Medicine and Health Sciences Commons^™

Epigenetic-Metabolic Interplay In The Dna Damage Response And Therapeutic Resistance Of Breast Cancer, Chandrima Das, Swagata Adhikari, Apoorva Bhattacharya, Sanjukta Chakraborty, Payel Mondal, Shalini S Yadav, Santanu Adhikary, Clayton R Hunt, Kamlesh K Yadav, Shruti Pandita, Siddhartha Roy, John A Tainer, Zamal Ahmed, Tej K Pandita

Faculty, Staff and Student Publications

Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic-metabolic …

Bi-Allelic Tti1 Variants Cause An Autosomal-Recessive Neurodevelopmental Disorder With Microcephaly, Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M R Taylor, Jennifer A Sullivan, Ayat N Asleh, Jaba Mitra, Mohamad A Dar, Amy Mcnamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R Roeder, Rebecca Okashah Littlejohn, Harpreet K Dibra, Philip J Byrd, Grant S Stewart, Bilgen B Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey-Anne Evans, Gabrielle Lemire, Grace E Vannoy, Anne O'Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F Buckley, Christel Thauvin, George K Essien Umanah, Lionel Van Maldergem, James R Lupski, Tony Roscioli, Valina L Dawson, Ted M Dawson, Stylianos E Antonarakis

Faculty, Staff and Student Publications

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of …

Effects Of Protein-Coding Variants On Blood Metabolite Measurements And Clinical Biomarkers In The Uk Biobank, Abhishek Nag, Ryan S Dhindsa, Lawrence Middleton, Xiao Jiang, Dimitrios Vitsios, Eleanor Wigmore, Erik L Allman, Anna Reznichenko, Keren Carss, Katherine R Smith, Quanli Wang, Benjamin Challis, Dirk S Paul, Andrew R Harper, Slavé Petrovski

Faculty, Staff and Students Publications

Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10

Evaluating The Impact Of Long Read Genomes In Rare Disease: A Systematic Analysis Of 1000 Hifi Genomes, Emily Farrow, Isabelle Thiffault, Ana S A Cohen, Tricia N. Zion, Adam Walter, Margaret Gibson, Chengpeng Bi, Warren A. Cheung, Jeffrey J. Johnston, T Pastinen

Posters

Introduction: Genomic technologies continue to advance at a rapid rate, leading to continued novel gene-disease discoveries. However, despite the exponential increase in new gene discoveries, diagnostic rates in rare disease continue to range from 30-50%. To evaluate the impact of long read genome sequencing (lrGS) in a rare disease cohort, lrGS was implemented systematically in an institution-wide research program, Genomic Answers for Kids (GA4K). Methods: Individuals enrolled in GA4K, with a suspected genetic disorder, that remained undiagnosed after exome or genome sequencing, were submitted for HiFi sequencing. Probands were sequenced to a target depth of 30X coverage. Analyses included copy …

A Case Of Hexasomy 15q Due To A Tricentric Supernumerary Chromosome 15, Emily Farrow, Laura A. Cross, Bonnie Sullivan, Keely M. Fitzgerald, Joseph Alaimo, Elena Repnikova, John Herriges, Lei Zhang

Posters

Background: A 7-month-old male with a history of developmental delay, plagiocephaly, hypotonia, chronic cough/congestion was admitted for abnormal movements. Prolonged EEG revealed focal epilepsy and epileptic spasms. Genetic testing revealed a complex structurally rearranged chromosome 15 which contains two inverted duplicated chromosome 15s joined together at one end, resulting in partial hexasomy for 15q. Case presentation: The proband was born to a G2P2 33-year-old mother following an uncomplicated pregnancy at 40 weeks 2 days gestation. At birth he was 6lbs 8oz, 20in long, and APGARs were 3/5/9 at 1/5/10 minutes. At delivery he was limp, pale and had poor tone …

Potential Mirna Biomarkers And Therapeutic Targets For Early Atherosclerotic Lesions, Genesio M. Karere, Jeremy P. Glenn, Ge Li, Ayati Konar, John L. Vandeberg, Laura A. Cox

School of Medicine Publications

Identification of potential therapeutic targets and biomarkers indicative of burden of early atherosclerosis that occur prior to advancement to life-threatening unstable plaques is the key to eradication of CAD prevalence and incidences. We challenged 16 baboons with a high cholesterol, high fat diet for 2 years and evaluated early-stage atherosclerotic lesions (fatty streaks, FS, and fibrous plaques, FP) in formalin-fixed common iliac arteries (CIA). We used small RNA sequencing to identify expressed miRNAs in CIA and in baseline blood samples of the same animals. We found 412 expressed miRNAs in CIA and 356 in blood samples. Eight miRNAs (miR-7975, -486-5p, …

Expansion Of The Genotypic And Phenotypic Spectrum Of Ctcf-Related Disorder Guides Clinical Management: 43 New Subjects And A Comprehensive Literature Review, Hannah Gabriela Valverde De Morales, Hsiao-Lin V Wang, Kathryn Garber, Xiaodong Cheng, Victor G Corces, Hong Li

Faculty, Staff and Student Publications

Monoallelic variants of CTCF cause an autosomal dominant neurodevelopmental disorder with a wide range of features, including impacts on the brain, growth, and craniofacial development. A growing number of subjects with CTCF-related disorder (CRD) have been identified due to the increased application of exome sequencing, and further delineation of the clinical spectrum of CRD is needed. Here, we examined the clinical features, including facial profiles, and genotypic spectrum of 107 subjects with identified CTCF variants, including 43 new and 64 previously described subjects. Among the 43 new subjects, 23 novel variants were reported. The cardinal clinical features in subjects with …

Mitochondrial Structure And Function Adaptation In Residual Triple Negative Breast Cancer Cells Surviving Chemotherapy Treatment, Mokryun L Baek, Junegoo Lee, Katherine E Pendleton, Mariah J Berner, Emily B Goff, Lin Tan, Sara A Martinez, Iqbal Mahmud, Tao Wang, Matthew D Meyer, Bora Lim, James P Barrish, Weston Porter, Philip L Lorenzi, Gloria V Echeverria

Faculty, Staff and Student Publications

Neoadjuvant chemotherapy (NACT) used for triple negative breast cancer (TNBC) eradicates tumors in ~45% of patients. Unfortunately, TNBC patients with substantial residual cancer burden have poor metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several chemotherapy agents …

Parents’ Decision-Making Regarding Whether To Receive Adult-Onset Only Genetic Findings For Their Children: Findings From The Babyseq Project, Stacey Pereira, Amanda M Gutierrez, Jill Oliver Robinson, Kurt D Christensen, Casie A Genetti, Carrie L Blout Zawatsky, Rebecca L Hsu, Bethany Zettler, Melissa Kurtz Uveges, Richard B Parad, Alan H Beggs, Ingrid A Holm, Robert C Green, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Most professional guidelines recommend against genetic screening for adult-onset only (AO) conditions until adulthood, yet others argue that there may be benefit to disclosing such results. We explored parents' decision-making on this issue in the BabySeq Project, a clinical trial of newborn genomic sequencing.

Methods: We conducted interviews with parents (N = 24) who were given the option to receive actionable AO results for their children. Interviews explored parents' motivations to receive and reasons to decline AO genetic disease risk information, their decision-making process, and their suggestions for supporting parents in making this decision.

Results: Parents noted several motivations …

Replication Competent Retrovirus Testing (Rcr) In The National Gene Vector Biorepository: No Evidence Of Rcr In 1,595 Post-Treatment Peripheral Blood Samples Obtained From 60 Clinical Trials, Kenneth Cornetta, Jing Yao, Kimberley House, Lisa Duffy, Prasad S Adusumilli, Rachel Beyer, Claire Booth, Malcolm Brenner, Kevin Curran, Bambi Grilley, Helen Heslop, Christian S Hinrichs, Rosandra N Kaplan, Hans-Peter Kiem, James Kochenderfer, Donald B Kohn, Sham Mailankody, Scott M Norberg, Roisin E O'Cearbhaill, Jennifer Pappas, Jae Park, Carlos Ramos, Antonio Ribas, Isabelle Rivière, Steven A Rosenberg, Craig Sauter, Nirali N Shah, Susan F Slovin, Adrian Thrasher, David A Williams, Tsai-Yu Lin

Center for Medical Ethics and Health Policy Staff Publications

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far …

Prospective Study Of Pain Outcomes Associated With Breast Surgery In Women With Nonhereditary Breast Cancer, Demetria J Smith-Graziani, Patricia A Parker, Susan K Peterson, Isabelle Bedrosian, Y Shen, Dalliah M Black, Sarah M Desnyder, Kelly K Hunt, Wenli Dong, Abenaa M Brewster

Faculty, Staff and Student Publications

Objective: To assess pain severity and interference with life in women after different types of breast cancer surgery and the demographic, treatment-related, and psychosocial variables associated with these pain outcomes.

Summary of background data: Data are conflicting regarding pain outcomes and quality of life (QOL) among women who undergo different types of breast surgery.

Methods: Women with nonhereditary breast cancer completed the brief pain inventory before surgery and at 1, 6, 12, and 18 months postsurgery. We assessed associations between pain outcomes and CPM status and mastectomy status using multivariable repeated measures models. We assessed associations between pain outcome and …

Global Epidemiology And Clinical Outcomes Of Carbapenem-Resistant Pseudomonas Aeruginosa And Associated Carbapenemases (Pop): A Prospective Cohort Study, Jinnethe Reyes, Lauren Komarow, Liang Chen, Lizhao Ge, Blake M Hanson, Eric Cober, Erica Herc, Thamer Alenazi, Keith S Kaye, Julia Garcia-Diaz, Lanjuan Li, Souha S Kanj, Zhengyin Liu, Jose M Oñate, Robert A Salata, Kalisvar Marimuthu, Hainv Gao, Zhiyong Zong, Sandra L Valderrama-Beltrán, Yunsong Yu, Paul Tambyah, Gregory Weston, Soraya Salcedo, Lillian M Abbo, Qing Xie, Karen Ordoñez, Minggui Wang, Martin E Stryjewski, Jose M Munita, David L Paterson, Scott Evans, Carol Hill, Keri Baum, Robert A Bonomo, Barry N Kreiswirth, Maria Virginia Villegas, Robin Patel, Cesar A Arias, Henry F Chambers, Vance G Fowler, Yohei Doi, David Van Duin, Michael J Satlin

Faculty, Staff and Student Publications

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA.

Methods: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day …

New Mouse Models With Hypomorphic Sumf1 Variants Mimic Attenuated Forms Of Multiple Sulfatase Deficiency, Nicolina Cristina Sorrentino, Maximiliano Presa, Sergio Attanasio, Vincenzo Cacace, Martina Sofia, Aamir Zuberi, Jennifer Ryan, Somdatta Ray, Igor Petkovic, Karthikeyan Radhakrishnan, Lars Schlotawa, Andrea Ballabio, Cathleen Lutz, Nicola Brunetti-Pierri

Duncan NRI Faculty and Staff Publications

Multiple sulfatase deficiency (MSD) is an ultrarare lysosomal storage disorder due to deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the enzyme responsible for the post-translational modification and activation of all sulfatases. Most MSD patients carry hypomorph SUMF1 variants resulting in variable degrees of residual sulfatase activities. In contrast, Sumf1 null mice with complete deficiency in all sulfatase enzyme activities, have very short lifespan with significant pre-wean lethality, owing to a challenging preclinical model. To overcome this limitation, we genetically engineered and characterized in mice two commonly …

Egr1 Drives Cell Proliferation By Directly Stimulating Tfeb Transcription In Response To Starvation, Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Susanna Ambrosio, Rossella De Cegli, Margherita Mutarelli, Lorenzo Vaccaro, Micheal J Ziller, Davide Cacchiarelli, Diego L Medina, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the …

Highly Synchronized Cortical Circuit Dynamics Mediate Spontaneous Pain In Mice, Weihua Ding, Lukas Fischer, Qian Chen, Ziyi Li, Liuyue Yang, Zerong You, Kun Hu, Xinbo Wu, Xue Zhou, Wei Chao, Peter Hu, Tewodros Mulugeta Dagnew, Daniel M Dubreuil, Shiyu Wang, Suyun Xia, Caroline Bao, Shengmei Zhu, Lucy Chen, Changning Wang, Brian Wainger, Peng Jin, Jianren Mao, Guoping Feng, Mark T Harnett, Shiqian Shen

Faculty, Staff and Student Publications

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a "normal" operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized …

Integrative Bioinformatic Analysis Of P53 And Pathway Alterations In Two Different Lung Cancer Subtypes, Yun Zhang, Abie Williams-Villalobo, Jyotsna D Godavarthi, Faith Shakoor, Shunbin Xiong, Bin Liu

Faculty, Staff and Student Publications

Whether p53, either wild type (WT) or mutant, plays cell-specific or uniform role remains controversial. Using The Cancer Genome Atlas, we examined p53 in the lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), two lung cancers with different cellular origins and frequent p53 mutation (52% and 83%, respectively). Mutant p53 more strongly correlates with different genomic alteration and protein expression profiles in LUAD than in LUSC. p53 mutation in LUAD and LUSC is associated with multiple exacerbated clinical outcomes. Although the presence of p53 mutation does not change the survival of LUAD patients, LUSC patients containing p53 mutation exhibit …

Common Kinase Mutations Do Not Impact Optimal Molecular Responses In Core Binding Factor Acute Myeloid Leukemia Treated With Fludarabine, Cytarabine, And G-Csf Based Regimens, Jayastu Senapati, Tareq Abuasab, Fadi G Haddad, Farhad Ravandi, Tapan Kadia, Courtney Dinardo, Naval Daver, Naveen Pemmaraju, Yesid Alvarado, Mark A Brandt, Hagop Kantarjian, Gautam Borthakur

Faculty, Staff and Student Publications

No abstract provided.

Understanding Itch In Cutaneous T-Cell Lymphoma: Exploring The Impact Of Comorbidities, Treatment Regimens, And Racial Differences On Quality Of Life, Tejas P Joshi, Madeleine Duvic

Faculty, Staff and Student Publications

No abstract provided.

Human Papillomavirus Status And Prognosis Of Oropharyngeal High-Grade Neuroendocrine Carcinoma, Luana G De Sousa, Felippe Lazar Neto, Eduardo A Dal Lago, Andrew Sikora, Ehab Hanna, Amy Moreno, Jack Phan, Bonnie S Glisson, Diana Bell, Renata Ferrarotto

Faculty, Staff and Student Publications

Background: The prognostic impact of human papillomavirus (HPV) infection or smoking on oropharyngeal high-grade neuroendocrine carcinoma (HG-NEC) is not established.

Methods: Retrospective study with patients with oropharyngeal HG-NEC seen at MD Anderson Cancer Center from 1997 to 2020, and previously reported patients with oropharyngeal HG-NEC and known p16 and HPV status from the literature review. Survival was estimated with the Kaplan-Meier method, and survival differences assessed with the log-rank test and Cox proportional hazards models.

Results: Thirty patients were included; most had a heavy (≥10 pack-years) smoking history (52%), locoregional disease (stage III-IVB; 77%), and p16-positive tumor (92%). HPV was …

Treatment Of Cancer-Related-Fatigue In Acute Hematological Malignancies: Results Of A Feasibility Study Of Using Cognitive Behavioral Therapy, Sriram Yennurajalingam, Marina Konopleva, Cindy L Carmack, Courtney D Dinardo, Melissa Gaffney, Hayley Kristen Michener, Zhanni Lu, Penny Stanton, Jing Ning, Wei Qiao, Eduardo Bruera

Faculty, Staff and Student Publications

Background: Despite cancer related fatigue (CRF) being the most common, and debilitating symptom in patients with recently diagnosed acute hematological malignancies (HM), there are limited effective treatments for CRF in HM. The aim of this study was to determine the feasibility of cognitive behavioral therapy (CBT) for CRF in HM.

Methods: In this preliminary longitudinal prospective study, HM patients diagnosed a median of one month previously with moderate to severe fatigue were enrolled. Patients received CBT in seven weekly sessions for eight weeks. Change in Functional Assessment of Cancer Illness Therapy (FACIT) - Fatigue (primary), FACT-G, Pittsburg Sleep Quality Index …

Trpv4 Functional Status In Cystic Cells Regulates Cystogenesis In Autosomal Recessive Polycystic Kidney Disease During Variations In Dietary Potassium, Kyrylo Pyrshev, Anna Stavniichuk, Viktor N Tomilin, Naghmeh Hassanzadeh Khayyat, Guohui Ren, Mariya Kordysh, Oleg Zaika, Mykola Mamenko, Oleh Pochynyuk

Faculty, Staff and Student Publications

Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca2+] i homeostasis and flow‐sensitive [Ca2+] i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP‐dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K+ intake modulates the rate of cystogenesis and mechanosensitive [Ca2+] i signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD). One month treatment with both high KCl (5% K+) and KB/C (5% K+ with bicarbonate/citrate) diets significantly increased TRPV4 …

Leukemic Phase Follicular Lymphoma In A Young Adult, Daniel Rivera, Wei Wang, Zubaidah Al-Jumaili, Zhihong Hu

Faculty, Staff and Student Publications

Background: Leukemic presentation of follicular lymphoma (FL) is uncommon, with most cases reported in older adults.

Design: This report describes an unusual case of a young adult diagnosed with leukemic phase of FL. We reviewed the existing literature on this rare presentation of the disease and its potential impact on patient outcomes.

Results: Leukemic phase of FL in young adults can be mistaken for other high-grade hematologic malignancies. Morphology assessment and ancillary testing, such as flow cytometry and FISH analysis, can assist in achieving an accurate diagnosis of the leukemic phase of FL. Notably, our young patient responded well to …

Unique Pathologic Features And Gene Expression Signatures Distinguish Blastoid High-Grade B-Cell Lymphoma From B-Acute Lymphoblastic Leukemia/Lymphoma, Lianqun Qiu, Jie Xu, Pei Lin, Evan N Cohen, Guilin Tang, Sa A Wang, Mahsa Khanlari, Wei Wang, Joseph D Khoury, Sergej Konoplev, C Cameron Yin, Jeffrey L Jorgensen, Francisco Vega, L Jeffrey Medeiros, Shaoying Li

Faculty, Staff and Student Publications

No abstract provided.

A Phase I, Open-Label, Dose Confirmation, Escalation, And Expansion Trial Of Bi 1810631 As Monotherapy In Patients With Advanced Or Metastatic Solid Tumors With Her2 Aberrations, John Heymach, Frans Opdam, Minal Barve, Neil Gibson, Behbood Sadrolhefazi, Josep Serra, Noboru Yamamoto

Faculty, Staff and Student Publications

Background: BI 1810631 is a human HER2-selective tyrosine kinase inhibitor that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertion mutations, whilst sparing EGFR signaling. This phase Ia/Ib, open-label, non-randomized study will determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 1810631 in patients with HER2 aberration-positive solid tumors (NCT04886804).

Patients and methods: In phase Ia, patients with histologically/cytologically confirmed HER2 aberration-positive advanced/metastatic solid tumors will receive BI 1810631 orally twice daily (BID) or once daily (QD) at escalating doses. Starting dose level is 15 mg BID; QD …

What Are Risk Factors For And Outcomes Of Late Amputation After Treatment For Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report, Erik J Geiger, Wei Liu, Deo Kumar Srivastava, Nicholas M Bernthal, Brent R Weil, Yutaka Yasui, Kirsten K Ness, Kevin R Krull, Robert E Goldsby, Kevin C Oeffinger, Leslie L Robison, Bryan V Dieffenbach, Christopher B Weldon, Mark C Gebhardt, Rebecca Howell, Andrew J Murphy, Wendy M Leisenring, Gregory T Armstrong, Eric J Chow, Rosanna L Wustrack

Faculty, Staff and Student Publications

Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.

Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What …

Association Of Insurance Type With Inpatient Surgical 30-Day Readmissions, Emergency Department Visits/Observation Stays, And Costs, Michael A Jacobs, Jeongsoo Kim, Jasmine C Tetley, Susanne Schmidt, Bradley B Brimhall, Virginia Mika, Chen-Pin Wang, Laura S Manuel, Paul Damien, Paula K Shireman

Faculty, Staff and Student Publications

Objective: To assess the association of Private, Medicare, and Medicaid/Uninsured insurance type with 30-day Emergency Department visits/Observation Stays (EDOS), readmissions, and costs in a safety-net hospital (SNH) serving diverse socioeconomic status patients.

Summary background data: Medicare's Hospital Readmission Reduction Program (HRRP) disproportionately penalizes SNHs.

Methods: This retrospective cohort study used inpatient National Surgical Quality Improvement Program (2013-2019) data merged with cost data. Frailty, expanded Operative Stress Score, case status, and insurance type were used to predict odds of EDOS and readmissions, as well as index hospitalization costs.

Results: The cohort had 1,477 Private; 1,164 Medicare; and 3,488 Medicaid/Uninsured cases with …

Meniscal And Articular Cartilage Predictors Of Outcome After Revision Acl Reconstruction: A 6-Year Follow-Up Cohort Study, Rick W Wright, Laura J Huston, Amanda K Haas, Jacquelyn S Pennings, Christina R Allen, Daniel E Cooper, Thomas M Deberardino, Warren R Dunn, Brett Brick A Lantz, Kurt P Spindler, Michael J Stuart, John P Albright, Annunziato Ned Amendola, Jack T Andrish, Christopher C Annunziata, Robert A Arciero, Bernard R Bach, Champ L Baker, Arthur R Bartolozzi, Keith M Baumgarten, Jeffery R Bechler, Jeffrey H Berg, Geoffrey A Bernas, Stephen F Brockmeier, Robert H Brophy, Charles A Bush-Joseph, J Brad Butler, John D Campbell, James L Carey, James E Carpenter, Brian J Cole, Jonathan M Cooper, Charles L Cox, R Alexander Creighton, Diane L Dahm, Tal S David, David C Flanigan, Robert W Frederick, Theodore J Ganley, Elizabeth A Garofoli, Charles J Gatt, Steven R Gecha, James Robert Giffin, Sharon L Hame, Jo A Hannafin, Christopher D Harner, Norman Lindsay Harris, Keith S Hechtman, Elliott B Hershman, Rudolf G Hoellrich, David C Johnson, Timothy S Johnson, Morgan H Jones, Christopher C Kaeding, Ganesh V Kamath, Thomas E Klootwyk, Bruce A Levy, C Benjamin Ma, G Peter Maiers, Robert G Marx, Matthew J Matava, Gregory M Mathien, David R Mcallister, Eric C Mccarty, Robert G Mccormack, Bruce S Miller, Carl W Nissen, Daniel F O'Neill, Brett D Owens, Richard D Parker, Mark L Purnell, Arun J Ramappa, Michael A Rauh, Arthur C Rettig, Jon K Sekiya, Kevin G Shea, Orrin H Sherman, James R Slauterbeck, Matthew V Smith, Jeffrey T Spang, Ltc Steven J Svoboda, Timothy N Taft, Joachim J Tenuta, Edwin M Tingstad, Armando F Vidal, Darius G Viskontas, Richard A White, James S Williams, Michelle L Wolcott, Brian R Wolf, James J York

Faculty, Staff and Student Publications

Background: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction.

Purpose: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient's outcome at 6-year follow-up.

Study design: Cohort study; Level of evidence, 3.

Methods: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and …

A Bidirectional Single-Cell Migration And Retrieval Chip For Quantitative Study Of Dendritic Cell Migration, Ning Shao, Yufu Zhou, Jun Yao, Pengchao Zhang, Yanni Song, Kai Zhang, Xin Han, Bin Wang, Xuewu Liu

Faculty, Staff and Student Publications

Dendritic cell (DC) migration is a fundamental step during execution of its adaptive immunity functions. Studying DC migration characteristics is critical for development of DC-dependent allergy treatments, vaccines, and cancer immunotherapies. Here, a microfluidics-based single-cell migration platform is described that enables high-throughput and precise bidirectional cell migration assays. It also allows selective retrieval of cell subpopulations that have different migratory potentials. Using this microfluidic platform, DC migration is investigated in response to different chemoattractants and inhibitors, quantitatively describe DC migration patterns and retrieve DC subpopulations of different migratory potentials for differential gene expression analysis. This platform opens an avenue for …

Burn Resuscitation Practices In North America: Results Of The Acute Burn Resuscitation Multicenter Prospective Trial (Abrupt), David G Greenhalgh, Robert Cartotto, Sandra L Taylor, Jeffrey R Fine, Giavonni M Lewis, David J Smith, Michael A Marano, Angela Gibson, Lucy A Wibbenmeyer, James H Holmes, Julie A Rizzo, Kevin N Foster, Anjay Khandelwal, Sarah Fischer, Mark R Hemmila, David Hill, Ariel M Aballay, Edward E Tredget, Jeremy Goverman, Herbert Phelan, Carlos J Jimenez, Anthony Baldea, Rajiv Sood

Faculty, Staff and Student Publications

Objectives: ABRUPT was a prospective, noninterventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, to design a future prospective randomized trial.

Summary background data: No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation.

Methods: Patients ≥18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols.

Results: Of 379 enrollees, two-thirds (253) were resuscitated with …

Author Correction: Neoadjuvant Relatlimab And Nivolumab In Resectable Melanoma, Rodabe N Amaria, Michael Postow, Elizabeth M Burton, Michael T Tetzlaff, Merrick I Ross, Carlos Torres-Cabala, Isabella C Glitza, Fei Duan, 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

No abstract provided.