Digital Commons Network^™

Bidirectional Associations Between Mental Health Disorders And Chronic Diabetic Complications In Individuals With Type 1 Or Type 2 Diabetes., Maya Watanabe, Evan L Reynolds, Mousumi Banerjee, Morten Charles, Kara Mizokami-Stout, Dana Albright, Lynn Ang, Joyce M Lee, Rodica Pop-Busui, Eva L Feldman, Brian C Callaghan

Health Services and Informatics Research

OBJECTIVE: To determine bidirectional associations between the timing of chronic diabetes complications (CDCs) and mental health disorders (MHDs) in individuals with type 1 or type 2 diabetes.

RESEARCH DESIGN AND METHODS: We used a nationally representative health care claims database to identify matched individuals with type 1 or 2 diabetes or without diabetes using a propensity score quasirandomization technique stratified by age (0-19, 20-39, 40-59, and ≥60 years). CDCs and MHDs were identified using ICD-9/10 codes. We fit Cox proportional hazards models with time-varying diagnoses of CDCs or MHDs to investigate their association with the hazard of developing MHDs or …

High-Sensitivity Troponin T, Nt-Probnp, And Cognitive Outcomes In Sprint, Devin Haney, Yuan Ma, Djhenne Dalmacy, Nicholas M Pajewski, Ihab Hajjar, James A De Lemos, Wenxin Zhang, Elsayed Z Soliman, Christie M Ballantyne, Vijay Nambi, Naveed Sattar, Anthony A Killeen, Joachim H Ix, Michael G Shlipak, Jarett D Berry, Simon B Ascher

Faculty, Staff and Students Publications

Background: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets.

Methods: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories.

Results: Over a median …

X-Linked Genetic Associations In Sporadic Thoracic Aortic Dissection, Fadi I Musfee, Goo Jun, Laura E Mitchell, Han Chen, Dongchuan Guo, Siddharth K Prakash, Shaunak Sanjay Adkar, Megan L Grove, Ryan Bohyun Choi, Derek Klarin, Million Veteran Program, Eric Boerwinkle, Dianna M Milewicz

Faculty, Staff and Students Publications

The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF < 0.01)-was associated with sporadic TAD in three cohorts of European descent (Discovery: 364 cases, 874 controls; Replication: 516 cases, 440,131 controls, and ARIC [Atherosclerosis Risk in Communities study]: 753 cases, 2247 controls). For analysis of common variants, we applied a sex-stratified logistic regression model followed by a meta-analysis of sex-specific odds ratios. Furthermore, we conducted a meta-analysis of overlapping common variants between the Discovery and Replication cohorts. For analysis of rare variants, we used a sex-stratified optimized sequence kernel association test model. Common variants results showed no statistically significant findings in the Discovery cohort. An intergenic common variant near SPANXN1 was statistically significant in the Replication cohort (p = 1.81 × 10-8). The highest signal from the meta-analysis of the Discovery and Replication cohorts was a ZNF182 intronic common variant (p = 3.5 × 10-6). In rare variants results, RTL9 reached statistical significance (p = 5.15 × 10-5). Although most of our results were statistically insignificant, our analysis is the most comprehensive X-chromosome association analysis of sporadic TAD to date.

Leveraging Preclinical Models Of Metastatic Breast Cancer, Diego A Pedroza, Yang Gao, Xiang H-F Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Women that present to the clinic with established breast cancer metastases have limited treatment options. Yet, the majority of preclinical studies are actually not directed at developing treatment regimens for established metastatic disease. In this review we will discuss the current state of preclinical macro-metastatic breast cancer models, including, but not limited to syngeneic GEMM, PDX and xenografts. Challenges within these models which are often overlooked include fluorophore-immunogenic neoantigens, differences in experimental vs spontaneous metastasis and tumor heterogeneity. Furthermore, due to cell plasticity in the tumor immune microenvironment (TIME) of the metastatic landscape, the treatment efficacy of newly approved immune …

Age Modifies The Association Between Severe Sleep Apnea And All-Cause Mortality, Amin Ramezani, Mehrnaz Azarian, Amir Sharafkhaneh, Arash Maghsoudi, Melissa B Jones, Thomas Penzel, Javad Razjouyan

Faculty, Staff and Students Publications

Purpose: While sleep apnea (SA) gets more prevalent with advancing age, the impact of age on the association between SA and health outcomes is not well known. We assessed the association between the severity of SA and all-cause mortality in different age groups using large longitudinal data.

Method: We applied a Natural Language Processing pipeline to extract the apnea-hypopnea index (AHI) from the physicians' interpretation of sleep studies performed at the Veteran Health Administration (FY 1999-2022). We categorized the participants as no SA (n-SA, AHI< 5) and severe SA (s-SA, AHI≥30). We grouped the cohort based on age: Young≤40; Middle-aged:40-65; and Older adults≥65; and calculated the odds ratio (aOR) of mortality adjusted for age, sex, race, ethnicity, BMI, and Charlson-Comorbidity Index (CCI) using n-SA as the reference.

Results: We identified 146,148 participants (age 52.23 ± 15.02; BMI 32.11 ± 6.05; male 86.7 …

Dominant Missense Variants In Srebf2 Are Associated With Complex Dermatological, Neurological, And Skeletal Abnormalities, Matthew J Moulton, Kristhen Atala, Yiming Zheng, Debdeep Dutta, Dorothy K Grange, Wen-Wen Lin, Daniel J Wegner, Jennifer A Wambach, Angela L Duker, Michael B Bober, Lisa Kratz, Carol A Wise, Ila Oxendine, Anas Khanshour, Undiagnosed Diseases Network, Michael F Wangler, Shinya Yamamoto, F Sessions Cole, Jonathan Rios, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation.

Methods: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences …

Optimal Timing Of Delivery For Pregnant Individuals With Mild Chronic Hypertension, Torri D Metz, Hui-Chien Kuo, Lorie Harper, Baha Sibai, Sherri Longo, George R Saade, Lorraine Dugoff, Kjersti Aagaard, Kim Boggess, Kirsten Lawrence, Brenna L Hughes, Joseph Bell, Rodney K Edwards, Kelly S Gibson, David M Haas, Lauren Plante, Brian Casey, Sean Esplin, Matthew K Hoffman, Kara K Hoppe, Janelle Foroutan, Methodius Tuuli, Michelle Y Owens, Hyagriv N Simhan, Heather Frey, Todd Rosen, Anna Palatnik, Susan Baker, Phyllis August, Uma M Reddy, Wendy Kinzler, Emily J Su, Iris Krishna, Nguyet A Nguyen, Mary E Norton, Daniel Skupski, Yasser Y El-Sayed, Dotun Ogunyemi, Ronald Librizzi, Leonardo Pereira, Everett F Magann, Mounira Habli, Shauna Williams, Giancarlo Mari, Gabriella Pridjian, David S Mckenna, Marc Parrish, Eugene Chang, Joanne Quiñones, Zorina S Galis, Namasivayam Ambalavanan, Rachel G Sinkey, Jeff M Szychowski, Alan T N Tita

Faculty, Staff and Students Publications

Objective: To investigate the optimal gestational age to deliver pregnant people with chronic hypertension to improve perinatal outcomes.

Methods: We conducted a planned secondary analysis of a randomized controlled trial of chronic hypertension treatment to different blood pressure goals. Participants with term, singleton gestations were included. Those with fetal anomalies and those with a diagnosis of preeclampsia before 37 weeks of gestation were excluded. The primary maternal composite outcome included death, serious morbidity (heart failure, stroke, encephalopathy, myocardial infarction, pulmonary edema, intensive care unit admission, intubation, renal failure), preeclampsia with severe features, hemorrhage requiring blood transfusion, or abruption. The primary …

Pnpla3, Obesity, And Heavy Alcohol Use In Cirrhosis Patients May Exert A Synergistic Increase Hepatocellular Carcinoma Risk, Aaron P Thrift, Fasiha Kanwal, Hyeyeun Lim, Hao Duong, Yanhong Liu, Amit G Singal, Saira Khaderi, Sumeet K Asrani, Christopher I Amos, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND & AIMS: In patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors.

METHODS: We analyzed data from 1911 patients in 2 multicenter prospective cohort studies in the United States. We classified patients according to alcohol consumption (current heavy vs not current heavy), obesity (body mass index ≥30 vs/m2), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs noncarrier). We examined the independent and joint …

The Impact Of Margins And Re-Resection In Pediatric Synovial Sarcoma, Andres F Espinoza, Priya B Shetty, Jillian C Jacobson, Hannah Todd, Kelley Harrell, Alfred F Trappey, John Doski, Eumenia C Castro, Nicole I Montgomery, M Fatih Okcu, Rajkumar Venkatramani, Dai H Chung, Sanjeev A Vasudevan

Faculty, Staff and Students Publications

INTRODUCTION: Synovial sarcoma is one of the most common soft tissue sarcomas in children. Guidelines regarding the adequate extent of resection margins and the role of re-resection are lacking. We sought to evaluate the adequate resection margin and the role of re-resection in predicting outcomes in children with synovial sarcomas.

METHODS: A cohort of 36 patients less than 18 years of age at diagnosis who were treated for localized synovial sarcoma at three tertiary pediatric hospitals between January 2004 and December 2020 were included in this study. Patient and tumor demographics, treatment information, and margin status after surgical resection were …

Phase Ii Study Of Samotolisib In Children And Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target Of Rapamycin Pathway Alterations: Pediatric Match Apec1621d, Theodore W Laetsch, Kathleen Ludwig, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Joyce Mhlanga, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, Donald Williams Parsons

Faculty, Staff and Students Publications

Purpose: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.

Methods: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was …

Satisfaction With Mode Of Delivery Of Genomic Sequencing Results In A Diverse National Sample Of Research Participants Through The Clinical Sequencing Evidence-Generating Research Consortium, Sarah Scollon, Jill O Robinson, Eunji Jo, Sabrina A Suckiel, Laura M Amendola, Ann Katherine M Foreman, Gail P Jarvik, Christine Rini, Tao Wang, Anne Slavotinek

Faculty, Staff and Students Publications

Purpose: Research that includes diverse patient populations is necessary to optimize implementation of telehealth.

Methods: As part of a Clinical Sequencing Evidence-Generating Research Consortium cross-site study, we assessed satisfaction with mode of return of results (RoR) delivery across a diverse sample of participants receiving genetic testing results in person vs telemedicine (TM).

Results: Ninety-eight percent of participants were satisfied with their mode of results delivery. Participants receiving results by TM were more likely to report a preference for receiving results in a different way and challenges with providers noticing difficulties with understanding. More than 90% reported satisfaction across all items …

Physician Infertility: A Structured Literature Review, Jordan G Kassab, Angelica Garcia Keeme-Sayre, Larry I Lipshultz

Faculty, Staff and Students Publications

Physician infertility has become a growing concern because of the increasingly high rates of infertility physicians experience associated with their strenuous work schedules, environmental exposures, and delayed family planning due to their necessitated years of training. Fortunately, there has been an increase in awareness, advocacy, and urgency for institutional support alongside this suboptimal association. This awareness is reflected in the vast existing literature regarding physician infertility; in this scoping review, we aggregated and assessed the current data as well as identified gaps in the available research. Including 56 articles regarding various aspects of the current state of physician infertility, we …

Low-Dose Ondansetron: A Candidate Prospective Precision Medicine To Treat Alcohol Use Disorder Endophenotypes, Bankole Johnson, Hannu Alho, Giovanni Addolorato, Otto Michael Lesch, Jonathan Chick, Lei Liu, Vinzant Schuyler

2020-Current year OA Pubs

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise …

Older And Better: A Narrative Review Of Successful Aging And Adaptation To Pain In Late Life, Emanuel Narcis Husu

Faculty, Staff and Students Publications

"Invariably, the self-assessed QoL was far better than I, as a physician, would have anticipated from the diseases and disabilities that you reported." -Ben Eiseman, MD, based on a survey of his octogenarian Yale University classmates.

Background: Chronic pain control is a high priority for the elderly; it is one of the most frequently encountered medical problems in this group. Chronic pain affects 60%-75% of people aged 65 years and older. Chronic pain's prevalence is even higher in those living in assisted living or nursing homes. Based on epidemiological data, the prevalence of chronic pain is directly proportional to age …

Initiation Of Metformin In Early Pregnancy Results In Fetal Bioaccumulation, Growth Restriction, And Renal Dysmorphology In A Primate Model, Erin Bolte, Tyler Dean, Brandon Garcia, Maxim D Seferovic, Kristin Sauter, Gwendolynn Hummel, Matthew Bucher, Feng Li, John Hicks, Xuan Qin, Melissa A Suter, Enrico R Barrozo, Michael Jochum, Cynthia Shope, Jacob E Friedman, Maureen Gannon, Stephanie R Wesolowski, Carrie E Mccurdy, Paul Kievit, Kjersti M Aagaard

Faculty, Staff and Students Publications

Background: In recent years, pragmatic metformin use in pregnancy has stretched to include prediabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, and (most recently) preeclampsia. However, with its expanded use, concerns of unintended harm have been raised.

Objective: This study developed an experimental primate model and applied ultrahigh performance liquid chromatography coupled to triple-quadrupole mass spectrometry for direct quantitation of maternal and fetal tissue metformin levels with detailed fetal biometry and histopathology.

Study design: Within 30 days of confirmed conception (defined as early pregnancy), 13 time-bred (timed-mated breeding) Rhesus dams with pregnancies designated for fetal necropsy were initiated on …

Utility Of Eosinophil Peroxidase As A Biomarker Of Eosinophilic Inflammation In Asthma, Monica Tang, Kaharu Sumino, Et Al.

2020-Current year OA Pubs

BACKGROUND: The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain.

OBJECTIVE: We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma.

METHODS: EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3.

RESULTS: Over 3 years, EPX levels in patients with asthma were higher than normal …

Evaluating The Psychometric Structure Of The Hamilton Rating Scale For Depression Pre- And Post-Treatment In Antidepressant Randomised Trials: Secondary Analysis Of 6843 Individual Participants From 20 Trials, David Byrne, Frank Doyle, Susan Brannick, Robert M Carney, Pim Cuijpers, Alexandra L Dima, Kenneth Freedland, Suzanne Guerin, David Hevey, Bishember Kathuria, Emma Wallace, Fiona Boland

2020-Current year OA Pubs

BACKGROUND: The 17-item Hamilton Rating Scale for Depression (HRSD-17) is the most popular depression measure in antidepressant clinical trials. Prior evidence indicates poor replicability and inconsistent factorial structure. This has not been studied in pooled randomised trial data, nor has a psychometrically optimal model been developed.

AIMS: To examine the psychometric properties of the HRSD-17 for pre-treatment and post-treatment clinical trial data in a large pooled database of antidepressant randomised controlled trial participants, and to determine an optimal abbreviated version.

METHOD: Data for 6843 participants were obtained from the data repository Vivli.org and randomly split into groups for exploratory (n …

Long-Term Trajectories Of Sleep Duration Are Associated With Incident Diabetes In Middle-To-Older-Aged Black And White Americans, Qian Xiao, Kelsie M Full, Martin K Rutter, Loren Lipworth

Faculty, Staff and Student Publications

AIMS/HYPOTHESIS: Both short and long sleep durations have been linked to higher diabetes risk. However, sleep duration may vary over time, and there has been limited research focusing on individual sleep trajectories and diabetes risk. There are substantial racial disparities in both sleep health and diabetes risk in the USA. Thus, it is important to understand the role of suboptimal sleep patterns in diabetes risk in different racial groups.

METHODS: We assessed long-term trajectories of sleep duration and incident diabetes in 22,285 Black adults (mean age ± SD, 51.1 ± 8.2 years; 64.8% women) and 13,737 White adults (mean age …

Changes In The Perceptions Of The Neighborhood Environment And Physical Activity Patterns Among Mexican Americans On The Texas-Mexico Border, Natalia I Heredia, Soo Kyung Park, Minjae Lee, Lisa Mitchell-Bennett, Paul Yeh, Rose Gowen, Arturo Rodriguez, Miryoung Lee, Belinda M Reininger

Faculty, Staff and Student Publications

INTRODUCTION: Little research on the association of neighborhood environment with physical activity in resource-poor communities has been done. This study assessed changes in perceptions of the neighborhood environment and the association between those perceptions and physical activity in Mexican Americans on the Texas-Mexico border in an area where there would be community efforts to enhance pedestrian and cycling infrastructure and programming.

METHODS: We analyzed data from a population-based cohort of Mexican American individuals on the Texas-Mexico border. From 2008 to 2018, interviewer-administered questionnaires were used to collect perceptions of neighborhood environment and physical activity at baseline, 5- and 10-year follow-ups, …

Characterizing Common And Rare Variations In Nontraditional Glycemic Biomarkers Using Multivariate Approaches On Multiancestry Aric Study, Debashree Ray, Stephanie J Loomis, Sowmya Venkataraghavan, Jiachen Zhang, Adrienne Tin, Bing Yu, Nilanjan Chatterjee, Elizabeth Selvin, Priya Duggal

Faculty, Staff and Student Publications

Genetic studies of nontraditional glycemic biomarkers, glycated albumin and fructosamine, can shed light on unknown aspects of type 2 diabetes genetics and biology. We performed a multiphenotype genome-wide association study of glycated albumin and fructosamine from 7,395 White and 2,016 Black participants in the Atherosclerosis Risk in Communities (ARIC) study on common variants from genotyped/imputed data. We discovered two genome-wide significant loci, one mapping to a known type 2 diabetes gene (ARAP1/STARD10) and another mapping to a novel region (UGT1A complex of genes), using multiomics gene-mapping strategies in diabetes-relevant tissues. We identified additional loci that were ancestry- and sex-specific (e.g., …

The Discover In-Hospital Cardiac Arrest (Discover Ihca) Study: An Investigation Of Hospital Practices After In-Hospital Cardiac Arrest, Luke Andrea, Nathaniel S Herman, Jacob Vine, Katherine M Berg, Saiara Choudhury, Mariana Vaena, Jordan E Nogle, Saleem M Halablab, Aarthi Kaviyarasu, Jonathan Elmer, Gabriel Wardi, Alex K Pearce, Conor Crowley, Micah T Long, J Taylor Herbert, Kipp Shipley, Brittany D Bissell Turpin, Michael J Lanspa, Adam Green, Shekhar A Ghamande, Akram Khan, Siddharth Dugar, Aaron M Joffe, Michael Baram, Cooper March, Nicholas J Johnson, Alexander Reyes, Krassimir Denchev, Michael Loewe, Ari Moskowitz

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

IMPORTANCE: In-hospital cardiac arrest (IHCA) is a significant public health burden. Rates of return of spontaneous circulation (ROSC) have been improving, but the best way to care for patients after the initial resuscitation remains poorly understood, and improvements in survival to discharge are stagnant. Existing North American cardiac arrest databases lack comprehensive data on the post-resuscitation period, and we do not know current post-IHCA practice patterns. To address this gap, we developed the Discover In-Hospital Cardiac Arrest (Discover IHCA) study, which will thoroughly evaluate current post-IHCA care practices across a diverse cohort.

OBJECTIVES: Our study collects granular data on post-IHCA …

The Burden Of Diagnostic Error In Dentistry: A Study On Periodontal Disease Misclassification, Bunmi Tokede, Alfa Yansane, Ryan Brandon, Guo-Hao Lin, Chun-Teh Lee, Joel White, Xiaoqian Jiang, Eric Lee, Alaa Alsaffar, Muhammad Walji, Elsbeth Kalenderian

Faculty, Staff and Student Publications

Background: Periodontal disease constitutes a widely prevalent category of non-communicable diseases and ranks among the top 10 causes of disability worldwide. Little however is known about diagnostic errors in dentistry. In this work, by retrospectively deploying an electronic health record (EHR)-based trigger tool, followed by gold standard manual review, we provide epidemiological estimates on the rate of diagnostic misclassification in dentistry through a periodontal use case.

Methods: An EHR-based trigger tool (a retrospective record review instrument that uses a list of triggers (or clues), i.e., data elements within the health record, to alert reviewers to the potential presence of a …

Sex Ratio At Birth Across 100 Years In Sweden And Risk Of Cardiovascular Disease And All-Cause Mortality – A National Register Study, Peter M Nilsson, Kristina Sundquist, Jan Sundquist, Casey Crump, Xinjun Li

Faculty, Staff and Student Publications

The human sex ratio at birth (SRB) undergoes temporary changes around a mean proportion of 0.51 male births. SRB has been well studied for historical, geographical, and secular trends, but until now not linked to health outcomes in the total population, e.g. for cardiovascular disease (CVD) or mortality during follow-up of birth cohorts. We used linkage analysis based on national registers in Sweden that cover all births from 1900 to 2016. SRB at birth was calculated by every 10-year birth cohort in all survivors living in 1997 for a follow-up analysis of risk of CVD and mortality with data from …

Long-Term Results Of The Sequential Combination Of Cladribine And Rituximab In Hairy Cell Leukemia, Jennifer Marvin-Peek, Wei-Ying Jen, Hagop M Kantarjian, David Mccue, Fadi G Haddad, William Wierda, Alessandra Ferrajoli, Jan Burger, Tareq Abusab, Jeffrey Jorgensen, Sa A Wang, Keyur Patel, Sanam Loghavi, Susan O'Brien, Farhad Ravandi

Faculty, Staff and Student Publications

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event free survival (EFS) or overall survival (OS). With a median follow up of 7·8 years (range: 0·40–18·8), eight patients have experienced disease relapse (5·8%), …

Radiation Therapy Quality Assurance Analysis Of Alliance A021501: Preoperative Mfolfirinox Or Mfolfirinox Plus Hypofractionated Radiation Therapy For Borderline Resectable Adenocarcinoma Of The Pancreas, Leila T Tchelebi, Diana Segovia, Koren Smith, Qian Shi, T J Fitzgerald, Michael D Chuong, Tyler J Zemla, Eileen M O'Reilly, Jeffrey A Meyerhardt, Eugene J Koay, Jessica Lowenstein, Ardaman Shergill, Matthew H G Katz, Joseph M Herman

Faculty, Staff and Student Publications

Purpose: Alliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered.

Methods and materials: SBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable …

Co-Targeting Sos1 Enhances The Antitumor Effects Of Krasg12c Inhibitors By Addressing Intrinsic And Acquired Resistance, Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann

Faculty, Staff and Student Publications

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by …

The Multi-Institutional Medullary Thyroid Cancer Collaborative Registry: Can A Rare Tumor Registry Accurately Represent The Real-World Patient Population?, Thomas Szabo Yamashita, Sophia M Williams-Perez, Sara Ehsan, Michelle Mulder, Daniel Kronenfeld, Chiang-Yu Huang, Hui Zhao, Kelly Merriman, Susan K Peterson, Mimi I Hu, Mark Zafereo, Julie Ann Sosa, Elizabeth G Grubbs

Faculty, Staff and Student Publications

Background: Large population-based registries, such as the Surveillance, Epidemiology and End Results (SEER) Registry, help in the study of rare tumors, including medullary thyroid cancer (MTC), but lack data to understand the natural history of the disease. The Medullary Thyroid Cancer Collaborative Registry (MTCCoRe) is an exhaustive multi-institutional collection of demographic, clinical, and pathological data. To determine the extent to which MTCCoRe represents the real-world MTC population, we compared the characteristics of patients enrolled in MTCCoRe with patients enrolled in population-based cancer registries.

Methods: Comparison of demographic and clinical characteristics of MTC patients who were enrolled in MTCCoRe, Texas Cancer …

Racialized Inequities In Live Birth After Cancer: A Population-Based Study Of 63,000 Female Adolescents And Young Adults With Cancer, Andrea C Betts, Michael E Roth, Karen Albritton, Sandi L Pruitt, Philip J Lupo, Jennifer S Wang, L Aubree Shay, Marlyn A Allicock, Caitlin C Murphy

Faculty, Staff and Student Publications

Introduction: Fertility after cancer is a top concern for adolescents and young adults with cancer (AYAs) (15-39 years old at diagnosis). The authors characterized live births after cancer by race and ethnicity ("race/ethnicity") in a population-based sample of female AYAs.

Methods: This study used Texas Cancer Registry data linked to birth certificates (1995-2016) to estimate cumulative incidence of live birth, based on first live birth after cancer, and compared differences by race/ethnicity. Proportional subdistribution hazards models were used to estimate associations between race/ethnicity and live birth, adjusted for diagnosis age, cancer type, stage, year, and prior live birth, overall and …

Resin-Based 90 Y Tumor Dose As A Predictor Of Duration Of Response And Survival In Patients With Surgically Unresectable Hepatocellular Carcinoma : A Prospective Single-Arm Study, Nima Kokabi, Linzi A Webster, Howard Dabbous, Anand Shah, David Brandon, James Galt, Minzhi Xing, Alexander Villalobos, Amir Davarpanahfakhr, S Cheenu Kappadath, David M Schuster

Faculty, Staff and Student Publications

Background: Personalized dosimetry improves overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with glass 90 Y radioembolization. This study evaluated personalized tumor dose (TD) as a predictor of OS, progression-free survival (PFS), and local duration of response (DOR) in patients with surgically unresectable HCC treated with resin 90 Y radioembolization.

Patients and methods: This prospective, single-center, single-arm clinical trial (NCT04172714) evaluated the efficacy of scout activity of resin 90 Y versus 99m Tc-MAA for treatment planning. A secondary aim of this study was to evaluate personalized dosimetry as a predictor of OS, PFS, and DOR. Partition …

Vascular Heterogeneity Of Tight Junction Claudins Guides Organotropic Metastasis, Xunian Zhou, Valerie S Lebleu, Eliot Fletcher-Sananikone, Jiha Kim, Jianli Dai, Bingrui Li, Chia-Chin Wu, Hikaru Sugimoto, Toru Miyake, Lisa M Becker, Olga V Volpert, Erica Lawson, Cristina Espinosa Da Silva, Sarah I Patel, Akane Kizu, Ehsan A Ehsanipour, Di Sha, Jose Antonio Karam, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking …