Medical Specialties Commons^™

Setd2 Loss And Atr Inhibition Synergize To Promote Cgas Signaling And Immunotherapy Response In Renal Cell Carcinoma, Xian-De Liu, Yan-Ting Zhang, Daniel J Mcgrail, Xuesong Zhang, Truong Lam, Anh Hoang, Elshad Hasanov, Ganiraju Manyam, Christine B Peterson, Haifeng Zhu, Shwetha V Kumar, Rehan Akbani, Patrick G Pilie, Nizar M Tannir, Guang Peng, Eric Jonasch

Faculty, Staff and Student Publications

PURPOSE: Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance it.

EXPERIMENTAL DESIGN: We investigated the effects of SET domain-containing protein 2 (SETD2) loss on the DNA damage response pathway, the cytosolic DNA-sensing pathway, the tumor immune microenvironment, and the response to ataxia telangiectasia and rad3-related (ATR) and checkpoint inhibition in RCC.

RESULTS: ATR inhibition activated the cyclic GMP-AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3)-dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory …

Safety And Tolerability Of A Novel Anti-Her2 Antibody-Drug Conjugate (Pf-06804103) In Patients With Her2-Expressing Solid Tumors: A Phase 1 Dose-Escalation Study, Funda Meric-Bernstam, Emiliano Calvo, Keun Seok Lee, Victor Moreno, Yeon Hee Park, Sun Young Rha, Pavani Chalasani, Wei Zhong, Li Zhou, Steven Pirie-Shepherd, Abraham C F Leung, Giuseppe Curigliano

Faculty, Staff and Student Publications

PF-06804103 is an anti-HER2 antibody–drug conjugate with auristatin payload. We evaluated its safety, tolerability, and antitumor activity in patients with advanced/unresectable or metastatic breast and gastric cancers. This multicenter, open-label, first-in-human, phase 1 study (NCT03284723) comprised dose escalation (P1) and dose expansion (P2). In P1, adults with HER2+ breast or gastric cancer received PF-06804103 0.15–5.0 mg/kg intravenously once/21 days (Q3W); in P2, patients with HER2+ or HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer received 3.0 or 4.0 mg/kg Q3W. The primary endpoints were dose-limiting toxicities (DLT) and safety (P1), and objective response rate (ORR) assessed using RECIST v1.1 (P2). …

Single-Cell Characterization Of Pulmonary Nodules Implicates Suppression Of Immunosurveillance Across Early Stages Of Lung Adenocarcinoma, Jane Yanagawa, Linh M Tran, Ramin Salehi-Rad, Raymond J Lim, Camelia Dumitras, Eileen Fung, William D Wallace, Ashley E Prosper, Gregory Fishbein, Conor Shea, Rui Hong, Bitta Kahangi, John J Deng, Adam C Gower, Bin Liu, Joshua D Campbell, Sarah A Mazzilli, Jennifer E Beane, Humam Kadara, Marc E Lenburg, Avrum E Spira, Denise R Aberle, Kostyantyn Krysan, Steven M Dubinett

Faculty, Staff and Student Publications

UNLABELLED: A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This …

Kinome Reprogramming Is A Targetable Vulnerability In Esr1 Fusion-Driven Breast Cancer, Xuxu Gou, Beom-Jun Kim, Meenakshi Anurag, Jonathan T Lei, Meggie N Young, Matthew V Holt, Diana Fandino, Craig T Vollert, Purba Singh, Mohammad A Alzubi, Anna Malovannaya, Lacey E Dobrolecki, Michael T Lewis, Shunqiang Li, Charles E Foulds, Matthew J Ellis

Faculty, Staff and Students Publications

Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen-binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET-resistant patient-derived xenograft model that harbors the ESR1-e6>YAP1 TAF were …

Association Of Parental Status And Gender With Burden Of Multidisciplinary Tumor Boards Among Oncology Physicians, Brittney L Chau, Jonnby S Laguardia, Sungjin Kim, Samuel C Zhang, Eric Pletcher, Nina N Sanford, Ann C Raldow, Lisa Singer, Jun Gong, Sukhmani K Padda, Mitchell Kamrava, Tara Cohen, Devarati Mitra, Katelyn M Atkins

Faculty, Staff and Student Publications

IMPORTANCE: Tumor boards are integral to the care of patients with cancer. However, data investigating the burden of tumor boards on physicians are limited.

OBJECTIVE: To investigate what physician-related and tumor board-related factors are associated with higher tumor board burden among oncology physicians.

DESIGN, SETTING, AND PARTICIPANTS: Tumor board burden was assessed by a cross-sectional convenience survey posted on social media and by email to Cedars-Sinai Medical Center cancer physicians between March 3 and April 3, 2022. Tumor board start times were independently collected by email from 22 top cancer centers.

MAIN OUTCOMES AND MEASURES: Tumor board burden was measured …

Chronic Kidney Disease Promotes Atrial Fibrillation Via Inflammasome Pathway Activation, Jia Song, Jose Alberto Navarro-Garcia, Jiao Wu, Arnela Saljic, Issam Abu-Taha, Luge Li, Satadru K Lahiri, Joshua A Keefe, Yuriana Aguilar-Sanchez, Oliver M Moore, Yue Yuan, Xiaolei Wang, Markus Kamler, William E Mitch, Gema Ruiz-Hurtado, Zhaoyong Hu, Sandhya S Thomas, Dobromir Dobrev, Xander Ht Wehrens, Na Li

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, Nlrp3-/- and WT mice were subjected to …

Safety And Immunogenicity Of Live Viral Vaccines In A Multicenter Cohort Of Pediatric Transplant Recipients, Amy G Feldman, Brenda L Beaty, Jose A Ferrolino, Gabriela Maron, Hillary K Weidner, Saira A Ali, Leandra Bitterfeld, Mary Alice Boulware, Kathleen M Campbell, Emily Carr, Shelley Chapman, Yeh-Chung Chang, Ryan Cunningham, Ronald H Dallas, Keerti L Dantuluri, Bryanna N Domenick, Noelle H Ebel, Scott Elisofon, Rima Fawaz, Marc Foca, Hayley A Gans, Vani V Gopalareddy, Cindy Gu, Nitika A Gupta, Katherine Harmann, Jessica Hollenbeck, Anna R Huppler, Catalina Jaramillo, Nagraj Kasi, Nanda Kerkar, Stacee Lerret, Steven J Lobritto, Maclovio J Lopez, Elizabeth Marini, Alisha Mavis, Sonia Mehra, Lynnette Moats, Sindhu Mohandas, Flor M Munoz, Krupa R Mysore, Ceren Onsan, Nadia Ovchinsky, Kerrigan Perkins, Stacy Postma, Lauren Pratscher, Elizabeth B Rand, Regina K Rowe, Danielle Schultz, Katherine Sear, Megan L Sell, Tanvi Sharma, Janis Stoll, Mychoua Vang, Dominique Villarin, Carly Weaver, Phoebe Wood, Olivia Woodford-Berry, George Yanni, Lara A Danziger-Isakov

Faculty, Staff and Students Publications

IMPORTANCE: Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions.

OBJECTIVE: To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody …

Heritable Traits And Lung Cancer Risk: A Two-Sample Mendelian Randomization Study, Rowland W Pettit, Jinyoung Byun, Younghun Han, Quinn T Ostrom, Cristian Coarfa, Melissa L Bondy, Christopher I Amos

Faculty, Staff and Students Publications

INTRODUCTION: Lung cancer is a complex polygenic disorder. Analysis with Mendelian randomization (MR) allows for genetically predicted risks to be estimated between exposures and outcomes.

METHODS: We analyzed 345 heritable traits from the United Kingdom Biobank and estimated their associated effects on lung cancer outcomes using two sample MR. In addition to estimating effects with overall lung cancer, adenocarcinoma, small cell lung cancer, and squamous cell lung cancers, we performed conditional effect modeling with multivariate MR (MVMR) and the traits of alcohol use, smoking initiation, average pre-tax income, and educational attainment.

RESULTS: Univariate MR provided evidence for increased age at …

The Clinicopathologic Significance Of Npm1 Mutation And Ability To Detect Mutated Npm1 By Immunohistochemistry In Non-Aml Myeloid Neoplasms., Hatem Kaseb, Valeria Visconte, Daniel S Socha, Genevieve M Crane, Lisa Durkin, James R Cook, Jaroslaw P Maciejewski, Eric D Hsi, Heesun J Rogers

Oncology Articles

NPM1 mutated non-AML myeloid neoplasms (MN; T p. L287F; 65%) than frameshift insertion/duplication (35%) with median variant allele frequency (VAF; 9.7%, range 5.1%-49.8%). Mutated NPM1 by IHC showed cytoplasmic positivity in 48% and positivity was associated with higher VAF. The median overall survival (OS) in this cohort was 70 months. Nine patients (26%) progressed to AML. OS in patients who progressed to AML was significantly shorter than the one of patients without progression to AML (OS 20 vs. 128 months, respectively, log rank p = 0.05). NPM1 mutated non-AML MN patients commonly had cytopenias, dysplasia, normal karyotype, mutations in multiple …

Longitudinal Follow-Up Of Netherton’S Syndrome, K. Petit, Christina E. Borchers, Julian Trevino

Dermatology Faculty Publications

Netherton’s Syndrome (NS) is a rare, autosomal recessivegenodermatosis caused by mutations in SPINK5 which encodes LETKI, aserine protease inhibitor.2,4 Consequently, unopposed kallikrein activityresults in an impaired skin barrier and desquamation.2 A triad of atopy,ichthyosis linearis circumflexa, and trichorrhexis invaginata (“bamboohair”) is characteristic of this disease.1 Associated findings includehypereosinophilia and elevated IgE. Histologically, a nonspecificpsoriasiform hyperplasia and dermal lymphocytic infiltrate may beobserved.1,6 Clinically, NS is frequently misdiagnosed as atopic dermatitis(AD) and proves difficult to treat.2 Dupilumab, an IL-4/IL-13 inhibitor withFDA approval for the treatment of atopic dermatitis and prurigo nodularis,may be a promising therapy for patients with NS.3 We present alongitudinal …

Pretibial Myxedema: An Unusual Presentation, Dāsha Giger, Christina E. Borchers, Samia Borchers

Dermatology Faculty Publications

Pretibial myxedema presents with indurated nodules or plaques that can be erythematous or vary in color from purple-brown to yellow. It is noted that a peau d’orange appearanceis a characteristic finding. These lesions are typically located on the anterolateral aspect of the lower legs. Non-pitting edema of the shins that evolves into elephantiasis is anotherpotential presentation seen in pretibial myxedema. It is often associated with hyperthyroidism, particularly Graves disease and is more commonly seen in women than men.Typically, it presents during the third or fourth decade of life. Differential diagnoses include but are not limited to stasis dermatitis, hypertrophic lichen …

A Refined Teach-Back Observation Tool: Validity Evidence In A Pediatric Setting, Mary Ann Abrams, Kristin Garton Crichton, Edward J. Oberle, Stacy Flowers, Timothy N. Crawford, Michael F. Perry, John D. Mahan, Suzanne Reed

Family Medicine Faculty Publications

Background: Teach Back (TB) is recommended to assess and ensure patient understanding, thereby promoting safety, quality, and equity. There are many TB trainings, typically lacking assessment tools with validity evidence. We used a pediatric resident competency-based communication curriculum to develop initial validity evidence and refinement recommendations for a Teach-back Observation Tool (T-BOT).

Objective: This study aimed to develop initial validity evidence for a refined T-BOT and provide guidance for further enhancements to improve essential TB skills training among pediatric residents.

Methods: After an interactive health literacy (HL) training, residents participated in recorded standardized patient (SP) encounters. Raters developed T-BOT scoring …

Does Spasticity Correlate With Motor Impairment In The Upper And Lower Limbs In Ambulatory Chronic Stroke Survivors??, Sheng Li, Jaskiran Ghuman, Javier Gonzalez-Buonomo, Xinran Huang, Aila Malik, Nuray Yozbatiran, Gerard E Francisco, Hulin Wu, Walter R Frontera

Faculty, Staff and Student Publications

OBJECTIVE: This study aimed to explore correlations between spasticity and motor impairments in the upper and lower limbs in ambulatory chronic stroke survivors.

DESIGN: We performed clinical assessments in 28 ambulatory chronic stroke survivors with spastic hemiplegia (female: 12; male: 16; mean ages = 57.8 ± 11.8 yrs; 76 ± 45 mos after stroke).

RESULTS: In the upper limb, spasticity index and Fugl-Meyer Motor Assessment showed a significant correlation. Spasticity index for the upper limb showed a significant negative correlation with handgrip strength of the affected side ( r = -0.4, P = 0.035) while Fugl-Meyer Motor Assessment for the …

Multilevel Community Engagement To Inform A Randomized Clinical Trial, Kirby L. Wycoff, Jabina G. Coleman, Christine M. Santoro, Leah L. Zullig, Niesha Darden, Porsche M. Holland, Jane F. Cruice, Shukriyyah Mitchell, Michelle Smith, Saleemah J. Mcneil, Sharon J. Herring

Counseling and Behavioral Health Faculty Papers

OBJECTIVE: To explore how patients, community-based perinatal support professionals, and health system clinicians and staff perceived facilitators and barriers to implementation of a randomized clinical trial (RCT) designed to optimize Black maternal heart health.

METHODS: This article describes the formative work that we believed needed to occur before the start of the Change of H.E.A.R.T (Here for Equity, Advocacy, Reflection and Transformation) RCT. We used a qualitative, descriptive design and community-based, participatory approach, the latter of which allowed our team to intentionally focus on avoiding harm and equalizing power dynamics throughout the research process. Data were collected between November 2021 …

Exaggerated Cutaneous Responses In Patients With Hematologic Malignancy, Trang Nguyen, Christina E. Borchers, Julian Trevino

Dermatology Faculty Publications

Eosinophilic dermatosis of hematologic malignancy (EDHM) is a cutaneous manifestation rarely seen in Chronic lymphocytic leukemia (CLL) and chronic myelomonocytic leukemia (CMML). EDHM, first described in 19651, is identified by treatment-resistant pruritic papules, eosinophil-rich dermal lymphohistiocytic infiltrate, exclusion of other causes of tissue eosinophilia, and preexisting diagnosis of hematologic malignancy2. Similarly, arthropod hypersensitivity reactions, or insect bite hypersensitivity, also cause significant discomfort and morbidity in individuals with hematologic malignancies. Proposed treatments exist, but assessing exaggerated skin reactions as prognostic markers requires further study. We outline two clinical cases illustrating the potential spectrum of EDHM encounters.

The Diagnostic Process Of Spinal Post-Traumatic Deformity: An Expert Survey Of 7 Cases, Consensus On Clinical Relevance Does Exist, Erin E.A. De Gendt, Lori M. Benneker, Andrei F. Joaquim, Mohammad El-Sharkawi, Gaurav R. Dhakal, Frank Kandziora, Jin Tee, Richard J. Bransford, Emiliano N. Vialle, Alexander R. Vaccaro, Eugen C. Popescu, Rishi M. Kanna, David W. Polly, Klaus J. Schnake, Pedro Berjano, Sergey Ryabykh, Marko Neva, Claudio Lamartina, Dominique A Rothenfluh, Stephan J. Lewis, Sander. P.J Muijs, F. Cumhur Oner

Rothman Institute Papers

STUDY DESIGN: Survey of cases.

OBJECTIVE: To evaluate the opinion of experts in the diagnostic process of clinically relevant Spinal Post-traumatic Deformity (SPTD).

SUMMARY OF BACKGROUND DATA: SPTD is a potential complication of spine trauma that can cause decreased function and quality of life impairment. The question of when SPTD becomes clinically relevant is yet to be resolved.

METHODS: The survey of 7 cases was sent to 31 experts. The case presentation was medical history, diagnostic assessment, evaluation of diagnostic assessment, diagnosis, and treatment options. Means, ranges, percentages of participants, and descriptive statistics were calculated.

RESULTS: Seventeen spinal surgeons reviewed …

Role Of Preoperative Nerve Conduction Studies For Penetrating Hand Injuries Involving The Median Palmar Cutaneous Nerve, Saral Patel, David Hutchinson, Sebastian D. Arango, Andrew J. Miller, Rowena Mcbeath

Department of Orthopaedic Surgery Faculty Papers

Penetrating lacerations to the hand are a common cause of nerve injury and can lead to debilitating pain and numbness in the distribution of the nerve affected. Owing to an overlap in the cutaneous innervation from different sensory nerves, clinically identifying the injured nerve can be difficult. We present a novel case of isolated injury to the palmar cutaneous nerve from a penetrating knife injury which was detected using 'comparison waveform' nerve conduction studies. Using this technique, we can isolate injuries to the palmar cutaneous branch of the median nerve (PCBmdn) from the median nerve, dorsal radial sensory nerve, and …

3-Year Follow-Up Of A Prospective, Multicenter Study Of The Amplatzer Piccolo™ Occluder For Transcatheter Patent Ductus Arteriosus Closure In Children ≥ 700 Grams., Brian H. Morray, Shyam K. Sathanandam, Thomas Forbes, Matthew Gillespie, Darren Berman, Aimee K. Armstrong, Shabana Shahanavaz, Thomas Jones, Toby A. Rockefeller, Henri Justino, David Nykanen, Courtney Weiler, Dan Gutfinger, Evan M. Zahn

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: This study describes 3-year follow-up of 200 infants weighing ≥ 700 grams who underwent transcatheter patent ductus arteriosus (PDA) closure with the Amplatzer Piccolo™ Occluder.

STUDY DESIGN: Between June 2017 and February 2019, 200 children were enrolled in this U.S. study (NCT03055858). PDA closure, survival, and device- or procedure-related events were evaluated. A total of 156 of the available 182 patients (86%) completed the study.

RESULTS: The implant success rate was 95.5% (191/200). At 3 years, PDA closure was observed in 100% (33/33) of patients. Survival was >95% with 9 reported deaths. No deaths were adjudicated as device- or …

Prevalence Of Age-Related Macular Degeneration And Associated Factors In Indian Cohort In A Tertiary Care Setting, Jacqueline Hamati, Sai Prashanthi, Raja Narayanan, Niroj Sahoo, Anthony Vipin Das, Padmaja Kumari Rani, Umesh Chandra Behera, Rohit Khanna, Gudlavalleti V.S. Murthy

Student Papers, Posters & Projects

PURPOSE: To report a big data analysis of risk and protective factors in patients with AMD, as well as report on the age-adjusted prevalence in a geriatric Indian cohort in a hospital setting.

METHODS: This retrospective, observational study of all patients older than 60 years of age. Multiple logistic regression was performed for the binary outcome and the presence of AMD. Variables analyzed include age, gender, socioeconomic status, occupation, urban-rural-metropolitan distribution, self-reported history of diabetes mellitus (DM), hypertension (HTN), or coronary artery disease (CAD), ocular comorbidities, history of cataract surgery, and presenting VA. Odds ratios (OR) and 99% confidence intervals …

Co-Targeting Bcl-Xl And Bcl-2 By Protac 753b Eliminates Leukemia Cells And Enhances Efficacy Of Chemotherapy By Targeting Senescent Cells, Yannan Jia, Lina Han, Cassandra L Ramage, Zhe Wang, Connie C Weng, Lei Yang, Simona Colla, Helen Ma, Weiguo Zhang, Michael Andreeff, Naval Daver, Nitin Jain, Naveen Pemmaraju, Kapil Bhalla, Satu Mustjoki, Peiyi Zhang, Guangrong Zheng, Daohong Zhou, Qi Zhang, Marina Konopleva

Faculty, Staff and Student Publications

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) …

An Efficient Strategy For Evaluating New Non-Invasive Screening Tests For Colorectal Cancer: The Guiding Principles, Robert S Bresalier, Carlo Senore, Graeme P Young, James Allison, Robert Benamouzig, Sally Benton, Patrick M M Bossuyt, Luis Caro, Beatriz Carvalho, Han-Mo Chiu, Veerle M H Coupé, Willemijn De Klaver, Clasine Maria De Klerk, Evelien Dekker, Sunil Dolwani, Callum G Fraser, William Grady, Lydia Guittet, Samir Gupta, Stephen P Halloran, Ulrike Haug, Geir Hoff, Steven Itzkowitz, Tim Kortlever, Anastasios Koulaouzidis, Uri Ladabaum, Beatrice Lauby-Secretan, Mārcis Leja, Bernard Levin, Theodore Robert Levin, Finlay Macrae, Gerrit A Meijer, Joshua Melson, Colm O'Morain, Susan Parry, Linda Rabeneck, David F Ransohoff, Roque Sáenz, Hiroshi Saito, Silvia Sanduleanu-Dascalescu, Robert E Schoen, Kevin Selby, Harminder Singh, Robert J C Steele, Joseph J Y Sung, Erin Leigh Symonds, Sidney J Winawer, Members Of The World Endoscopy Colorectal Cancer Screening New Test Evaluation Expert Working Group

Faculty, Staff and Student Publications

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers.

DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles.

RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a …

Evaluation Of The Natural History Of Disease By Combining Incident And Prevalent Cohorts: Application To The Nun Study, Daewoo Pak, Jing Ning, Richard J Kryscio, Yu Shen

Faculty, Staff and Student Publications

The Nun study is a well-known longitudinal epidemiology study of aging and dementia that recruited elderly nuns who were not yet diagnosed with dementia (i.e., incident cohort) and who had dementia prior to entry (i.e., prevalent cohort). In such a natural history of disease study, multistate modeling of the combined data from both incident and prevalent cohorts is desirable to improve the efficiency of inference. While important, the multistate modeling approaches for the combined data have been scarcely used in practice because prevalent samples do not provide the exact date of disease onset and do not represent the target population …

A Self-Configuring Deep Learning Network For Segmentation Of Temporal Bone Anatomy In Cone-Beam Ct Imaging, Andy S Ding, Alexander Lu, Zhaoshuo Li, Manish Sahu, Deepa Galaiya, Jeffrey H Siewerdsen, Mathias Unberath, Russell H Taylor, Francis X Creighton

Faculty, Staff and Student Publications

OBJECTIVE: Preoperative planning for otologic or neurotologic procedures often requires manual segmentation of relevant structures, which can be tedious and time-consuming. Automated methods for segmenting multiple geometrically complex structures can not only streamline preoperative planning but also augment minimally invasive and/or robot-assisted procedures in this space. This study evaluates a state-of-the-art deep learning pipeline for semantic segmentation of temporal bone anatomy.

STUDY DESIGN: A descriptive study of a segmentation network.

SETTING: Academic institution.

METHODS: A total of 15 high-resolution cone-beam temporal bone computed tomography (CT) data sets were included in this study. All images were co-registered, with relevant anatomical structures …

Garetosmab In Fibrodysplasia Ossificans Progressiva: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial, Maja Di Rocco, Eduardo Forleo-Neto, Robert J Pignolo, Richard Keen, Philippe Orcel, Thomas Funck-Brentano, Christian Roux, Sami Kolta, Annalisa Madeo, Judith S Bubbear, Jacek Tabarkiewicz, Małgorzata Szczepanek, Javier Bachiller-Corral, Angela M Cheung, Kathryn M Dahir, Esmée Botman, Pieter G Raijmakers, Mona Al Mukaddam, Lianne Tile, Cynthia Portal-Celhay, Neena Sarkar, Peijie Hou, Bret J Musser, Anita Boyapati, Kusha Mohammadi, Scott J Mellis, Andrew J Rankin, Aris N Economides, Dinko Gonzalez Trotter, Gary A Herman, Sarah J O'Meara, Richard Delgizzi, David M Weinreich, George D Yancopoulos, E Marelise W Eekhoff, Frederick S Kaplan

Faculty, Staff and Student Publications

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths …

Young-Onset Rectal Cancer: Unique Tumoral Microbiome And Correlation With Response To Neoadjuvant Therapy, Michael G White, Ashish Damania, Jumanah Alshenaifi, Pranoti Sahasrabhojane, Oliver Peacock, Jillian Losh, Matthew C Wong, Zuzana Lutter-Berkova, George J Chang, Andrew Futreal, Jennifer A Wargo, Nadim J Ajami, Scott Kopetz, Y Nancy You

Faculty, Staff and Student Publications

OBJECTIVE: External exposures, the host, and the microbiome interact in oncology. We aimed to investigate tumoral microbiomes in young-onset rectal cancers (YORCs) for profiles potentially correlative with disease etiology and biology.

BACKGROUND: YORC is rapidly increasing, with 1 in 4 new rectal cancer cases occurring under the age of 50 years. Its etiology is unknown.

METHODS: YORC (old) or later-onset rectal cancer (LORC, ≥50 y old) patients underwent pretreatment biopsied of tumor and tumor-adjacent normal (TAN) tissue. After whole genome sequencing, metagenomic analysis quantified microbial communities comparing tumors versus TANs and YORCs versus LORCs, controlling for multiple testing. Response to …

Refphase: Multi-Sample Phasing Reveals Haplotype-Specific Copy Number Heterogeneity, Thomas B K Watkins, Emma C Colliver, Matthew R Huska, Tom L Kaufmann, Emilia L Lim, Cody B Duncan, Kerstin Haase, Peter Van Loo, Charles Swanton, Nicholas Mcgranahan, Roland F Schwarz

Faculty, Staff and Student Publications

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient's disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample phasing. We demonstrate Refphase's ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.

Emphasizing Others’ Persistence Can Promote Unwarranted Social Inferences In Children And Adults, Jamie Amemiya, Gail D Heyman, Caren M Walker

Faculty, Staff and Student Publications

People often hear stories about individuals who persist to overcome their constraints. While these stories can be motivating, emphasizing others’ persistence may promote unwarranted judgments about constrained individuals who do not persist. Using a developmental social inference task (Study 1a: n = 124 U.S. children, 5 to 12 years of age; Study 1b [n = 135] and Study 2 [n = 120]: U.S. adults), the present research tested whether persistence stories lead people to infer that a constrained individual who does not persist, and instead accepts the lower-quality option that is available to them, prefers it over a …

Prevalence Of Pituitary Hormone Dysfunction Following Radiotherapy For Sinonasal And Nasopharyngeal Malignancies, Kevin J Contrera, Jack Phan, Steven G Waguespack, Mohammed Aldehaim, Xin Wang, Tze Yee Lim, Dianna B Roberts, C David Fuller, Michael T Spiotto, Shaan M Raza, Franco Demonte, Ehab Y Hanna, Shirley Y Su

Faculty, Staff and Student Publications

BACKGROUND: There are limited studies and no surveillance protocols on pituitary dysfunction for adults who underwent anterior skull base radiation.

METHODS: Cross-sectional study of 50 consecutive patients with sinonasal or nasopharyngeal cancer who underwent definitive radiotherapy. The mean radiation doses, prevalence of pituitary dysfunction, and associated factors were calculated.

RESULTS: Pituitary hormone levels were abnormal in 23 (46%) patients, including 6 (12%) with symptomatic abnormalities requiring treatment. The most common hormonal abnormality was hyperprolactinemia (30%), central hypothyroidism (8%) and central hypogonadism (6%). Patients with abnormal pituitary hormone values received higher mean radiation doses to the pituitary gland (1143 cGy, P …

Single-Agent Lenalidomide Maintenance After Upfront Autologous Stem Cell Transplant For Newly Diagnosed Multiple Myeloma: The Md Anderson Experience, Oren Pasvolsky, Denái R Milton, Adeel Masood, Sophiya S Sami, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Arsalan Saeed, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

The optimal duration of lenalidomide (Len) maintenance for patients with multiple myeloma (MM) after autologous stem cell transplantation (autoHCT) is unknown. We conducted a retrospective single-center analysis of adult MM patients that received upfront autoHCT between 2005 and 2021, followed by single-agent Len maintenance. A total of 1167 patients were included with a median age of 61.4 (range 25.4-82.3) years, and high-risk chromosomal abnormalities in 19%. Median duration of maintenance was 22.3 (range 0.03-139.6) months. After a median follow-up of 47.9 (range 2.9-171.7) months, median PFS and OS for the entire cohort were 56.6 (95% CI 48.2-61.4) months and 111.3 …

A Machine Learning Approach That Measures Ph Using Acidocest Mri Of Iopamidol, Tianzhe Li, Julio Cárdenas-Rodríguez, Priya N Trakru, Mark D Pagel

Faculty, Staff and Student Publications

Tumor acidosis is an important biomarker for aggressive tumors, and extracellular pH (pHe) of the tumor microenvironment can be used to predict and evaluate tumor responses to chemotherapy and immunotherapy. AcidoCEST MRI measures tumor pHe by exploiting the pH-dependent chemical exchange saturation transfer (CEST) effect of iopamidol, an exogenous CT agent repurposed for CEST MRI. However, all pH fitting methodologies for acidoCEST MRI data have limitations. Herein we present results of the application of machine learning for extracting pH values from CEST Z-spectra of iopamidol. We acquired 36,000 experimental CEST spectra from 200 phantoms of iopamidol prepared at five concentrations, …