Medical Sciences Commons^™

Platelets Increase The Expression Of Pd-L1 In Ovarian Cancer, Min Soon Cho, Hani Lee, Ricardo Gonzalez-Delgado, Dan Li, Tomoyuki Sasano, Wendolyn Carlos-Alcalde, Qing Ma, Jinsong Liu, Anil K Sood, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

The interactions between platelets and cancer cells activate platelets and enhance tumor growth. Platelets increase proliferation and epithelial-mesenchymal transition in cancer cells, inhibit anoikis, enhance the extravasation of cancer cells, and protect circulating tumor cells against natural killer cells. Here, we have identified another mechanism by which platelets dampen the immune attack on cancer cells. We found that platelets can blunt the antitumor immune response by increasing the expression of inhibitory immune checkpoint (PD-L1) on ovarian cancer cells in vitro and in vivo. Platelets increased PD-L1 in cancer cells via contact-dependent (through NF-κB signaling) and contact-independent (through TFGβR1/Smad signaling) pathways. …

Inhibition Of Mitochondrial Complex I Reverses Notch1-Driven Metabolic Reprogramming In T-Cell Acute Lymphoblastic Leukemia, Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva

Faculty, Staff and Student Publications

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with …

Making National Cancer Institute-Designated Comprehensive Cancer Center Knowledge Accessible To Community Oncologists Via An Online Tumor Board: Longitudinal Observational Study, Maitri Kalra, Elizabeth Henry, Kelly Mccann, Meghan S Karuturi, Jean G Bustamante Alvarez, Amanda Parkes, Robert Wesolowski, Mei Wei, Sarah S Mougalian, Gregory Durm, Angel Qin, Caitlin Schonewolf, Meghna Trivedi, Avan J Armaghani, Frederick H Wilson, Wade T Iams, Anita A Turk, Praveen Vikas, Michael Cecchini, Sam Lubner, Priyadarshini Pathak, Kristen Spencer, Vadim S Koshkin, Matthew K Labriola, Catherine H Marshall, Katy E Beckermann, Marina N Sharifi, Anthony C Bejjani, Varsha Hotchandani, Samir Housri, Nadine Housri

Faculty, Staff and Student Publications

Background: Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community.

Objective: Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community.

Methods: We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated …

One-Pot, One-Step Synthesis Of Drug-Loaded Magnetic Multimicelle Aggregates, Chang Soo Kim, Dmitry Nevozhay, Rebeca Romero Aburto, Ashok Pehere, Lan Pang, Rebecca Dillard, Ziqiu Wang, Clayton Smith, Kelsey Boitnott Mathieu, Marie Zhang, John D Hazle, Robert C Bast, Konstantin Sokolov

Faculty, Staff and Student Publications

Lipid-based formulations provide a nanotechnology platform that is widely used in a variety of biomedical applications because it has several advantageous properties including biocompatibility, reduced toxicity, relative ease of surface modifications, and the possibility for efficient loading of drugs, biologics, and nanoparticles. A combination of lipid-based formulations with magnetic nanoparticles such as iron oxide was shown to be highly advantageous in a growing number of applications including magnet-mediated drug delivery and image-guided therapy. Currently, lipid-based formulations are prepared by multistep protocols. Simplification of the current multistep procedures can lead to a number of important technological advantages including significantly decreased processing …

An Observational Retrospective Study Of Adverse Events And Behavioral Outcomes During Pediatric Dental Sedation, Kawtar Zouaidi, Gregory Olson, Helen H Lee, Elsbeth Kalenderian, Muhammad F Walji

Faculty, Staff and Student Publications

Purpose: The purpose of this study was to examine a university-based dental electronic health records (EHR) database to identify sedation-related adverse events (AEs) and assess patients' behavioral outcomes during routine pediatric dental sedations (PDSs) in a dental school clinic.

Methods: A database was screened for patients younger than 18 years old who had received dental sedation in 2019. The qualifying EHRs were then accessed and sedations were reviewed for AEs, which were categorized using a 12-point classification system and the Tracking and Reporting Outcomes of Procedural Sedation Tool. Patient behaviors were assessed using provider progress notes and categorized as presence/ …

An Evidence-Based Lexical Pattern Approach For Quality Assurance Of Gene Ontology Relations, Rashmie Abeysinghe, Yuntao Yang, Mason Bartels, W Jim Zheng, Licong Cui

Faculty, Staff and Student Publications

Gene Ontology (GO) is widely used in the biological domain. It is the most comprehensive ontology providing formal representation of gene functions (GO concepts) and relations between them. However, unintentional quality defects (e.g. missing or erroneous relations) in GO may exist due to the large size of GO concepts and complexity of GO structures. Such quality defects would impact the results of GO-based analyses and applications. In this work, we introduce a novel evidence-based lexical pattern approach for quality assurance of GO relations. We leverage two layers of evidence to suggest potentially missing relations in GO as follows. We first …

Chronic Lymphocytic Leukemia Progression Diagnosis With Intrinsic Cellular Patterns Via Unsupervised Clustering, Pingjun Chen, Siba El Hussein, Fuyong Xing, Muhammad Aminu, Aparajith Kannapiran, John D Hazle, L Jeffrey Medeiros, Ignacio I Wistuba, David Jaffray, Joseph D Khoury, Jia Wu

Faculty, Staff and Student Publications

Identifying the progression of chronic lymphocytic leukemia (CLL) to accelerated CLL (aCLL) or transformation to diffuse large B-cell lymphoma (Richter transformation; RT) has significant clinical implications as it prompts a major change in patient management. However, the differentiation between these disease phases may be challenging in routine practice. Unsupervised learning has gained increased attention because of its substantial potential in data intrinsic pattern discovery. Here, we demonstrate that cellular feature engineering, identifying cellular phenotypes via unsupervised clustering, provides the most robust analytic performance in analyzing digitized pathology slides (accuracy = 0.925, AUC = 0.978) when compared to alternative approaches, such …

Rapid Acceleration Of Kras-Mutant Pancreatic Carcinogenesis Via Remodeling Of Tumor Immune Microenvironment By Pparδ, Yi Liu, Yasunori Deguchi, Daoyan Wei, Fuyao Liu, Micheline J Moussalli, Eriko Deguchi, Donghui Li, Huamin Wang, Lovie Ann Valentin, Jennifer K Colby, Jing Wang, Xiaofeng Zheng, Haoqiang Ying, Mihai Gagea, Baoan Ji, Jiaqi Shi, James C Yao, Xiangsheng Zuo, Imad Shureiqi

Faculty, Staff and Student Publications

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This …

Prioritization Of Risk Genes In Multiple Sclerosis By A Refined Bayesian Framework Followed By Tissue-Specificity And Cell Type Feature Assessment, Andi Liu, Astrid M Manuel, Yulin Dai, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Multiple sclerosis (MS) is a debilitating immune-mediated disease of the central nervous system that affects over 2 million people worldwide, resulting in a heavy burden to families and entire communities. Understanding the genetic basis underlying MS could help decipher the pathogenesis and shed light on MS treatment. We refined a recently developed Bayesian framework, Integrative Risk Gene Selector (iRIGS), to prioritize risk genes associated with MS by integrating the summary statistics from the largest GWAS to date (n = 115,803), various genomic features, and gene-gene closeness.

RESULTS: We identified 163 MS-associated prioritized risk genes (MS-PRGenes) through the Bayesian framework. …

Immunogenomic Intertumor Heterogeneity Across Primary And Metastatic Sites In A Patient With Lung Adenocarcinoma, Runzhe Chen, Jun Li, Junya Fujimoto, Lingzhi Hong, Xin Hu, Kelly Quek, Ming Tang, Akash Mitra, Carmen Behrens, Chi-Wan Chow, Peixin Jiang, Latasha D Little, Curtis Gumbs, Xingzhi Song, Jianhua Zhang, Dongfeng Tan, John V Heymach, Ignacio Wistuba, P Andrew Futreal, Don L Gibbons, Lauren A Byers, Jianjun Zhang, Alexandre Reuben

Faculty, Staff and Student Publications

Background: Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy.

Methods: In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. …

Lncrnas Uc145 And Prkg1-As1 Determine The Functional Output Of Dkk1 In Regulating The Wnt Signaling Pathway In Gastric Cancer, Jung-Ho Yoon, Hyojoo Byun, Cristina Ivan, George A Calin, Dahyun Jung, Sangkil Lee

Faculty, Staff and Student Publications

DKK1 inhibits the canonical Wnt signaling pathway that is known to be involved in various cancers. However, whether DKK1 acts as an oncogene or tumor suppressor gene remains controversial. Furthermore, the DKK1-regulating mechanism in gastric cancer has not yet been defined. The aim of this study was to explore whether the ultraconserved region UC.145 regulates epigenetic changes in DKK1 expression in gastric cancer. Microarray analysis revealed that UC.145 exhibited the highest binding affinity to EZH2, a histone methyltransferase. The effects of UC.145 inactivation were assessed in gastric cancer cell lines using siRNA. The results indicated that UC.145 triggers DKK1 methylation …

Ezh2 Engages Tgfβ Signaling To Promote Breast Cancer Bone Metastasis Via Integrin Β1-Fak Activation, Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang, Dihua Yu

Faculty, Staff and Student Publications

Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type …

Identification Of Biomarkers Of Response To Preoperative Talazoparib Monotherapy In Treatment Naïve Gbrca+ Breast Cancers, Xuan Liu, Zhongqi Ge, Fei Yang, Alejandro Contreras, Sanghoon Lee, Jason B White, Yiling Lu, Marilyne Labrie, Banu K Arun, Stacy L Moulder, Gordon B Mills, Helen Piwnica-Worms, Jennifer K Litton, Jeffrey T Chang

Faculty, Staff and Student Publications

Germline mutations in BRCA1 or BRCA2 exist in ~2-7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked …

Racial And Ethnic Differences In Genomic Profiling Of Early Onset Colorectal Cancer, David M Hein, Weiye Deng, Marylena Bleile, Syed Ali Kazmi, Brooke Rhead, Francisco M De La Vega, Amy L Jones, Radhika Kainthla, Wen Jiang, Brandi Cantarel, Nina N Sanford

Faculty, Staff and Student Publications

The incidence and mortality of early onset colorectal cancer (EOCRC) is rising; outcomes appear to differ by race and ethnicity. We aimed to assess differences in mutational landscape and gene expression of EOCRC by racial and ethnic groups (non-Hispanic Asian, non-Hispanic Black, non-Hispanic White, White Hispanic) using data from the American Association for Cancer Research Project GENIE (10.2) and University of Texas Southwestern, the latter enriched in Hispanic patients. All statistical tests were 2-sided. Of 1752 EOCRC patients, non-Hispanic Black patients had higher rates of KRAS mutations (60.9%; P = .001, q = 0.015), and non-Hispanic White and non-Hispanic Black …

Bi-Order Multimodal Integration Of Single-Cell Data, Jinzhuang Dou, Shaoheng Liang, Vakul Mohanty, Qi Miao, Yuefan Huang, Qingnan Liang, Xuesen Cheng, Sangbae Kim, Jongsu Choi, Yumei Li, Li Li, May Daher, Rafet Basar, Katayoun Rezvani, Rui Chen, Ken Chen

Faculty, Staff and Student Publications

Integration of single-cell multiomics profiles generated by different single-cell technologies from the same biological sample is still challenging. Previous approaches based on shared features have only provided approximate solutions. Here, we present a novel mathematical solution named bi-order canonical correlation analysis (bi-CCA), which extends the widely used CCA approach to iteratively align the rows and the columns between data matrices. Bi-CCA is generally applicable to combinations of any two single-cell modalities. Validations using co-assayed ground truth data and application to a CAR-NK study and a fetal muscle atlas demonstrate its capability in generating accurate multimodal co-embeddings and discovering cellular identity.

Central Nervous System Immune Interactome Is A Function Of Cancer Lineage, Tumor Microenvironment, And Stat3 Expression, Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M Sonabend, Craig Horbinski, Roel Verhaak, Anand Shankar, Santhoshi N Krishnan, Frederick S Varn, Víctor A Arrieta, Pravesh Gupta, Sherise D Ferguson, Jason T Huse, Gregory N Fuller, James P Long, Daniel E Winkowski, Ben A Freiberg, Charles David James, Leonidas C Platanias, Maciej S Lesniak, Jared K Burks, Amy B Heimberger

Faculty, Staff and Student Publications

BACKGROUND

Immune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.

METHODS

En bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.

RESULTS

Within gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163⁺ macrophages were evident throughout the TME of metastatic …

Evidence Supporting A Role For The Immune Checkpoint Protein B7-H3 In Nk Cell-Mediated Cytotoxicity Against Aml, Anudishi Tyagi, Stanley Ly, Fouad El-Dana, Bin Yuan, Appalaraju Jaggupilli, Sabrina Grimm, Marina Konopleva, Hans-Jörg Bühring, V Lokesh Battula

Faculty, Staff and Student Publications

We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop …

A Bayesian Group Sequential Design For Randomized Biosimilar Clinical Trials With Adaptive Information Borrowing From Historical Data, Wen Zhang, Zhiying Pan, Ying Yuan

Faculty, Staff and Student Publications

At the time of developing a biosimilar, the reference product has been on market for years and thus ample data are available on its efficacy and characteristics. We develop a Bayesian adaptive design for randomized biosimilar clinical trials to leverage the rich historical data on the reference product. This design takes a group sequential approach. At each interim, we employ the elastic meta-analytic-predictive (EMAP) prior methodology to adaptively borrow information from the historical data of the reference product to make go/no-go decision based on Bayesian posterior probabilities. In addition, the randomization ratio between the test and reference arms is adaptively …

Bhlhe40 Regulates The T-Cell Effector Function Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery J Salmon, Alexander S Shavkunov, Qi Miao, Nicholas N Jarjour, Sunita Keshari, Ekaterina Esaulova, Charmelle D Williams, Jeffrey P Ward, Anna M Highsmith, Josué E Pineda, Reshma Taneja, Ken Chen, Brian T Edelson, Matthew M Gubin

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell-dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti-PD-1 and anti-CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor antigen-specific CD8+ and CD4+ T cells and that T cells require BHLHE40 for effective ICT in mice bearing immune-edited tumors. Single-cell RNA sequencing of intratumoral immune cells in BHLHE40-deficient mice revealed differential …

Tumor Immune Microenvironment Of Brain Metastases: Toward Unlocking Antitumor Immunity, Matthew R Strickland, Christopher Alvarez-Breckenridge, Justin F Gainor, Priscilla K Brastianos

Faculty, Staff and Student Publications

UNLABELLED: Brain metastasis (BrM) is a devastating complication of solid tumors associated with poor outcomes. Immune-checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, but determinants of response are incompletely understood. Given the rising incidence of BrM, improved understanding of immunobiologic principles unique to the central nervous system (CNS) and dissection of those that govern the activity of ICIs are paramount toward unlocking BrM-specific antitumor immunity. In this review, we seek to discuss the current clinical landscape of ICI activity in the CNS and CNS immunobiology, and we focus, in particular, on the role of glial cells in the CNS …

Hypomethylating Agent And Venetoclax With Flt3 Inhibitor “Triplet” Therapy In Older/Unfit Patients With Flt3 Mutated Aml, Musa Yilmaz, Hagop Kantarjian, Nicholas J Short, Patrick Reville, Marina Konopleva, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Abhishek Maiti, Elias Jabbour, Nitin Jain, Ghayas Issa, Koichi Takahashi, Koji Sasaki, Maro Ohanian, Sherry Pierce, Guillin Tang, Sanam Loghavi, Keyur Patel, Sa A Wang, Guillermo Garcia-Manero, Michael Andreeff, Farhad Ravandi, Naval Daver

Faculty, Staff and Student Publications

In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a …

Diminished Immune Surveillance During Histologic Progression Of Intraductal Papillary Mucinous Neoplasms Offers A Therapeutic Opportunity For Cancer Interception, Sharia Hernandez, Edwin Roger Parra, Naohiro Uraoka, Ximing Tang, Yu Shen, Wei Qiao, Mei Jiang, Shanyu Zhang, Barbara Mino, Wei Lu, Renganayaki Pandurengan, Cara Haymaker, Kajsa Affolter, Courtney L Scaife, Michele Yip-Schneider, C Max Schmidt, Matthew A Firpo, Sean J Mulvihill, Eugene J Koay, Huamin Wang, Ignacio I Wistuba, Anirban Maitra, Luisa M Solis, Subrata Sen

Faculty, Staff and Student Publications

Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.

Experimental design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples …

Overall Survival In Phase 3 Clinical Trials And The Surveillance, Epidemiology, And End Results Database In Patients With Metastatic Colorectal Cancer, 1986-2016: A Systematic Review, Chan Shen, Daniel Tannenbaum, Robert Horn, Jane Rogers, Cathy Eng, Shouhao Zhou, Benny Johnson, Scott Kopetz, Van Morris, Michael Overman, Christine Parseghian, George J Chang, Maria A Lopez-Olivo, Raghav Kanwal, Lee M Ellis, Arvind Dasari

Faculty, Staff and Student Publications

Importance: Phase 3 trials for patients with metastatic colorectal cancer (mCRC) have been conducted with varying designs and often with surrogate end points for overall survival (OS).

Objectives: To critically examine the factors associated with clinically relevant improvement in OS (defined as ≥2 months) in these trials and to evaluate their association with outcomes reflected in Surveillance, Epidemiology, and End Results (SEER) registry data.

Evidence review: Medline, EMBASE, Cochrane, Web of Science, ClinicalTrials.gov, EU Clinical Trials Register, and the International Clinical Trials Registry Platform were searched for phase 3 trials of systemic therapy for patients with mCRC by decade (1986-1996, …

Genomic Correlates Of Outcome In Tumor-Infiltrating Lymphocyte Therapy For Metastatic Melanoma, Caitlin A Creasy, Yuzhong Jeff Meng, Marie-Andrée Forget, Tatiana Karpinets, Katarzyna Tomczak, Chip Stewart, Carlos A Torres-Cabala, Shari Pilon-Thomas, Amod A Sarnaik, James J Mulé, Levi Garraway, Matias Bustos, Jianhua Zhang, Sapna P Patel, Adi Diab, Isabella C Glitza, Cassian Yee, Hussein Tawbi, Michael K Wong, Jennifer Mcquade, Dave S B Hoon, Michael A Davies, Patrick Hwu, Rodabe N Amaria, Cara Haymaker, Rameen Beroukhim, Chantale Bernatchez

Faculty, Staff and Student Publications

Purpose: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.

Experimental design: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.

Results: Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved …

Implementation Of Preemptive Dna Sequence-Based Pharmacogenomics Testing Across A Large Academic Medical Center: The Mayo-Baylor Right 10k Study, Liewei Wang, Steven E Scherer, Suzette J Bielinski, Donna M Muzny, Leila A Jones, John Logan Black, Ann M Moyer, Jyothsna Giri, Richard R Sharp, Eric T Matey, Jessica A Wright, Lance J Oyen, Wayne T Nicholson, Mathieu Wiepert, Terri Sullard, Timothy B Curry, Carolyn R Rohrer Vitek, Tammy M Mcallister, Jennifer L St Sauver, Pedro J Caraballo, Konstantinos N Lazaridis, Eric Venner, Xiang Qin, Jianhong Hu, Christie L Kovar, Viktoriya Korchina, Kimberly Walker, Harshavardhan Doddapaneni, Tsung-Jung Wu, Ritika Raj, Shawn Denson, Wen Liu, Gauthami Chandanavelli, Lan Zhang, Qiaoyan Wang, Divya Kalra, Mary Beth Karow, Kimberley J Harris, Hugues Sicotte, Sandra E Peterson, Amy E Barthel, Brenda E Moore, Jennifer M Skierka, Michelle L Kluge, Katrina E Kotzer, Karen Kloke, Jessica M Vander Pol, Heather Marker, Joseph A Sutton, Adrijana Kekic, Ashley Ebenhoh, Dennis M Bierle, Michael J Schuh, Christopher Grilli, Sara Erickson, Audrey Umbreit, Leah Ward, Sheena Crosby, Eric A Nelson, Sharon Levey, Michelle Elliott, Steve G Peters, Naveen Pereira, Mark Frye, Fadi Shamoun, Matthew P Goetz, Iftikhar J Kullo, Robert Wermers, Jan A Anderson, Christine M Formea, Razan M El Melik, John D Zeuli, Joseph R Herges, Carrie A Krieger, Robert W Hoel, Jodi L Taraba, Scott R St Thomas, Imad Absah, Matthew E Bernard, Stephanie R Fink, Andrea Gossard, Pamela L Grubbs, Therese M Jacobson, Paul Takahashi, Sharon C Zehe, Susan Buckles, Michelle Bumgardner, Colette Gallagher, Kelliann Fee-Schroeder, Nichole R Nicholas, Melody L Powers, Ahmed K Ragab, Darcy M Richardson, Anthony Stai, Jaymi Wilson, Joel E Pacyna, Janet E Olson, Erica J Sutton, Annika T Beck, Caroline Horrow, Krishna R Kalari, Nicholas B Larson, Hongfang Liu, Liwei Wang, Guilherme S Lopes, Bijan J Borah, Robert R Freimuth, Ye Zhu, Debra J Jacobson, Matthew A Hathcock, Sebastian M Armasu, Michaela E Mcgree, Ruoxiang Jiang, Tyler H Koep, Jason L Ross, Matthew G Hilden, Kathleen Bosse, Bronwyn Ramey, Isabelle Searcy, Eric Boerwinkle, Richard A Gibbs, Richard M Weinshilboum

Faculty, Staff and Student Publications

PURPOSE: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping.

METHODS: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 …

Genetic Correlates In Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated With Hyper-Cvad Plus Dasatinib Or Ponatinib, Yuya Sasaki, Hagop M Kantarjian, Nicholas J Short, Feng Wang, Ken Furudate, Hidetaka Uryu, Rebecca Garris, Nitin Jain, Koji Sasaki, Farhad Ravandi, Marina Konopleva, Guillermo Garcia-Manero, Latasha Little, Curtis Gumbs, Li Zhao, P Andrew Futreal, Koichi Takahashi, Elias Jabbour

Faculty, Staff and Student Publications

Recurring genetic abnormalities have been identified in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Among them, IKZF1 deletion was associated with poor prognosis in patients treated with imatinib-based or dasatinib-based regimens. However, the molecular determinants for clinical outcomes in ponatinib-treated patients remain unknown. We systematically analyzed genetic alterations in adults with Ph-positive ALL uniformly treated in clinical trials with dasatinib-based regimens or a ponatinib-based regimen and investigated the molecular determinants for treatment outcomes using pretreatment specimens collected from adults with Ph-positive ALL treated with Hyper-CVAD plus dasatinib or ponatinib. DNA sequencing and SNP microarray were performed and recurrent genetic abnormalities …

Molecular, Histological, And Clinical Characteristics Of Oligodendrogliomas: A Multi-Institutional Retrospective Study, Antonio Dono, Kristin Alfaro-Munoz, Yuanqing Yan, Carlos A Lopez-Garcia, Zaid Soomro, Garret Williford, Takeshi Takayasu, Lindsay Robell, Nazanin K Majd, John De Groot, Yoshua Esquenazi, Carlos Kamiya-Matsuoka, Leomar Y Ballester

Faculty, Staff and Student Publications

Background: Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and 1p/19q-codeleted molecular oligodendrogliomas (mODG). However, factors that affect prognosis in mODG have not been thoroughly studied. In addition, the benefits of adjuvant radiation and temozolomide (TMZ) in mODGs remain to be determined.

Objective: To evaluate the role of PIK3CA mutations in mODGs.

Methods: One hundred seven mODGs (2008-2019) diagnosed at 2 institutions were included. A retrospective review of clinical characteristics, molecular alterations, treatments, and outcomes was performed.

Results: The median age was 37 years, and 61 patients (57%) were male. …

Ovarian Cancer Reporting Lexicon For Computed Tomography (Ct) And Magnetic Resonance (Mr) Imaging Developed By The Sar Uterine And Ovarian Cancer Disease-Focused Panel And The Esur Female Pelvic Imaging Working Group, Atul B Shinagare, Elizabeth A Sadowski, Hyesun Park, Olga R Brook, Rosemarie Forstner, Sumer K Wallace, Jeanne M Horowitz, Neil Horowitz, Marcia Javitt, Priyanka Jha, Aki Kido, Yulia Lakhman, Susanna I Lee, Lucia Manganaro, Katherine E Maturen, Stephanie Nougaret, Liina Poder, Gaiane M Rauch, Caroline Reinhold, Evis Sala, Isabelle Thomassin-Naggara, Herbert Alberto Vargas, Aradhana Venkatesan, Olivera Nikolic, Andrea G Rockall

Faculty, Staff and Student Publications

Objectives: Imaging evaluation is an essential part of treatment planning for patients with ovarian cancer. Variation in the terminology used for describing ovarian cancer on computed tomography (CT) and magnetic resonance (MR) imaging can lead to ambiguity and inconsistency in clinical radiology reports. The aim of this collaborative project between Society of Abdominal Radiology (SAR) Uterine and Ovarian Cancer (UOC) Disease-focused Panel (DFP) and the European Society of Uroradiology (ESUR) Female Pelvic Imaging (FPI) Working Group was to develop an ovarian cancer reporting lexicon for CT and MR imaging.

Methods: Twenty-one members of the SAR UOC DFP and ESUR FPI …

Rhoa-Rock Competes With Yap To Regulate Amoeboid Breast Cancer Cell Migration In Response To Lymphatic-Like Flow, Amina Mohammadalipour, Miguel F Diaz, Megan Livingston, Adesuwa Ewere, Allen Zhou, Paulina D Horton, Loretta T Olamigoke, John M Lamar, John P Hagan, Hyun J Lee, Pamela L Wenzel

Faculty, Staff and Student Publications

Lymphatic drainage generates force that induces prostate cancer cell motility via activation of Yes-associated protein (YAP), but whether this response to fluid force is conserved across cancer types is unclear. Here, we show that shear stress corresponding to fluid flow in the initial lymphatics modifies taxis in breast cancer, whereas some cell lines use rapid amoeboid migration behavior in response to fluid flow, a separate subset decrease movement. Positive responders displayed transcriptional profiles characteristic of an amoeboid cell state, which is typical of cells advancing at the edges of neoplastic tumors. Regulation of the HIPPO tumor suppressor pathway and YAP …

The Microrna-183/96/182 Cluster Inhibits Lung Cancer Progression And Metastasis By Inducing An Interleukin-2-Mediated Antitumor Cd8+ Cytotoxic T-Cell Response, Samrat T Kundu, B Leticia Rodriguez, Laura A Gibson, Amanda N Warner, Mabel G Perez, Rakhee Bajaj, Jared J Fradette, Caleb A Class, Luisa M Solis, Frank R Rojas Alvarez, Ignacio I Wistuba, Lixia Diao, Fengju Chen, Mohit Sachdeva, Jing Wang, David G Kirsch, Chad J Creighton, Don L Gibbons

Faculty, Staff and Student Publications

Here, Kundu et al. investigated the role of the microRNA-183/96/182 cluster (m96cl) in lung cancer and used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of K-Ras mutant autochthonous lung adenocarcinomas. Overall, the authors identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.