Medical Specialties Commons^™

Effect Of Quality Of Life On Radiation Adherence For Patients With Cervical Cancer In An Urban Safety Net Health System, Alison K Yoder, Elizabeth Dong, Xiaoman Yu, Alfredo Echeverria, Shelly Sharma, Jane Montealegre, Michelle S Ludwig

Faculty, Staff and Students Publications

PURPOSE: Outcomes for patients undergoing chemoradiation for cervical cancer are dependent on adherence to radiation therapy (RT). In other diseases, quality of life (QoL) is associated with treatment adherence, but the association between QoL and RT adherence for patients with cervical cancer remains unclear.

METHODS AND MATERIALS: This prospective study included patients undergoing RT for cervical cancer from 2017 to 2021 at an urban safety net hospital. The Functional Assessment of Cancer Therapy-Cervical Cancer Version 4 was used to assess QoL based on 5 subscales (physical, functional, social and emotional, and cervical-cancer specific). The survey was administered at radiation consult, …

Epigenetic Age Acceleration Among Survivors Of Pediatric Medulloblastoma And Primitive Neuroectodermal Tumor, Rachel D Harris, Melissa A Richard, Maria Monica J Gramatges, Kevin Wilhelm, Michael E Scheurer, Philip J Lupo, Austin L Brown

Faculty, Staff and Students Publications

Survivors of childhood central nervous system (CNS) tumors experience early-onset aging-related phenotypes. DNA methylation (DNAm) age is an emerging epigenetic biomarker of physiologic age and may be predictive of chronic health conditions in long-term survivors. This report describes the course of epigenetic age acceleration using post-diagnosis blood samples (median: 3.9 years post-diagnosis; range: 0.04–15.96) from 83 survivors of pediatric CNS tumors. Epigenetic age acceleration was detected in 72% of patients, with an average difference between chronologic and dnam age of 2.58 years (95% Ci: 1.75–3.41, p < 0.001). Time from diagnosis to sample collection correlated with the magnitude of epigenetic age acceleration.

Oral Manifestations Of Acute Lymphocytic Leukemia, Angela Yepes Dds, Ms, Mba, Juan Yepes Dds, Md, Mph, Ms, Drph, James E. Jones Dmd, Msd, Edd, Phd

The Journal of the Michigan Dental Association

Leukemia is the most prevalent malignancy of leukocytes and can occur in children and adults. Oral manifestations are part of the complexity of signs and symptoms in patients with leukemia and, in some patients, oral manifestations precede systemic manifestations. Oral signs of leukemia include spontaneous bleeding, gingival enlargement, and whiteness of the oral mucosa. Head and neck lymphadenopathy is common in patients with leukemia. Oral manifestations are the result of the direct invasion of immature cells in the oral cavity tissues or indirectly caused by the replacement of the normal blood cells for immature cells causing anemia, leucopenia, and thrombocytopenia. …

Impact Of Structured Reporting Template On The Quality Of Hrct Radiology Reports For Interstitial Lung Disease, Han G. Ngo, Girish B. Nair, Sayf Al-Katib

Posters

This QI study compared the completeness of HRCT radiology reports before and after the implementation of a disease-specific structured reporting template for suspected cases of interstitial lung disease (ILD).

Dose To The Left Anterior Descending Artery Correlates With Cardiac Events After Irradiation For Breast Cancer, Brittany Silverman, Andrew Zureick, Vincent Grzywacz, Muayad Almahariq, Aleksander Vayntraub, Joshua Dilworth

Posters

Although global heart dose has been associated with late cardiac toxic effects in patients who received radiation therapy for breast cancer, data detailing the clinical significance of cardiac substructure dosimetry are limited. We investigated whether dose to the left anterior descending artery (LAD) correlates with adverse cardiac events.

Incidence Of Primary End Point Changes Among Active Cancer Phase 3 Randomized Clinical Trials, Marcus A Florez, Joseph Abi Jaoude, Roshal R Patel, Ramez Kouzy, Timothy A Lin, Brian De, Esther J Beck, Cullen M Taniguchi, Bruce D Minsky, Clifton D Fuller, J Jack Lee, Michael Kupferman, Kanwal P Raghav, Michael J Overman, Charles R Thomas, Ethan B Ludmir

Faculty, Staff and Student Publications

IMPORTANCE: Primary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity).

OBJECTIVES: To assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used publicly available data for complete oncology phase 3 …

Influence Of Pretreatment Magnetic Resonance Imaging On Local Therapy Decisions For Intermediate-Risk Prostate Cancer Patients, Christian Skowronski, Andrew Shanholtzer, Brent Yelton, Muayad Almahariq, Daniel Krauss

Posters

Prostate cancer has the third highest incidence rate and is the second leading cause of cancer death for men in the United States. Magnetic resonance imaging (MRI) provides superior soft tissue delineation serving as a valuable tool for both diagnosis and treatment planning. With minimal data regarding utility on diagnosis and treatment planning for intermediate-risk prostate cancer, the National Comprehensive Cancer Network’s guidelines indicate MRI as optional in intermediate-risk prostate cancer evaluation. This project aims to elucidate whether MRI affects radiation treatment decisions for intermediate-risk prostate cancer.

Outcomes Of Locally Advanced Lung Cancer Patients Treated With 60 Gy Vs. 70 Gy, Batoul Nasser, Muyad Almahariq, Inga Grills

Posters

The standard form of treatment for locally advanced lung cancer is to prescribe the conventional dose of 60 Gy radiation therapy (RT) concurrently with chemotherapy. However, five-year overall survival is still less than 20%. These outcomes remain poor due to both distant and local regional recurrence. The literature suggests that local regional control and overall survival is strongly associated with doses of radiotherapy that are higher than 60 Gy. However, when escalating radiation dose was prescribed exceeding 70 Gy, the overall survival rates plateaued. The primary goal of this study is to determine if there is a marked difference in …

Neddylation Inhibition Sensitises Renal Medullary Carcinoma Tumours To Platinum Chemotherapy, Daniel D Shapiro, Niki Millward Zacharias, Durga N Tripathi, Menuka Karki, Jean-Philippe Bertocchio, Melinda Soeung, Rong He, Mary E Westerman, Jianjun Gao, Priya Rao, Truong N A Lam, Eric Jonasch, Luigi Perelli, Emily H Cheng, Alessandro Carugo, Timothy P Heffernan, Cheryl L Walker, Giannicola Genovese, Nizar M Tannir, Jose A Karam, Pavlos Msaouel

Faculty, Staff and Student Publications

BACKGROUND: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC.

METHODS: We evaluated the IC50 concentrations of the neddylation‐activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat …

Effect Of Comorbidities And Choice Of Treatment On Overall Survival In Elderly Patients With Acute Myeloid Leukemia: A Beaumont Experience, Bilal M. Ali, Emma Herrman, James Huang Huang, Mohammad Muhsin Chisti

Posters

First line therapy for Acute Myeloid Leukemia (AML) is 7+3 regimen. It often cannot be used in elderly patients due to intensity. Venetoclax + hypomethylating agent (HMA) is approved for AML treatment in these patients. We investigate the efficacy of this treatment in a community setting where patients do not have the same resources available to them as a large academic center. Primary outcome was survival of patients greater than 60 years of age with a diagnosis of AML who received 7+3 therapy versus those who received venetoclax + HMA. Secondary outcomes included characteristics of those who received the two …

Development Of A Computable Phenotype Using Electronic Health Records For Venous Thromboembolism In Medical Inpatients: The Medical Inpatient Thrombosis And Hemostasis Study, Ryan M Thomas, Katherine Wilkinson, Insu Koh, Ang Li, Janine S A Warren, Nicholas S Roetker, Nicholas L Smith, Chris E Holmes, Timothy B Plante, Allen B Repp, Mary Cushman, Neil A Zakai

Faculty, Staff and Students Publications

BACKGROUND: Accurate and efficient methods to identify venous thromboembolism (VTE) events in hospitalized people are needed to support large-scale studies. Validated computable phenotypes using a specific combination of discrete, searchable elements in electronic health records to identify VTE and distinguish between hospital-acquired (HA)-VTE and present-on-admission (POA)-VTE would greatly facilitate the study of VTE, obviating the need for chart review.

OBJECTIVES: To develop and validate computable phenotypes for POA- and HA-VTE in adults hospitalized for medical reasons.

METHODS: The population included admissions to medical services from 2010 to 2019 at an academic medical center. POA-VTE was defined as VTE diagnosed within …

Alveolar Rhabdomyosarcoma Has Superior Response Rates To Vinorelbine Compared To Embryonal Rhabdomyosarcoma In Patients With Relapsed/Refractory Disease: A Meta-Analysis, Wendy Allen-Rhoades, Philip J Lupo, Michael E Scheurer, Yueh-Yun Chi, John F Kuttesch, Rajkumar Venkatramani, William H Meyer, Leo Mascarenhas

Faculty, Staff and Students Publications

BACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.

AIMS: The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.

MATERIALS & METHODS: Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose …

The Prevalence And Determinants Of Nafld And Mafld And Their Severity In The Va Primary Care Setting, Aaron P Thrift, Theresa H Nguyen, Codey Pham, Maya Balakrishnan, Fasiha Kanwal, Rohit Loomba, Hao T Duong, David Ramsey, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND & AIMS: A recent panel of international experts proposed the disease acronym metabolic (dysfunction)-associated fatty liver disease (MAFLD) in lieu of nonalcoholic fatty liver disease (NAFLD). We aimed to estimate the burden of and risk factors for NAFLD and MAFLD, and to examine the concordance between definitions in a Veterans population.

METHODS: We conducted a cross-sectional study among randomly selected patients within primary care at the Houston Veterans Affairs (VA) facility. Participants completed a survey, provided blood, and underwent Fibroscan. In the absence of heavy alcohol, hepatitis C virus and hepatitis B virus, a controlled attenuation parameter median ≥290 …

Comparison Of Neurocognitive And Quality-Of-Life Outcomes In Pediatric Craniopharyngioma Patients Treated With Partial Resection And Radiotherapy Versus Gross-Total Resection Only, Guillermo Aldave, M Fatih Okcu, Murali Chintagumpala, Lucia Ruggieri, Charles G Minard, Fatema Malbari, Lisa E Mash, Arnold C Paulino, Susan Mcgovern, Uma Ramaswamy, William Whitehead, Lisa S Kahalley

Faculty, Staff and Students Publications

OBJECTIVE: The optimal management of pediatric craniopharyngioma patients remains controversial, shifting from radical resection (gross-total resection [GTR]) to a more conservative approach with partial resection/biopsy followed by radiotherapy (PR+RT). To the authors' knowledge, no previous studies have compared neurocognitive and quality-of-life (QOL) outcomes between the two main treatments. In this study, the authors compared changes in intellectual, adaptive, and QOL scores in children treated for craniopharyngioma with GTR and those treated with PR+RT.

METHODS: Patients underwent annual neurocognitive and QOL evaluations for up to 10 years posttreatment, including the Full-Scale IQ, Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working …

Neighborhood-Level Factors Contribute To Disparities In Hepatocellular Carcinoma Incidence In Texas, Abiodun O Oluyomi, Hashem B El-Serag, Adegboyega Olayode, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Texas has the highest hepatocellular carcinoma (HCC) incidence rates in the continental United States, but these rates vary by race-ethnicity. We examined racial-ethnic disparities through a geospatial analysis of the social determinants of health.

METHODS: Using data from the Texas Cancer Registry, we assembled 11,547 HCC cases diagnosed between 2011 and 2015 into Texas's census tracts geographic units. Twenty-nine neighborhood measures representing demographics and socioeconomic, and employment domains were retrieved from the U.S. Census Bureau. We performed a series of aspatial and spatially weighted regression models to identify neighborhood-level characteristics associated with HCC risk.

RESULTS: We found …

The Application Of An Extracellular Vesicle-Based Biosensor In Early Diagnosis And Prediction Of Chemoresponsiveness In Ovarian Cancer, Meshach Asare-Werehene, Robert A Hunter, Emma Gerber, Arkadiy Reunov, Isaiah Brine, Chia-Yu Chang, Chia-Ching Chang, Dar-Bin Shieh, Dylan Burger, Hanan Anis, Benjamin K Tsang

Faculty, Staff and Student Publications

BACKGROUND: Ovarian cancer (OVCA) is the most fatal gynecological cancer with late diagnosis and plasma gelsolin (pGSN)-mediated chemoresistance representing the main obstacles to treatment success. Since there is no reliable approach to diagnosing patients at an early stage as well as predicting chemoresponsiveness, there is an urgent need to develop a diagnostic platform for such purposes. Small extracellular vesicles (sEVs) are attractive biomarkers given their potential accuracy for targeting tumor sites.

METHODS: We have developed a novel biosensor which utilizes cysteine-functionalized gold nanoparticles that simultaneously bind to cisplatin (CDDP) and plasma/cell-derived EVs, affording us the advantage of predicting OVCA chemoresponsiveness, …

Specific Causes Of Excess Late Mortality And Association With Modifiable Risk Factors Among Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study Cohort, Stephanie B Dixon, Qi Liu, Eric J Chow, Kevin C Oeffinger, Paul C Nathan, Rebecca M Howell, Wendy M Leisenring, Matthew J Ehrhardt, Kirsten K Ness, Kevin R Krull, Ann C Mertens, Melissa M Hudson, Leslie L Robison, Yutaka Yasui, Gregory T Armstrong

Faculty, Staff and Student Publications

Background: 5-year survival after childhood cancer does not fully describe life-years lost due to childhood cancer because there are a large number of deaths occurring beyond 5-years (late mortality) related to cancer and cancer treatment. Specific causes of health-related (non-recurrence, non-external) late mortality and risk reduction through modifiable lifestyle and cardiovascular risk factors are not well described. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk.

Methods: In this multi-institutional, hospital-based, …

Patterns Of Diagnostic Evaluation And Determinants Of Treatment In Older Patients With Non-Transfusion Dependent Myelodysplastic Syndromes, Sudipto Mukherjee, Weichuan Dong, Nicholas K. Schiltz, Kurt C. Stange, Jennifer Cullen, Aaron T. Gerds, Hetty E. Carraway, Abhay Singh, Anjali S. Advani, Siran M. Koroukian

Faculty Scholarship

Background: Older patients with myelodysplastic syndromes (MDS), particularly those with no or one cytopenia and no transfusion dependence, typically have an indolent course. Approximately, half of these receive the recommended diagnostic evaluation (DE) for MDS. We explored factors determining DE in these patients and its impact on subsequent treatment and outcomes. Patients and Methods: We used 2011-2014 Medicare data to identify patients ≥66 years of age diagnosed with MDS. We used Classification and Regression Tree (CART) analysis to identify combinations of factors associated with DE and its impact on subsequent treatment. Variables examined included demographics, comorbidities, nursing home status, and …

Genetic Loci Of Beta-Aminoisobutyric Acid Are Associated With Aging-Related Mild Cognitive Impairment, Einat Granot-Hershkovitz, Brian Spitzer, Yunju Yang, Wassim Tarraf, Bing Yu, Eric Boerwinkle, Myriam Fornage, Thomas H Mosley, Charles Decarli, Bruce S Kristal, Hector M González, Tamar Sofer

Faculty, Staff and Student Publications

We studied the genetic associations of a previously developed Metabolomic Risk Score (MRS) for Mild Cognitive Impairment (MCI) and beta-aminoisobutyric acid metabolite (BAIBA)-the metabolite highlighted by results from a genome-wide association study (GWAS) of the MCI-MRS, and assessed their association with MCI in datasets of diverse race/ethnicities. We first performed a GWAS for the MCI-MRS and BAIBA, in Hispanic/Latino adults (n = 3890) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We identified ten independent genome-wide significant (p value <5 × 10-8) variants associated with MCI-MRS or BAIBA. Variants associated with the MCI-MRS are located in the Alanine-Glyoxylate Aminotransferase 2 (AGXT2 gene), which is known to be associated with BAIBA metabolism. Variants associated with BAIBA are located in the AGXT2 gene and in the SLC6A13 gene. Next, we tested the variants' association with MCI in independent datasets of n = 3178 HCHS/SOL older individuals, n = 3775 European Americans, and n = 1032 African Americans from the Atherosclerosis Risk In Communities (ARIC) study. Variants were considered associated with MCI if their p value <0.05 in the meta-analysis of the three datasets and their direction of association was consistent with expectation. Rs16899972 and rs37369 from the AGXT2 region were associated with MCI. Mediation analysis supported the mediation effect of BAIBA between the two genetic variants and MCI (p value = 0.004 for causal mediated effect). In summary, genetic variants in the AGXT2 region are associated with MCI in Hispanic/Latino, African, and European American populations in the USA, and their effect is likely mediated by changes in BAIBA levels.

The Predictive Impact Of Dual Somatostatin Receptor/Fluorodeoxyglucose (Fdg) Positron Emission Tomography (Pet) In Metastatic Gastroenteropancreatic Neuroendocrine Tumors (Gep-Nets): Review Of Literature And A Single Institution Experience, Amr Mohamed, Sylvia L Asa, Zhenghong Lee, Sree H Tirumani, Qiubai Li, Norbert Avril, David Bajor, Amit Mahipal, Sakti Chakrabarti, J Eva Selfridge, Arash Kardan

Faculty, Staff and Students Publications

Treatment with radiolabelled somatostatin analogs, a form of peptide receptor radionuclide therapy (PRRT), has changed the management of patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who have suboptimal benefit and rapidly progress on PRRT, indicating that accurate prognostic and predictive markers are urgently needed. Currently, most of the literature concentrate on the prognostic impact of the dual positron emission tomography (PET) scan with very few information regarding the predictive value. We report a case series and review the literature to summarizes the predictive value of combined somatostatin receptor (SSTR) and fluorodeoxyglucose (FDG) PET in …

Rapid Hepatomegaly From Ruxolitinib Discontinuation Syndrome, Ryan Jansen Van Rensburg, Shayna Hale, Anna Calara, Kulveer Dabb, Uday Dandamudi, Parth Desai

HCA Healthcare Journal of Medicine

Introduction

Ruxolitinib (RUX) is a Food and Drug Administration-approved Janus Kinase (JAK) inhibitor shown to be effective in improving hypercatabolic symptoms and splenomegaly in patients with myelofibrosis (MF). RUX therapy provides symptomatic benefits for MF patients but is often discontinued for various reasons including worsening cytopenias. Ruxolitinib Discontinuation Syndrome (RDS) involves an acute cytokine-storm rebound phenomenon that can manifest as an acute relapse of symptoms, worsening splenomegaly, respiratory distress, systemic inflammatory response syndrome, or disseminated intravascular coagulopathy.

Case Presentation

We present the case of a patient with JAK2-positive post-polycythemia vera MF, whose RUX therapy was discontinued due to an active …

Optimized 18f-Fdg Pet-Ct Method To Improve Accuracy Of Diagnosis Of Metastatic Cancer., Richard Black, Jelle Barentsz, David Howell, David G Bostwick, Stephen B Strum

Oncology Articles

The diagnosis of cancer by FDG PET-CT is often inaccurate owing to subjectivity of interpretation. We compared the accuracy of a novel normalized (standardized) method of interpretation with conventional non-normalized SUV. Patients (

Head And Neck Tumor Histopathological Image Representation With Pre- Trained Convolutional Neural Network And Vision Transformer, Ranny Rahaningrum Herdiantoputri, Daisuke Komura, Tohru Ikeda, Shumpei Ishikawa

Journal of Dentistry Indonesia

Image representation via machine learning is an approach to quantitatively represent histopathological images of head and neck tumors for future applications of artificial intelligence-assisted pathological diagnosis systems. Objective: This study compares image representations produced by a pre-trained convolutional neural network (VGG16) to those produced by a vision transformer (ViT-L/14) in terms of the classification performance of head and neck tumors. Methods: W hole-slide images of five oral t umor categories (n = 319 cases) were analyzed. Image patches were created from manually annotated regions at 4096, 2048, and 1024 pixels and rescaled to 256 pixels. Image representations were …

Alternative Splicing Of Gsdmb Modulates Killer Lymphocyte-Triggered Pyroptosis, Qing Kong, Shiyu Xia, Xingxin Pan, Kaixiong Ye, Zhouyihan Li, Haoyan Li, Xiaoqiang Tang, Nidhi Sahni, S Stephen Yi, Xing Liu, Hao Wu, Michael B Elowitz, Judy Lieberman, Zhibin Zhang

Faculty, Staff and Student Publications

Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic …

Enhancing Cancer Diagnosis With Real-Time Feedback: Tumor Metabolism Through Hyperpolarized 1-13c Pyruvate Mrsi, Gaurav Sharma, José S Enriquez, Ryan Armijo, Muxin Wang, Pratip Bhattacharya, Shivanand Pudakalakatti

Faculty, Staff and Student Publications

This review article discusses the potential of hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) as a noninvasive technique for identifying altered metabolism in various cancer types. Hyperpolarization significantly improves the signal-to-noise ratio for the identification of 13C-labeled metabolites, enabling dynamic and real-time imaging of the conversion of [1-13C] pyruvate to [1-13C] lactate and/or [1-13C] alanine. The technique has shown promise in identifying upregulated glycolysis in most cancers, as compared to normal cells, and detecting successful treatment responses at an earlier stage than multiparametric MRI in breast and prostate cancer patients. The review provides a concise overview of the applications …

A Precision Environmental Health Approach To Prevention Of Human Disease, Andrea Baccarelli, Dana C Dolinoy, Cheryl Lyn Walker

Faculty, Staff and Students Publications

Human health is determined by the interaction of our environment with the genome, epigenome, and microbiome, which shape the transcriptomic, proteomic, and metabolomic landscape of cells and tissues. Precision environmental health is an emerging field leveraging environmental and system-level ('omic) data to understand underlying environmental causes of disease, identify biomarkers of exposure and response, and develop new prevention and intervention strategies. In this article we provide real-life illustrations of the utility of precision environmental health approaches, identify current challenges in the field, and outline new opportunities to promote health through a precision environmental health framework.

The Genomic Landscape Of Familial Glioma, Dong-Joo Choi, Georgina Armstrong, Brittney Lozzi, Prashanth Vijayaraghavan, Sharon E Plon, Terence C Wong, Eric Boerwinkle, Donna M Muzny, Hsiao-Chi Chen, Richard A Gibbs, Quinn T Ostrom, Beatrice Melin, Benjamin Deneen, Melissa L Bondy, Gliogene Consortium, Genomics England Research Consortium, Matthew N Bainbridge, Christopher I Amos, Jill S Barnholtz-Sloan, Jonine L Bernstein, Elizabeth B Claus, Richard S Houlston, Dora Il'yasova, Robert B Jenkins, Christoffer Johansen, Daniel Lachance, Rose Lai, Beatrice S Melin, Ryan T Merrell, Sara H Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, J C Ambrose, P Arumugam, R Bevers, M Bleda, F Boardman-Pretty, C R Boustred, H Brittain, M A Brown, M J Caulfield, G C Chan, A Giess, J N Griffin, A Hamblin, S Henderson, T J P Hubbard, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, A Kousathanas, L Lahnstein, A Lakey, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, M Mcentagart, F Minneci, J Mitchell, L Moutsianas, M Mueller, N Murugaesu, A C Need, P O'Donovan, C A Odhams, C Patch, D Perez-Gil, M B Pereira, J Pullinger, T Rahim, A Rendon, T Rogers, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, S C Smith, A Sosinsky, A Stuckey, M Tanguy, A L Taylor Tavares, E R A Thomas, S R Thompson, A Tucci, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki

Faculty, Staff and Student Publications

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to …

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Mice, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Faculty, Staff and Student Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …

Consensus Proposal For Revised International Working Group 2023 Response Criteria For Higher-Risk Myelodysplastic Syndromes, Amer M Zeidan, Uwe Platzbecker, Jan Philipp Bewersdorf, Maximilian Stahl, Lionel Adès, Uma Borate, David Bowen, Rena Buckstein, Andrew Brunner, Hetty E Carraway, Naval Daver, Maria Díez-Campelo, Theo De Witte, Amy E Dezern, Fabio Efficace, Guillermo Garcia-Manero, Jacqueline S Garcia, Ulrich Germing, Aristoteles Giagounidis, Elizabeth A Griffiths, Robert P Hasserjian, Eva Hellström-Lindberg, Marcelo Iastrebner, Rami Komrokji, Austin G Kulasekararaj, Luca Malcovati, Yasushi Miyazaki, Olatoyosi Odenike, Valeria Santini, Guillermo Sanz, Phillip Scheinberg, Reinhard Stauder, Arjan A Van De Loosdrecht, Andrew H Wei, Mikkael A Sekeres, Pierre Fenaux

Faculty, Staff and Student Publications

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria …

Positive Selection Of Somatically Mutated Clones Identifies Adaptive Pathways In Metabolic Liver Disease, Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes …