Genetic Phenomena Commons^™

Performance Of Ct-Based Deep Learning In Diagnostic Assessment Of Suspicious Lateral Lymph Nodes In Papillary Thyroid Cancer: A Prospective Diagnostic Study, Guibin Zheng, Haicheng Zhang, Fusheng Lin, Mark Zafereo, Neil Gross, Peng Sun, Yang Liu, Haiqing Sun, Guochang Wu, Shujian Wei, Jia Wu, Ning Mao, Guojun Li, Guoyang Wu, Haitao Zheng, Xicheng Song

Faculty, Staff and Student Publications

Background: Preoperative evaluation of the metastasis status of lateral lymph nodes (LNs) in papillary thyroid cancer is challenging. Strategies for using deep learning to diagnosis of lateral LN metastasis require additional development and testing. This study aimed to build a deep learning-based model to distinguish benign lateral LNs from metastatic lateral LNs in papillary thyroid cancer and test the model's diagnostic performance in a real-world clinical setting.

Methods: This was a prospective diagnostic study. An ensemble model integrating a three-dimensional residual network algorithm with clinical risk factors available before surgery was developed based on computed tomography images of lateral LNs …

Impact Of Rural Residence On The Presentation, Management And Survival Of Patients With Non-Metastatic Muscle-Invasive Bladder Carcinoma, Furkan Dursun, Ahmed Elshabrawy, Hanzhang Wang, Dharam Kaushik, Michael A Liss, Robert S Svatek, John L Gore, Ahmed M Mansour

Faculty, Staff and Student Publications

Purpose: To assess the impact of rural and remote residence on the receipt of guidelines-recommended treatment, quality of treatment and overall survival (OS) in patients with non-metastatic muscle-invasive bladder cancer (MIBC).

Materials and methods: Patients with MIBC were identified using National Cancer Database. Patients were classified into three residential areas. Logistic regression models were used to assess associations between geographic residence and receipt of radical cystectomy (RC) or chemoradiation therapy (CRT). Models were fitted to assess quality benchmarks of RC and CRT.

Results: We identified 71,395 patients. Of those 58,874 (82.5%) were living in Metro areas, 8,534 (11.9%) in urban-rural …

Remotely Delivered Cancer Genetic Testing In The Making Genetic Testing Accessible (Magenta) Trial: A Randomized Clinical Trial, Elizabeth M Swisher, Nadine Rayes, Deborah Bowen, Christine B Peterson, Barbara M Norquist, Tara Coffin, Kathleen Gavin, Deborah Polinsky, Jamie Crase, Jamie N Bakkum-Gamez, Stephanie V Blank, Mark F Munsell, Denise Nebgen, Gini F Fleming, Olufunmilayo I Olopade, Sherman Law, Alicia Zhou, Douglas A Levine, Alan D'Andrea, Karen H Lu

Faculty, Staff and Student Publications

Importance: Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress.

Objective: To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing.

Design, setting, and participants: Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US …

Next-Generation Chimeric Antigen Receptors For T- And Natural Killer-Cell Therapies Against Cancer, Ye Li, Katayoun Rezvani, Hind Rafei

Faculty, Staff and Student Publications

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, …

Clinical Outcome And Therapeutic Impact On Neuroendocrine Neoplasms Of The Breast: A National Cancer Database Study, Libo Yang, Heather Lin, Yu Shen, Madhuchhanda Roy, Constance Albarracin, Qingqing Ding, Lei Huo, Hui Chen, Bing Wei, Hong Bu, Isabelle Bedrosian, Yun Wu

Faculty, Staff and Student Publications

Purpose: Neuroendocrine neoplasms (NENs) of the breast are rare and not well-studied. NEN are subcategorized as well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC). The objectives of the current study were to review the clinicopathologic features of NENs, therapeutic efficacy of current systemic therapy and clinical outcomes of NEN of the breast.

Methods: Between 2004 and 2015, 420 NET, 205 NEC, 146 Adenocarcinoma with NE differentiation (ACNED) and 1,479,520 of invasive carcinoma, not otherwise specified (IC-NOS) of the breast were identified in the National Caner Database. Overall survival was compared among groups using Kaplan-Meier method and Log-rank test. …

Stepwise Requirements For Polymerases Δ And Θ In Theta-Mediated End Joining, Susanna Stroik, Juan Carvajal-Garcia, Dipika Gupta, Alyssa Edwards, Adam Luthman, David W Wyatt, Rachel L Dannenberg, Wanjuan Feng, Thomas A Kunkel, Gaorav P Gupta, Mark Hedglin, Richard Wood, Sylvie Doublié, Eli Rothenberg, Dale A Ramsden

Faculty, Staff and Student Publications

Timely repair of chromosomal double-strand breaks is required for genome integrity and cellular viability. The polymerase theta-mediated end joining pathway has an important role in resolving these breaks and is essential in cancers defective in other DNA repair pathways, thus making it an emerging therapeutic target1 It requires annealing of 2-6 nucleotides of complementary sequence, microhomologies, that are adjacent to the broken ends, followed by initiation of end-bridging DNA synthesis by polymerase θ. However, the other pathway steps remain inadequately defined, and the enzymes required for them are unknown. Here we demonstrate requirements for exonucleolytic digestion of unpaired 3' tails …

Model-Informed Drug Development Of Autologous Car-T Cell Therapy: Strategies To Optimize Car-T Cell Exposure Leveraging Cell Kinetic/Dynamic Modeling, Anna M Mc Laughlin, Peter A Milligan, Cassian Yee, Martin Bergstrand

Faculty, Staff and Student Publications

Autologous Chimeric antigen receptor (CAR-T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long-term response. Low CAR-T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR-T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, "clear" dose-exposure relationships do not seem to exist for any of the currently approved CAR-T cell products. In other …

Care After Premenopausal Risk-Reducing Salpingo-Oophorectomy In High-Risk Women: Scoping Review And International Consensus Recommendations, Denise R Nebgen, Susan M Domchek, Joanne Kotsopoulos, Joanne A De Hullu, Emma J Crosbie, Vincent Singh Paramanandam, Monique M A Brood-Van Zanten, Barbara M Norquist, Theresa Guise, Serge Rozenberg, Allison W Kurian, Holly J Pederson, Nese Yuksel, Rachel Michaelson-Cohen, Sharon L Bober, Agnaldo Lopes Da Silva Filho, Nora Johansen, F Guidozzi, D Gareth Evans, Usha Menon, Sheryl A Kingsberg, C Bethan Powell, Giovanni Grandi, Claudia Marchetti, Michelle Jacobson, Donal J Brennan, Martha Hickey

Faculty, Staff and Student Publications

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Egfr Tyrosine Kinase Inhibitors For The Treatment Of Metastatic Non-Small Cell Lung Cancer Harboring Uncommon Egfr Mutations: A Podcast, Xiuning Le, Eric Nadler, Daniel B Costa, John Victor Heymach

Faculty, Staff and Student Publications

See the video and supplementary file.

Germline Sequencing Analysis To Inform Clinical Gene Panel Testing For Aggressive Prostate Cancer, Burcu F Darst, Ed Saunders, Tokhir Dadaev, Xin Sheng, Peggy Wan, Loreall Pooler, Lucy Y Xia, Stephen Chanock, Sonja I Berndt, Ying Wang, Alpa V Patel, Demetrius Albanes, Stephanie J Weinstein, Vincent Gnanapragasam, Chad Huff, Fergus J Couch, Alicja Wolk, Graham G Giles, Tu Nguyen-Dumont, Roger L Milne, Mark M Pomerantz, Julie A Schmidt, Ruth C Travis, Timothy J Key, Konrad H Stopsack, Lorelei A Mucci, William J Catalona, Beth Marosy, Kurt N Hetrick, Kimberly F Doheny, Robert J Macinnis, Melissa C Southey, Rosalind A Eeles, Fredrik Wiklund, David V Conti, Zsofia Kote-Jarai, Christopher A Haiman

Faculty, Staff and Student Publications

Importance: Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease.

Objective: To identify genes associated with aggressive PCa.

Design, setting, and participants: A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 …

Considerations For Intensity Modulated Total Body Or Total Marrow And Lymphoid Irradiation, David Parsons, Tze Yee Lim, Jose R Teruel, Paulina Galavis, Stefano Agostinelli, Jieming Liang, Pietro Mancosu, Amanda Cherpak, Dennis N Stanley, Kang-Hyun Ahn, Bingqi Guo, Yesenia Gonzalez, Jay Burmeister, Jeffrey Y C Wong, Xuejun Gu, Grace Gwe-Ya Kim

Faculty, Staff and Student Publications

We compiled a sampling of the treatment techniques of intensity-modulated total body irradiation, total marrow irradiation and total marrow and lymphoid irradiation utilized by several centers across North America and Europe. This manuscript does not serve as a consensus guideline, but rather is meant to serve as a convenient reference for centers that are considering starting an intensity-modulated program.

Opioid-Free Discharge After Pancreatic Resection Through A Learning Health System Paradigm, Artem Boyev, Anish J Jain, Timothy E Newhook, Laura R Prakash, Yi-Ju Chiang, Morgan L Bruno, Elsa M Arvide, Whitney L Dewhurst, Michael P Kim, Jessica E Maxwell, Naruhiko Ikoma, Rebecca A Snyder, Jeffrey E Lee, Matthew H G Katz, Ching-Wei D Tzeng

Faculty, Staff and Student Publications

Importance: Postoperative opioid overprescribing leads to persistent opioid use and excess pills at risk for misuse and diversion. A learning health system paradigm using risk-stratified pancreatectomy clinical pathways (RSPCPs) may lead to reduction in inpatient and discharge opioid volume.

Objective: To analyze the outcomes of 2 iterative RSPCP updates on inpatient and discharge opioid volumes.

Design, setting, and participants: This cohort study included 832 consecutive adult patients at an urban comprehensive cancer center who underwent pancreatic resection between October 2016 and April 2022, comprising 3 sequential pathway cohorts (version [V] 1, October 1, 2016, to January 31, 2019 [n = …

Valosin-Containing Protein (Vcp/P97) Is Prognostically Unfavorable In Pediatric Aml, And Negatively Correlates With Unfolded Protein Response Proteins Ire1 And Grp78: A Report From The Children’S Oncology Group, Fieke W Hoff, Yihua Qiu, Brandon D Brown, Robert B Gerbing, Amanda R Leonti, Rhonda E Ries, Alan S Gamis, Richard Aplenc, Edward Anders Kolb, Todd A Alonzo, Soheil Meshinchi, Gaye N Jenkins, Terzah M Horton, Steven M Kornblau

Faculty, Staff and Student Publications

Purpose: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the main mechanisms of ER-mediated cell stress adaptation. Targeting the cell stress response is a promising therapeutic approach in acute myeloid leukemia (AML).

Experimental design: Protein expression levels of valosin-containing protein (VCP), a chief element of ERAD, were measured in peripheral blood samples from in 483 pediatric AML patients using reverse phase protein array methodology. Patients participated in the Children's Oncology Group AAML1031 phase 3 clinical trial that randomized patients to standard chemotherapy (cytarabine …

Methods For Objective Assessment Of Skin Involvement In Systemic Sclerosis, Ruhani Desai, Harshdeep Chawla, Kirill Larin, Shervin Assassi

Faculty, Staff and Student Publications

Purpose of review: Skin fibrosis is the most prominent disease manifestation of systemic sclerosis (SSc). Although the treatment for other SSc manifestations has expanded over the years, there is limited progress in identifying effective treatment options for SSc skin involvement. This is in part due to limitations in the utilized outcome measures for assessment of skin fibrosis. This review focuses on different emerging assessment tools for SSc skin involvement and their potential use for clinical care and multicenter trials.

Recent findings: Durometer and other device-based methodologies requiring application of direct pressure to the affected skin have been studied in SSc. …

Interobserver Variability And Challenges In Intraoperative Frozen Section Evaluation Of Pancreatic Margins In Pancreatectomy Specimens, Sadhna Dhingra, Melissa W Taggart, Wai Chin Foo, Asif Rashid, Maria Luisa Machado Heredia, Sarah B May, George Van Buren, William E Fisher, Huamin Wang

Faculty, Staff and Student Publications

Objective: Frozen-section evaluation of the pancreatic margin is challenging. We aimed to determine interobserver variability among gastrointestinal pathologists for the assessment of frozen sections of pancreatic margins with marked chronic pancreatitis and to determine the challenging histological features in discrepant cases.

Methods: We identified 45 patients who underwent pancreas resection for pancreatic ductal adenocarcinoma and showed marked chronic pancreatitis at pancreatic margin. Deidentified first levels of frozen-sections of the pancreatic margins from all cases were independently reviewed by 5 experienced gastrointestinal pathologists for the presence of carcinoma and/or high-grade dysplasia.

Results: Interobserver agreement among pathologists was calculated as kappa coefficients …

Blood-Based Migration Signature Biomarker Panel Discriminates Early Stage New Onset Diabetes Related Pancreatic Ductal Adenocarcinoma From Type 2 Diabetes, Seetharaman Balasenthil, Suyu Liu, Jianliang Dai, William R Bamlet, Gloria Petersen, Suresh T Chari, Anirban Maitra, Nanyue Chen, Subrata Sen, Ann Mcneill Killary

Faculty, Staff and Student Publications

Background and aims: While type 2 diabetes is a well-known risk factor for pancreatic ductal adenocarcinoma (PDAC), PDAC-induced new-onset diabetes (PDAC-NOD) is a manifestation of underlying PDAC. In this study, we sought to identify potential blood-based biomarkers for distinguishing PDAC-NOD from type 2 diabetes (T2DM) without PDAC.

Materials and methods: By ELISA analysis, a migration signature biomarker panel comprising tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FNIII-C) and CA 19-9 was analyzed in plasma samples from 50 PDAC-NOD and 50 T2DM controls.

Results: Both TFPI (area under the curve (AUC) 0.71) and TNC-FNIII-C (AUC 0.69) outperformed CA 19-9 (AUC 0.60) …

Texas Youth Depression And Suicide Research Network (Tx-Ydsrn) Research Registry And Learning Healthcare Network: Rationale, Design, And Baseline Characteristics, Madhukar H Trivedi, Abu Minhajuddin, Holli Slater, Regina Baronia, Joseph C Blader, Jamon Blood, Ryan Brown, Cynthia Claassen, Melissa Defilippis, David Farmer, Cynthia Garza, Jennifer L Hughes, Beth D Kennard, Israel Liberzon, Sarah Martin, Taryn L Mayes, Jair C Soares, Cesar A Soutullo, Eric A Storch, Sarah M Wakefield

Faculty, Staff and Student Publications

Background: American youth are seriously impacted by depression and suicide. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) Participant Registry Study was initiated in 2020 to develop predictive models for treatment outcomes in youth with depression and/or suicidality. This report presents the study rationale, design and baseline characteristics of the first 1000 participants.

Methods: TX-YDSRN consists of the Network Hub (coordinating center), 12 medical school "Nodes" (manage/implement study), each with 1-5 primary care, inpatient, and/or outpatient Sub-Sites (recruitment, data collection). Participants are 8-20-year-olds who receive treatment or screen positive for depression and/or suicidality. Baseline data include mood and suicidality …

Immune Cell Identity Behind The Ktrans Mapping Of Mouse Glioblastoma, Yanrong Zhang, Olivier Keunen, Anna Golebiewska, Marco Gerosa, Jing Wang, Sara Natasha Ghobadi, Ai Huang, Qingyi Hou, Frezghi G Habte, Ningrui Li, Gerry Grant, Ramasamy Paulmurugan, Kevin S Lee, Max Wintermark

Faculty, Staff and Student Publications

Dynamic contrast-enhanced MR imaging (DCE-MRI) can assess the integrity of the blood brain barrier (BBB) and has been used in GBM patients to determine glioma grade, predict prognosis, evaluate treatment response, and differentiate treatment-induced effect from recurrence. The volume transfer constant Ktrans is the most frequently used metric in tumor assessment. Based on previous studies that a higher WHO grade of brain tumor was associated with greater impairments of immunity and and that Ktrans value was associated with the pathological grading, the relationship between differential composition of immune cells in GBM tissue and dynamic changes in Ktrans mapping was anticipated …

Real-Time Liver Motion Estimation Via Deep Learning-Based Angle-Agnostic X-Ray Imaging, Hua-Chieh Shao, Yunxiang Li, Jing Wang, Steve Jiang, You Zhang

Faculty, Staff and Student Publications

Background: Real-time liver imaging is challenged by the short imaging time (within hundreds of milliseconds) to meet the temporal constraint posted by rapid patient breathing, resulting in extreme under-sampling for desired 3D imaging. Deep learning (DL)-based real-time imaging/motion estimation techniques are emerging as promising solutions, which can use a single X-ray projection to estimate 3D moving liver volumes by solved deformable motion. However, such techniques were mostly developed for a specific, fixed X-ray projection angle, thereby impractical to verify and guide arc-based radiotherapy with continuous gantry rotation.

Purpose: To enable deformable motion estimation and 3D liver imaging from individual X-ray …

Engineering Cannabidiol Synergistic Carbon Monoxide Nanocomplexes To Enhance Cancer Therapy Via Excessive Autophagy, Chang Xiao, Yue Sun, Jialong Fan, William Nguyen, Simin Chen, Ying Long, Wei Chen, Aiguo Zhu, Bin Liu

Faculty, Staff and Student Publications

Although carbon monoxide (CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability, the efficiency was often compromised by protective autophagy (mitophagy). Herein, cannabidiol (CBD) is integrated into biomimetic carbon monoxide nanocomplexes (HMPOC@M) to address this issue by inducing excessive autophagy. The biomimetic membrane not only prevents premature drugs leakage, but also prolongs blood circulation for tumor enrichment. After entering the acidic tumor microenvironment, carbon monoxide (CO) donors are stimulated by hydrogen oxide (H2O2) to disintegrate into CO and Mn2+. The comprehensive effect of CO/Mn2+ and CBD can induce ROS-mediated cell apoptosis. In addition, …