Medicine and Health Sciences Commons^™

Postoperative Bioactive Adrenomedullin Is Associated With The Onset Of Ards And Adverse Outcomes In Patients Undergoing Open Thoracoabdominal Aortic Surgery, Panagiotis Doukas, Oliver Hartmann, Jelle Frankort, Birte Arlt, Hanif Krabbe, Michael Johan Jacobs, Andreas Greiner, Jan Paul Frese, Alexander Gombert

Faculty, Staff and Student Publications

Cytokine-mediated systemic inflammation after open thoracoabdominal aortic aneurysm (TAAA) repairs plays a pivotal role in disrupting circulatory homeostasis, potentially leading to organ dysfunction. The bioactive form of adrenomedullin (bio-ADM) is a peptide hormone with immunomodulatory and vasomotor effects, making it a potential diagnostic agent in these cases. This retrospective, bicentric study, conducted between January 2019 and December 2022, recruited 36 elective open TAAA repair patients in two German centres. Serum and plasma samples were collected at multiple time points to measure bio-ADM levels. The primary objective was to evaluate the association of bio-ADM levels with the onset of acute respiratory …

Companion-002 A Clinical Trial Of Investigational Drug Ctx-009 Plus Paclitaxel Vs Paclitaxel In Second Line Advanced Btc, Nilofer Azad, Olivia Aranha, Et Al.

2020-Current year OA Pubs

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with …

Well-Child Visits For Early Detection And Management Of Maternal Postpartum Hypertensive Disorders, Farah H Amro, Kim C Smith, Syed S Hashmi, Michelle S Barratt, Rachel Carlson, Kristen Mariah Sankey, Michal Fishel Bartal, Sean C Blackwell, Suneet P Chauhan, Baha M Sibai

Faculty, Staff and Student Publications

IMPORTANCE: Innovative approaches are needed to address the increasing rate of postpartum morbidity and mortality associated with hypertensive disorders.

OBJECTIVE: To determine whether assessing maternal blood pressure (BP) and associated symptoms at time of well-child visits is associated with increased detection of postpartum preeclampsia and need for hospitalization for medical management.

DESIGN, SETTING, AND PARTICIPANTS: This is a pre-post quality improvement (QI) study. Individuals who attended the well-child visits between preimplementation (December 2017 to December 2018) were compared with individuals who enrolled after the implementation of the QI program (March 2019 to December 2019). Individuals were enrolled at an academic …

Delays To Antibiotics In The Emergency Department And Risk Of Mortality In Children With Sepsis., Roni D. Lane, Troy Richardson, Halden F. Scott, Raina M. Paul, Fran Balamuth, Matthew A. Eisenberg, Ruth Riggs, W Charles Huskins, Christopher M. Horvat, Grant E. Keeney, Leslie Hueschen, Justin M. Lockwood, Vishal Gunnala, Bryan P. Mckee, Nikhil Patankar, Venessa Lynn Pinto, Amanda M. Sebring, Matthew P. Sharron, Jennifer Treseler, Jennifer J. Wilkes, Jennifer K. Workman

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Pediatric consensus guidelines recommend antibiotic administration within 1 hour for septic shock and within 3 hours for sepsis without shock. Limited studies exist identifying a specific time past which delays in antibiotic administration are associated with worse outcomes.

OBJECTIVE: To determine a time point for antibiotic administration that is associated with increased risk of mortality among pediatric patients with sepsis.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from 51 US children's hospitals in the Improving Pediatric Sepsis Outcomes collaborative. Participants included patients aged 29 days to less than 18 years with sepsis recognized within 1 hour …

Combining Novel Thrombectomy Devices For Intracardiac Mass Extraction: The Kong And Godzilla Of Mass Extraction, Hussam Al Hennawi, Ahmad Abulshamat, Ali Sheikh, Hisham Qandeel, Kiril Zakharov, Appa Bandi, Mohammed Qintar

Abington Jefferson Health Papers

Transcatheter extraction of an intracardiac mass is a newer approach that may lead to nonsurgical treatment of complex cardiac masses. We present a case in which thrombectomy devices were combined to extract a right atrial mass, which highlights new frontiers in the treatment of complex transcatheter mass extraction. The combined use of two transcatheter thrombectomy devices (Kong and Godzilla) may provide a powerful addition to the existing armamentarium.

Impact Of Simulation Exercises On Total Laparoscopic Hysterectomy Surgical Outcomes: A Systematic Review And Meta-Analysis, Tricia Giglio-Ayers, Fabrizio Zullo, Alicia Hersey, Indira Ranaweera, Lara Ouellette, Daniele Di Mascio, Christine E Foley, Stephen M Wagner

Library Staff Publications

BACKGROUND: As resources into gynecological surgical simulation training increase, research showing an association with improved clinical outcomes is needed.

OBJECTIVE: To evaluate the association between surgical simulation training for total laparoscopic hysterectomy (TLH) and rates of intraoperative vascular/visceral injury (primary outcome) and operative time.

SEARCH STRATEGY: We searched Medline OVID, Embase, Web of Science, Cochrane, and CINAHL databases from the inception of each database to April 5, 2022. Selection Critera: Randomized controlled trials (RCTs) or cohort studies of any size published in English prior to April 4, 2022.

DATA COLLECTION AND ANALYSIS: The summary measures were reported as relative risks …

Riluzole For Degenerative Cervical Myelopathy: A Secondary Analysis Of The Csm-Protect Trial, Michael G. Fehlings, Karlo M. Pedro, Mohammed Ali Alvi, Jetan H. Badhiwala, Henry Ahn, H. Francis Farhadi, Christopher I. Shaffrey, Ahmad Nassr, Praveen Mummaneni, Paul M. Arnold, W. Bradley Jacobs, K. Daniel Riew, Michael Kelly, Darrel S. Brodke, Alex Vaccaro, Alan Hilibrand, Jason Wilson, James Harrop, S. Tim Yoon, Kee D. Kim, Daryl R. Fourney, Carlo Santaguida, Eric M. Massicotte, Peng Huang

Department of Orthopaedic Surgery Faculty Papers

IMPORTANCE: The modified Japanese Orthopaedic Association (mJOA) scale is the most common scale used to represent outcomes of degenerative cervical myelopathy (DCM); however, it lacks consideration for neck pain scores and neglects the multidimensional aspect of recovery after surgery.

OBJECTIVE: To use a global statistical approach that incorporates assessments of multiple outcomes to reassess the efficacy of riluzole in patients undergoing spinal surgery for DCM.

DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of prespecified secondary end points within the Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-PROTECT) trial, a multicenter, double-blind, phase 3 randomized clinical …

Semirecumbent Positioning During Anesthesia Recovery And Postoperative Hypoxemia: A Randomized Clinical Trial, Xinghe Wang, Kedi Guo, Jia Sun, Yuping Yang, Yan Wu, Xihui Tang, Yuqing Xu, Qingsong Chen, Si Zeng, Liwei Wang, Su Liu

Faculty, Staff and Student Publications

IMPORTANCE: The efficacy of a semirecumbent position (SRP) in reducing postoperative hypoxemia during anesthesia emergence is unclear despite its widespread use.

OBJECTIVE: To determine the differences in postoperative hypoxemia between patients in an SRP and a supine position.

DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was performed at a tertiary hospital in China between March 20, 2021, and May 10, 2022. Patients scheduled to undergo laparoscopic upper abdominal surgery under general anesthesia were enrolled. Study recruitment and follow-up are complete.

INTERVENTIONS: Patients were randomized to 1 of the following positions at the end of the operation until leaving the …

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.

Ketamine Vs Electroconvulsive Therapy For Treatment-Resistant Depression: A Secondary Analysis Of A Randomized Clinical Trial, Manish Kumar Jha, Samuel T Wilkinson, Kamini Krishnan, Katherine A Collins, Gerard Sanacora, James Murrough, Fernando Goes, Murat Altinay, Amy Aloysi, Ali Asghar-Ali, Brian Barnett, Lee Chang, Sara Costi, Donald Malone, Sina Nikayin, Steven E Nissen, Robert Ostroff, Irving Reti, Kathy Wolski, Dong Wang, Bo Hu, Sanjay J Mathew, Amit Anand

Staff and Researcher Publications

IMPORTANCE: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD.

OBJECTIVE: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT.

DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were …

Delays To Antibiotics In The Emergency Department And Risk Of Mortality In Children With Sepsis, Roni D Lane, Troy Richardson, Halden F Scott, Raina M Paul, Fran Balamuth, Matthew A Eisenberg, Ruth Riggs, W Charles Huskins, Christopher M Horvat, Grant E Keeney, Leslie A Hueschen, Justin M Lockwood, Vishal Gunnala, Bryan P Mckee, Nikhil Patankar, Venessa Lynn Pinto, Amanda M Sebring, Matthew P Sharron, Jennifer Treseler, Jennifer J Wilkes, Jennifer K Workman

Faculty, Staff and Students Publications

IMPORTANCE: Pediatric consensus guidelines recommend antibiotic administration within 1 hour for septic shock and within 3 hours for sepsis without shock. Limited studies exist identifying a specific time past which delays in antibiotic administration are associated with worse outcomes.

OBJECTIVE: To determine a time point for antibiotic administration that is associated with increased risk of mortality among pediatric patients with sepsis.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from 51 US children's hospitals in the Improving Pediatric Sepsis Outcomes collaborative. Participants included patients aged 29 days to less than 18 years with sepsis recognized within 1 hour …

An Atlas Characterizing The Shared Genetic Architecture Of Inflammatory Bowel Disease With Clinical And Behavioral Traits, Vikram R Shaw, Jinyoung Byun, Rowland W Pettit, Jason K Hou, Kyle M Walsh, Younghun Han, Christopher I Amos

Faculty, Staff and Students Publications

BACKGROUND: Inflammatory bowel disease (IBD) development is a complex, multifactorial process that involves extrinsic and intrinsic factors such as host genetics, the immune system, the gut microbiome, and environmental risks. To help understand the genetic contribution of clinical, behavioral, psychiatric, and diet-related traits, we aim to provide a deep and comprehensive characterization of the shared genetic architecture between IBD and hundreds of potentially related traits.

METHODS: Utilizing publicly available summary statistics from a previously published IBD genome-wide association study and hundreds of traits from the United Kingdom BioBank (UKBB), we performed linkage disequilibrium score regression (LDSR) analysis to estimate cross-trait …

Self-Reported Functional Vision In Ush2a-Associated Retinal Degeneration As Measured By The Michigan Retinal Degeneration Questionnaire, Bela Parekh, Jacque L Duncan, Lassana Samarakoon, Michele Melia, Maria Fernanda Abalem, Chris A Andrews, Isabelle Audo, Allison R Ayala, Chris Bradley, Janet K Cheetham, Gislin Dagnelie, Todd A Durham, Rachel M Huckfeldt, Gabrielle D Lacy, Brett Malbin, Michel Michaelides, David C Musch, Nicholas Peck-Dimit, Katarina Stingl, Christina Y Weng, Alex Z Zmejkoski, K Thiran Jayasundera

Faculty, Staff and Students Publications

PURPOSE: The purpose of this study was to evaluate self-reported functional vision (FV) and the impact of vision loss in patients with USH2A-associated retinal degeneration using a patient-reported outcome (PRO) measure, the Michigan Retinal Degeneration Questionnaire (MRDQ), to correlate MRDQ scores with well-established visual function measurements.

DESIGN: An observational cross-sectional study (n = 93) of participants who had Usher Syndrome Type 2 (USH2, n = 55) or autosomal recessive non-syndromic retinitis pigmentosa (ARRP; n = 38) associated with biallelic variants in the USH2A gene.

METHODS: The study protocol was approved by all ethics boards and informed consent was obtained from …

Individuals With Jak1 Variants Are Affected By Syndromic Features Encompassing Autoimmunity, Atopy, Colitis, And Dermatitis, Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, …

Phantasus, A Web Application For Visual And Interactive Gene Expression Analysis, Maksim Kleverov, Daria Zenkova, Vladislav Kamenev, Margarita Sablina, Maxim N Artyomov, Alexey A Sergushichev

2020-Current year OA Pubs

Transcriptomic profiling became a standard approach to quantify a cell state, which led to the accumulation of huge amount of public gene expression datasets. However, both reuse of these datasets or analysis of newly generated ones requires significant technical expertise. Here, we present Phantasus: a user-friendly web application for interactive gene expression analysis which provides a streamlined access to more than 96,000 public gene expression datasets, as well as allows analysis of user-uploaded datasets. Phantasus integrates an intuitive and highly interactive JavaScript-based heatmap interface with an ability to run sophisticated R-based analysis methods. Overall Phantasus allows users to go all …

Generalized Genetic Liability To Substance Use Disorders, Alex P. Miller, Ryan Bogdan, Arpana Agrawal, Alexander S. Hatoum

2020-Current year OA Pubs

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common …

Hexamerization: Explaining The Original Sin Of Igg-Mediated Complement Activation In Acute Lung Injury, Hrishikesh S. Kulkarni

2020-Current year OA Pubs

Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for …

Cannabis, Tobacco Use, And Covid-19 Outcomes, Nicholas B Griffith, Timothy B Baker, Brendan T Heiden, Nina Smock, Giang Pham, Jingling Chen, Justin Yu, James Reddy, Albert M Lai, Eric Hogue, Laura J Bierut, Li-Shiun Chen

2020-Current year OA Pubs

IMPORTANCE: It is unclear whether cannabis use is associated with adverse health outcomes in patients with COVID-19 when accounting for known risk factors, including tobacco use.

OBJECTIVE: To examine whether cannabis and tobacco use are associated with adverse health outcomes from COVID-19 in the context of other known risk factors.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used electronic health record data from February 1, 2020, to January 31, 2022. This study included patients who were identified as having COVID-19 during at least 1 medical visit at a large academic medical center in the Midwest US.

EXPOSURES: Current cannabis …

Severe Pediatric Neurological Manifestations With Sars-Cov-2 Or Mis-C Hospitalization And New Morbidity, Conall Francoeur, Kristin P Guilliams, Shannon C Agner, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity.

OBJECTIVE: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge.

DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021.

EXPOSURE: Severe neurological manifestations, which included acute encephalopathy, seizures or status …

Assessing The Feasibility Of A Multimodal Liquid Biopsy For The Diagnosis Of Hpv-Associated Oropharyngeal Squamous Cell Carcinoma., James S. Lewis, Saskia Naegele, Vasileios Efthymiou, Mitra Mehrad, Kim A. Ely, Tim Waterboer, Krystle A. Lang Kuhs, Seth J. Davis, Kelsey Richard, Dipon Das, Daniel L. Faden

Markey Cancer Center Faculty Publications

OBJECTIVES: In this feasibility study, we explored the combined use of circulating tumor human papillomavirus (HPV) DNA (ctHPVDNA) and HPV serology as diagnostic tests for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).

METHODS: Among patients with research-banked serum or plasma at diagnosis, IgG antibodies to oncoproteins from HPV types 16, 18, 31, 33, 35, 45, 52, and 58 were detected with multiplex serology. Positivity for HPV 16 was defined based on detection of combinations of anti-E6, E1, E2, and E7 and for other high-risk types on detection of anti-E6 and anti-E7. Circulating tumor HPV DNA was detected by custom digital droplet …

Klrg1 Cell Depletion As A Novel Therapeutic Strategy In Patients With Mature T-Cell Lymphoma Subtypes, Bimarzhan Assatova, Robert Willim, Christopher Trevisani, Garrett Haskett, Khyati Maulik Kariya, Kusha Chopra, Sung Rye Park, Michael Yevgeniy Tolstorukov, Sean M Mccabe, Jessica Duffy, Abner Louissaint, Jani Huuhtanen, Dipabarna Bhattacharya, Satu Mustjoki, Min Jung Koh, Foster Powers, Elizabeth A Morgan, Lei Yang, Brandy Pinckney, Matthew J Cotton, Andrew Crabbe, Jessica Beth Ziemba, Ian Brain, Tayla B Heavican-Foral, Javeed Iqbal, Ronald Nemec, Anna Baird Rider, Josie Germain Ford, Min Ji Koh, Nora Scanlan, David J Feith, Thomas P Loughran, Won Seog Kim, Jaehyuk Choi, Juliette Roels, Lena Boehme, Tom Putteman, Tom Taghon, Jeffrey A Barnes, P Connor Johnson, Eric D Jacobsen, Steven A Greenberg, David M Weinstock, Salvia Jain

Faculty, Staff and Student Publications

Purpose: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.

Experimental design: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.

Results: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 …

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 …

Maintenance Pembrolizumab Therapy In Patients With Metastatic Her2-Negative Breast Cancer With Prior Response To Chemotherapy, Toshiaki Iwase, Evan N Cohen, Hui Gao, Angela Alexander, Megumi Kai, Vivian Chiv, Xiaoping Wang, Savitri Krishnamurthy, Diane Liu, Yu Shen, Kumiko Kida, Alexandre Reuben, Rachel M Layman, David L Ramirez, Debasish Tripathy, Stacy L Moulder, Clinton Yam, Vicente Valero, Bora Lim, James M Reuben, Naoto T Ueno

Faculty, Staff and Student Publications

Purpose: Accumulating toxicities hinder indefinite chemotherapy for many patients with metastatic/recurrent HER2-negative breast cancer. We conducted a phase II trial of pembrolizumab monotherapy following induction chemotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative inflammatory breast cancer (IBC) and non-IBC triple-negative breast cancer (TNBC) and a biomarker study.

Patients and methods: Patients with a complete response, partial response, or stable disease (SD) after at least three cycles of chemotherapy for HER2-negative breast cancer received pembrolizumab, regardless of programmed death-ligand 1 expression. Pembrolizumab (200 mg) was administered every 3 weeks until disease progression, intolerable toxicity, or 2 …

Efficacy And Safety Of Adagrasib Plus Cetuximab In Patients With Krasg12c-Mutated Metastatic Colorectal Cancer, Rona Yaeger, Nataliya V Uboha, Meredith S Pelster, Tanios S Bekaii-Saab, Minal Barve, Joel Saltzman, Joshua K Sabari, Julio A Peguero, Andrew Scott Paulson, Pasi A Jänne, Marcia Cruz-Correa, Kenna Anderes, Karen Velastegui, Xiaohong Yan, Hirak Der-Torossian, Samuel J Klempner, Scott E Kopetz

Faculty, Staff and Student Publications

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months …

Telomere Dysfunction Alters Intestinal Stem Cell Dynamics To Promote Cancer, Kyle A Labella, Wen-Hao Hsu, Jiexi Li, Yutao Qi, Yonghong Liu, Jingjing Liu, Chia-Chin Wu, Yang Liu, Zingzhi Song, Yiyun Lin, Jonathan M Blecher, Shan Jiang, Xiaoying Shang, Jincheng Han, Denise J Spring, Jianhua Zhang, Yan Xia, Ronald A Depinho

Faculty, Staff and Student Publications

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, …

A Process To Reanalyze Clinical Dna Sequencing Data For Biomarker Matching In The Lung-Map Master Protocol, Joel W Neal, Katherine Minichiello, Ryan Brennick, Richard S P Huang, Matthew C Hiemenz, Cornel Amler, Jyoti Patel, Roy Herbst, Karen L Reckamp, Hossein Borghaei, Louise Highleyman, Mary W Redman, Lincoln W Pasquina, David E Kozono

Faculty, Staff and Student Publications

For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) …

Epicardial Inflow Versus Myocardial Distribution: Average Regional Transmural Coronary Flow Is Not Enough, Nils P Johnson, K Lance Gould

Faculty, Staff and Student Publications

No abstract provided.

Methylthioadenosine Phosphorylase Genomic Loss In Advanced Gastrointestinal Cancers, Natalie Y L Ngoi, Tin-Yun Tang, Catia F Gaspar, Dean C Pavlick, Gregory M Buchold, Emma L Scholefield, Vamsi Parimi, Richard S P Huang, Tyler Janovitz, Natalie Danziger, Mia A Levy, Shubham Pant, Anaemy Danner De Armas, David Kumpula, Jeffrey S Ross, Milind Javle, Jordi Rodon Ahnert

Faculty, Staff and Student Publications

BACKGROUND: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker.

MATERIALS AND METHODS: We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI …

Cell-Free Dna Concentration As A Biomarker Of Response And Recurrence In Her2-Negative Breast Cancer Receiving Neoadjuvant Chemotherapy, Mark Jesus M Magbanua, Ziad Ahmed, Rosalyn W Sayaman, Lamorna Brown Swigart, Gillian L Hirst, Christina Yau, Denise M Wolf, Wen Li, Amy L Delson, Jane Perlmutter, Paula Pohlmann, W Fraser Symmans, Douglas Yee, Nola M Hylton, Laura J Esserman, Angela M Demichele, Hope S Rugo, Laura J Van 'T Veer

Faculty, Staff and Student Publications

Purpose: We previously demonstrated the clinical significance of circulating tumor DNA (ctDNA) in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy (NAC). Here, we compared its predictive and prognostic value with cell-free DNA (cfDNA) concentration measured in the same samples from the same patients.

Experimental design: 145 patients with hormone receptor (HR)-positive/HER2-negative and 138 triple-negative breast cancer (TNBC) with ctDNA data from a previous study were included in the analysis. Associations of serial cfDNA concentration with residual cancer burden (RCB) and distant recurrence-free survival (DRFS) were examined.

Results: In TNBC, we observed a modest negative correlation between cfDNA concentration 3 …

Taro: Tree-Aggregated Factor Regression For Microbiome Data Integration, Aditya K Mishra, Iqbal Mahmud, Philip L Lorenzi, Robert R Jenq, Jennifer A Wargo, Nadim J Ajami, Christine B Peterson

Faculty, Staff and Student Publications

MOTIVATION: Although the human microbiome plays a key role in health and disease, the biological mechanisms underlying the interaction between the microbiome and its host are incompletely understood. Integration with other molecular profiling data offers an opportunity to characterize the role of the microbiome and elucidate therapeutic targets. However, this remains challenging to the high dimensionality, compositionality, and rare features found in microbiome profiling data. These challenges necessitate the use of methods that can achieve structured sparsity in learning cross-platform association patterns.

RESULTS: We propose Tree-Aggregated factor RegressiOn (TARO) for the integration of microbiome and metabolomic data. We leverage information …