Samer Srour, Muzaffar Qazilbash

Faculty, Staff and Student Publications

Improvement of autologous stem-cell transplantation (ASCT) for myeloma is needed. Building on our prior work, we prospectively evaluated panobinostat and gemcitabine/busulfan/melphalan (GemBuMel) with ASCT in this population. Patients aged 18-65 years with relapsed/refractory or high-risk myeloma and adequate end-organ function were eligible. Treatment included panobinostat (20 mg/day, days -9 to -2) and GemBuMel (days -8 to -2). Patients were enrolled in 1st (ASCT-1) or 2nd ASCT (ASCT-2) cohorts. We compared their outcomes with all our other concurrent ASCT patients who met eligibility criteria but received melphalan or BuMel off study, matched for age, prior therapy lines, high-risk cytogenetics, and response …

Convergent Mapk Pathway Alterations Mediate Acquired Resistance To Fgfr Inhibitors In Fgfr2 Fusion-Positive Cholangiocarcinoma, Timothy P Diperi, Ming Zhao, Kurt W Evans, Kaushik Varadarajan, Tyler Moss, Stephen Scott, Michael P Kahle, Charnel C Byrnes, Huiqin Chen, Sunyoung S Lee, Abdel-Baset Halim, Hiroshi Hirai, Volker Wacheck, Lawrence N Kwong, Jordi Rodon, Milind Javle, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Background & aims: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA).

Methods: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance …

Phase 2 Study Of Inotuzumab Ozogamicin For Measurable Residual Disease In Acute Lymphoblastic Leukemia In Remission, Elias Jabbour, Fadi G Haddad, Nicholas J Short, Jayastu Senapati, Nitin Jain, Koji Sasaki, Jeffrey Jorgensen, Sa A Wang, Yesid Alvarado, Xuemei Wang, Courtney Dinardo, Lucia Masarova, Tapan Kadia, Rebecca S Garris, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10-4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) …

Shape Anisotropy-Governed High-Performance Nanomagnetosol For In Vivo Magnetic Particle Imaging Of Lungs, Saumya Nigam, Jeotikanta Mohapatra, Ashley V Makela, Hanaan Hayat, Jessi Mercedes Rodriguez, Aixia Sun, Elizabeth Kenyon, Nathan A Redman, Dana Spence, George Jabin, Bin Gu, Mohamed Ashry, Lorenzo F Sempere, Arijit Mitra, Jinxing Li, Jiahui Chen, Guo-Wei Wei, Steven Bolin, Brett Etchebarne, J Ping Liu, Christopher H Contag, Ping Wang

Faculty, Staff and Student Publications

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has shown extensive lung manifestations in vulnerable individuals, putting lung imaging and monitoring at the forefront of early detection and treatment. Magnetic particle imaging (MPI) is an imaging modality, which can bring excellent contrast, sensitivity, and signal-to-noise ratios to lung imaging for the development of new theranostic approaches for respiratory diseases. Advances in MPI tracers would offer additional improvements and increase the potential for clinical translation of MPI. Here, a high-performance nanotracer based on shape anisotropy of magnetic nanoparticles is developed and its use in MPI imaging …

Inspiring New Science To Guide Healthcare In Turner Syndrome: Rationale, Design, And Methods For The Insights Registry, Roopa Kanakatti Shankar, Alexandra Carl, Jennifer R Law, Vaneeta Bamba, Wendy J Brickman, Siddharth K Prakash, Tazim Dowlut Mcelroy, Susan Howell, Iris Gutmark Little, Karen O Klein, Catherina T Pinnaro, Kelly Ranallo, Marybel Good, Shanlee M Davis

Faculty, Staff and Student Publications

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate …

Transmission Of Amyloid-Β Pathology In Humans: A Perspective On Clinical Evidence, Celso S G Catumbela, Rodrigo Morales

Faculty, Staff and Student Publications

No abstract provided.

Correction: Il-1Α Mediates Innate And Acquired Resistance To Immunotherapy In Melanoma, Shubhra Singh, Zhilan Xiao, Karishma Bavisi, Jason Roszik, Brenda D Melendez, Zhiqiang Wang, Mark J Cantwell, Richard E Davis, Greg Lizee, Patrick Hwu, Sattva S Neelapu, Willem W Overwijk, Manisha Singh

Faculty, Staff and Student Publications

No abstract provided.

Trps1 And Gata3 Expression In Invasive Breast Carcinoma With Apocrine Differentiation, Jing Wang, Yan Peng, Hongxia Sun, Phyu P Aung, Erika Resetkova, Clinton Yam, Aysegul A Sahin, Lei Huo, Qingqing Ding

Faculty, Staff and Student Publications

Context.—: The recently identified immunohistochemical marker TRPS1 is highly sensitive and specific for invasive breast carcinoma, especially triple-negative breast carcinoma. However, TRPS1 expression in special morphologic subtypes of breast cancer is unclear.

Objective.—: To investigate the expression of TRPS1 in invasive breast cancer with apocrine differentiation, in comparison to the expression of GATA3.

Design.—: A total of 52 invasive breast carcinomas with apocrine differentiation, comprising 41 triple-negative breast carcinomas and 11 estrogen receptor (ER) and progesterone receptor (PR)-negative, human epidermal growth factor receptor 2 (HER2)-positive cases, along with 11 triple-negative breast carcinomas without apocrine differentiation, were evaluated for TRPS1 and …

Clicksam: Fine-Tuning Segment Anything Model Using Click Prompts For Ultrasound Image Segmentation, Aimee Guo, Grace Fei, Hemanth Pasupuleti, Jing Wang

Faculty, Staff and Student Publications

The newly released Segment Anything Model (SAM) is a popular tool used in image processing due to its superior segmentation accuracy, variety of input prompts, training capabilities, and efficient model design. However, its current model is trained on a diverse dataset not tailored to medical images, particularly ultrasound images. Ultrasound images tend to have a lot of noise, making it difficult to segment out important structures. In this project, we developed ClickSAM, which fine-tunes the Segment Anything Model using click prompts for ultrasound images. ClickSAM has two stages of training: the first stage is trained on single-click prompts centered …

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia And Thrombocytosis: A Report From The Bcr::Abl1 Pathology Group, Daniel Rivera, Wei Cui, Juehua Gao, Deniz Peker, Qian-Yun Zhang, Rajan Dewar, Lianqun Qiu, Sergej Konoplev, Zhihong Hu, Koji Sasaki, Aileen Y Hu, Shuyu E, Meng Liu, Hong Fang, Wei Wang, Guilin Tang, Jane F Apperley, Andreas Hochhaus, Jorge E Cortes, Joseph D Khoury, L Jeffrey Medeiros, Elias Jabbour, Shimin Hu

Faculty, Staff and Student Publications

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, …

Azithromycin Reduces Hemoglobin-Induced Innate Neuroimmune Activation, Chirayu D Pandya, Hemendra J Vekaria, Miriam Zamorano, Amanda L Trout, Rodney M Ritzel, Gary U Guzman, Christopher Bolden, Patrick G Sullivan, John C Gensel, Brandon A Miller

Faculty, Staff and Student Publications

Neonatal intraventricular hemorrhage (IVH) releases blood products into the lateral ventricles and brain parenchyma. There are currently no medical treatments for IVH and surgery is used to treat a delayed effect of IVH, post-hemorrhagic hydrocephalus. However, surgery is not a cure for intrinsic brain injury from IVH, and is performed in a subacute time frame. Like many neurological diseases and injuries, innate immune activation is implicated in the pathogenesis of IVH. Innate immune activation is a pharmaceutically targetable mechanism to reduce brain injury and post-hemorrhagic hydrocephalus after IVH. Here, we tested the macrolide antibiotic azithromycin, which has immunomodulatory properties, to …

Genetic Intratumor Heterogeneity Remodels The Immune Microenvironment And Induces Immune Evasion In Brain Metastasis Of Lung Cancer, Xin Wang, Hua Bai, Jiyang Zhang, Zhijie Wang, Jianchun Duan, Hongqing Cai, Zheng Cao, Qingtang Lin, Xiaosheng Ding, Yiting Sun, Wei Zhang, Xiaoya Xu, Hao Chen, Dadong Zhang, Xiaoli Feng, Jinghai Wan, Jianjun Zhang, Jie He, Jie Wang

Faculty, Staff and Student Publications

Introduction: Brain metastasis, with the highest incidence in patients with lung cancer, significantly worsens prognosis and poses challenges to clinical management. To date, how brain metastasis evades immune elimination remains unknown.

Methods: Whole-exome sequencing and RNA sequencing were performed on 30 matched brain metastasis, primary lung adenocarcinoma, and normal tissues. Data from The Cancer Genome Atlas primary lung adenocarcinoma cohort, including multiplex immunofluorescence, were used to support the findings of bioinformatics analysis.

Results: Our study highlights the key role of intratumor heterogeneity of genomic alterations in the metastasis process, mainly caused by homologous recombination deficiency or other somatic copy number …

Phase 1/2 Trial Of Avelumab Combined With Utomilumab (4–1bb Agonist), Pf-04518600 (Ox40 Agonist), Or Radiotherapy In Patients With Advanced Gynecologic Malignancies, Anne Knisely, Jibran Ahmed, Bettzy Stephen, Sarina A Piha-Paul, Daniel Karp, Abdulrazzak Zarifa, Siqing Fu, David Sanghyun Hong, Jordi Rodon Ahnert, Timothy A Yap, Apostolia M Tsimberidou, Anas Alshawa, Ecaterina E Dumbrava, Yali Yang, Juhee Song, Funda Meric-Bernstam, Amir A Jazaeri, Aung Naing

Faculty, Staff and Student Publications

Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.

Methods: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the …

Deep Learning-Based Automatic Segmentation Of Cardiac Substructures For Lung Cancers, Xinru Chen, Raymond P Mumme, Kelsey L Corrigan, Yuki Mukai-Sasaki, Efstratios Koutroumpakis, Nicolas L Palaskas, Callistus M Nguyen, Yao Zhao, Kai Huang, Cenji Yu, Ting Xu, Aji Daniel, Peter A Balter, Xiaodong Zhang, Joshua S Niedzielski, Sanjay S Shete, Anita Deswal, Laurence E Court, Zhongxing Liao, Jinzhong Yang

Faculty, Staff and Student Publications

Purpose: Accurate and comprehensive segmentation of cardiac substructures is crucial for minimizing the risk of radiation-induced heart disease in lung cancer radiotherapy. We sought to develop and validate deep learning-based auto-segmentation models for cardiac substructures.

Materials and methods: Nineteen cardiac substructures (whole heart, 4 heart chambers, 6 great vessels, 4 valves, and 4 coronary arteries) in 100 patients treated for non-small cell lung cancer were manually delineated by two radiation oncologists. The valves and coronary arteries were delineated as planning risk volumes. An nnU-Net auto-segmentation model was trained, validated, and tested on this dataset with a split ratio of 75:5:20. …

Genomic Staging Of Multifocal Lung Squamous Cell Carcinomas Is Independent Of The Comprehensive Morphologic Assessment, Sanja Dacic, Xuanye Cao, Neus Bota-Rabassedas, Beatriz Sanchez-Espiridion, Sabina Berezowska, Yuchen Han, Jin-Haeng Chung, Mary Beth Beasley, Lin Dongmei, David Hwang, Mari Mino-Kenudson, Yuko Minami, Mauro Papotti, Natasha Rekhtman, Anja C Roden, Erik Thunnissen, Ming-Sound Tsao, Yasushi Yatabe, Akihiko Yoshida, Linghua Wang, Douglas J Hartman, Jacob A Jerome, Humam Kadara, Teh-Ying Chou, Ignacio I Wistuba

Faculty, Staff and Student Publications

Introduction: Morphologic and molecular data for staging of multifocal lung squamous cell carcinomas (LSCCs) are limited. In this study, whole exome sequencing (WES) was used as the gold standard to determine whether multifocal LSCC represented separate primary lung cancers (SPLCs) or intrapulmonary metastases (IPMs). Genomic profiles were compared with the comprehensive morphologic assessment.

Methods: WES was performed on 20 tumor pairs of multifocal LSCC and matched normal lymph nodes using the Illumina NovaSeq6000 S4-Xp (Illumina, San Diego, CA). WES clonal and subclonal analysis data were compared with histologic assessment by 16 thoracic pathologists. In addition, the immune gene profiling of …

The Future Of Targeting Cytotoxic T-Lymphocyte-Associated Protein-4: Is There A Role?, Anna Maria Di Giacomo, Michael Lahn, Alexander Mm Eggermont, Bernard Fox, Ramy Ibrahim, Padmanee Sharma, James P Allison, Michele Maio

Faculty, Staff and Student Publications

The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable …

Experiences Of Patients With Peritoneal Carcinomatosis-Related Complex Care Needs And Their Caregivers, Rachel A Pozzar, Jaclyn A Wall, Anna Tavormina, Embree Thompson, Andrea C Enzinger, Ursula A Matulonis, Susana Campos, Larissa A Meyer, Alexi A Wright

Faculty, Staff and Student Publications

Background: Patients with peritoneal carcinomatosis (PC) frequently undergo palliative procedures, yet these patients and their caregivers report being unprepared to manage ostomies, drains, and other complex care needs at home. The purpose of this study was to characterize the unique needs of these patients and their caregivers during care transitions.

Methods: Patients completed measures of health status and advance care planning, caregivers completed measures of preparedness and burden, and all participants completed measures of depression and anxiety. Participants detailed their experiences in individual, semi-structured interviews. We analyzed data using descriptive statistics and conventional content analysis.

Results: Sixty-one patients and 39 …