Biomedical Informatics Commons^™

Real-World Trends, Rural-Urban Differences, And Socioeconomic Disparities In Utilization Of Narrow Versus Broad Next-Generation Sequencing Panels, Yiqing Zhao, Anastasios Dimou, Zachary C Fogarty, Jun Jiang, Hongfang Liu, William B Wong, Chen Wang

Faculty, Staff and Student Publications

UNLABELLED: Advances in genetic technology have led to the increasing use of genomic panels in precision oncology practice, with panels ranging from a couple to hundreds of genes. However, the clinical utilization and utility of oncology genomic panels, especially among vulnerable populations, is unclear. We examined the association of panel size with socioeconomic status and clinical trial matching. We retrospectively identified 9,886 eligible adult subjects in the Mayo Clinic Health System who underwent genomic testing between January 1, 2016 and June 30, 2020. Patient data were retrieved from structured and unstructured data sources of institutional collections, including cancer registries, clinical …

Health Economic Consequences Associated With Covid-19-Related Delay In Melanoma Diagnosis In Europe, Lara V Maul, Dagmar Jamiolkowski, Rebecca A Lapides, Alina M Mueller, Axel Hauschild, Claus Garbe, Paul Lorigan, Jeffrey E Gershenwald, Paolo Antonio Ascierto, Georgina V Long, Michael Wang-Evers, Richard A Scolyer, Babak Saravi, Matthias Augustin, Alexander A Navarini, Stefan Legge, István B Németh, Ágnes J Jánosi, Simone Mocellin, Anita Feller, Dieter Manstein, Alexander Zink, Julia-Tatjana Maul, Alessandra Buja, Kaustubh Adhikari, Elisabeth Roider

Faculty, Staff and Student Publications

IMPORTANCE: The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet.

OBJECTIVE: To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous …

Evaluation Of A Tiered Opioid Prescription Algorithm In An Eras Pathway: Exploring Opportunities For Further Refinement, M Sol Basabe, Tina S Suki, Mark F Munsell, Maria D Iniesta, Juan E Garcia Lopez, Robert Tyler Hillman, Katherine Cain, Sarah Huepenbecker, Gabriel Mena, Jolyn S Taylor, Pedro T Ramirez, Larissa A Meyer

Faculty, Staff and Student Publications

Background: Opioid over-prescription is wasteful and contributes to the opioid crisis. We implemented a personalized tiered discharge opioid protocol and education on opioid disposal to minimize over-prescription.

Objective: To evaluate the intervention by investigating opioid use post-discharge for women undergoing abdomino-pelvic surgery, and patient adherence to opioid disposal education.

Methods: We analyzed post-discharge opioid consumption among 558 patients. Eligible patients included those who underwent elective gynecologic surgery, were not taking scheduled opioids pre-operatively, and received discharge opioids according to a tiered prescribing algorithm. A survey assessing discharge opioid consumption and disposal safety knowledge was distributed on post-discharge day 21. Over-prescription …

Neurologic Morbidity And Functional Independence In Adult Survivors Of Childhood Cancer, Stefanie C Vuotto, Mingjuan Wang, M Fatih Okcu, Daniel C Bowers, Nicole J Ullrich, Kirsten K Ness, Chenghong Li, Deo Kumar Srivastava, Rebecca M Howell, Todd M Gibson, Wendy M Leisenring, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

OBJECTIVE: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies.

METHODS: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal …

Phase 2 Study Of Inotuzumab Ozogamicin For Measurable Residual Disease In Acute Lymphoblastic Leukemia In Remission, Elias Jabbour, Fadi G Haddad, Nicholas J Short, Jayastu Senapati, Nitin Jain, Koji Sasaki, Jeffrey Jorgensen, Sa A Wang, Yesid Alvarado, Xuemei Wang, Courtney Dinardo, Lucia Masarova, Tapan Kadia, Rebecca S Garris, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10-4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) …

Intracranial Volume Is Driven By Both Genetics And Early Life Exposures: The Sol-Inca-Mri Study, Tamar Sofer, Einat Granot-Hershkovitz, Wassim Tarraf, Paola Filigrana, Carmen R Isasi, Shakira F Suglia, Robert Kaplan, Kent Taylor, Martha L Daviglus, Fernando D Testai, Donglin Zeng, Jianwen Cai, Myriam Fornage, Hector M González, Charles Decarli

Faculty, Staff and Student Publications

Intracranial volume (ICV) reflects maximal brain development and is associated with later-life cognitive abilities. We quantified ICV among first- and second-generation Hispanic and Latino adults from the Study of Latinos-Investigation of Cognitive Aging - MRI (SOL-INCA-MRI), estimated ICV heritability, and tested its associations with previously reported genetic variants, both individually and as a genetic risk score (GRS). We also estimated the association of ICV with early life environmental measures: nativity or age of immigration and parental education. The estimated heritability of ICV was 19% (95% CI, 0.1%-56%) in n=1781 unrelated SOL-INCA-MRI individuals. Four of 10 tested genetic variants were associated …

Sox11+ Large B-Cell Neoplasms: Cyclin D1-Negative Blastoid/Pleomorphic Mantle Cell Lymphoma Or Large B-Cell Lymphoma?, Shaoying Li, Guilin Tang, Preetesh Jain, Pei Lin, Jie Xu, Roberto N Miranda, Joanne Cheng, C Cameron Yin, M James You, Michael L Wang, L Jeffrey Medeiros

Faculty, Staff and Student Publications

Large or blastoid B-cell neoplasms that are SOX11+ are a diagnostic dilemma and raise a differential diagnosis of cyclin D1-negative blastoid/pleomorphic mantle cell lymphoma (MCL) versus diffuse large B-cell lymphoma (DLBCL) or blastoid high-grade B-cell lymphoma (HGBL) with aberrant SOX11 expression. Here we report a study cohort of 13 SOX11+ large/blastoid B-cell neoplasms. Fluorescence in situ hybridization analysis was negative for CCND1 rearrangement in all 13 cases; 1 of 8 (12.5%) cases tested showed CCND2 rearrangement and 2 (25%) cases had extracopies of CCND2. Gene expression profiling showed that the study group had a gene expression signature similar to cyclin …

Characteristics And Outcomes Of Patients With Multiple Myeloma Who Developed Therapy-Related Acute Myeloid Leukemia And Myelodysplastic Syndrome After Autologous Cell Transplantation, Fevzi F Yalniz, Uri Greenbaum, Oren Pasvolsky, Denái R Milton, Rashmi Kanagal-Shamanna, Jeremy Ramdial, Samer Srour, Rohtesh Mehta, Amin Alousi, Uday R Popat, Yago Nieto, Partow Kebriaei, Gheath Al-Atrash, Betul Oran, Chitra Hosing, Sairah Ahmed, Richard E Champlin, Elizabeth J Shpall, Muzaffar H Qazilbash, Qaiser Bashir

Faculty, Staff and Student Publications

Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1 January and 31 December 2018 and later developed t-MDS/AML. Among the 2982 patients who underwent at least 1 Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n = 52; AML, n = 3). The median age at t-MDS/AML diagnosis was 66 years (range 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis …

Gli1-Altered Mesenchymal Tumors With Actb Or Ptch1 Fusion: A Molecular And Clinicopathologic Analysis, Darcy A Kerr, Jeffrey M Cloutier, Matthew Margolis, Douglas A Mata, Nathalie J Rodrigues Simoes, William C Faquin, Dora Dias-Santagata, Shefali Chopra, Gregory W Charville, Sintawat Wangsiricharoen, Alexander J Lazar, Wei-Lien Wang, Andrew E Rosenberg, Julie Y Tse

Faculty, Staff and Student Publications

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, …

Oral Toxicities Associated With Immune Checkpoint Inhibitors: Meta-Analyses Of Clinical Trials, Akanksha Srivastava, Graciela M Nogueras-Gonzalez, Yimin Geng, Jasdev Singh, Jeffrey N Myers, Yisheng Li, Mark S Chambers

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their oral toxicity profile is not well elucidated. This review aimed to investigate the prevalence of oral toxicities including xerostomia, mucositis/stomatitis, dysgeusia, dysphagia, oral/oropharyngeal pain, oral infections, angular cheilitis, osteonecrosis, osteomyelitis, and oral mucosal reactions with ICIs. A review protocol was registered with PROSPERO (ID: CRD42023391674). A systematic search of ClinicalTrials.gov was conducted as of April 10, 2022. Studies were selected, assessed, and data extracted using PRISMA guidelines. Oral toxicity data were extracted from study arms using a single immunotherapy drug. Meta-analyses were conducted to summarize prevalence of oral toxicities using …

Allogeneic Stem Cell Therapy For Acute Ischemic Stroke: The Phase 2/3 Treasure Randomized Clinical Trial, Kiyohiro Houkin, Toshiya Osanai, Shinichiro Uchiyama, Kazuo Minematsu, Akihiko Taguchi, Katsuhiko Maruichi, Yoshimasa Niiya, Katsuyuki Asaoka, Yoshihiro Kuga, Katsumi Takizawa, Koichi Haraguchi, Shinichi Yoshimura, Kazumi Kimura, Koji Tokunaga, Atsuo Aoyama, Fusao Ikawa, Chikanori Inenaga, Tatsuya Abe, Atsushi Tominaga, Shinichi Takahashi, Kohsuke Kudo, Miki Fujimura, Taku Sugiyama, Masaki Ito, Masahito Kawabori, David C Hess, Sean I Savitz, Teruyuki Hirano

Faculty, Staff and Student Publications

IMPORTANCE: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke.

OBJECTIVE: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset.

DESIGN, SETTING, AND PARTICIPANTS: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were …

Ex Vivo Expanded Cord Blood Natural Killer Cells Combined With Rituximab And High-Dose Chemotherapy And Autologous Stem Cell Transplantation For B Cell Non-Hodgkin Lymphoma, Yago Nieto, Pinaki Banerjee, Indresh Kaur, Kun Hee Kim, Dexing Fang, Peter F Thall, Lori Griffin, Melissa Barnett, Rafet Basar, Chitra Hosing, Jeremy Ramdial, Samer Srour, May Daher, David Marin, Xianli Jiang, Ken Chen, Richard Champlin, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Relapse is the major cause of failure of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) for B cell non-Hodgkin lymphomas (B-NHL). Improvement strategies include use in combination with effective immunotherapies. We hypothesized that the combination of rituximab/HDC/ASCT with expanded cord blood (CB)-derived natural killer (NK) cells is safe and active in B-NHL. Patients with B-NHL age 15 to 70 years and appropriate ASCT candidates were eligible for the study. The CB units were selected without considering HLA match with the recipient. The CB NK cells were expanded from day -19 to day -5. Treatment included rituximab on days …

Association Between Circulating Inflammatory Markers And Adult Cancer Risk: A Mendelian Randomization Analysis, James Yarmolinsky, Jamie W Robinson, Daniela Mariosa, Ville Karhunen, Jian Huang, Niki Dimou, Neil Murphy, Kimberley Burrows, Emmanouil Bouras, Karl Smith-Byrne, Sarah J Lewis, Tessel E Galesloot, Lambertus A Kiemeney, Sita Vermeulen, Paul Martin, Demetrius Albanes, Lifang Hou, Polly A Newcomb, Emily White, Alicja Wolk, Anna H Wu, Loïc Le Marchand, Amanda I Phipps, Daniel D Buchanan, International Lung Cancer Consortium, Practical Consortium, Sizheng Steven Zhao, Dipender Gill, Stephen J Chanock, Mark P Purdue, George Davey Smith, Paul Brennan, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Chris I Amos, Rayjean J Hung, Abbas Dehghan, Mattias Johansson, Marc J Gunter, Kostas K Tsilidis, Richard M Martin

Faculty, Staff and Student Publications

BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.

METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were …

Long-Term Non-Progression And Risk Factors For Disease Progression Among Children Living With Hiv In Botswana And Uganda: A Retrospective Cohort Study, Samuel Kyobe, Grace Kisitu, Savannah Mwesigwa, John Farirai, Eric Katagirya, Gaone Retshabile, Lesedi Williams, Angela Mirembe, Lesego Ketumile, Misaki Wayengera, John Mukisa, Gaseene Sebetso, Thabo Diphoko, Marion Amujal, Edgar Kigozi, Fred Katabazi, Ronald Oceng, Busisiwe Mlotshwa, Koketso Morapedi, Betty Nsangi, Edward Wampande, Masego Tsimako, Chester Brown, Ishmael Kasvosve, Moses Joloba, Gabriel Anabwani, Sununguko Mpoloka, Graeme Mardon, Adeodata Kekitiinwa, Neil A Hanchard, Jacqueline Kyosiimire-Lugemwa, Mogomotsi Matshaba, Dithan Kiragga

Faculty, Staff and Students Publications

OBJECTIVES: We utilize a large retrospective study cohort derived from electronic medical records to estimate the prevalence of long-term non-progression (LTNP) and determine the factors associated with progression among children infected with HIV in Botswana and Uganda.

METHODS: Electronic medical records from large tertiary HIV clinical centers in Botswana and Uganda were queried to identify LTNP children 0-18 years enrolled between June 2003 and May 2014 and extract demographic and nutritional parameters. Multivariate subdistribution hazard analyses were used to examine demographic factors and nutritional status in progression in the pre-antiretroviral therapy era.

RESULTS: Between the two countries, 14,246 antiretroviral therapy-naïve …

Expression Of Atoh1, Gfi1, And Pou4f3 In The Mature Cochlea Reprograms Nonsensory Cells Into Hair Cells, Melissa M Mcgovern, Ishwar V Hosamani, Yichi Niu, Ken Y Nguyen, Chenghang Zong, Andrew K Groves

Faculty, Staff and Students Publications

Mechanosensory hair cells of the mature mammalian organ of Corti do not regenerate; consequently, loss of hair cells leads to permanent hearing loss. Although nonmammalian vertebrates can regenerate hair cells from neighboring supporting cells, many humans with severe hearing loss lack both hair cells and supporting cells, with the organ of Corti being replaced by a flat epithelium of nonsensory cells. To determine whether the mature cochlea can produce hair cells in vivo, we reprogrammed nonsensory cells adjacent to the organ of Corti with three hair cell transcription factors: Gfi1, Atoh1, and Pou4f3. We generated numerous hair cell–like …

Systematic Review Of Mortality And Survival Rates For Apds, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical …

Short-Term Impact Of Low-Intensity Exercise With Blood Flow Restriction On Mild Knee Osteoarthritis In Older Adults: A Pilot Study, Kang-Ho Kim, Seung-Ho Kang, Nackhwan Kim, Jaehyeong Choi, Seok Kang

Faculty, Staff and Student Publications

This pilot study aimed to investigate the immediate impact of low-intensity exercises with blood flow restriction (BFR) on older adults with knee osteoarthritis (KOA). Fifteen patients with KOA who were over 50 years old, participated and underwent low-intensity resistance knee exercises at 30% of their one-repetition maximum with BFR three times/week for two weeks. Pre- and post-exercise assessments included pain levels, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, isokinetic knee strength, lower extremity muscle volume (via leg circumference and muscle thickness), functional performance tests (timed up-and-go [TUG] and sit-to-stand [STS]), skeletal muscle index (SMI) using bioelectrical impedance analysis, …

Mypathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment Of A Tissue-Agnostic Cohort Of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors, Christopher J Sweeney, John D Hainsworth, Ron Bose, Howard A Burris, Razelle Kurzrock, Charles Swanton, Claire F Friedman, David R Spigel, Tania Szado, Katja Schulze, Richard Price, Julia Malato, Amy A Lo, Jonathan Levy, Yong Wang, Wei Yu, Funda Meric-Bernstam

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 MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor …

Analysis Of Breast Cancer Mortality In The Us-1975 To 2019, Jennifer L Caswell-Jin, Liyang P Sun, Diego Munoz, Ying Lu, Yisheng Li, Hui Huang, John M Hampton, Juhee Song, Jinani Jayasekera, Clyde Schechter, Oguzhan Alagoz, Natasha K Stout, Amy Trentham-Dietz, Sandra J Lee, Xuelin Huang, Jeanne S Mandelblatt, Donald A Berry, Allison W Kurian, Sylvia K Plevritis

Faculty, Staff and Student Publications

IMPORTANCE: Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear.

OBJECTIVE: To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality.

DESIGN, SETTING, AND PARTICIPANTS: Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by …

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

The Irish National Chronic Obstructive Pulmonary Disease Quality Improvement Collaborative: An Adaptive Learning Collaborative, Orla Woods, Rachel Macdonell, John Brennan, Lucia Prihodova, Breda Cushen, Richard W Costello, Timothy J Mcdonnell

Faculty, Staff and Student Publications

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the the most common disease-specific cause of adult emergency hospital admissions in Ireland. Preliminary groundwork indicated that treatment of acute exacerbations of COPD (AECOPD) in Ireland is not standardised between public hospitals. Applying Institute for Healthcare Improvement Breakthrough Series and Model for Improvement methodologies, Royal College of Physicians of Ireland designed and conducted a novel flexible and adaptive quality improvement (QI) collaborative which, using embedded evaluation, aimed to deliver QI teaching to enable teams to implement bespoke, locally applicable changes to improve and standardise acute COPD care at presentation, admission and discharge stages …

Sirtuin 2 Inhibition Modulates Chromatin Landscapes Genome-Wide To Induce Senescence In Atrx-Deficient Malignant Glioma, Prit Benny Malgulwar, Carla Danussi, Sharvari Dharmaiah, William Johnson, Anand Singh, Kunal Rai, Arvind Rao, Jason T Huse

Faculty, Staff and Student Publications

BACKGROUND: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped.

METHODS: We utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s).

RESULTS: CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator …

A Phase 2 Trial Of Cd24fc For Prevention Of Graft-Versus-Host Disease, John Magenau, Samantha Jaglowski, Joseph Uberti, Sherif S Farag, Mary Mansour Riwes, Attaphol Pawarode, Sarah Anand, Monalisa Ghosh, John Maciejewski, Thomas Braun, Martin Devenport, Susan Lu, Bhramori Banerjee, Carolyn Dasilva, Steven Devine, Mei-Jie Zhang, Linda J Burns, Yang Liu, Pan Zheng, Pavan Reddy

Faculty, Staff and Students Publications

Patients who undergo human leukocyte antigen–matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor–based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, …

A Syndromic Neurodevelopmental Disorder Caused By Rare Variants In Ppfia3, Maimuna S Paul, Sydney L Michener, Hongling Pan, Hiuling Chan, Jessica M Pfliger, Jill A Rosenfeld, Vanesa C Lerma, Alyssa Tran, Megan A Longley, Richard A Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L Mester, Maria J Guillen Sacoto, Richard Person, Pamela P Mcdonnell, Stacey R Cohen, Laina Lusk, Ana S A Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé-Pichon, Hyun Yong Koh, Annapurna Poduri, Jeffrey Bolton, Cordula Knopp, Dong Sun Julia Suh, Andrea Maier, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Reza Maroofian, Gerald Bradley Schaefer, Vijayalakshmi Ramakumaran, Pradeep Vasudevan, Chitra Prasad, Matthew Osmond, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E Scheffer, Gemma L Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A Bacino, Brendan H Lee, Hsiao-Tuan Chao

Faculty, Staff and Students Publications

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity …

Effect Of Acupuncture Vs Sham Acupuncture On Patients With Poststroke Motor Aphasia: A Randomized Clinical Trial, Boxuan Li, Shizhe Deng, Bifang Zhuo, Bomo Sang, Junjie Chen, Menglong Zhang, Guang Tian, Lili Zhang, Yuzheng Du, Peng Zheng, Gonglei Yue, Zhihong Meng

Faculty, Staff and Student Publications

IMPORTANCE: Motor aphasia is common among patients with stroke. Acupuncture is recommended as an alternative therapy for poststroke aphasia, but its efficacy remains uncertain.

OBJECTIVE: To investigate the effects of acupuncture on language function, neurological function, and quality of life in patients with poststroke motor aphasia.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, sham-controlled, randomized clinical trial was conducted in 3 tertiary hospitals in China from October 21, 2019, to November 13, 2021. Adult patients with poststroke motor aphasia were enrolled. Data analysis was performed from February to April 2023.

INTERVENTIONS: Eligible participants were randomly allocated (1:1) to manual acupuncture (MA) …

Effect Of S-Ketamine On Postoperative Nausea And Vomiting In Patients Undergoing Video-Assisted Thoracic Surgery: A Randomized Controlled Trial, Yu Qi, Meiyan Zhou, Wenting Zheng, Yaqi Dong, Weihua Li, Long Wang, Haijun Xu, Miao Zhang, Dunpeng Yang, Liwei Wang, Hai Zhou

Faculty, Staff and Student Publications

PURPOSE: Postoperative nausea and vomiting (PONV) frequently occur in patients after surgery. In this study, the authors investigated whether perioperative S-ketamine infusion could decrease the incidence of PONV in patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy.

PATIENTS AND METHODS: This prospective, randomized, double-blinded, controlled study was conducted a total of 420 patients from September 2021 to May 2023 at Xuzhou Central Hospital in China, who underwent elective VATS lobectomy under general anesthesia with tracheal intubation. The patients were randomly assigned to either the S-ketamine group or the control group. The S-ketamine group received a bolus injection of 0.5 mg/kg S-ketamine …

Association Between Symptom Burden And Early Lymphatic Abnormalities After Regional Nodal Irradiation For Breast Cancer, Alison K Yoder, Tianlin Xu, Peter Youssef, Sarah Desnyder, Kathryn E Marqueen, Lynn Isales, Ruitao Lin, Benjamin D Smith, Wendy A Woodward, Michael C Stauder, Eric A Strom, Melissa B Aldrich, Simona F Shaitelman

Faculty, Staff and Student Publications

PURPOSE: Dermal backflow visualized on near-infrared fluorescence lymphatic imaging (NIRF-LI) signals preclinical lymphedema that precedes the development of volumetrically defined lymphedema. We sought to evaluate whether dermal backflow correlates with patient-reported lymphedema outcomes (PRLO) surveys in breast cancer patients treated with regional nodal irradiation (RNI).

METHODS AND MATERIALS: Patients with breast cancer planned for axillary dissection and RNI prospectively underwent perometry, NIRF-LI, and PRLOs (the Lymphedema Symptom Intensity and Distress Survey [LSIDS] and QuickDASH) at baseline, after surgery, and at 6, 12, and 18 months after radiation. Clinical lymphedema was defined as an arm volume increase ≥5% over baseline. Trends …

Hpv Vaccination In Africa In The Covid-19 Era: A Cross-Sectional Survey Of Healthcare Providers' Knowledge, Training, And Recommendation Practices, Joel Fokom Domgue, Issimouha Dille, Sharon Kapambwe, Robert Yu, Freddy Gnangnon, Lameck Chinula, Gad Murenzi, Nomonde Mbatani, Mala Pande, Fatoumata Sidibe, Joseph Kamgno, Bangaly Traore, Hicham El Fazazi, Mamadou Diop, Pierre-Marie Tebeu, Mohenou Isidore Diomande, Fabrice Lecuru, Isaac Adewole, Marie Plante, Partha Basu, Jean-Marie Dangou, Sanjay Shete

Faculty, Staff and Student Publications

INTRODUCTION: Although the burden of cervical cancer in Africa is highest, HPV vaccination coverage remains alarmingly low in this region. Providers' knowledge and recommendation are key drivers of HPV vaccination uptake. Yet, evidence about providers' knowledge and recommendation practices about the HPV vaccine against a backdrop of emerging vaccine hesitancy fueled by the COVID-19 pandemic is lacking in Africa.

METHODS: A cross-sectional study was conducted in 2021-2022 among healthcare providers involved in cervical cancer prevention activities in Africa. They were invited to report prior training, the availability of the HPV vaccine in their practice, whether they recommended the HPV vaccine, …

Rare Genomic Copy Number Variants Implicate New Candidate Genes For Bicuspid Aortic Valve, Steven G Carlisle, Hasan Albasha, Hector I Michelena, Anna Sabate-Rotes, Lisa Bianco, Julie De Backer, Laura Muiño Mosquera, Anji T Yetman, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S Hui, Anthony Caffarelli, Yuli Y Kim, Dongchuan Guo, Rodolfo Citro, Margot De Marco, Justin T Tretter, Kim L Mcbride, Dianna M Milewicz, Simon C Body, Siddharth K Prakash, Ebav Investigators, Bavcon Investigators

Faculty, Staff and Student Publications

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control …

Exploratory Pilot Study To Characterize The Immune Landscapes Of Malignant Pleural Effusions And Their Corresponding Primary Tumors From Patients With Breast Carcinoma And Lung Adenocarcinoma, Caddie Laberiano-Fernandez, Qiong Gan, Sophia Mei Wang, Auriole Tamegnon, Ignacio Wistuba, Esther Yoon, Sinchita Roy-Chowdhuri, Edwin Roger Parra

Faculty, Staff and Student Publications

Introduction: Malignant pleural effusion (MPE) is a frequent complication of advanced malignancies. In this pilot study, we characterized the immune landscapes of MPEs, compared them to their primary tumor (PT) samples from breast carcinoma (BC) and lung adenocarcinoma (LADC), and tested the utility of multiplexed image technology in cytological samples.

Materials and methods: We evaluated the immune contexture of 6 BC and 5 LADC MPEs and their PTs using 3 multiplex immunofluorescence panels. We explored the associations between sample characteristics and pleural effusion-free survival.

Results: No MPE samples had positive programmed death-ligand 1 expression in malignant cells, although 3 of …