Biomedical Informatics Commons^™

Integrative Multi-Omics Analyses To Identify The Genetic And Functional Mechanisms Underlying Ovarian Cancer Risk Regions, Eileen O Dareng, Simon G Coetzee, Jonathan P Tyrer, Pei-Chen Peng, Will Rosenow, Stephanie Chen, Brian D Davis, Felipe Segato Dezem, Ji-Heui Seo, Robbin Nameki, Alberto L Reyes, Katja K H Aben, Hoda Anton-Culver, Natalia N Antonenkova, Gerasimos Aravantinos, Elisa V Bandera, Laura E Beane Freeman, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Marcus Q Bernardini, Line Bjorge, Amanda Black, Natalia V Bogdanova, Kelly L Bolton, James D Brenton, Agnieszka Budzilowska, Ralf Butzow, Hui Cai, Ian Campbell, Rikki Cannioto, Jenny Chang-Claude, Stephen J Chanock, Kexin Chen, Georgia Chenevix-Trench, Aocs Group, Yoke-Eng Chiew, Linda S Cook, Anna Defazio, Joe Dennis, Jennifer A Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana M Eccles, Gabrielle Ene, Peter A Fasching, James M Flanagan, Renée T Fortner, Florentia Fostira, Aleksandra Gentry-Maharaj, Graham G Giles, Marc T Goodman, Jacek Gronwald, Christopher A Haiman, Niclas Håkansson, Florian Heitz, Michelle A T Hildebrandt, Estrid Høgdall, Claus K Høgdall, Ruea-Yea Huang, Allan Jensen, Michael E Jones, Daehee Kang, Beth Y Karlan, Anthony N Karnezis, Linda E Kelemen, Catherine J Kennedy, Elza K Khusnutdinova, Lambertus A Kiemeney, Susanne K Kjaer, Jolanta Kupryjanczyk, Marilyne Labrie, Diether Lambrechts, Melissa C Larson, Nhu D Le, Jenny Lester, Lian Li, Jan Lubiński, Michael Lush, Jeffrey R Marks, Keitaro Matsuo, Taymaa May, John R Mclaughlin, Iain A Mcneish, Usha Menon, Stacey Missmer, Francesmary Modugno, Melissa Moffitt, Alvaro N Monteiro, Kirsten B Moysich, Steven A Narod, Tu Nguyen-Dumont, Kunle Odunsi, Håkan Olsson, N Charlotte Onland-Moret, Sue K Park, Tanja Pejovic, Jennifer B Permuth, Anna Piskorz, Darya Prokofyeva, Marjorie J Riggan, Harvey A Risch, Cristina Rodríguez-Antona, Mary Anne Rossing, Dale P Sandler, V Wendy Setiawan, Kang Shan, Honglin Song, Melissa C Southey, Helen Steed, Rebecca Sutphen, Anthony J Swerdlow, Soo Hwang Teo, Kathryn L Terry, Pamela J Thompson, Liv Cecilie Vestrheim Thomsen, Linda Titus, Britton Trabert, Ruth Travis, Shelley S Tworoger, Ellen Valen, Els Van Nieuwenhuysen, Digna Velez Edwards, Robert A Vierkant, Penelope M Webb, Opal Study Group, Clarice R Weinberg, Rayna Matsuno Weise, Nicolas Wentzensen, Emily White, Stacey J Winham, Alicja Wolk, Yin-Ling Woo, Anna H Wu, Li Yan, Drakoulis Yannoukakos, Nur Zeinomar, Wei Zheng, Argyrios Ziogas, Andrew Berchuck, Ellen L Goode, David G Huntsman, Celeste L Pearce, Susan J Ramus, Thomas A Sellers, Ovarian Cancer Association Consortium (Ocac), Matthew L Freedman, Kate Lawrenson, Joellen M Schildkraut, Dennis Hazelett, Jasmine T Plummer, Siddhartha Kar, Michelle R Jones, Paul D P Pharoah, Simon A Gayther

Faculty, Staff and Student Publications

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value < 5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value < 10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate < 0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Primary Cytoreduction And Survival For Patients With Less-Common Epithelial Ovarian Cancer, Koji Matsuo, Ling Chen, Maximilian Klar, Lynda D Roman, Anil K Sood, David M Gershenson, Jason D Wright

Faculty, Staff and Student Publications

This cohort study examines the association between primary cytoreduction status and survival for patients with less-common, advanced-stage epithelial ovarian carcinoma.

Development Of A Novel Comprehensive Hepatocellular Carcinoma Outcome Prognostic Scoring System With Integration Of Imaging Features, Hop S Tran Cao, Russell G Witt, Khaled M Elsayes, Ali A Baiomy, Lianchun Xiao, Sarah Palmquist, Sunyoung S Lee, Yehia I Mohamed, Armeen Mahvash, Ching-Wei D Tzeng, Yun Shin Chun, Eugene Jon Koay, Asif Rashid, Manal M Hassan, James C Yao, Jean-Nicolas Vauthey, Ahmed O Kaseb

Faculty, Staff and Student Publications

Background: Accurate prognostic stratification of hepatocellular carcinoma (HCC) is vital for clinical trial enrollment and treatment allocation. Multiple scoring systems have been created to predict patient survival, but no standardized scoring systems account for radiologic tumor features. We sought to create a generalizable scoring system for HCC which incorporates standardized radiologic tumor features and more accurately predicts overall survival (OS) than established systems.

Methods: Clinicopathologic parameters were collected from a prospectively collected cohort of patients with HCC treated at a single institution. Imaging studies were evaluated for tumor characteristics. Patients were randomly divided into a training set for identification of …

Risk-Benefit Trade-Offs And Precision Utilities In Phase I-Ii Clinical Trials, Pavlos Msaouel, Juhee Lee, Peter F Thall

Faculty, Staff and Student Publications

Background: Identifying optimal doses in early-phase clinical trials is critically important. Therapies administered at doses that are either unsafe or biologically ineffective are unlikely to be successful in subsequent clinical trials or to obtain regulatory approval. Identifying appropriate doses for new agents is a complex process that involves balancing the risks and benefits of outcomes such as biological efficacy, toxicity, and patient quality of life.

Purpose: While conventional phase I trials rely solely on toxicity to determine doses, phase I-II trials explicitly account for both efficacy and toxicity, which enables them to identify doses that provide the most favorable risk-benefit …

Plasmacytoid Urothelial Carcinoma Of The Urinary Bladder-A Clinicopathological And Molecular Analysis Of 52 Cases, Lan Zheng, Hui Chen, Jianping Zhao, Sinchita Roy-Chowdhuri, Ashish M Kamat, Omar Alhalabi, Jianjun Gao, Arlene Siefker-Radtke, Donna E Hansel, Bogdan Czerniak, Charles C Guo

Faculty, Staff and Student Publications

Plasmacytoid urothelial carcinoma (UC) is a rare histologic subtype of bladder cancer that is associated with an aggressive clinical behavior. We analyzed the clinicopathologic and molecular features of plasmacytoid UC in 52 patients from a single institute. The patients included 44 men and 8 women, with a mean age of 64 years (range, 41-91 years). All bladder cancers were high-grade UC, and plasmacytoid component accounted for a mean of 47% of bladder tumors (range, 5-100%). Distinct gene mutations were found in most plasmacytoid UCs (n = 49); the most common mutations were TP53 (n = 30), followed by TERT (n …

Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation In Unresectable Egfr-Mutant Nsclc: A Multicenter Retrospective Cohort Study, Amin H Nassar, So Yeon Kim, Jacqueline V Aredo, Jamie Feng, Frances Shepherd, Chao Xu, David Kaldas, Jhanelle E Gray, Thomas J Dilling, Joel W Neal, Heather A Wakelee, Yufei Liu, Steven H Lin, Tariq Abuali, Arya Amini, Yunan Nie, Tejas Patil, Anastasiya Lobachov, Jair Bar, Bailey Fitzgerald, Yu Fujiwara, Thomas U Marron, Rohit Thummalapalli, Helena Yu, Dwight H Owen, John Sharp, Saira Farid, Pedro Rocha, Edurne Arriola, Angelica D'Aiello, Haiying Cheng, Ryan Whitaker, Kaushal Parikh, Yash Ashara, Luxi Chen, Kamya Sankar, Jeremy P Harris, Misako Nagasaka, Adanma Ayanambakkam, Ana I Velazquez, Meera Ragavan, Jessica J Lin, Zofia Piotrowska, Molly Wilgucki, Joshua Reuss, Heike Luders, Christian Grohe, Javier Baena Espinar, Ella Feiner, Salman R Punekar, Shruti Gupta, Ticiana Leal, David J Kwiatkowski, Raymond H Mak, Elio Adib, Abdul Rafeh Naqash, Sarah B Goldberg

Faculty, Staff and Student Publications

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.

Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology …

Immune Infiltration At The Primary Tumor Is Associated With Clinical Outcome Of Patients With Extranodal Extension Of Lymph Node Metastasis In Oral Cancer, Chieko Michikawa, Frederico O Gleber-Netto, Curtis R Pickering, Xiayu Rao, Jing Wang, Andrew G Sikora, Jeffrey N Myers, Mitchell J Frederick

Faculty, Staff and Student Publications

Background: Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown.

Methods: We identified 234 human papillomavirus-negative (HPV-) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival.

Results: Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The …

Impact Of Renal Cell Carcinoma Molecular Subtypes On Immunotherapy And Targeted Therapy Outcomes, Renée Maria Saliby, Chris Labaki, Tejas R Jammihal, Wanling Xie, Maxine Sun, Valisha Shah, Eddy Saad, M Harry Kane, Soki Kashima, Katherine Sadak, Talal El Zarif, Deepak Poduval, Robert J Motzer, Thomas Powles, Brian I Rini, Laurence Albiges, Sumanta K Pal, Bradley A Mcgregor, Rana R Mckay, Sabina Signoretti, Eliezer M Van Allen, Sachet A Shukla, Toni K Choueiri, David A Braun

Faculty, Staff and Student Publications

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.

Focal Adhesion Kinase-Yap Signaling Axis Drives Drug-Tolerant Persister Cells And Residual Disease In Lung Cancer, Franziska Haderk, Yu-Ting Chou, Lauren Cech, Celia Fernández-Méndez, Johnny Yu, Victor Olivas, Ismail M Meraz, Dora Barbosa Rabago, D Lucas Kerr, Carlos Gomez, David V Allegakoen, Juan Guan, Khyati N Shah, Kari A Herrington, Oghenekevwe M Gbenedio, Shigeki Nanjo, Mourad Majidi, Whitney Tamaki, Yashar K Pourmoghadam, Julia K Rotow, Caroline E Mccoach, Jonathan W Riess, J Silvio Gutkind, Tracy T Tang, Leonard Post, Bo Huang, Pilar Santisteban, Hani Goodarzi, Sourav Bandyopadhyay, Calvin J Kuo, Jeroen P Roose, Wei Wu, Collin M Blakely, Jack A Roth, Trever G Bivona

Faculty, Staff and Student Publications

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling …

Treatment Outcomes In Patients With Metastatic Renal Cell Carcinoma With Sarcomatoid And/Or Rhabdoid Dedifferentiation After Progression On Immune Checkpoint Therapy, Andrew W Hahn, Devaki Shilpa Surasi, Paul V Viscuse, Tharakeswara K Bathala, Andrew J Wiele, Matthew T Campbell, Amado J Zurita, Amishi Y Shah, Eric Jonasch, Jianjun Gao, Sangeeta Goswami, Omar Alhalabi, Priya Rao, Kanishka Sircar, Nizar M Tannir, Pavlos Msaouel

Faculty, Staff and Student Publications

BACKGROUND: Metastatic RCC with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is an aggressive disease associated with improved response to immune checkpoint therapy (ICT). The outcomes of patients treated with VEGFR-targeted therapies (TT) following ICT progression have not been investigated.

PATIENTS AND METHODS: Retrospective review of 57 patients with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (S + R) dedifferentiation who received any TT after progression on ICT at an academic cancer center. Clinical endpoints of interest included time on TT, overall survival (OS) from initiation of TT, and objective response rate (ORR) by RECIST version 1.1. Multivariable models adjusted for …

Neoadjuvant Chemoimmunotherapy For Nsclc: A Systematic Review And Meta-Analysis, Mark Sorin, Connor Prosty, Louis Ghaleb, Kathy Nie, Khaled Katergi, Muhammad H Shahzad, Laurie-Rose Dubé, Aline Atallah, Anikka Swaby, Matthew Dankner, Trafford Crump, Logan A Walsh, Pierre O Fiset, Boris Sepesi, Patrick M Forde, Tina Cascone, Mariano Provencio, Jonathan D Spicer

Faculty, Staff and Student Publications

IMPORTANCE: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%.

OBJECTIVE: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials.

DATA SOURCES: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of …

A Randomized Trial Of Two Remote Health Care Delivery Models On The Uptake Of Genetic Testing And Impact On Patient-Reported Psychological Outcomes In Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, And Testing (Generate) Study, Nicolette J Rodriguez, C Sloane Furniss, Matthew B Yurgelun, Chinedu Ukaegbu, Pamela E Constantinou, Ileana Fortes, Alyson Caruso, Alison N Schwartz, Jill E Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott H Nelson, Sydney Okumura, Alicia Y Zhou, Tara B Coffin, Hajime Uno, Miki Horiguchi, Allyson J Ocean, Florencia Mcallister, Andrew M Lowy, Alison P Klein, Lisa Madlensky, Gloria M Petersen, Judy E Garber, Scott M Lippman, Michael G Goggins, Anirban Maitra, Sapna Syngal

Faculty, Staff and Student Publications

Background & aims: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes.

Methods: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session …

Survival Disparities In Non-Hispanic Black And White Cervical Cancer Patients Vary By Histology And Are Largely Explained By Modifiable Factors, Calen W Kucera, Nicole P Chappell, Chunqiao Tian, Michael T Richardson, Christopher M Tarney, Chad A Hamilton, John K Chan, Daniel S Kapp, Charles A Leath, Yovanni Casablanca, Christine Rojas, Collin A Sitler, Lari Wenzel, Ann Klopp, Nathaniel L Jones, Rodney P Rocconi, John H Farley, Timothy D O'Connor, Craig D Shriver, Nicholas W Bateman, Thomas P Conrads, Neil T Phippen, G Larry Maxwell, Kathleen M Darcy

Faculty, Staff and Student Publications

Purpose: We investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities.

Methods: Non-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma …

Clinical And Prognostic Differences In Oropharyngeal Squamous Cell Carcinoma In Usa And Denmark, Two Hpv High-Prevalence Areas, Amanda-Louise Fenger Carlander, Simone Kloch Bendtsen, Jacob H Rasmussen, Kathrine Kronberg Jakobsen, Martin Garset-Zamani, Christian Grønhøj, Jeppe Friborg, Katherine Hutcheson, Faye M Johnson, Clifton D Fuller, Amy C Moreno, Toyin Babarinde, Neil D Gross, Jeffrey N Myers, Christian Von Buchwald

Faculty, Staff and Student Publications

BACKGROUND: Uncertainty persists regarding clinical and treatment variations crucial to consider when comparing high human papillomavirus (HPV)-prevalence oropharyngeal squamous cell carcinoma (OPSCC) cohorts for accurate patient stratification and replicability of clinical trials across different geographical areas.

METHODS: OPSCC patients were included from The University of Texas MD Anderson Cancer Center (UTMDACC), USA and from The University Hospital of Copenhagen, Denmark from 2015-2020, (n = 2484). Outcomes were 3-year overall survival (OS) and recurrence-free interval (RFI). Subgroup analyses were made for low-risk OPSCC patients (T1-2N0M0) and high-risk patients (UICC8 III-IV).

RESULTS: There were significantly more HPV-positive (88.2 % vs. 63.1 %), …

Artificial Intelligence-Powered Assessment Of Pathologic Response To Neoadjuvant Atezolizumab In Patients With Nsclc: Results From The Lcmc3 Study, Sanja Dacic, William D Travis, Jennifer M Giltnane, Filip Kos, John Abel, Stephanie Hilz, Junya Fujimoto, Lynette Sholl, Jon Ritter, Farah Khalil, Yi Liu, Amaro Taylor-Weiner, Murray Resnick, Hui Yu, Fred R Hirsch, Paul A Bunn, David P Carbone, Valerie Rusch, David J Kwiatkowski, Bruce E Johnson, Jay M Lee, Stephanie R Hennek, Ilan Wapinski, Alan Nicholas, Ann Johnson, Katja Schulze, Mark G Kris, Ignacio I Wistuba

Faculty, Staff and Student Publications

Introduction: Pathologic response (PathR) by histopathologic assessment of resected specimens may be an early clinical end point associated with long-term outcomes with neoadjuvant therapy. Digital pathology may improve the efficiency and precision of PathR assessment. LCMC3 (NCT02927301) evaluated neoadjuvant atezolizumab in patients with resectable NSCLC and reported a 20% major PathR rate.

Methods: We determined PathR in primary tumor resection specimens using guidelines-based visual techniques and developed a convolutional neural network model using the same criteria to digitally measure the percent viable tumor on whole-slide images. Concordance was evaluated between visual determination of percent viable tumor (n = …

Pathological Response In Resectable Non-Small Cell Lung Cancer: A Systematic Literature Review And Meta-Analysis, Nathalie A Waser, Melanie Quintana, Bernd Schweikert, Jamie E Chaft, Lindsay Berry, Ahmed Adam, Lien Vo, John R Penrod, Joseph Fiore, Donald A Berry, Sarah Goring

Faculty, Staff and Student Publications

BACKGROUND: Surrogate endpoints for overall survival in patients with resectable non-small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study's main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival.

METHODS: A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non-small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard …

Multi-Omics Analysis Reveals Immune Features Associated With Immunotherapy Benefit In Patients With Squamous Cell Lung Cancer From Phase Iii Lung-Map S1400i Trial, Edwin Roger Parra, Jiexin Zhang, Dzifa Yawa Duose, Edgar Gonzalez-Kozlova, Mary W Redman, Hong Chen, Ganiraju C Manyam, Gayatri Kumar, Jianhua Zhang, Xingzhi Song, Rossana Lazcano, Mario L Marques-Piubelli, Caddie Laberiano-Fernandez, Frank Rojas, Baili Zhang, Len Taing, Aashna Jhaveri, Jacob Geisberg, Jennifer Altreuter, Franziska Michor, James Provencher, Joyce Yu, Ethan Cerami, Radim Moravec, Kasthuri Kannan, Rajyalakshmi Luthra, Gheath Alatrash, Hsin-Hui Huang, Hui Xie, Manishkumar Patel, Kai Nie, Jocelyn Harris, Kimberly Argueta, James Lindsay, Roshni Biswas, Stephen Van Nostrand, Seunghee Kim-Schulze, Jhanelle E Gray, Roy S Herbst, Ignacio I Wistuba, Scott Gettinger, Karen Kelly, Lyudmila Bazhenova, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Cara Haymaker

Faculty, Staff and Student Publications

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need.

EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink.

RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse …

Vhl Governs M6a Modification And Pik3r3 Mrna Stability In Clear Cell Renal Cell Carcinomas, Hyemin Lee, Li Zhuang, Boyi Gan

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N6-Methyladenosine (m6A), a prevalent posttranscriptional modification, plays an important role in cancer progression. Clear cell renal cell carcinoma (ccRCC) is chiefly associated with the loss of the von Hippel-Lindau (VHL) gene, encoding a component of the E3 ubiquitin ligase complex. In this issue of the JCI, Zhang and colleagues unveiled a function of VHL beyond its canonical role as an E3 ubiquitin ligase in regulating hypoxia-inducible factors (HIFs). It also governed m6A modification by orchestrating the assembly of m6A writer proteins METTL3 and METTL14, thereby stabilizing PIK3R3 mRNA. Mechanistically, PIK3R3 contributed to p85 ubiquitination, which restrained PI3K/AKT signaling and consequently …

Enhancing Nsclc Recurrence Prediction With Pet/Ct Habitat Imaging, Ctdna, And Integrative Radiogenomics-Blood Insights, Sheeba J Sujit, Muhammad Aminu, Tatiana V Karpinets, Pingjun Chen, Maliazurina B Saad, Morteza Salehjahromi, John D Boom, Mohamed Qayati, James M George, Haley Allen, Mara B Antonoff, Lingzhi Hong, Xin Hu, Simon Heeke, Hai T Tran, Xiuning Le, Yasir Y Elamin, Mehmet Altan, Natalie I Vokes, Ajay Sheshadri, Julie Lin, Jianhua Zhang, Yang Lu, Carmen Behrens, Myrna C B Godoy, Carol C Wu, Joe Y Chang, Caroline Chung, David A Jaffray, Ignacio I Wistuba, J Jack Lee, Ara A Vaporciyan, Don L Gibbons, John Heymach, Jianjun Zhang, Tina Cascone, Jia Wu

Faculty, Staff and Student Publications

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these …

Nardilysin-Regulated Scission Mechanism Activates Polo-Like Kinase 3 To Suppress The Development Of Pancreatic Cancer, Jie Fu, Jianhua Ling, Ching-Fei Li, Chi-Lin Tsai, Wenjuan Yin, Junwei Hou, Ping Chen, Yu Cao, Ya'an Kang, Yichen Sun, Xianghou Xia, Zhou Jiang, Kenei Furukawa, Yu Lu, Min Wu, Qian Huang, Jun Yao, David H Hawke, Bih-Fang Pan, Jun Zhao, Jiaxing Huang, Huamin Wang, E I Mustapha Bahassi, Peter J Stambrook, Peng Huang, Jason B Fleming, Anirban Maitra, John A Tainer, Mien-Chie Hung, Chunru Lin, Paul J Chiao

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find …

Application Of Deep Learning On Mammographies To Discriminate Between Low And High-Risk Dcis For Patient Participation In Active Surveillance Trials, Sena Alaeikhanehshir, Madelon M Voets, Frederieke H Van Duijnhoven, Esther H Lips, Emma J Groen, Marja C J Van Oirsouw, Shelley E Hwang, Joseph Y Lo, Jelle Wesseling, Ritse M Mann, Jonas Teuwen

Faculty, Staff and Student Publications

BACKGROUND: Ductal Carcinoma In Situ (DCIS) can progress to invasive breast cancer, but most DCIS lesions never will. Therefore, four clinical trials (COMET, LORIS, LORETTA, AND LORD) test whether active surveillance for women with low-risk Ductal carcinoma In Situ is safe (E. S. Hwang et al., BMJ Open, 9: e026797, 2019, A. Francis et al., Eur J Cancer. 51: 2296-2303, 2015, Chizuko Kanbayashi et al. The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA), L. E. Elshof et al., Eur J Cancer, 51, 1497-510, 2015). Low-risk is defined as grade I or II DCIS. Because …

Targeting Branched N-Glycans And Fucosylation Sensitizes Ovarian Tumors To Immune Checkpoint Blockade, Hao Nie, Pratima Saini, Taito Miyamoto, Liping Liao, Rafal J Zielinski, Heng Liu, Wei Zhou, Chen Wang, Brennah Murphy, Martina Towers, Tyler Yang, Yuan Qi, Toshitha Kannan, Andrew Kossenkov, Hiroaki Tateno, Daniel T Claiborne, Nan Zhang, Mohamed Abdel-Mohsen, Rugang Zhang

Faculty, Staff and Student Publications

Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their …

Druggable Site Near The Upper Vestibule Determines The High Affinity And P2x3 Homotrimer Selectivity Of Sivopixant/S-600918 And Its Analogue Ddtpa, Dong-Ping Wang, Meng Zhang, Ming Li, Xiao-Na Yang, Changzhu Li, Peng Cao, Michael X Zhu, Yun Tian, Ye Yu, Yun-Tao Lei

Faculty, Staff and Student Publications

Background and purpose: The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF-219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S-600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3-(4-([3-chloro-4-isopropoxyphenyl]amino)-3-(4-methylbenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)propanoic acid (DDTPA), exhibit both high affinity …

Delta Radiomic Features Predict Resection Margin Status And Overall Survival In Neoadjuvant-Treated Pancreatic Cancer Patients, Kai Wang, John D Karalis, Ahmed Elamir, Alessandro Bifolco, Megan Wachsmann, Giovanni Capretti, Paola Spaggiari, Sebastian Enrico, Kishore Balasubramanian, Nafeesah Fatimah, Giada Pontecorvi, Martina Nebbia, Adam Yopp, Ravi Kaza, Ivan Pedrosa, Herbert Zeh, Patricio Polanco, Alessandro Zerbi, Jing Wang, Todd Aguilera, Matteo Ligorio

Faculty, Staff and Student Publications

Background: Neoadjuvant therapy (NAT) emerged as the standard of care for patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgery; however, surgery is morbid, and tools to predict resection margin status (RMS) and prognosis in the preoperative setting are needed. Radiomic models, specifically delta radiomic features (DRFs), may provide insight into treatment dynamics to improve preoperative predictions.

Methods: We retrospectively collected clinical, pathological, and surgical data (patients with resectable, borderline, locally advanced, and metastatic disease), and pre/post-NAT contrast-enhanced computed tomography (CT) scans from PDAC patients at the University of Texas Southwestern Medical Center (UTSW; discovery) and Humanitas Hospital (validation cohort). …

Survival Outcomes And Toxicity Of Adjuvant Immunotherapy After Definitive Concurrent Chemotherapy With Proton Beam Radiation Therapy For Patients With Inoperable Locally Advanced Non-Small Cell Lung Carcinoma, Kelsey L Corrigan, Ting Xu, Yuki Sasaki, Ruitao Lin, Aileen B Chen, James W Welsh, Steven H Lin, Joe Y Chang, Matthew S Ning, Saumil Gandhi, Michael S O'Reilly, Carl M Gay, Mehmet Altan, Charles Lu, Tina Cascone, Efstratios Koutroumpakis, Ajay Sheshadri, Xiaodong Zhang, Li Liao, X Ronald Zhu, John V Heymach, Quynh-Nhu Nguyen, Zhongxing Liao

Faculty, Staff and Student Publications

Introduction: Adjuvant immunotherapy (IO) following concurrent chemotherapy and photon radiation therapy confers an overall survival (OS) benefit for patients with inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC); however, outcomes of adjuvant IO after concurrent chemotherapy with proton beam therapy (CPBT) are unknown. We investigated OS and toxicity after CPBT with adjuvant IO versus CPBT alone for inoperable LA-NSCLC.

Materials and methods: We analyzed 354 patients with LA-NSCLC who were prospectively treated with CPBT with or without adjuvant IO from 2009 to 2021. Optimal variable ratio propensity score matching (PSM) matched CPBT with CPBT + IO patients. Survival was estimated …

Trajectories Of Health Care Contact Days For Patients With Stage Iv Non-Small Cell Lung Cancer, Arjun Gupta, Paul Nguyen, Danielle Kain, Andrew G Robinson, Amit A Kulkarni, David H Johnson, Carolyn J Presley, Anne H Blaes, Gabrielle B Rocque, Ishani Ganguli, Christopher M Booth, Timothy P Hanna

Faculty, Staff and Student Publications

Importance: Patients with stage IV non-small cell lung cancer (NSCLC) experience substantial morbidity and mortality. Contact days (ie, the number of days with health care contact outside the home) measure how much of a person's life is consumed by health care, yet little is known about patterns of contact days for patients with NSCLC.

Objective: To describe the trajectories of contact days in patients with stage IV NSCLC and how trajectories vary by receipt of cancer-directed treatment in routine practice.

Design, setting, and participants: A retrospective, population-based decedent cohort study was conducted in Ontario, Canada. Participants included adults aged 20 …

Clinical Management, Monitoring, And Prophylaxis Of Adverse Events Of Special Interest Associated With Datopotamab Deruxtecan, Rebecca S Heist, Jacob Sands, Aditya Bardia, Toshio Shimizu, Aaron Lisberg, Ian Krop, Noboru Yamamoto, Takahiro Kogawa, Saba Al-Hashimi, Simon S M Fung, Anat Galor, Francesca Pisetzky, Priyanka Basak, Cindy Lau, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in …

Surgical Outcomes After Chemotherapy Plus Nivolumab And Chemotherapy Plus Nivolumab And Ipilimumab In Patients With Non-Small Cell Lung Cancer, Hope Feldman, Boris Sepesi, Cheuk H Leung, Heather Lin, Annikka Weissferdt, Apar Pataer, William N William, Garrett L Walsh, David C Rice, Jack A Roth, Reza J Mehran, Wayne L Hofstetter, Mara B Antonoff, Ravi Rajaram, Don L Gibbons, J Jack Lee, John V Heymach, Ara A Vaporciyan, Stephen G Swisher, Tina Cascone

Faculty, Staff and Student Publications

Objective: Chemotherapy plus nivolumab is the standard of care neoadjuvant treatment for patients with resectable stage IB to IIIA non-small cell lung cancer. The influence of dual checkpoint blockade with chemotherapy on surgical outcomes remains unknown. We aimed to determine operative complexity and perioperative outcomes associated with neoadjuvant chemotherapy and nivolumab with or without ipilimumab.

Methods: A total of 44 patients with stage IB (≥4 cm) to IIIA non-small cell lung cancer were treated on sequential platform arms of the NEOSTAR trial. A total of 22 patients were treated with nivolumab + chemotherapy, and 22 patients were treated with ipilimumab …

Neuroendocrine Neoplasms Of The Ovary: A Review Of 63 Cases, Alejandra Flores Legarreta, Reem Saab, Naomi R Gonzales, Gary B Chisholm, Shannon N Westin, R Tyler Hillman, Michael Frumovitz

Faculty, Staff and Student Publications

Objective: To describe the clinicopathological characteristics and survival outcomes of ovarian neuroendocrine neoplasms from a curated registry.

Methods: This is a retrospective cross-sectional study of patients in our registry with confirmed ovarian neuroendocrine neoplasms. We excluded patients with small cell carcinoma not otherwise specified, small cell hypercalcemic type, and those with neuroendocrine 'features' or 'differentiation.' Clinicopathological characteristics were described in two separate groups: patients with carcinoid tumors and patients with neuroendocrine carcinomas. Progression-free and overall survival were estimated with the Kaplan-Meier product-limit estimator in these two groups, and multivariable analysis was done to identify predictors of survival for neuroendocrine carcinomas …

Prognostic Value Of Tumor Volume Doubling Time In Lung-Metastatic Adenoid Cystic Carcinoma, Eduardo A Dal Lago, Luana G Sousa, Zixi Yang, Camilla O Hoff, Flavia Bonini, Matthew Sawyer, Kaiwen Wang, Whitney Lewis, Kareem A Wahid, Ehab Y Hanna, Adel El-Naggar, Clifton D Fuller, Suprateek Kundu, Myrna Godoy, Renata Ferrarotto

Faculty, Staff and Student Publications

Objectives: Lung metastases in adenoid cystic carcinoma (ACC) usually have indolent growth and the optimal timing to start systemic therapy is not established. We assessed ACC lung metastasis tumor growth dynamics and compared the prognostic value of time to progression (TTP) and tumor volume doubling time (TVDT).

Methods: The study included ACC patients with ≥1 pulmonary metastasis (≥5 mm) and at least 2 chest computed tomography scans. Radiology assessment was performed from the first scan showing metastasis until treatment initiation or death. Up to 5 lung nodules per patient were segmented for TVDT calculation. To assess tumor growth rate (TGR), …