Medical Specialties Commons^™

Ush2a Mutation And Specific Driver Mutation Subtypes Are Associated With Clinical Efficacy Of Immune Checkpoint Inhibitors In Lung Cancer, Dexin Yang, Yuqin Feng, Haohua Lu, Kelie Chen, Jinming Xu, Peiwei Li, Tianru Wang, Dajing Xia, Yihua Wu

Faculty, Staff and Student Publications

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog

Itch And Janus Kinase Inhibitors, Yujin Han, Yu Ri Woo, Sang Hyun Cho, Jeong Deuk Lee, Hei Sung Kim

Faculty, Staff and Student Publications

Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for …

Baseline Extracellular Vesicle Tgf-Β Is A Predictive Biomarker For Response To Immune Checkpoint Inhibitors And Survival In Non-Small Cell Lung Cancer, Diego De Miguel-Perez, Alessandro Russo, Muthukumar Gunasekaran, Francesco Buemi, Lisa Hester, Xiaoxuan Fan, Brandon A Carter-Cooper, Rena G Lapidus, Ariel Peleg, Marisol Arroyo-Hernández, Andres F Cardona, Aung Naing, Fred R Hirsch, Philip C Mack, Sunjay Kaushal, Maria Jose Serrano, Vincenzo Adamo, Oscar Arrieta, Christian Rolfo

Faculty, Staff and Student Publications

Background: Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-β (TGF-β), can be found free in …

Staphylococcus Aureus Breast Implant Infection Isolates Display Recalcitrance To Antibiotic Pocket Irrigants, Jesus M Duran Ramirez, Jana Gomez, Blake M Hanson, Taha Isa, Terence M Myckatyn, Jennifer N Walker

Faculty, Staff and Student Publications

Breast implant-associated infections (BIAIs) are the primary complication following placement of breast prostheses in breast cancer reconstruction. Given the prevalence of breast cancer, reconstructive failure due to infection results in significant patient distress and health care expenditures. Thus, effective BIAI prevention strategies are urgently needed. This study tests the efficacy of one infection prevention strategy: the use of a triple antibiotic pocket irrigant (TAPI) against Staphylococcus aureus, the most common cause of BIAIs. TAPI, which consists of 50,000 U bacitracin, 1 g cefazolin, and 80 mg gentamicin diluted in 500 mL of saline, is used to irrigate the breast implant …

Influence Of County-Level Geographic/Ancestral Origin On Glioma Incidence And Outcomes In Us Hispanics, Kyle M Walsh, Corey Neff, Melissa L Bondy, Carol Kruchko, Jason T Huse, Christopher I Amos, Jill S Barnholtz-Sloan, Quinn T Ostrom

Faculty, Staff and Student Publications

BACKGROUND: Glioma incidence is 25% lower in Hispanics than White non-Hispanics. The US Hispanic population is diverse, and registry-based analyses may mask incidence differences associated with geographic/ancestral origins.

METHODS: County-level glioma incidence data in Hispanics were retrieved from the Central Brain Tumor Registry of the United States. American Community Survey data were used to determine the county-level proportion of the Hispanic population of Mexican/Central American and Caribbean origins. Age-adjusted incidence rate ratios and incidence rate ratios (IRRs) quantified the glioma incidence differences across groups. State-level estimates of admixture in Hispanics were obtained from published 23andMe data.

RESULTS: Compared to predominantly …

Response Assessment In Pediatric Craniopharyngioma: Recommendations From The Response Assessment In Pediatric Neuro-Oncology (Rapno) Working Group, Lindsey M Hoffman, Camilo Jaimes, Kshitij Mankad, David M Mirsky, Benita Tamrazi, Christopher L Tinkle, Cassie Kline, Aparna Ramasubramanian, Fatema Malbari, Ross Mangum, Holly Lindsay, Vincent Horne, David J Daniels, Sameer Keole, David R Grosshans, Tina Young Poussaint, Roger Packer, Sergio Cavalheiro, Brigitte Bison, Todd C Hankinson, Hermann L Müller, Ute Bartels, Katherine E Warren, Murali Chintagumpala

Faculty, Staff and Student Publications

BACKGROUND: Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized.

METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively.

RESULTS: Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor …

Ambient Oxygen Levels Regulate Intestinal Dysbiosis And Gvhd Severity After Allogeneic Stem Cell Transplantation, Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos Da Silva, Marcel R M Van Den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M Schmidt, Yatrik M Shah, Robert R Jenq, Gregory Dick, Pavan Reddy

Faculty, Staff and Student Publications

The severity of T cell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in …

Survival Improvement For Patients With Metastatic Colorectal Cancer Over Twenty Years, Fadl A Zeineddine, Mohammad A Zeineddine, Abdelrahman Yousef, Yue Gu, Saikat Chowdhury, Arvind Dasari, Ryan W Huey, Benny Johnson, Bryan Kee, Michael S Lee, Maria Pia Morelli, Van K Morris, Michael J Overman, Christine Parseghian, Kanwal Raghav, Jason Willis, Robert A Wolff, Yoshikuni Kawaguchi, Jean-Nicolas Vauthey, Ryan Sun, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Over the past two decades of successive clinical trials in metastatic colorectal cancer (CRC), the median overall survival of both control and experimental arms has steadily improved. However, the incremental change in survival for metastatic CRC patients not treated on trial has not yet been quantified. We performed a retrospective review of 1420 patients with de novo metastatic CRC who received their primary treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 2004 through 2019. Median OS was roughly stable for patients diagnosed between 2004 and 2012 (22.6 months) but since has steadily improved for those diagnosed …

Computational Investigation Of A Series Of Small Molecules As Potential Compounds For Lysyl Hydroxylase-2 (Lh2) Inhibition, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Xudong Yang, Chengwen Liu, Zhifeng Jing, Juhoon Lee, Matthew Harger, Ally K Smith, Miguel Espinoza, Hou-Fu Guo, Jonathan M Kurie, Kevin N Dalby, Pengyu Ren, G Andrés Cisneros

Faculty, Staff and Student Publications

The catalytic function of lysyl hydroxylase-2 (LH2), a member of the Fe(II)/αKG-dependent oxygenase superfamily, is to catalyze the hydroxylation of lysine to hydroxylysine in collagen, resulting in stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs). Reports show that high amounts of LH2 lead to the accumulation of HLCCs, causing fibrosis and specific types of cancer metastasis. Some members of the Fe(II)/αKG-dependent family have also been reported to have intramolecular O

Rna Profiling Of Human Dorsal Root Ganglia Reveals Sex Differences In Mechanisms Promoting Neuropathic Pain, Pradipta R Ray, Stephanie Shiers, James P Caruso, Diana Tavares-Ferreira, Ishwarya Sankaranarayanan, Megan L Uhelski, Yan Li, Robert Y North, Claudio Tatsui, Gregory Dussor, Michael D Burton, Patrick M Dougherty, Theodore J Price

Faculty, Staff and Student Publications

Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia. We sequenced …

Cd70 Is A Therapeutic Target Upregulated In Emt-Associated Egfr Tyrosine Kinase Inhibitor Resistance, Monique B Nilsson, Yan Yang, Simon Heeke, Sonia A Patel, Alissa Poteete, Hibiki Udagawa, Yasir Y Elamin, Cesar A Moran, Yukie Kashima, Thiruvengadam Arumugam, Xiaoxing Yu, Xiaoyang Ren, Lixia Diao, Li Shen, Qi Wang, Minying Zhang, Jacqulyne P Robichaux, Chunhua Shi, Allyson N Pfeil, Hai Tran, Don L Gibbons, Jason Bock, Jing Wang, John D Minna, Susumu S Kobayashi, Xiuning Le, John V Heymach

Faculty, Staff and Student Publications

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. …

Phase Ib Study Of Telisotuzumab Vedotin In Combination With Erlotinib In Patients With C-Met Protein-Expressing Non-Small-Cell Lung Cancer, D Ross Camidge, Fabrice Barlesi, Jonathan W Goldman, Daniel Morgensztern, Rebecca Heist, Everett Vokes, Alex Spira, Eric Angevin, Wu-Chou Su, David S Hong, John H Strickler, Monica Motwani, Martin Dunbar, Apurvasena Parikh, Elysa Noon, Vincent Blot, Jun Wu, Karen Kelly

Faculty, Staff and Student Publications

Purpose: Overexpression of c-Met protein and epidermal growth factor receptor (EGFR) mutations can co-occur in non-small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met-positive (+) NSCLC.

Patients and methods: This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age …

Associations Of Financial Toxicity With Symptoms And Unplanned Healthcare Utilization Among Cancer Patients Taking Oral Chemotherapy At Home: A Prospective Observational Study, Yongfeng Chen, Zhenxiang Chen, Haiyun Jin, Yanrong Chen, Jinbing Bai, Guifen Fu

Faculty, Staff and Student Publications

Background: Cancer patients with financial toxicity experience psychological distress and often miss medical appointments and quit treatments early, which could be a barrier to the effective management of oral chemotherapy drugs at home. This study explores whether financial toxicity predicts symptoms and unplanned healthcare utilization among cancer patients taking oral chemotherapy at home, which will contribute to the safe management of oral chemotherapy.

Methods: Data in this study was from a prospective observational study, which was conducted between October 2018 and December 2019. 151 patients completed the Comprehensive Score for Financial Toxicity at discharge and completed the MD Anderson Symptom …

Deep Learning For Detecting And Elucidating Human T-Cell Leukemia Virus Type 1 Integration In The Human Genome, Haodong Xu, Johnathan Jia, Hyun-Hwan Jeong, Zhongming Zhao

Faculty, Staff and Student Publications

Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus, is the causative agent for adult T cell leukemia/lymphoma and many other human diseases. Accurate and high throughput detection of HTLV-1 virus integration sites (VISs) across the host genomes plays a crucial role in the prevention and treatment of HTLV-1-associated diseases. Here, we developed DeepHTLV, the first deep learning framework for VIS prediction de novo from genome sequence, motif discovery, and cis-regulatory factor identification. We demonstrated the high accuracy of DeepHTLV with more efficient and interpretive feature representations. Decoding the informative features captured by DeepHTLV resulted in eight representative clusters …

Fgl2-Targeting T Cells Exhibit Antitumor Effects On Glioblastoma And Recruit Tumor-Specific Brain-Resident Memory T Cells, Qingnan Zhao, Jiemiao Hu, Lingyuan Kong, Shan Jiang, Xiangjun Tian, Jing Wang, Rintaro Hashizume, Zhiliang Jia, Natalie Wall Fowlkes, Jun Yan, Xueqing Xia, Sofia F Yi, Long Hoang Dao, David Masopust, Amy B Heimberger, Shulin Li

Faculty, Staff and Student Publications

Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 …

Health Benefits And Cost-Effectiveness Of Children's Oncology Group Breast Cancer Screening Guidelines For Chest-Irradiated Hodgkin Lymphoma Survivors, F Lennie Wong, Janie M Lee, Wendy M Leisenring, Joseph P Neglia, Rebecca M Howell, Susan A Smith, Kevin C Oeffinger, Chaya S Moskowitz, Tara O Henderson, Ann Mertens, Paul C Nathan, Yutaka Yasui, Wendy Landier, Gregory T Armstrong, Leslie L Robison, Smita Bhatia

Faculty, Staff and Student Publications

Purpose: To evaluate the outcomes and cost-effectiveness of the Children's Oncology Group Guideline recommendation for breast cancer (BC) screening using mammography (MAM) and breast magnetic resonance imaging (MRI) in female chest-irradiated childhood Hodgkin lymphoma (HL) survivors. Digital breast tomosynthesis (DBT), increasingly replacing MAM in practice, was also examined.

Methods: Life years (LYs), quality-adjusted LYs (QALYs), BC mortality, health care costs, and false-positive screen frequencies of undergoing annual MAM, DBT, MRI, MAM + MRI, and DBT + MRI from age 25 to 74 years were estimated by microsimulation. BC risks and non-BC mortality were estimated from female 5-year survivors of …

A Phase Ib/Ii Study Of Lenvatinib And Pembrolizumab In Advanced Endometrial Carcinoma (Study 111/Keynote-146): Long-Term Efficacy And Safety Update, Vicky Makker, Carol Aghajanian, Allen L Cohn, Margarita Romeo, Raquel Bratos, Marcia S Brose, Mark Messing, Lea Dutta, Corina E Dutcus, Jie Huang, Emmett V Schmidt, Robert Orlowski, Matthew H Taylor

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff …

Editorial: Precision Medicine In Obstetrics: Pregnancy Complication, Serena Bertozzi, Bruna Corradetti, Arrigo Fruscalzo, Ambrogio P Londero

Faculty, Staff and Students Publications

No abstract provided.

Early Restrictive Or Liberal Fluid Management For Sepsis-Induced Hypotension, Nathan I Shapiro, Ivor S Douglas, Roy G Brower, Samuel M Brown, Matthew C Exline, Adit A Ginde, Michelle N Gong, Colin K Grissom, Douglas Hayden, Catherine L Hough, Weixing Huang, Theodore J Iwashyna, Alan E Jones, Akram Khan, Poying Lai, Kathleen D Liu, Chadwick D Miller, Katherine Oldmixon, Pauline K Park, Todd W Rice, Nancy Ringwood, Matthew W Semler, Jay S Steingrub, Daniel Talmor, B Taylor Thompson, Donald M Yealy, Wesley H Self

Faculty, Staff and Student Publications

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited.

METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that …

The Landscape Of Immunotherapy For Retroperitoneal Sarcoma, Alicia A Gingrich, Elise F Nassif, Christina L Roland, Emily Z Keung

Faculty, Staff and Student Publications

Significant multidisciplinary scientific effort has been undertaken to understand the heterogeneous family of neoplasms that comprise soft tissue sarcomas. Within this family of neoplasms, outcomes for retroperitoneal sarcomas (RPS) are currently limited given a lack of effective therapies. In this review, we focus on immunotherapy and its relationship with the common RPS histologic subtypes. Although initial outcomes for RPS patients with immune checkpoint inhibition alone have been somewhat disappointing, subsequent analyses on histologies, the tumor microenvironment, sarcoma immune class, tumor infiltrating lymphocytes and genetic analysis for tumor mutational burden have yielded insight into the interplay between sarcomas and immunotherapy. Such …

North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: Position On Standards Of Care And Areas Of Need, Naveen Pemmaraju, Hagop Kantarjian, Kendra Sweet, Eunice Wang, Jayastu Senapati, Nathaniel R Wilson, Marina Konopleva, Arthur E Frankel, Vikas Gupta, Ruben Mesa, Matthew Ulrickson, Edward Gorak, Sumeet Bhatia, Tulin Budak-Alpdogan, James Mason, Maria Teresa Garcia-Romero, Norma Lopez-Santiago, Gabriela Cesarman-Maus, Pankit Vachhani, Sangmin Lee, Vijaya Raj Bhatt, William Blum, Roland B Walter, Dale Bixby, Ivana Gojo, Madeleine Duvic, Raajit K Rampal, Marcos De Lima, James Foran, Amir T Fathi, Aric Cameron Hall, Meagan A Jacoby, Jeffrey Lancet, Gabriel Mannis, Anthony S Stein, Alice Mims, David Rizzieri, Rebecca Olin, Alexander Perl, Gary Schiller, Paul Shami, Richard M Stone, Stephen Strickland, Matthew J Wieduwilt, Naval Daver, Farhad Ravandi, Sumithira Vasu, Monica Guzman, Gail J Roboz, Joseph Khoury, Muzaffar Qazilbash, Phyu P Aung, Branko Cuglievan, Yazan Madanat, Mohamed A Kharfan-Dabaja, Anna Pawlowska, Justin Taylor, Martin Tallman, Prajwal Dhakal, Andrew A Lane

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets …

Efficacy And Clinicogenomic Correlates Of Response To Immune Checkpoint Inhibitors Alone Or With Chemotherapy In Non-Small Cell Lung Cancer, Lingzhi Hong, Muhammad Aminu, Shenduo Li, Xuetao Lu, Milena Petranovic, Maliazurina B Saad, Pingjun Chen, Kang Qin, Susan Varghese, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Amy Spelman, Yasir Y Elamin, Marcelo V Negrao, Ferdinandos Skoulidis, Carl M Gay, Tina Cascone, Saumil J Gandhi, Steven H Lin, Percy P Lee, Brett W Carter, Carol C Wu, Mara B Antonoff, Boris Sepesi, Jeff Lewis, Don L Gibbons, Ara A Vaporciyan, Xiuning Le, J Jack Lee, Sinchita Roy-Chowdhuri, Mark J Routbort, Justin F Gainor, John V Heymach, Yanyan Lou, Jia Wu, Jianjun Zhang, Natalie I Vokes

Faculty, Staff and Student Publications

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes …

Improving Traditional Registrational Trial End Points: Development And Application Of A Desirability Of Outcome Ranking End Point For Complicated Urinary Tract Infection Clinical Trials, Jessica Howard-Anderson, Toshimitsu Hamasaki, Weixiao Dai, Deborah Collyar, Daniel Rubin, Sumathi Nambiar, Tori Kinamon, Carol Hill, Steven P Gelone, David Mariano, Takamichi Baba, Thomas L Holland, Sarah B Doernberg, Henry F Chambers, Vance G Fowler, Scott R Evans, Helen W Boucher

Faculty, Staff and Student Publications

BACKGROUND: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience.

METHODS: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, …

Association Of Circulating Mtdna With Cvd In Hemodialysis Patients And In Vitro Effect Of Exogenous Mtdna On Cardiac Microvascular Inflammation, Zhen Fan, Ya Feng, Li Zang, Yi Guo, Xiao-Yi Zhong

Faculty, Staff and Student Publications

BACKGROUND: Chronic kidney disease (CKD) patients sustain a fairly high prevalence of cardiovascular disease (CVD). Microvascular inflammation is an early manifestation of CVD, and the released mitochondrial DNA (MtDNA) has been proposed to be a crucial integrator of inflammatory signals. Herein, the aim of this study was to determine the relationship between CVD, microvessel, and circulating MtDNA in the settings of uremia.

METHODS: Forty-two maintenance hemodialysis (MHD) patients and 36 health controls were enrolled in this study. Plasma cell-free MtDNA was detected by TaqMan-based qPCR assay. CVD risk markers including high-sensitive C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), fibrinogen, and …

Clinical And Molecular Analyses Of Recurrent Gram-Negative Bloodstream Infections, Andrew Bock, Blake M Hanson, Felicia Ruffin, Joshua B Parsons, Lawrence P Park, Batu Sharma-Kuinkel, Michael Mohnasky, Cesar A Arias, Vance G Fowler, Joshua T Thaden

Faculty, Staff and Student Publications

Background: The causes and clinical characteristics of recurrent gram-negative bacterial bloodstream infections (GNB-BSI) are poorly understood.

Methods: We used a cohort of patients with GNB-BSI to identify clinical characteristics, microbiology, and risk factors associated with recurrent GNB-BSI. Bacterial genotyping (pulsed-field gel electrophoresis [PFGE] and whole-genome sequencing [WGS]) was used to determine whether episodes were due to relapse or reinfection. Multivariable logistic regression was used to identify risk factors for recurrence.

Results: Of the 1423 patients with GNB-BSI in this study, 60 (4%) had recurrent GNB-BSI. Non-White race (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.38-4.01; P = .002), admission …

An Epithelial-Immune Circuit Amplifies Inflammasome And Il-6 Responses To Sars-Cov-2, Katherine C Barnett, Yuying Xie, Takanori Asakura, Dingka Song, Kaixin Liang, Sharon A Taft-Benz, Haitao Guo, Shuangshuang Yang, Kenichi Okuda, Rodney C Gilmore, Jennifer F Loome, Thomas H Oguin Iii, Gregory D Sempowski, Scott H Randell, Mark T Heise, Yu Leo Lei, Richard C Boucher, Jenny P-Y Ting

Faculty, Staff and Student Publications

Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, …

Incidence And Clearance Of Anal Human Papillomavirus Infection In 16 164 Individuals, According To Human Immunodeficiency Virus Status, Sex, And Male Sexuality: An International Pooled Analysis Of 34 Longitudinal Studies, Feixue Wei, Marc T Goodman, Ningshao Xia, Jun Zhang, Anna R Giuliano, Gypsyamber D'Souza, Nancy A Hessol, Maarten F Schim Van Der Loeff, Jianghong Dai, Karin Neukam, Alexandra De Pokomandy, I Mary Poynten, Ronald B Geskus, Joaquin Burgos, Isabelle Etienney, Anna-Barbara Moscicki, Maria Gabriella Donà, Maura L Gillison, Alan G Nyitray, Rebecca G Nowak, Evy Yunihastuti, Huachun Zou, Carmen Hidalgo-Tenorio, Nittaya Phanuphak, Jean-Michel Molina, Alice M Schofield, Stephen Kerr, Song Fan, Yong Lu, Jason J Ong, Admire T Chikandiwa, Sirinya Teeraananchai, Nicola Squillace, Dorothy J Wiley, Joel M Palefsky, Damien Georges, Catharina J Alberts, Gary M Clifford

Faculty, Staff and Student Publications

Background: Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized.

Methods: We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their …

Life-Threatening Complications Of Influenza Vs Coronavirus Disease 2019 (Covid-19) In Us Children, Natasha B Halasa, Andrew J Spieker, Cameron C Young, Samantha M Olson, Margaret M Newhams, Justin Z Amarin, Kristin L Moffitt, Mari M Nakamura, Emily R Levy, Vijaya L Soma, Rana Talj, Scott L Weiss, Julie C Fitzgerald, Elizabeth H Mack, Aline B Maddux, Jennifer E Schuster, Bria M Coates, Mark W Hall, Stephanie P Schwartz, Adam J Schwarz, Michele Kong, Philip C Spinella, Laura L Loftis, Gwenn E Mclaughlin, Charlotte V Hobbs, Courtney M Rowan, Melania M Bembea, Ryan A Nofziger, Christopher J Babbitt, Cindy Bowens, Heidi R Flori, Shira J Gertz, Matt S Zinter, John S Giuliano, Janet R Hume, Natalie Z Cvijanovich, Aalok R Singh, Hillary A Crandall, Neal J Thomas, Melissa L Cullimore, Manish M Patel, Adrienne G Randolph, Pediatric Intensive Care Influenza, Overcoming Covid-19 Investigators

Faculty, Staff and Student Publications

Background: Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.

Methods: We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.

Results: Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 …

Bintrafusp Alfa: A Bifunctional Fusion Protein Targeting Pd-L1 And Tgf-Β, In Patients With Pretreated Colorectal Cancer: Results From A Phase I Trial, Alexander Spira, Michael S Wertheim, Edward J Kim, Benjamin Tan, Heinz-Josef Lenz, Petros Nikolinakos, Patricia L Rich, Genevieve Jehl, Andreas Machl, Rena Ito, James L Gulley, Scott Kopetz

Faculty, Staff and Student Publications

Colorectal cancer (CRC) is a heterogeneous and complex disease with limited treatment options. Targeting transforming growth factor β (TGF-β) and programmed death ligand 1 pathways may enhance antitumor efficacy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. We report results from an expansion cohort of a phase I study (NCT02517398) in patients with heavily pretreated advanced CRC treated with bintrafusp alfa. As of May 15, 2020, 32 patients with advanced CRC had received …

Production Of A Monoclonal Antibody For The Detection Of Forchlorfenuron: Application In An Indirect Enzyme-Linked Immunosorbent Assay And Immunochromatographic Strip, Xingmei Lei, A M Abd El-Aty, Lingyuan Xu, Jing Zhao, Jia Li, Song Gao, Yun Zhao, Yongxin She, Fen Jin, Jing Wang, Lufei Zheng, Maojun Jin, Bruce D Hammock

Faculty, Staff and Student Publications

In this study, a monoclonal antibody (mAb) specific to forchlorfenuron (CPPU) with high sensitivity and specificity was produced and designated (9G9). To detect CPPU in cucumber samples, an indirect enzyme-linked immunosorbent assay (ic-ELISA) and a colloidal gold nanobead immunochromatographic test strip (CGN-ICTS) were established using 9G9. The half-maximal inhibitory concentration (IC50) and the LOD for the developed ic-ELISA were determined to be 0.19 ng/mL and 0.04 ng/mL in the sample dilution buffer, respectively. The results indicate that the sensitivity of the antibodies prepared in this study (9G9 mAb) was higher than those reported in the previous literature. On the other …