Medical Genetics Commons^™

Cd70 Is A Therapeutic Target Upregulated In Emt-Associated Egfr Tyrosine Kinase Inhibitor Resistance, Monique B Nilsson, Yan Yang, Simon Heeke, Sonia A Patel, Alissa Poteete, Yasir Y Elamin, Yukie Kashima, Thiruvengadam Arumugam, Xiaoxing Yu, Xiaoyang Ren, Lixia Diao, Li Shen, Qi Wang, Minying Zhang, Jacqulyne P Robichaux, Chunhua Shi, Allyson N Pfeil, Hai Tran, Don L Gibbons, Jason Bock, Jing Wang, John D Minna, Susumu S Kobayashi, Xiuning Le, John V Heymach

Faculty, Staff and Student Publications

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. …

Health Benefits And Cost-Effectiveness Of Children's Oncology Group Breast Cancer Screening Guidelines For Chest-Irradiated Hodgkin Lymphoma Survivors, F Lennie Wong, Janie M Lee, Wendy M Leisenring, Joseph P Neglia, Rebecca M Howell, Kevin C Oeffinger, Tara O Henderson, Ann Mertens, Paul C Nathan, Yutaka Yasui, Wendy Landier, Gregory T Armstrong, Leslie L Robison, Smita Bhatia

Faculty, Staff and Student Publications

Purpose: To evaluate the outcomes and cost-effectiveness of the Children's Oncology Group Guideline recommendation for breast cancer (BC) screening using mammography (MAM) and breast magnetic resonance imaging (MRI) in female chest-irradiated childhood Hodgkin lymphoma (HL) survivors. Digital breast tomosynthesis (DBT), increasingly replacing MAM in practice, was also examined.

Methods: Life years (LYs), quality-adjusted LYs (QALYs), BC mortality, health care costs, and false-positive screen frequencies of undergoing annual MAM, DBT, MRI, MAM + MRI, and DBT + MRI from age 25 to 74 years were estimated by microsimulation. BC risks and non-BC mortality were estimated from female 5-year survivors of …

A Phase Ib/Ii Study Of Lenvatinib And Pembrolizumab In Advanced Endometrial Carcinoma (Study 111/Keynote-146): Long-Term Efficacy And Safety Update, Vicky Makker, Carol Aghajanian, Allen L Cohn, Margarita Romeo, Raquel Bratos, Mark Messing, Corina E Dutcus, Jie Huang, Emmett V Schmidt, Robert Orlowski, Matthew H Taylor

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff …

Associations Of Financial Toxicity With Symptoms And Unplanned Healthcare Utilization Among Cancer Patients Taking Oral Chemotherapy At Home: A Prospective Observational Study, Yongfeng Chen, Zhenxiang Chen, Haiyun Jin, Yanrong Chen, Jinbing Bai

Faculty, Staff and Student Publications

Background: Cancer patients with financial toxicity experience psychological distress and often miss medical appointments and quit treatments early, which could be a barrier to the effective management of oral chemotherapy drugs at home. This study explores whether financial toxicity predicts symptoms and unplanned healthcare utilization among cancer patients taking oral chemotherapy at home, which will contribute to the safe management of oral chemotherapy.

Methods: Data in this study was from a prospective observational study, which was conducted between October 2018 and December 2019. 151 patients completed the Comprehensive Score for Financial Toxicity at discharge and completed the MD Anderson Symptom …

Phase Ib Study Of Telisotuzumab Vedotin In Combination With Erlotinib In Patients With C-Met Protein-Expressing Non-Small-Cell Lung Cancer, D Ross Camidge, Fabrice Barlesi, Jonathan W Goldman, Daniel Morgensztern, Rebecca Heist, Alex Spira, Wu-Chou Su, David S Hong, John H Strickler, Monica Motwani, Martin Dunbar, Apurvasena Parikh, Elysa Noon, Vincent Blot, Jun Wu, Karen Kelly

Faculty, Staff and Student Publications

Purpose: Overexpression of c-Met protein and epidermal growth factor receptor (EGFR) mutations can co-occur in non-small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met-positive (+) NSCLC.

Patients and methods: This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age …

North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: Position On Standards Of Care And Areas Of Need, Naveen Pemmaraju, Hagop Kantarjian, Kendra Sweet, Eunice Wang, Jayastu Senapati, Marina Konopleva, Vikas Gupta, Ruben Mesa, Matthew Ulrickson, Edward Gorak, Sumeet Bhatia, Tulin Budak-Alpdogan, James Mason, Maria Teresa Garcia-Romero, Norma Lopez-Santiago, Gabriela Cesarman-Maus, Pankit Vachhani, Sangmin Lee, Vijaya Raj Bhatt, William Blum, Roland B Walter, Dale Bixby, Ivana Gojo, Madeleine Duvic, Raajit K Rampal, Marcos De Lima, James Foran, Amir T Fathi, Aric Cameron Hall, Meagan A Jacoby, Jeffrey Lancet, Gabriel Mannis, Anthony S Stein, Alice Mims, David Rizzieri, Rebecca Olin, Alexander Perl, Gary Schiller, Paul Shami, Richard M Stone, Stephen Strickland, Matthew J Wieduwilt, Naval Daver, Farhad Ravandi, Sumithira Vasu, Monica Guzman, Gail J Roboz, Joseph Khoury, Muzaffar Qazilbash, Phyu P Aung, Branko Cuglievan, Yazan Madanat, Mohamed A Kharfan-Dabaja, Anna Pawlowska, Justin Taylor, Martin Tallman, Prajwal Dhakal, Andrew A Lane

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets …

Incidence And Clearance Of Anal Human Papillomavirus Infection In 16 164 Individuals, According To Human Immunodeficiency Virus Status, Sex, And Male Sexuality: An International Pooled Analysis Of 34 Longitudinal Studies, Feixue Wei, Marc T Goodman, Ningshao Xia, Jun Zhang, Anna R Giuliano, Nancy A Hessol, Jianghong Dai, Karin Neukam, Alexandra De Pokomandy, I Mary Poynten, Ronald B Geskus, Joaquin Burgos, Isabelle Etienney, Anna-Barbara Moscicki, Maria Gabriella Donà, Maura L Gillison, Alan G Nyitray, Rebecca G Nowak, Evy Yunihastuti, Huachun Zou, Carmen Hidalgo-Tenorio, Nittaya Phanuphak, Jean-Michel Molina, Alice M Schofield, Stephen Kerr, Song Fan, Yong Lu, Jason J Ong, Admire T Chikandiwa, Sirinya Teeraananchai, Nicola Squillace, Dorothy J Wiley, Joel M Palefsky, Damien Georges, Catharina J Alberts, Gary M Clifford

Faculty, Staff and Student Publications

Background: Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized.

Methods: We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their …

Bintrafusp Alfa: A Bifunctional Fusion Protein Targeting Pd-L1 And Tgf-Β, In Patients With Pretreated Colorectal Cancer: Results From A Phase I Trial, Alexander Spira, Michael S Wertheim, Edward J Kim, Benjamin Tan, Heinz-Josef Lenz, Patricia L Rich, Andreas Machl, Rena Ito, James L Gulley, Scott Kopetz

Faculty, Staff and Student Publications

Colorectal cancer (CRC) is a heterogeneous and complex disease with limited treatment options. Targeting transforming growth factor β (TGF-β) and programmed death ligand 1 pathways may enhance antitumor efficacy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. We report results from an expansion cohort of a phase I study (NCT02517398) in patients with heavily pretreated advanced CRC treated with bintrafusp alfa. As of May 15, 2020, 32 patients with advanced CRC had received …

Clinical And Molecular Analyses Of Recurrent Gram-Negative Bloodstream Infections, Andrew Bock, Blake M Hanson, Felicia Ruffin, Joshua B Parsons, Lawrence P Park, Michael Mohnasky, Vance G Fowler, Joshua T Thaden

Faculty, Staff and Student Publications

Background: The causes and clinical characteristics of recurrent gram-negative bacterial bloodstream infections (GNB-BSI) are poorly understood.

Methods: We used a cohort of patients with GNB-BSI to identify clinical characteristics, microbiology, and risk factors associated with recurrent GNB-BSI. Bacterial genotyping (pulsed-field gel electrophoresis [PFGE] and whole-genome sequencing [WGS]) was used to determine whether episodes were due to relapse or reinfection. Multivariable logistic regression was used to identify risk factors for recurrence.

Results: Of the 1423 patients with GNB-BSI in this study, 60 (4%) had recurrent GNB-BSI. Non-White race (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.38-4.01; P = .002), admission …

Life-Threatening Complications Of Influenza Vs Coronavirus Disease 2019 (Covid-19) In Us Children, Natasha B Halasa, Andrew J Spieker, Cameron C Young, Samantha M Olson, Margaret M Newhams, Kristin L Moffitt, Emily R Levy, Vijaya L Soma, Rana Talj, Scott L Weiss, Julie C Fitzgerald, Elizabeth H Mack, Aline B Maddux, Jennifer E Schuster, Bria M Coates, Mark W Hall, Stephanie P Schwartz, Adam J Schwarz, Michele Kong, Philip C Spinella, Laura L Loftis, Gwenn E Mclaughlin, Charlotte V Hobbs, Courtney M Rowan, Melania M Bembea, Ryan A Nofziger, Christopher J Babbitt, Cindy Bowens, Heidi R Flori, Shira J Gertz, Matt S Zinter, John S Giuliano, Janet R Hume, Natalie Z Cvijanovich, Aalok R Singh, Hillary A Crandall, Neal J Thomas, Melissa L Cullimore, Manish M Patel, Adrienne G Randolph, Pediatric Intensive Care Influenza, Overcoming Covid-19 Investigators

Faculty, Staff and Student Publications

Background: Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.

Methods: We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.

Results: Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 …

Dynamic Cone-Beam Ct Reconstruction Using Spatial And Temporal Implicit Neural Representation Learning (Stinr), You Zhang, Hua-Chieh Shao, Tinsu Pan, Tielige Mengke

Faculty, Staff and Student Publications

Objective. Dynamic cone-beam CT (CBCT) imaging is highly desired in image-guided radiation therapy to provide volumetric images with high spatial and temporal resolutions to enable applications including tumor motion tracking/prediction and intra-delivery dose calculation/accumulation. However, dynamic CBCT reconstruction is a substantially challenging spatiotemporal inverse problem, due to the extremely limited projection sample available for each CBCT reconstruction (one projection for one CBCT volume).

Approach. We developed a simultaneous spatial and temporal implicit neural representation (STINR) method for dynamic CBCT reconstruction. STINR mapped the unknown image and the evolution of its motion into spatial and temporal multi-layer perceptrons (MLPs), and …

Patient-Reported Symptoms At Discharge And Risk Of Complications After Gynecologic Surgery, Xin Shelley Wang, Pedro T Ramirez, Qiuling Shi, Mona Kamal, Araceli Garcia-Gonzalez, Charles S Cleeland

Faculty, Staff and Student Publications

Objective: Current gaps in knowledge limit clinicians from fully implementing patient-reported outcomes in routine post-operative care.

Methods: This prospective study assessed symptoms via the gynecologic module of the MD Anderson Symptom Inventory (MDASI-PeriOp-GYN) in patients who underwent open laparotomy.

Results: At discharge, patient-reported moderate to severe (≥4 on a 0-10 scale) abdominal bloating or abdominal cramping, combined with length of stay of ≥4 days, were found to be associated with a higher risk of 30-day post-operative grade II-IV complications by the Clavien-Dindo system (all p values < 0.01). Also, length of stay of ≥4 days and moderate to severe urinary urgency at discharge were found to be associated with the need for re-admission (all p values < 0.01).

Conclusion: This study defined the clinically meaningful symptoms that related to the risk of …

Factors For Poor Oral Health In Long-Term Childhood Cancer Survivors, Tushar Patni, Chun-Teh Lee, Yimei Li, Sue Kaste, Liang Zhu, Melissa M Hudson, Ana Neumann, Leslie L Robison

Faculty, Staff and Student Publications

Background: Survivors of childhood cancer are at risk for therapy-related dental diseases. The purpose of the study was to investigate the associations between clinical, socioeconomic, and demographic factors and oral diseases in the St. Jude Lifetime Cohort (SJLIFE) participants.

Methods: We performed a retrospective medical chart review and evaluated longitudinal self-reported dental outcomes in 4856 childhood cancer survivors and 591 community controls participating in the St. Jude Lifetime Cohort (SJLIFE) study. Univariate and multivariable logistic regression models were used to assess the impact of socioeconomic factors, treatment exposures and patient demographics on dental outcomes.

Results: Cancer survivors were more likely …

Spatial Regulation Of The Glycocalyx Component Podocalyxin Is A Switch For Prometastatic Function, Alvaro Román-Fernández, Mohammed A Mansour, Fernanda G Kugeratski, Jayanthi Anand, Emma Sandilands, Kai Rakovic, Erin M Cumming, Ji Park, Konstantina Nikolatou, Sergio Lilla, Robin Shaw, David Strachan, Susan Mason, Rachana Patel, Lynn Mcgarry, Archana Katoch, Kirsteen J Campbell, Colin Nixon, Crispin J Miller, Hing Y Leung, John Le Quesne, James C Norman, Sara Zanivan, Karen Blyth, David M Bryant

Faculty, Staff and Student Publications

The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within …

Response To: What Is Missing From The 2022 Practice Recommendation Updates From The World Consensus Conference On Bia-Alcl?, Fabio Santanelli Di Pompeo, Mark W Clemens, Michael Atlan, Giovanni Botti, Peter G Cordeiro, Arianna Di Napoli, Cara L Haymaker, Steven M Horwitz, Kelly Hunt, Peter Lennox, Patrick Mallucci, Roberto N Miranda, Alexandre M Munhoz, Demosthenes Panagiotakos, Eric C Swanson, Suzanne D Turner, Guido Firmani, Michail Sorotos

Faculty, Staff and Student Publications

No abstract provided.

Effective Treatment Of Low-Risk Acute Gvhd With Itacitinib Monotherapy, Aaron Etra, Alexandra Capellini, Amin Alousi, Monzr M Al Malki, Hannah Choe, William J Hogan, Francis Ayuk, Janna Baez, Isha Gandhi, Stelios Kasikis, Sigrun Gleich, Elizabeth Hexner, Matthias Hoepting, Urvi Kapoor, Steven Kowalyk, Deukwoo Kwon, Amelia Langston, Marco Mielcarek, George Morales, Umut Özbek, Muna Qayed, Ran Reshef, Wolf Rösler, Nikolaos Spyrou, Rachel Young, Yi-Bin Chen, James L M Ferrara, John E Levine

Faculty, Staff and Student Publications

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those …

Structure Of The Lysosomal Mtorc1-Tfeb-Rag-Ragulator Megacomplex, Zhicheng Cui, Gennaro Napolitano, Mariana E G De Araujo, Alessandra Esposito, Jlenia Monfregola, Lukas A Huber, Andrea Ballabio, James H Hurley

Duncan NRI Faculty and Staff Publications

The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy1. The phosphorylation of TFEB by the mechanistic target of rapamycin complex 1 (mTORC1)2–5 is unique in its mTORC1 substrate recruitment mechanism, which is strictly dependent on the amino acid-mediated activation of the RagC GTPase activating protein FLCN6,7. TFEB lacks the TOR signalling motif responsible for the recruitment of other mTORC1 substrates. We used cryogenic-electron microscopy to determine the structure of TFEB as presented to mTORC1 for phosphorylation, which we refer to as the ‘megacomplex’. Two full Rag–Ragulator complexes …

Superficial Low-Grade Fibromyxoid Sarcoma, Shira Ronen, Jennifer S Ko, Brian P Rubin, Scott E Kilpatrick, Wei-Lien Wang, John R Goldblum

Faculty, Staff and Student Publications

Background: Low-grade fibromyxoid sarcoma (LGFMS) typically involves deep soft tissue (beneath the fascia) of the proximal extremities and trunk. Long-term follow-up has shown a high rate of local recurrence, metastasis, and death. To the best of our knowledge, there is only one previous large series focusing on superficial LGFMS suggesting superficial tumors are disproportionately more common in children and may have a better prognosis. Our study's primary goals are to confirm these findings and increase general awareness that LGFMS may arise in superficial soft tissue.

Methods: We retrieved our cases of superficial LGFMS diagnosed between 2008 and 2020. Available slides …

Phase Ii Trial Of Weekly Erlotinib Dosing To Reduce Duodenal Polyp Burden Associated With Familial Adenomatous Polyposis, N Jewel Samadder, Nathan Foster, Ryan P Mcmurray, Carol A Burke, Elena Stoffel, Rohit Das, E Vilar, Gautam Mankaney, Navtej Buttar, Selvi Thirumurthi, Danielle K Turgeon, Michael Sossenheimer, Michelle Westover, Ellen Richmond, Asad Umar, Gary Della'zanna, Luz M Rodriguez, Eva Szabo, David Zahrieh, Paul J Limburg

Faculty, Staff and Student Publications

Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate.

Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP.

Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres.

Exposures: Participants self-administered 350 mg of erlotinib …

Hematopoietic Cell Transplantation In The Management Of Myelodysplastic Syndrome: An Evidence-Based Review From The American Society For Transplantation And Cellular Therapy Committee On Practice Guidelines, Zachariah Defilipp, Stefan O Ciurea, Corey Cutler, Marie Robin, Erica D Warlick, Andrew M Brunner, Alison R Walker, Nicolaus Kröger, Nelli Bejanyan, Ehab Atallah, Roni Tamari, Melhem M Solh, Mary-Elizabeth Percival, Marcos De Lima, Bart Scott, Betul Oran, Guillermo Garcia-Manero, Mehdi Hamadani, Paul Carpenter, Amy E Dezern

Faculty, Staff and Student Publications

The sole curative therapy for myelodysplastic syndrome (MDS) is allogeneic hematopoietic cell transplantation (HCT). Here this therapeutic modality is reviewed and critically evaluated in the context of the evidence. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of MDS experts comprising transplantation and nontransplantation physicians developed consensus treatment recommendations. This review summarizes the standard MDS indications for HCT and addresses areas of controversy. Recent prospective trials have confirmed that allogeneic HCT confers survival benefits in patients with advanced or high-risk MDS …

A Genome-Wide Association Study Identified Novel Genetic Susceptibility Loci For Oral Cancer In Taiwan, Da-Tian Bau, Ting-Yuan Liu, Chia-Wen Tsai, Wen-Shin Chang, Jian Gu, Liang-Chun Shih

Faculty, Staff and Student Publications

Taiwan has the highest incidence rate of oral cancer in the world. Although oral cancer is mostly an environmentally induced cancer, genetic factors also play an important role in its etiology. Genome-wide association studies (GWAS) have identified nine susceptibility regions for oral cancers in populations of European descent. In this study, we performed the first GWAS of oral cancer in Taiwan with 1529 cases and 44,572 controls. We confirmed two previously reported loci on the 6p21.33 (HLA-B) and 6p21.32 (HLA-DQ gene cluster) loci, highlighting the importance of the human leukocyte antigen and, hence, the immunologic mechanisms in oral carcinogenesis. The …

Spatiotemporal View Of Malignant Histogenesis And Macroevolution Via Formation Of Polyploid Giant Cancer Cells, Xiaoran Li, Yanping Zhong, Xudong Zhang, Anil K Sood, Jinsong Liu

Faculty, Staff and Student Publications

To understand how malignant tumors develop, we tracked cell membrane, nuclear membrane, spindle, and cell cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade serous carcinoma organoids using long-term time-lapse imaging. Single cells underwent traditional mitosis to generate tissue with uniform nuclear size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, nuclear fusion, and karyokinesis without cytokinesis. PGCCs underwent restitution multipolar endomitosis, nuclear fragmentation, and micronuclei formation to increase nuclear contents and heterogeneity. At the cellular level, the development of PGCCs was associated with forming transient intracellular cells, termed fecundity cells. The fecundity cells …

A Multicenter Study Of Clinical Impact Of Variant Of Uncertain Significance Reclassification In Breast, Ovarian And Colorectal Cancer Susceptibility Genes, Sukh Makhnoon, Brooke Levin, Megan Ensinger, Kristin Mattie, Robert J Volk, Tito Mendoza, Laila Samiian, Generosa Grana, Andrew Grainger, Banu Arun, Brian H Shirts, Susan K Peterson

Faculty, Staff and Student Publications

BACKGROUND: Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) that have an unknown impact on health but can be clarified through reclassification. There is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, and racial/ethnic differences.

METHODS: This was a retrospective analysis of persons with and without a personal history of cancer carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer predisposition genes seen at four cancer care settings (in Texas, Florida, Ohio, and New Jersey) …

Improved Benefit Of Continuing Luspatercept Therapy: Sub-Analysis Of Patients With Lower-Risk Mds In The Medalist Study, Ulrich Germing, Pierre Fenaux, Uwe Platzbecker, Rena Buckstein, Valeria Santini, Aylin Yucel, Shannon Fabre, George Zhang, Roberto Zoffoli, Xianwei Ha, Dimana Miteva, Christina Hughes, Rami S Komrokji, Amer M Zeidan, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, …

A 24-Month Updated Analysis Of The Comparative Effectiveness Of Zuma-5 (Axi-Cel) Vs Scholar-5 External Control In Relapsed/Refractory Follicular Lymphoma, M Lia Palomba, Paola Ghione, Anik R Patel, Myrna Nahas, Sara Beygi, Steve Kanters, Sally W Wade, Markqayne D Ray, Jessica Owen, Sattva S Neelapu, John Gribben, John Radford, Sabela Bobillo

Faculty, Staff and Student Publications

Background: In the ZUMA-5 trial (Clinical trials identification: NCT03105336), axicabtagene ciloleucel (axi-cel; a chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients and clear superiority relative to the SCHOLAR-5 external control cohort. We update this comparison using the ZUMA-5 24-month data.

Research design and methods: The SCHOLAR-5 cohort is comprised of r/r FL patients who initiated ≥3rd line of therapy after July 2014 and meeting ZUMA-5 eligibility criteria. Groups were balanced for patient characteristics through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. The overall response …

Azacitidine Monotherapy In Patients With Treatment-Naïve Higher-Risk Myelodysplastic Syndrome: A Systematic Literature Review And Meta-Analysis, Ken Hasegawa, Andrew H Wei, Guillermo Garcia-Manero, Naval G Daver, Nishanthan Rajakumaraswamy, Rebecca J Chan, Preston Tse, Jiajun Yan, Michael J Zoratti, Feng Xie, David A Sallman

Faculty, Staff and Student Publications

Background: The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes.

Materials and methods: We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for …

Sox17: A Highly Sensitive And Specific Immunomarker For Ovarian And Endometrial Carcinomas, Xudong Zhang, Jun Yao, Na Niu, Xiaoran Li, Yan Liu, Elizabeth D Euscher, Diana Bell, Anil K Sood, Guoliang Wang, Barrett C Lawson, Preetha Ramalingam, Anais Malpica, Aysegul A Sahin, Qingqing Ding, Jinsong Liu

Faculty, Staff and Student Publications

PAX8 is the most commonly used immunomarker to link a carcinoma to the gynecologic tract; however, it lacks specificity. Through mining The Cancer Genome Atlas mRNA expression profile data, we identified SOX17 as a potential specific marker at the mRNA level for gynecologic tumors. To evaluate the utility of this marker in the identification of the gynecologic origin of a given carcinoma, we performed immunochemical staining in a large cohort of ovarian and endometrial cancer cases (n = 416), together with a large cohort of solid tumors from other organs (n = 1544) in tissue microarrays. Similar to PAX8, SOX17 …

Profiling Human Pathogenic Repeat Expansion Regions By Synergistic And Multi-Level Impacts On Molecular Connections, Cong Fan, Ken Chen, Yukai Wang, Edward V Ball, Peter D Stenson, Albino Bacolla, John A Tainer, David N Cooper, Huiying Zhao

Faculty, Staff and Student Publications

Whilst DNA repeat expansions cause numerous heritable human disorders, their origins and underlying pathological mechanisms are often unclear. We collated a dataset comprising 224 human repeat expansions encompassing 203 different genes, and performed a systematic analysis with respect to key topological features at the DNA, RNA and protein levels. Comparison with controls without known pathogenicity and genomic regions lacking repeats, allowed the construction of the first tool to discriminate repeat regions harboring pathogenic repeat expansions (DPREx). At the DNA level, pathogenic repeat expansions exhibited stronger signals for DNA regulatory factors (e.g. H3K4me3, transcription factor-binding sites) in exons, promoters, 5'UTRs and …

Gender Bias In The Evaluation Of Surgical Performance: Results Of A Prospective Randomized Trial, Mara B Antonoff, Hope Feldman, Jessica G Y Luc, Paula I Iaeger, M Laura Rubin, Ara A Vaporciyan

Faculty, Staff and Student Publications

Objective: The study aims to determine the influence of trainee gender on assessments of coronary anastomosis performance.

Summary of background data: Understanding the impact of gender bias on the evaluation of trainees may enable us to identify and utilize assessment tools that are less susceptible to potential bias.

Methods: Cardiothoracic surgeons were randomized to review the video performance of trainees who were described by either male or female pronouns. All participants viewed the same video of a coronary anastomosis and were asked to grade technique using either a Checklist or Global Rating Scale (GRS). Effect of trainee gender on scores …

E Pluribus Unum: Prospective Acceptability Benchmarking From The Contouring Collaborative For Consensus In Radiation Oncology Crowdsourced Initiative For Multiobserver Segmentation, Diana Lin, Kareem A Wahid, Benjamin E Nelms, Renjie He, Mohammed A Naser, Michael V Sherer, Abdallah S R Mohamed, Michael Cislo, James D Murphy, Clifton D Fuller, Erin F Gillespie

Faculty, Staff and Student Publications

Purpose: Contouring Collaborative for Consensus in Radiation Oncology (C3RO) is a crowdsourced challenge engaging radiation oncologists across various expertise levels in segmentation. An obstacle to artificial intelligence (AI) development is the paucity of multiexpert datasets; consequently, we sought to characterize whether aggregate segmentations generated from multiple nonexperts could meet or exceed recognized expert agreement.

Approach: Participants who contoured ≥1 region of interest (ROI) for the breast, sarcoma, head and neck (H&N), gynecologic (GYN), or gastrointestinal (GI) cases were identified as a nonexpert or recognized expert. Cohort-specific ROIs were combined into single simultaneous truth and performance level estimation (STAPLE) consensus segmentations. …