Medical Specialties Commons^™

Comparative Performance Of Predictive Nomograms For Pathological Upstaging In Clinical T1 Renal Masses: An Independent External Validation, Michael Vainrib, Amos Neheman, Omri Schwarztuch Gildor

Faculty, Staff and Students Publications

Background: Preoperative identification of pathological upstaging (≥ pT3a) in clinical T1 (cT1) renal masses is critical for surgical planning. We externally validated three established predictive models, Barra, Nocera, and Mei, to assess their discrimination, calibration, and clinical utility in a contemporary cohort.

Patients and methods: We retrospectively reviewed patients undergoing surgery for cT1 renal masses at our institution. The primary endpoint was pathological upstaging to pT3a. Model performance was evaluated using the Area Under the Curve (AUC) for discrimination and the Brier Score for overall accuracy. Calibration was assessed using parametric and nonparametric Loess-smoothed curves. Clinical utility was quantified using …

Measuring Quality Of Life In Advanced Chronic Liver Disease With Fact-Hep: Findings From The Pal Liver Trial, Manisha Verma, Binu John, Don Rockey, Sid Barritt, Victor Navarro, Linda Shaw, Andrzej Kosinski, Elliot Tapper, Archita Desai

Einstein Health Papers

BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly incorporated into hepatology research, yet few have been rigorously evaluated, particularly among patients with decompensated cirrhosis. The Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) captures multidimensional liver disease-specific burden, while the disease-agnostic PROMIS-29 assesses physical and mental health broadly. We evaluated the performance of FACT-Hep and its relationship to PROMIS-29 among participants with cirrhosis or hepatocellular carcinoma (HCC) enrolled in a prospective multicenter clinical trial.

METHODS: Baseline data were analyzed from 935 participants enrolled in the PAL LIVER trial. This study enrolled patients with Child-Turcotte-Pugh (CTP) B/C cirrhosis and/or with HCC. Health-related quality of …

Development Of A Structurally Distinct Topbp1 Inhibitor That Enhances Parp Blockade And Reverses Osimertinib Resistance, Yang Xiao, Lidija A Wilhelms Garan, Helena Folly-Kossi, Weei-Chin Lin

Faculty, Staff and Students Publications

Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship–driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, …

Early-Onset Colorectal Cancer With Liver-Only Metastases: A Retrospective Cohort Study Integrating Prospectively Collected Real-World Clinical And Molecular Data From An Australian National Database (2009–2024) To Guide Treatment Planning, Savio G. Barreto, Christos S. Karapetis, Shahid Ullah, Matthew Burge, Susan Caird, Angus Campbell, Azim Jalali, Ross Jennens, Muhammad A. Khattak, Belinda Lee, Stephanie H. Lim, Shehara Mendis, Louise Nott, Timothy J. Price, Jeremy D. Shapiro, Jeanne Tie, Javier Torres, Colin Williams, Rachel Wong, Vanessa Wong, Peter Gibbs

Research outputs 2022 to 2026

Objective: To leverage the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (an Australian cancer database) to explore the ideal timing and sequence of therapies and the factors influencing these decisions in colorectal cancer (CRC) patients with liver-only metastases to inform contemporary decision-making and future trials.

Study Type: Retrospective registry-based cohort study using the TRACC registry.

Setting and Participants: Consecutive patients with liver-only metastatic CRC enrolled in the TRACC registry.

Main Outcome Measures: To explore cancer biology, intended treatment at presentation, actual treatment received and the resultant outcomes for early-onset CRC (EOCRC) (≤ 50 years) and late-onset CRC (LOCRC) …

Cost-Effectiveness Of Hes V2.0 And Galad For Hepatocellular Carcinoma Surveillance In Patients With Cirrhosis, Mary Linton B Peters, Ali Hajjar, Anthony E Samir, Leigh Anne Dageforde, Fasiha Kanwal, Jagpreet Chhatwal

Faculty, Staff and Students Publications

Background: Ultrasound-based surveillance for HCC is limited by suboptimal sensitivity and low adherence. Blood-based biomarkers are potential alternatives for routine HCC surveillance. We aimed to define optimal sensitivity, specificity, and cost parameters under which blood-based biomarkers could serve as cost-effective alternatives in patients with cirrhosis.

Methods: We developed a microsimulation model of the natural history of HCC in individuals with compensated cirrhosis. We compared the cost-effectiveness of biannual surveillance using 2 blood-based biomarkers-HES V2.0 and GALAD-versus ultrasound-based surveillance across a range of sensitivity, specificity, test costs, and adherence levels. Outcomes included quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios …

Asynchronous Transitions From High-Risk Hepatoblastoma To Carcinoma, Sonal Somvanshi, Roma Patel, Priyanka Rao, Tuan M Tran, Yen-Ping Yeh, Keng-Shih Chang, Yi-Tzu Lo, Jessica Epps, Kathleen A Scorsone, Hua-Sheng Chiu, Emporia Faith Hollingsworth, Cintia R Perez, Mohammad Javad Najaf Panah, Barry Zorman, Jordan Muscal, Milton J Finegold, John A Goss, Rita Alaggio, Angshumoy Roy, Kevin E Fisher, Andras Heczey, Sarah Woodfield, Sanjeev Vasudevan, Kalyani Patel, Ting-Wen Chen, Dolores Lopez-Terrada, Pavel Sumazin

Faculty, Staff and Students Publications

Background & aims: Most pediatric hepatocellular tumors are classified as hepatoblastoma (HB) or hepatocellular carcinoma (HCC), yet a subset exhibits mixed histological and molecular features. These hepatoblastomas with carcinoma features (HBCs) include cases provisionally designated as hepatocellular neoplasm-not otherwise specified (HCN-NOS). Their biology remains poorly understood, with unresolved questions about their cellular composition and outcomes. It is unclear whether HBCs comprise hybrid cells with combined HB and HCC characteristics (HBC cells) or admixtures of distinct HB and HCC cells. We characterized the biology, etiology, cellular composition, and evolutionary dynamics of HBCs.

Methods: We performed multi-omics profiling - including single-nucleus RNA …

Fgfr3::Tacc3 Fusion And Notch1 Loss-Of-Function In A Case Of Hpv-Associated Sinonasal Squamous Cell Carcinoma: Diagnostic Challenge And Implications For Targeted Therapy, Pei Ying, Songlin Zhang, Li Liang

Faculty, Staff and Students Publications

Sinonasal squamous cell carcinoma (SNSCC) comprises a heterogeneous group of tumors with emerging molecular subtypes. Human papillomavirus (HPV)-associated SNSCC is a distinct entity, although actionable genomic alterations beyond HPV-driven pathways remain underexplored. Distinguishing HPV-associated SNSCC from carcinoma ex inverted papilloma can be particularly challenging in limited biopsy specimens, as these lesions may appear morphologically similar. We report a case of HPV-associated SNSCC with concurrent FGFR3::TACC3 fusion and NOTCH1 p.C1416 stop-gain mutation.

Oncocytic Intraductal Carcinoma Of The Parotid Gland With Strn::Alk Fusion, Hong Yu, Fouad El-Dana, Xu Cao, Li Liang, Pei Ying, Songlin Zhang

Faculty, Staff and Students Publications

Intraductal carcinoma (IDC) of the salivary gland is an uncommon epithelial neoplasm characterized by a predominantly intraductal or intracystic proliferation rimmed by a myoepithelial cell layer. Advances in molecular profiling have revealed recurrent gene fusions in IDC, most frequently involving RET, although fusions implicating other kinase genes have also been described. Among these, ALK rearrangements are rare and remain poorly characterized. Herein, we report a case of oncocytic IDC of the parotid gland harboring a STRN::ALK fusion, further expanding the molecular landscape of this tumor. Although this fusion has been previously reported in intercalated duct IDC, to our knowledge, this …

Lymph Node Dissection And Postoperative Complications After Lung Cancer Resection, Isheeta Madeka, Khaled Noueihed, Jacob Woodroof, Shale Mack, Hamza Rshaidat, Gregory L Whitehorn, Sneha Alaparthi, Scott H. Koeneman, Tyler R. Grenda, Nathaniel R. Evans, Iii, Olugbenga T. Okusanya

Department of Surgery Faculty Papers

Importance: Current lung cancer guidelines recommend lymph node sampling (LNS) with the 3 + 1 rule, which recommends station-based sampling with at least 3 N2 (mediastinal) and 1 N1 (hilar) nodal stations. Although there is oncologic benefit to rigorous LNS, potential negative impacts on surgical outcomes have not been well investigated. As adoption of the 3 + 1 rule increases given its formalization as guideline-concordant care, associations with adverse outcomes are crucial to characterize.

Objective: To evaluate whether satisfying the 3 + 1 rule is associated with increased postoperative complications.

Design, setting, and participants: This retrospective cohort study used the …

Axitinib-Pembrolizumab And Adverse Event Management In Patients With Advanced Renal Cell Carcinoma, Neil Shah, Yaa Ababio, Anthony Eccleston, Dharanija Rao, Scott Kelly, Jane Chang, Sarah Lucht, Caleb Paydar, Bryce Van Doren, Emily Bland, William John, Sarah Giegerich, Jalyna Laney, Bruce Feinberg, Kevin Zarrabi

Kimmel Cancer Center Faculty Papers

IMPORTANCE: Understanding approaches to managing treatment-related adverse events (AEs) in immunotherapy and tyrosine kinase inhibitor-based treatments in a clinical setting is critical for reaching optimal patient outcomes.

OBJECTIVE: To investigate the management of AEs in community practices during first-line axitinib plus pembrolizumab therapy for advanced renal cell carcinoma (aRCC).

DESIGN, SETTING, AND PARTICIPANTS: This study comprised a cross-sectional electronic physician survey and a multisite, retrospective cohort study of the medical records of US patients with aRCC who initiated first-line axitinib-pembrolizumab between April 22, 2019, and January 31, 2024. Data were analyzed from September 18 to December 20, 2024.

EXPOSURE: First-line …

Antibody-Drug Conjugates Beyond Her2 In Non-Small Cell Lung Cancer (Nsclc): Mechanisms, Emerging Targets, And Future Directions., Ahmed Ismail, Aakash Desai, George R Simon, Yanis Boumber

Oncology Articles

Antibody-drug conjugates (ADCs) are a rapidly evolving class of oncology therapeutics that enable precise delivery of potent cytotoxic agents to tumor cells while minimizing systemic toxicity. While HER2-targeted ADCs such as trastuzumab deruxtecan (T-DXd) in HER2-mutant, Datopotamab deruxtecan (Dato-Dxd) in EGFR-mutant, and telisotumumab vedotin (Teliso-V) in MET IHC 3+ expressing lung cancer have already established a clinical role in non-small cell lung cancer (NSCLC), multiple ADCs targeting alternative antigens, including additional TROP2 ADCs, HER3, MET, CEACAM5, B7-H3, Nectin-4, and others, are now in advanced clinical development. This review synthesizes the current evidence for non-HER2 ADCs in NSCLC, highlighting mechanisms of …

Seeing Skin, Seeking Evidence: Lessons From A Dermatology Internship, Isabella Floyd

Health, Human Performance and Recreation Undergraduate Honors Theses

Background: Indoor tanning exposes individuals to artificial ultraviolet (UV) radiation through devices such as tanning beds and sunlamps, increasing the risk of skin damage and malignancy. Prior research suggests associations between indoor tanning and melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC), with potential variation based on age of initiation and cumulative exposure.

Purpose: The purpose of this literature review was to examine the association between indoor tanning and skin cancer risk, with a focus on age at first exposure, frequency, and duration of tanning bed use across melanoma, BCC, and SCC outcomes.

Methodology: A structured literature review …

Carcinoma Of The Bladder Diagnosed Incidentally Following Cesarean Section, Fatima Hussain, Mimi Rogers

Central & West Texas and San Antonio GME Research Day 2026

No abstract provided.

Constitutive Ampk Activation Prevents Hepatocellular Carcinoma Development Through Inhibition Of Hnf4Α Activity, Fiyad Alsarmi, Boyuan Sang, Nagireddy Putluri, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality and is largely driven by metabolic disorders such as obesity and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a master regulator of metabolism, and its activation has been proposed as a therapeutic strategy for treating metabolic disorders. However, although AMPK activity is down-regulated in HCC, the precise role of AMPK in HCC development has not been clearly delineated. Here, we investigated the ability of constitutive AMPK activation to prevent HCC development using a constitutively active AMPK transgenic mouse model and a pharmacological AMPK activator. We observed that AMPK …

Influence Of Gut Microbiota On Response To Immune Check Point Inhibitors In Masld Patients With Hcc: Unraveling The Connection, Megha Bhongade, Karim Adhem, Ximena I Ramirez-Morales, Ahmed O Kaseb, Joseph Petrosino, Manal M Hassan, Prasun K Jalal

Faculty, Staff and Students Publications

Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment for various cancers, including advanced hepatocellular carcinoma (HCC). However, a significant proportion of patients with HCC, particularly those with metabolic dysfunction-associated liver disease (MASLD), exhibit resistance to ICI therapy. Studies have revealed that the presence of specific gut bacteria, such as Akkermansia, Bifidobacterium, and Lachnoclostridium, is associated with improved outcomes with ICI-treated HCC patients. Conversely, the overgrowth of bacteria like Enterobacteriaceae is linked to resistance to therapy. This review investigates the role of gut microbiota in shaping immune checkpoint inhibitor responses in MASLD-related hepatocellular carcinoma, focusing on how dysbiosis may …

The Association Between Physical Activity, Sedentary Time, And Sleep With Risk Of Hepatocellular Carcinoma In Patients With Cirrhosis, Hao Duong, Laith Elserag, Amit G Singal, Nicole E Rich, Saira Khaderi, Sumeet K Asrani, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

Background: The majority of hepatocellular carcinoma (HCC) cases arise in patients with cirrhosis, with known major risk factors of hepatitis B (HBV) or C (HCV) infection, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). However, the impact of additional risk factors that act independently or jointly on the pathogenesis of HCC in cirrhosis patients is unknown. The aim of this study was to determine whether sleep, sedentariness, or physical activity levels play a role in the progression of cirrhosis to HCC.

Methods: We systematically collected data on sleep, sedentary time, and physical activity from the ongoing prospective …

Initial Site Of Metastasis Influences Prognosis In Pancreatic Ductal Adenocarcinoma, Eleanor Mancheski, David Baek, Wilbur Bowne, Harish Lavu, Charles Yeo, Avinoam Nevler

Department of Surgery Faculty Papers

INTRODUCTION: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a highly aggressive malignancy. Prior studies suggest that the initial site of metastasis may impact prognosis. This study investigates whether overall survival in mPDAC patients differs between patients first presenting with lung metastases versus those presenting with liver metastases.

METHODS: This retrospective analysis utilized the multi-institutional TriNetX database, identifying patients with histologically diagnosed PDAC who initially presented with either liver or lung metastases. Demographic, histologic, and outcome data were collected and analyzed. Patients were matched 1:1 using a nearest neighbor propensity score (PS) algorithm, and Kaplan-Meier survival analyses were performed. Cox regression was …

Unraveling The Nexus: Tumor Mutational Burden, Pd-L1 Expression, And Oncogenic Alterations In Non-Small Cell Lung Cancer Cytology Specimens, Min Dai, Francis Anthony San Lucas, Hector Alvarez, Leomar Ballester, Hui Chen, Asif Rashid, Mark J Routbort, Gloria Sura, Keith Sweeney, Gokce Toruner, Peng Wei, Richard Yang, Hyvan Dang, Rajyalakshmi Luthra, Sinchita Roy-Chowdhuri

Faculty, Staff and Student Publications

Background: PD-L1 expression and tumor mutational burden (TMB) are biomarkers for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC); however, patients harboring oncogenic alterations have limited benefit from ICIs. The impact of oncogenic alterations on TMB and PD-L1 tumor proportion score in lung cytology specimens is poorly understood. Herein, the association between oncogenic alterations, TMB, and PD-L1 in NSCLC cytology specimens is explored.

Methods: Next-generation sequencing results from 312 NSCLC cytology specimens were retrospectively reviewed that interrogate 610 genes and select immuno-oncology signatures. TMB and PD-L1 immunohistochemical expression across oncogenic alterations were analyzed to explore associations.

Results: …

Multiparametric Mri To Predict Response To Irreversible Electroporation Plus Anti-Pd-1 Immunotherapy In Pancreatic Ductal Adenocarcinoma, Qizhen Cao, Mark D Pagel, Charles V Kingsley, Jingfei Ma, James P Long, Seth T Gammon, Sanaz Javadi, Chun Li

Faculty, Staff and Student Publications

Purpose: To investigate contrast-enhanced T1-weighted MRI and diffusion-weighted magnetic resonance imaging (DWI) for early prediction of tumor response to combined irreversible electroporation (IRE) and anti-PD-1 immunotherapy.

Methods: Murine pancreatic ductal adenocarcinoma (PDAC) cells KRAS* were inoculated into the pancreas of C57BL/6 mice. IRE was performed when tumors became palpable. After IRE, mice received six intraperitoneal injections of anti-PD-1 over 2 weeks. T2-weighted MRI, T1-weighted MRI with macromolecular contrast agent poly(L-glutamic acid)-conjugated gadolinium (PG-Gd), and DWI were performed before and after IRE. Survival was analyzed using Kaplan-Meier curves. Mice surviving at least 100 days without recurrence after IRE were considered complete …

Outcomes With Single Tremelimumab Regular Interval Durvalumab (Stride) For Unresectable Hepatocellular Carcinoma In The Us Veterans Administration, Shalini Bansal, Priya Amin, Courtney Williamson, Stephen Valerio, David Kaplan

Student Papers, Posters & Projects

Background: HIMALAYA demonstrated that STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) compared with sorafenib in participants with unresectable hepatocellular carcinoma (HCC). This retrospective, real-world cohort study evaluated outcomes with STRIDE in veterans with HCC. Methods: Patients diagnosed with HCC between 1 January 2008 and 28 February 2024 who received ≥1 dose of STRIDE for unresectable disease were included. Data were collected from the Veteran Affairs Corporate Data Warehouse. Safety and efficacy were evaluated overall and for subgroups of patients with Child–Pugh A versus Child–Pugh B cirrhosis, viral versus non-viral HCC, and those with versus without prior …

Radiation Doses To Cardiac Substructures Predict Elevation In High-Sensitivity Cardiac Troponin T Levels In Radiation Therapy For Lung Cancer, Xinru Chen, Xiaodong Zhang, Ting Xu, Radhe Mohan, Ruitao Lin, Mei Chen, Rachel C Maguire, Yao Zhao, Efstratios Koutroumpakis, Nicolas L Palaskas, Anita Deswal, Ali Ajdari, Joshua S Niedzielski, Sanjay S Shete, Laurence E Court, Jinzhong Yang, Zhongxing Liao

Faculty, Staff and Student Publications

Purpose: Cardiotoxicity is a major concern for patients undergoing thoracic radiation therapy. This study compared the predictive power of radiation dose-volume histogram (DVH) parameters and radiomic/dosiomic features of the whole heart (WH) and cardiac substructures for elevated circulating high-sensitivity cardiac troponin T (hs-cTnT), a biomarker for early detection of cardiac adverse events.

Methods and materials: A retrospective cohort of 160 patients with non-small cell lung cancer (NSCLC) from a completed prospective trial and a prospective cohort of 57 patients with NSCLC enrolled in an ongoing trial were analyzed. The endpoint was hs-cTnT elevation, indicated by an increase of ≥5 ng/L …

Influence Of Body Composition On The Efficacy Of Nivolumab Plus Ipilimumab For Metastatic Clear Cell Renal Cell Carcinoma, Kabir Grewal, Maria Julia Moura Nascimento Santos, Pankaj Kumar Chauhan, Kai Yu, Nizar M Tannir, Neha Venkatesh, Amado J Zurita, Andrew C Johns, Matthew T Campbell, Sangeeta Goswami, Jianjun Gao, Eric Jonasch, Jennifer L Mcquade, Omar Alhalabi, Pavlos Msaouel, Andrew W Hahn

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitor therapy (ICI) with nivolumab+ipilimumab is a first-line (1L) standard for metastatic clear cell renal cell carcinoma (ccRCC), yet outcomes remain heterogeneous. Increasing evidence suggests that host factors influence the tumor microenvironment and response to ICI. Although higher body mass index (BMI) has been associated with improved outcomes in several malignancies, BMI is an imprecise surrogate for underlying adipose and muscle compartments. We evaluated the association between body composition and outcomes with 1L nivolumab+ipilimumab in metastatic ccRCC.

Methods: We retrospectively analyzed patients with mccRCC treated with 1L nivolumab+ipilimumab at MD Anderson Cancer Center between June 2015 and …

An Ai Approach To Differentiating Lung Squamous Cell Carcinoma From Metastases Of Other Origins, Mark G Evans, Jennifer Ribeiro, Todd Maney, Anthony Helmstetter, Jennifer Johnson, Anthony Karnezis, Casey Bales, George Sledge, David Spetzler, Ari Vanderwalde, Matthew Oberley, Balazs Halmos, Hossein Borghaei, Farah Abdulla, David Bryant, Fred Hirsch, Hassan Ghani

Department of Medical Oncology Faculty Papers

IMPORTANCE: Distinguishing primary lung squamous cell carcinoma (SCC) from squamous metastases to the lung is a clinical challenge due to histopathologic similarities. Accurate diagnosis is essential to guide treatment decisions.

OBJECTIVE: To assess the utility of an artificial intelligence (AI) approach that includes evaluation of key orthogonal evidence in distinguishing primary lung SCCs from metastatic tumors of other tissue origins.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used GPSai, a tissue-of-origin AI model run automatically on each sample submitted for molecular profiling, to flag potential misdiagnoses among research-eligible cases submitted as lung SCC. Molecularly profiled cases within the Caris Life …

Linkage Disequilibrium Score Regression Identifies Genetic Correlations Between Hepatocellular Carcinoma And Clinically Relevant Traits, Aaron P Thrift, Catherine Zhu, Donghui Li, Rikita I Hatia, Robin Kate Kelley, Sean P Cleary, Anna S Lok, Paige M Bracci, Jennifer B Permuth, Roxana Bucur, Jennifer Knox, Jian-Min Yuan, Amit G Singal, Prasun K Jalal, R Mark Ghobrial, Yuko Kono, Dimpy P Shah, Mindie H Nguyen, Neehar D Parikh, Richard Kim, Hui-Chen Wu, Hashem El-Serag, Ping Chang, Yun Shin Chun, Jian Gu, Chad Huff, Asif Rashid, Lu-Yu Hwang, Alison P Klein, Saira A Khaderi, Ahmed O Kaseb, Kathrine A Mcglynn, Lewis R Roberts, Manal M Hassan, Christopher I Amos

Faculty, Staff and Students Publications

Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome-wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co-development with hepatitis C virus-negative (HCV-negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV-negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale …

Hes V2.0 Validation And Performance Compared To Galad And Asap In The Heds Cohort, K Rajender Reddy, Neehar Parikh, Amit G Singal, Jorge A Marrero, Aaron P Thrift, Jagpreet Chhatwal, Ziding Feng, Stephanie Page-Lester, Qingchun Jin, Nabihah Tayob, Fasiha Kanwal

Faculty, Staff and Students Publications

Background & aims: We previously developed HES V2.0, a biomarker panel (age, ALT, platelets, etiology, AFP, AFP-L3, DCP, and their 1-year gradients) for early detection of hepatocellular carcinoma (HCC) among patients with cirrhosis. We externally validated HES V2.0 and compared its performance with HES V1.0, GALAD, and ASAP.

Methods: We conducted a PRoBE (prospective specimen-collection, retrospective blinded-evaluation) cohort study in the HEDS (Hepatocellular Carcinoma Early Detection Strategy) cohort of 1,485 patients with cirrhosis, of whom 119 developed HCC. Patient- and test-level true positive rates (TPR) for HCC were calculated at 6, 12, and 24 months before diagnosis, using thresholds at …

Validation Of Longitudinal Biomarker Screening Algorithms For Hcc Detection In Patients With Cirrhosis, Neehar D Parikh, Anna S Lok, Camden Lopez, Stephanie Page-Lester, Lewis R Roberts, Rajender Reddy, Michelle Luster, Saira Khaderi, Sumeet K Asrani, Hashem B El-Serag, Fasiha Kanwal, Ziding Feng, Nabihah Tayob

Faculty, Staff and Students Publications

Background: Blood-based biomarker panels, including GALAD, have been proposed as an alternative to abdominal ultrasound for hepatocellular carcinoma (HCC) surveillance. Studies suggest longitudinal evaluation of biomarkers can improve test performance; however, no large studies have validated these findings.

Methods: We leveraged the HCC Early Detection Strategy (HEDS) study (n=1019 patients with cirrhosis; 99 incident HCC) and Texas HCC Consortium (THCCC) (n=2345 patients with cirrhosis; 126 incident HCC) to compare the performance of fixed-threshold GALAD (cutoff of -1.36), and 4 longitudinal algorithms: longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD. The HEDS cohort was used to derive longitudinal algorithms, and external validation was …

Nci9673 (Part B): Etctn Randomized Phase Ii Study Of Nivolumab With Or Without Ipilimumab In Refractory, Metastatic Squamous Cell Carcinoma Of The Anal Canal, Van K Morris, Kristen K Ciombor, Lianchun Xiao, Joshua K Ochieng, Enrica Marmonti, Benjamin A Weinberg, John Hays, Sarbajit Mukherjee, Olivia Aranha, Syma Iqbal, Tony Shields, Al B Benson, Syed Kazmi, Christopher Lieu, Howard Hochster, Jennifer Whisenant, Cara Haymaker, Cathy Eng

Faculty, Staff and Student Publications

Purpose: In the previously completed NCI9673 (part A) single-arm study, the antiprogrammed death (PD)-ligand-1 antibody nivolumab demonstrated efficacy for patients with metastatic anal cancer. In NCI9673 (Part B), we evaluated the anticytotoxic T-cell lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in combination with nivolumab for patients with incurable anal cancer.

Methods: In this phase II NCI ETCTN trial, 100 patients with refractory, incurable anal cancer were randomly assigned to receive nivolumab (480 mg IV once every 4 weeks) alone or with ipilimumab (1 mg/kg IV once every 8 weeks). The primary end point was progression-free survival (PFS). Secondary endpoints included radiographic response, …

Syndecan-1-Targeted Therapeutic Antibody Impairs Macropinocytosis And Elicits Antitumor Immunity In Pancreatic Cancer, Zecheng Yang, Madelaine S Theardy, Shuaitong Chen, Yongkun Wei, Mitsunobu Takeda, Xiaofei Wang, Jennifer Li, Prapassorn Thirasastr, Jangho Park, Yangxi Zheng, Long T Vien, Khalida M Wani, Huamin Wang, Sisi Gao, Tim Heffernan, Lawrence Kwong, Ignacio I Wistuba, Laura Bover, Giulio F Draetta, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of just 13%. While the development and early clinical use of small molecules targeting oncogenic KRAS mutations, key drivers of PDAC, have shown promise, resistance to these targeted therapies remains a significant challenge. We recently identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical KRAS effector protein that promotes nutrient salvage and tumor growth. Here, we report the development of a human-specific monoclonal antibody (anti-SDC1 mAb) that inhibits PDAC cell proliferation in vitro and suppresses PDAC tumor growth in vivo. Mechanistically, …

Local Delivery Of Mir-27a* Using Ultrasound-Targeted Microbubble Cavitation Inhibits Squamous Cell Carcinoma Growth, Nikhil S Chari, Cheng Chen, Thiruganesh Ramasamy, Xucai Chen, Geetika Wadhwa, Stephen Y Lai

Faculty, Staff and Student Publications

Objective: Ultrasound-targeted microbubble (MB) cavitation (UTMC) is an image-guided therapeutic oligonucleotide delivery platform utilizing intravenously injected gas-filled ultrasound contrast agents, which carry the therapeutic on the MB shell. During transit of MBs in the microcirculation of target tissue, ultrasound causes MB oscillation, facilitating endocytosis-independent payload uptake within insonified cells. Here, we tested the hypothesis that UTMC-mediated miR-27a* delivery will reduce tumor growth rate and result in accumulation of miR-27a* within tumor cells and the tumor microenvironment.

Methods: We used UTMC to deliver miR-27a* to SCC-VII cells in vitro and in SCC-VII mouse tumor models. Pulsed ultrasound was delivered during intravenous …

The Origin Of Hepatocellular Carcinoma Depends On Metabolic Zonation, Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Lin Li, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J Siegwart, Stephen S Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. Although the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown whether cancers arise from some zones but not others and whether there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 (catenin beta 1) and Arid2 (AT-rich interaction domain 2) mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), in mouse models showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The …