Life Sciences Commons^™

Treatment-Related Pulmonary Adverse Events Induced By Chemoradiation And Durvalumab Affect Survival In Locally Advanced Non-Small Cell Lung Cancer, Ting Xu, Lirong Wu, Saumil Gandhi, Wang Jing, Quyhn-Nhu Nguyen, Joe Y Chang, Ajay Sheshadri, Mehmet Altan, Percy P Lee, Steven H Lin, Zhongxing Liao

Faculty, Staff and Student Publications

Purpose: We compared treatment-related pulmonary adverse events (TRPAE), progression-free survival (PFS), and overall survival (OS) among locally advanced non-small cell lung cancer (NSCLC) patients who received concurrent chemoradiotherapy (CRT) versus CRT followed by immune check point inhibitor (ICI) immunotherapy (CRTI).

Materials and methods: TRPAE was defined as any pulmonary events as defined in CTCAE v.5 occurring within 12 months after completion of radiotherapy. Outcomes were compared between CRT and CTRI by Cox proportional hazard regression and Kaplan-Meier analyses. We also assessed if TRPAE-induced discontinuation of ICI affected survival.

Results: We analyzed 326 patients treated between July 2010 and November 2019; …

Structural Brain Alterations Associated With Suicidal Thoughts And Behaviors In Young People: Results From 21 International Studies From The Enigma Suicidal Thoughts And Behaviours Consortium, Laura S Van Velzen, Maria R Dauvermann, Lejla Colic, Luca M Villa, Hannah S Savage, Alyssa H Zhu, Adrián I Campos, Lauren E Salminen, Sonia Ambrogi, Rosa Ayesa-Arriola, Nerisa Banaj, Zeynep Başgöze, Jochen Bauer, Karina Blair, Robert James Blair, Katharina Brosch, Yuqi Cheng, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Baptiste Couvy-Duchesne, Benedicto Crespo-Facorro, Kathryn R Cullen, Udo Dannlowski, Christopher G Davey, Katharina Dohm, Janice M Fullerton, Ali Saffet Gonul, Ian H Gotlib, Dominik Grotegerd, Tim Hahn, Ben J Harrison, Mengxin He, Ian B Hickie, Tiffany C Ho, Frank Iorfino, Andreas Jansen, Fabrice Jollant, Tilo Kircher, Bonnie Klimes-Dougan, Melissa Klug, Elisabeth J Leehr, Elizabeth T C Lippard, Katie A Mclaughlin, Susanne Meinert, Adam Bryant Miller, Philip B Mitchell, Benson Mwangi, Igor Nenadić, Amar Ojha, Bronwyn J Overs, Julia-Katharina Pfarr, Fabrizio Piras, Kai G Ringwald, Gloria Roberts, Georg Romer, Marsal Sanches, Margaret A Sheridan, Jair C Soares, Gianfranco Spalletta, Frederike Stein, Giana I Teresi, Diana Tordesillas-Gutiérrez, Aslihan Uyar-Demir, Nic J A Van Der Wee, Steven J Van Der Werff, Robert R J M Vermeiren, Alexandra Winter, Mon-Ju Wu, Tony T Yang, Paul M Thompson, Miguel E Rentería, Neda Jahanshad, Hilary P Blumberg, Anne-Laura Van Harmelen, Enigma Suicidal Thoughts And Behaviours Consortium, Lianne Schmaal

Faculty, Staff and Student Publications

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample …

Clinical Impact Of Ceftriaxone Resistance In Escherichia Coli Bloodstream Infections: A Multicenter Prospective Cohort Study, Pranita D Tamma, Lauren Komarow, Lizhao Ge, Julia Garcia-Diaz, Erica S Herc, Cesar A Arias, Elie Saade, Loren G Miller, Jesse T Jacob, Michael J Satlin, Martin Krsak, W Charles Huskins, Sorabh Dhar, Samuel A Shelburne, Carol Hill, Keri R Baum, Minal Bhojani, Kerryl E Greenwood-Quaintance, Suzannah M Schmidt-Malan, Robin Patel, Scott R Evans, Henry F Chambers, Vance G Fowler, David Van Duin, Antibacterial Resistance Leadership Group

Faculty, Staff and Student Publications

Background

Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common.

Methods

This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding.

Results

Notable differences between patients infected with CRO-R and CRO-S …

An Automated Treatment Planning Framework For Spinal Radiation Therapy And Vertebral-Level Second Check, Tucker J Netherton, Callistus Nguyen, Carlos E Cardenas, Caroline Chung, Ann H Klopp, Dong Joo Rhee, Rebecca Howell, Peter Balter, Laurence E Court

Faculty, Staff and Student Publications

Purpose: Complicating factors such as time pressures, anatomic variants in the spine, and similarities in adjacent vertebrae are associated with incorrect level treatments of the spine. The purpose of this work was to mitigate such challenges by fully automating the treatment planning process for diagnostic and simulation computed tomography (CT) scans.

Methods and materials: Vertebral bodies are labeled on CT scans of any length using 2 intendent deep-learning models-mirroring 2 different experts labeling the spine. Then, a U-Net++ architecture was trained, validated, and tested to contour each vertebra (n = 220 CT scans). Features from the CT and auto-contours were …

International Delphi Consensus Guidelines For Follow-Up After Prophylactic Total Gastrectomy: The Life After Prophylactic Total Gastrectomy (Lap-Tg) Study, Geoffrey Roberts, Patrick R Benusiglio, Tanya Bisseling, Daniel Coit, Jeremy L Davis, Theresa A Guise, Kirsty Harris, Paul Furman Mansfield, Jeremy Rossaak, Karen Chelcun Schreiber, Peter P Stanich, Vivian E Strong, Pardeep Kaurah

Faculty, Staff and Student Publications

Background: Prophylactic total gastrectomy (PTG) remains the only means of preventing gastric cancer for people with genetic mutations predisposing to Hereditary Diffuse Gastric Cancer (HDGC), mainly in the CDH1 gene. The small but growing cohort of people undergoing PTG at a young age are expected to have a life-expectancy close to the general population, however, knowledge of the long-term effects of, and monitoring requirements after, PTG is limited. This study aims to define the standard of care for follow-up after PTG.

Methods: Through a combination of literature review and two-round Delphi consensus of major HDGC/PTG units and physicians, and patient …

Flow Cytometry Immunophenotypic Features Of Pure Erythroid Leukemia And The Distinction From Reactive Erythroid Precursors, Hong Fang, Sa A Wang, M James You, Shimin Hu, Roberto N Miranda, Pei Lin, Jie Xu, Beenu Thakral, Ellen J Schlette, Siba El Hussein, Carlos Bueso-Ramos, L Jeffrey Medeiros, Wei Wang

Faculty, Staff and Student Publications

BACKGROUND: The immunophenotype of pure erythroid leukemia (PEL) as determined by flow cytometry immunophenotypic analysis is not well characterized. The immunophenotypic difference between PEL and reactive conditions is under-explored.

METHODS: We assessed and compared the immunophenotype of 24 PEL cases and 28 reactive cases containing early erythroid precursors by flow cytometry.

RESULTS: The neoplastic erythroid cells in all PEL cases were positive for CD36 and CD71. CD45 was also positive in all cases, but the expression level was often dimmer than granulocytes. CD117 expression ranged from partial to uniform, and CD235a was often only positive in the CD117-dim to negative …

Stroke Genetics Informs Drug Discovery And Risk Prediction Across Ancestries, Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Frederick K Kamanu, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K Georgakis, Ilana Caro, Kristi Krebs, Yi-Ching Liaw, Felix C Vaura, Kuang Lin, Bendik Slagsvold Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee-Joon Bae, Ganesh Chauhan, Michael R Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel-Márquez, Marianne Nygaard, Hampton L Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J Knol, Adam J Lewis, Renae L Judy, Tetsuro Ago, Philippe Amouyel, Nicole D Armstrong, Mark K Bakker, Traci M Bartz, David A Bennett, Joshua C Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W Cole, Phil L De Jager, Rafael De Cid, Matthias Endres, Leslie E Ferreira, Mirjam I Geerlings, Natalie C Gasca, Vilmundur Gudnason, Jun Hata, Jing He, Alicia K Heath, Yuk-Lam Ho, Aki S Havulinna, Jemma C Hopewell, Hyacinth I Hyacinth, Michael Inouye, Mina A Jacob, Christina E Jeon, Christina Jern, Masahiro Kamouchi, Keith L Keene, Takanari Kitazono, Steven J Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J Launer, Keon-Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S Markus, Nicholas A Marston, Thomas Meitinger, Braxton D Mitchell, Felipe A Montellano, Takayuki Morisaki, Thomas H Mosley, Mike A Nalls, Børge G Nordestgaard, Martin J O'Donnell, Yukinori Okada, N Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M Psaty, Stephen S Rich, Jonathan Rosand, Marc S Sabatine, Ralph L Sacco, Danish Saleheen, Else Charlotte Sandset, Veikko Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia L Satizabal, Carsten O Schmidt, Atsushi Shimizu, Nicholas L Smith, Kelly L Sloane, Yoichi Sutoh, Yan V Sun, Kozo Tanno, Steffen Tiedt, Turgut Tatlisumak, Nuria P Torres-Aguila, Hemant K Tiwari, David-Alexandre Trégouët, Stella Trompet, Anil Man Tuladhar, Anne Tybjærg-Hansen, Marion Van Vugt, Riina Vibo, Shefali S Verma, Kerri L Wiggins, Patrik Wennberg, Daniel Woo, Peter W F Wilson, Huichun Xu, Qiong Yang, Kyungheon Yoon, Compass Consortium, Invent Consortium, Dutch Parelsnoer Initiative (Psi) Cerebrovascular Disease Study Group, Estonian Biobank, Precise4q Consortium, Finngen Consortium, Ninds Stroke Genetics Network (Sign), Megastroke Consortium, Siren Consortium, China Kadoorie Biobank Collaborative Group, Va Million Veteran Program, International Stroke Genetics Consortium (Isgc), Biobank Japan, Charge Consortium, Gigastroke Consortium, Iona Y Millwood, Christian Gieger, Toshiharu Ninomiya, Hans J Grabe, J Wouter Jukema, Ina L Rissanen, Daniel Strbian, Young Jin Kim, Pei-Hsin Chen, Ernst Mayerhofer, Joanna M M Howson, Marguerite R Irvin, Hieab Adams, Sylvia Wassertheil-Smoller, Kaare Christensen, Mohammad A Ikram, Tatjana Rundek, Bradford B Worrall, G Mark Lathrop, Moeen Riaz, Eleanor M Simonsick, Janika Kõrv, Paulo H C França, Ramin Zand, Kameshwar Prasad, Ruth Frikke-Schmidt, Frank-Erik De Leeuw, Thomas Liman, Karl Georg Haeusler, Ynte M Ruigrok, Peter Ulrich Heuschmann, W T Longstreth, Keum Ji Jung, Lisa Bastarache, Guillaume Paré, Scott M Damrauer, Daniel I Chasman, Jerome I Rotter, Christopher D Anderson, John-Anker Zwart, Teemu J Niiranen, Myriam Fornage, Yung-Po Liaw, Sudha Seshadri, Israel Fernández-Cadenas, Robin G Walters, Christian T Ruff, Mayowa O Owolabi, Jennifer E Huffman, Lili Milani, Yoichiro Kamatani, Martin Dichgans, Stephanie Debette

Faculty, Staff and Student Publications

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary …

Longitudinal Associations Of Risk Factors And Hepatocellular Carcinoma In Patients With Cured Hepatitis C Virus Infection, Jennifer R Kramer, Yumei Cao, Liang Li, Donna Smith, Jagpreet Chhatwal, Fasiha Kanwal

Faculty, Staff and Student Publications

Introduction: There are limited data on the effect and evolution of risk factors for hepatocellular carcinoma (HCC) in patients with virologically cured hepatitis C virus (HCV) infection.

Methods: We conducted a retrospective cohort study of patients with HCV who achieved sustained virological response with direct-acting antivirals from 130 Veterans Administration hospitals during 2014-2018, followed through 2021. Cox proportional hazards models were constructed at 3 landmark times (baseline and 12 and 24 months after sustained virological response) to examine associations between demographic, clinical, and behavioral factors and HCC risk, stratified by cirrhosis status.

Results: Among 92,567 patients (32% cirrhosis), 3,247 cases …

Nab-Paclitaxel, Capecitabine, And Radiation Therapy After Induction Chemotherapy In Treating Patients With Locally Advanced And Borderline Resectable Pancreatic Cancer: Phase 1 Trial And Imaging-Based Biomarker Validation, Eugene J Koay, Mohamed Zaid, Maureen Aliru, Polycarpe Bagereka, Arie Van Wieren, Galia Jacobson, Michael Overman, Gauri Varadhachary, Shubham Pant, Huamin Wang, Ching-Wei Tzeng, Naruhiko Ikoma, Michael Kim, Jeffrey E Lee, Matthew Hg Katz, Eric Tamm, Priya Bhosale, Cullen M Taniguchi, Emma B Holliday, Grace L Smith, Ethan B Ludmir, Bruce D Minsky, Christopher H Crane, Albert C Koong, Prajnan Das, Xuemei Wang, Milind Javle, Sunil Krishnan

Faculty, Staff and Student Publications

PURPOSE: Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.

METHODS AND MATERIALS: Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m

RESULTS: Twenty-three patients started and finished …

An Optimized Bioassay For Screening Combined Anticoronaviral Compounds For Efficacy Against Feline Infectious Peritonitis Virus With Pharmacokinetic Analyses Of Gs-441524, Remdesivir, And Molnupiravir In Cats, Sarah Cook, Luke Wittenburg, Victoria C Yan, Jacob H Theil, Diego Castillo, Sonyia Williams, Chun Li, Florian L Muller, Brian G Murphy

Faculty, Staff and Student Publications

Feline infectious peritonitis (FIP) is a fatal disease of cats that currently lacks licensed and affordable vaccines or antiviral therapeutics. The disease has a spectrum of clinical presentations including an effusive ("wet") form and non-effusive ("dry") form, both of which may be complicated by neurologic or ocular involvement. The feline coronavirus (FCoV) biotype, termed feline infectious peritonitis virus (FIPV), is the etiologic agent of FIP. The objective of this study was to determine and compare the in vitro antiviral efficacies of the viral protease inhibitors GC376 and nirmatrelvir and the nucleoside analogs remdesivir (RDV), GS-441524, molnupiravir (MPV; EIDD-2801), and β-D-N

T Cells Specific For Α-Myosin Drive Immunotherapy-Related Myocarditis, Margaret L Axelrod, Wouter C Meijers, Elles M Screever, Juan Qin, Mary Grace Carroll, Elie Tannous, Ayaka Sugiura, Brandie C Taylor, Ann Hanna, Shaoyi Zhang, Kaushik Amancherla, Warren Tai, Jordan J Wright, Spencer C Wei, Susan R Opalenik, Abigail L Toren, Jeffrey C Rathmell, P Brent Ferrell, Elizabeth J Phillips, Simon Mallal, Douglas B Johnson, James P Allison, Javid J Moslehi, Justin M Balko

Faculty, Staff and Student Publications

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, …

Low-Dose Dasatinib 50 Mg/Day Versus Standard-Dose Dasatinib 100 Mg/Day As Frontline Therapy In Chronic Myeloid Leukemia In Chronic Phase: A Propensity Score Analysis, Elias Jabbour, Koji Sasaki, Fadi G Haddad, Ghayas C Issa, Jeffrey Skinner, Musa Yilmaz, Prithviraj Bose, Philip Thompson, Yesid Alvarado, Nitin Jain, Guillermo Garcia-Manero, Koichi Takahashi, Gautam Borthakur, Naveen Pemmaraju, Sherry Pierce, Hagop Kantarjian

Faculty, Staff and Student Publications

Low-dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). No randomized trials have compared the outcome with standard-dose dasatinib. This study aims to compare the outcome of patients with CML-CP treated with frontline dasatinib 50 versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML-CP treated with low-dose dasatinib (N = 83) or standard-dose dasatinib (N = 150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response …

Handwashing Results In Incomplete Nicotine Removal From Fingers Of Individuals Who Smoke: A Randomized Controlled Experiment, Thomas F Northrup, Angela L Stotts, Robert Suchting, Amir M Khan, Michelle R Klawans, Eunha Hoh, Georg E Matt, Penelope J E Quintana

Faculty, Staff and Student Publications

Objective: Tobacco residue, also known as third-hand smoke (THS), contains toxicants and lingers in dust and on surfaces and clothes. THS also remains on hands of individuals who smoke, with potential transfer to infants during visitation while infants are hospitalized in neonatal intensive care units (NICUs), raising concerns (e.g., hindered respiratory development) for vulnerable infants. Previously unexplored, this study tested handwashing (HW) and sanitization efficacy for finger-nicotine removal in a sample of adults who smoked and were visiting infants in an NICU.

Study design: A cross-sectional sample was recruited to complete an interview, carbon monoxide breath samples, and three nicotine …

Immune Dysfunction Signatures Predict Outcomes And Define Checkpoint Blockade-Unresponsive Microenvironments In Acute Myeloid Leukemia, Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Benjamin Dickins, Michael Kramer, Hanna A Knaus, Bruce R Blazar, Vedran Radojcic, Joshua F Zeidner, Andrea Arruda, Bofei Wang, Hussein A Abbas, Mark D Minden, Sarah K Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik

Faculty, Staff and Student Publications

Background

Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8⁺ T cells and whether they have prognostic relevance.

METHODS

We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).

Results

We show that senescent-like bone marrow CD8⁺ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival …

Rad Regulation Of Cav12 Channels Controls Cardiac Fight-Or-Flight Response, Arianne Papa, Sergey I Zakharov, Alexander N Katchman, Jared S Kushner, Bi-Xing Chen, Guoxia Liu, Robyn J Eisert, Gary A Bradshaw, Wen Dun, Shah R Ali, Aaron Rodriques, Karen Zhou, Veli Topkara, Mu Yang, John P Morrow, Emily J Tsai, Arthur Karlin, Elaine Wan, Marian Kalocsay, Geoffrey S Pitt, Henry M Colecraft, Manu Ben-Johny, Steven O Marx

Faculty, Staff and Student Publications

Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart's innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for β-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of β-adrenergic contractile response and diminished …

A Semi-Mechanistic Dose-Finding Design In Oncology Using Pharmacokinetic/Pharmacodynamic Modeling, Xiao Su, Yisheng Li, Peter Müller, Chia-Wei Hsu, Haitao Pan

Faculty, Staff and Student Publications

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting …

Ambulatory Monitoring Of Subglottal Pressure Estimated From Neck-Surface Vibration In Individuals With And Without Voice Disorders, Juan P Cortés, Jon Z Lin, Katherine L Marks, Víctor M Espinoza, Emiro J Ibarra, Robert E Hillman

Faculty, Staff and Student Publications

The aerodynamic voice assessment of subglottal air pressure can discriminate between speakers with typical voices from patients with voice disorders, with further evidence validating subglottal pressure as a clinical outcome measure. Although estimating subglottal pressure during phonation is an important component of a standard voice assessment, current methods for estimating subglottal pressure rely on non-natural speech tasks in a clinical or laboratory setting. This study reports on the validation of a method for subglottal pressure estimation in individuals with and without voice disorders that can be translated to connected speech to enable the monitoring of vocal function and behavior in …

Identification Of Key Genes Associated With Cancer Stem Cell Characteristics In Wilms’ Tumor Based On Bioinformatics Analysis, Cheng Su, Jie Zheng, Siyu Chen, Jinwei Tuo, Jinxia Su, Shaohua Chen

Faculty, Staff and Student Publications

BACKGROUND: Nephroblastoma, also known as Wilms' tumor (WT), remains one of the major causes of tumor-related deaths worldwide in children. Cancer stem cells (CSCs) are considered to be the main culprits in cancer resistance and disease recurrence, which are reported in multiple types of tumors. However, the research on CSCs in WT is limited. Therefore, our study aimed to identify the key genes related to CSCs in WT to provide new ideas for treating WT.

METHODS: The RNA-seq and clinical data of WT samples were obtained from the University of California Santa Cruz (UCSC) Xena database, which included 120 WT …

International Delphi Consensus Guidelines For Follow-Up After Prophylactic Total Gastrectomy: The Life After Prophylactic Total Gastrectomy (Lap-Tg) Study, Geoffrey Roberts, Patrick R Benusiglio, Tanya Bisseling, Daniel Coit, Jeremy L Davis, Theresa A Guise, Kirsty Harris, Paul Furman Mansfield, Jeremy Rossaak, Karen Chelcun Schreiber, Peter P Stanich, Vivian E Strong, Pardeep Kaurah

Faculty, Staff and Student Publications

BACKGROUND: Prophylactic total gastrectomy (PTG) remains the only means of preventing gastric cancer for people with genetic mutations predisposing to Hereditary Diffuse Gastric Cancer (HDGC), mainly in the CDH1 gene. The small but growing cohort of people undergoing PTG at a young age are expected to have a life-expectancy close to the general population, however, knowledge of the long-term effects of, and monitoring requirements after, PTG is limited. This study aims to define the standard of care for follow-up after PTG.

METHODS: Through a combination of literature review and two-round Delphi consensus of major HDGC/PTG units and physicians, and patient …

Optimisation Of Imaging Parameters During Ct Guided Interventional Procedures In Patients With Total Hip Arthroplasty, Anish Patel, Christine Azzopardi, Scott Evans, A Mark Davies, Steven James

Faculty, Staff and Student Publications

OBJECTIVE: To determine the optimal KV and mAs settings during CT guided injections in the presence of a total hip arthroplasty so that image quality is maintained whist keeping the dose as low as reasonably achievable.

METHODS: A total hip arthroplasty phantom with needles with differing gauges was scanned using different CT parameters (from low dose to high dose) and evaluating if this had any effect on needle conspicuity. Conspicuity was graded from 1 to 3 by 2 independent blinded reviewers.

RESULTS: Irrespective of the CT settings used (high dose or low dose parameters) needle conspicuity was not adversely affected …

Anatomical Validation Of Automatic Respiratory Motion Correction For Coronary 18f-Sodium Fluoride Positron Emission Tomography By Expert Measurements From Four-Dimensional Computed Tomography, Martin Lyngby Lassen, Evangelos Tzolos, Tinsu Pan, Jacek Kwiecinski, Sebastien Cadet, Daniel Berman

Faculty, Staff and Student Publications

BACKGROUND: Respiratory motion correction is of importance in studies of coronary plaques employing

PURPOSE: To investigate the accuracy of the motion correction employed in a software (FusionQuant) used for evaluation of

METHODS: This study included 23 patients who undertook thoracic PET scans for the assessment of coronary plaques using

RESULTS: In total, 19 coronary plaques were identified in 16 patients. No statistical differences were observed for the maximum respiratory motion observed in x, y, and the 3D motion fields (magnitude and direction) between the CT and PET (X direction: 4D CT = 2.5 ± 1.5 mm, PET = 2.4 ± …

The Safety Of Deutetrabenazine For Chorea In Huntington Disease: An Open-Label Extension Study, Samuel Frank, Claudia Testa, Mary C Edmondson, Jody Goldstein, Elise Kayson, David Oakes, Christina Vaughan, Jacquelyn Whaley, Nicholas Gross, Mark Forrest Gordon, Juha-Matti Savola, Huntington Study Group/Arc-Hd Investigators And Coordinators

Faculty, Staff and Student Publications

BACKGROUND: Deutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease.

OBJECTIVE: We aimed to evaluate the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease.

METHODS: This open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington's Disease Rating Scale total motor score and total maximal chorea …

Risks Of Depression And Suicide After Diagnosis With Heart Failure: A National Cohort Study, Casey Crump, Jan Sundquist, Kenneth S Kendler, Weiva Sieh, Alexis C Edwards

Faculty, Staff and Student Publications

BACKGROUND: Heart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear.

OBJECTIVES: In this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort.

METHODS: A national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used …

Quantitative Mri Of Chronic Pancreatitis: Results From A Multi-Institutional Prospective Study, Magnetic Resonance Imaging As A Non-Invasive Method For Assessment Of Pancreatic Fibrosis (Minimap), Temel Tirkes, Dhiraj Yadav, Darwin L Conwell, Paul R Territo, Xuandong Zhao, Anil K Dasyam, Sudhakar K Venkatesh, Naoki Takahashi, Ashley Wachsman, Liang Li, Yan Li, Stephen J Pandol, Walter G Park, Santhi S Vege, Phil A Hart, Mark Topazian, Dana K Andersen, Evan L Fogel, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Purpose: To determine if quantitative MRI techniques can be helpful to evaluate chronic pancreatitis (CP) in a setting of multi-institutional study.

Methods: This study included a subgroup of participants (n = 101) enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study (NCT03099850) from February 2019 to May 2021. MRI was performed on 1.5 T using Siemens and GE scanners at seven clinical centers across the USA. Quantitative MRI parameters of the pancreas included T1 relaxation time, extracellular volume (ECV) fraction, apparent diffusion coefficient (ADC), and fat signal fraction. We report the diagnostic …

Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis And Muscle Wasting Through Metabolic Reprogramming In Pancreatic Cancer, Zhijun Zhou, Yu Ren, Jingxuan Yang, Mingyang Liu, Xiuhui Shi, Kar-Ming Fung, Michael S Bronze, Yuqing Zhang, Courtney W Houchen, Min Li

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. Acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is an acetyl-enzyme A synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the nonselective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.

METHODS: Clinical significance of ACSS2 was analyzed using samples from patients with pancreatic cancer. ACSS2-knockout cells were established using the clustered regularly interspaced short palindromic repeats-associated protein …

Neoadjuvant Relatlimab And Nivolumab In Resectable Melanoma, Rodabe N Amaria, Michael Postow, Elizabeth M Burton, Michael T Tetzlaff, Merrick I Ross, Isabella C Glitza, Denái R Milton, Klaus Busam, Lauren Simpson, Jennifer L Mcquade, Michael K Wong, Jeffrey E Gershenwald, Jeffrey E Lee, Ryan P Goepfert, Emily Z Keung, Sarah B Fisher, Allison Betof-Warner, Alexander N Shoushtari, Margaret Callahan, Daniel Coit, Edmund K Bartlett, Danielle Bello, Parisa Momtaz, Courtney Nicholas, Aidi Gu, Xuejun Zhang, Brinda Rao Korivi, Madhavi Patnana, Sapna P Patel, Adi Diab, Anthony Lucci, Victor G Prieto, Michael A Davies, James P Allison, Padmanee Sharma, Jennifer A Wargo, Charlotte Ariyan, Hussein A Tawbi

Faculty, Staff and Student Publications

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid …

The Equilibrium Of Tumor Suppression: Dubs As Active Regulators Of Pten, Audrey Christine, Mi Kyung Park, Su Jung Song, Min Sup Song

Faculty, Staff and Student Publications

PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have …

Prognostic Significance Of Preoperative And Postoperative Ca 19–9 Normalization In Pancreatic Adenocarcinoma Treated With Neoadjuvant Therapy Or Surgery First, Timothy P Diperi, Timothy E Newhook, Laura R Prakash, Naruhiko Ikoma, Jessica E Maxwell, Jeffrey E Lee, Ching-Wei D Tzeng

Faculty, Staff and Student Publications

BACKGROUND: Normal(ization) of serum carbohydrate 19-9 (CA19-9) before/after surgery has not been compared in patients with pancreatic adenocarcinoma (PDAC) treated with neoadjuvant therapy (NT) versus surgery-first (SF).

METHODS: Characteristics for patients with PDAC who underwent resection from July 2011 to October 2018 were collected. Patients with pre-/postoperative CA19-9, bilirubin/dL, and initial CA19-9 > 1 U/ml were included. Overall survival (OS) and recurrence-free survival (RFS) were compared by pre-/postoperative CA19-9.

RESULTS: In patients receiving NT, normal pre/postoperative CA19-9 ("NT

CONCLUSIONS: While a normal(ized) postoperative CA19-9 may result in similar survival as preoperative normal(ization), postoperative normalization failed to occur in nearly 30% of …

Estimation Of Tumor Cell Total Mrna Expression In 15 Cancer Types Predicts Disease Progression, Shaolong Cao, Jennifer R Wang, Shuangxi Ji, Peng Yang, Yaoyi Dai, Matthew D Montierth, Xiao Zhao, Jingxiao Chen, Jaewon James Lee, Paola A Guerrero, Nicholas Spetsieris, Nikolai Engedal, Sinja Taavitsainen, Kaixian Yu, Julie Livingstone, Vinayak Bhandari, Shawna M Hubert, Najat C Daw, P Andrew Futreal, Eleni Efstathiou, Bora Lim, Andrea Viale, Jianjun Zhang, Matti Nykter, Bogdan A Czerniak, Powel H Brown, Charles Swanton, Pavlos Msaouel, Anirban Maitra, Scott Kopetz, Peter Campbell, Terence P Speed, Paul C Boutros, Hongtu Zhu, Alfonso Urbanucci, Jonas Demeulemeester, Peter Van Loo, Wenyi Wang

Faculty, Staff and Student Publications

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene …

Is Loss Of P53 A Driver Of Ductal Carcinoma In Situ Progression?, Rhiannon L Morrissey, Alastair M Thompson, Guillermina Lozano

Faculty, Staff and Student Publications

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive carcinoma. Multiple studies have shown that DCIS lesions typically possess a driver mutation associated with cancer development. Mutation in the TP53 tumour suppressor gene is present in 15-30% of pure DCIS lesions and in ~30% of invasive breast cancers. Mutations in TP53 are significantly associated with high-grade DCIS, the most likely form of DCIS to progress to invasive carcinoma. In this review, we summarise published evidence on the prevalence of mutant TP53 in DCIS (including all DCIS subtypes), discuss the availability of mouse models for the study of DCIS …