Medical Specialties Commons^™

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, Susan A Smith, Kevin C Oeffinger, Chaya S Moskowitz, 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 …

Early Restrictive Or Liberal Fluid Management For Sepsis-Induced Hypotension, Nathan I Shapiro, Ivor S Douglas, Roy G Brower, Samuel M Brown, Matthew C Exline, Adit A Ginde, Michelle N Gong, Colin K Grissom, Douglas Hayden, Catherine L Hough, Weixing Huang, Theodore J Iwashyna, Alan E Jones, Akram Khan, Poying Lai, Kathleen D Liu, Chadwick D Miller, Katherine Oldmixon, Pauline K Park, Todd W Rice, Nancy Ringwood, Matthew W Semler, Jay S Steingrub, Daniel Talmor, B Taylor Thompson, Donald M Yealy, Wesley H Self

Faculty, Staff and Student Publications

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited.

METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that …

The Landscape Of Immunotherapy For Retroperitoneal Sarcoma, Alicia A Gingrich, Elise F Nassif, Christina L Roland, Emily Z Keung

Faculty, Staff and Student Publications

Significant multidisciplinary scientific effort has been undertaken to understand the heterogeneous family of neoplasms that comprise soft tissue sarcomas. Within this family of neoplasms, outcomes for retroperitoneal sarcomas (RPS) are currently limited given a lack of effective therapies. In this review, we focus on immunotherapy and its relationship with the common RPS histologic subtypes. Although initial outcomes for RPS patients with immune checkpoint inhibition alone have been somewhat disappointing, subsequent analyses on histologies, the tumor microenvironment, sarcoma immune class, tumor infiltrating lymphocytes and genetic analysis for tumor mutational burden have yielded insight into the interplay between sarcomas and immunotherapy. Such …

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, Nathaniel R Wilson, Marina Konopleva, Arthur E Frankel, 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 …

Efficacy And Clinicogenomic Correlates Of Response To Immune Checkpoint Inhibitors Alone Or With Chemotherapy In Non-Small Cell Lung Cancer, Lingzhi Hong, Muhammad Aminu, Shenduo Li, Xuetao Lu, Milena Petranovic, Maliazurina B Saad, Pingjun Chen, Kang Qin, Susan Varghese, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Amy Spelman, Yasir Y Elamin, Marcelo V Negrao, Ferdinandos Skoulidis, Carl M Gay, Tina Cascone, Saumil J Gandhi, Steven H Lin, Percy P Lee, Brett W Carter, Carol C Wu, Mara B Antonoff, Boris Sepesi, Jeff Lewis, Don L Gibbons, Ara A Vaporciyan, Xiuning Le, J Jack Lee, Sinchita Roy-Chowdhuri, Mark J Routbort, Justin F Gainor, John V Heymach, Yanyan Lou, Jia Wu, Jianjun Zhang, Natalie I Vokes

Faculty, Staff and Student Publications

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes …

Improving Traditional Registrational Trial End Points: Development And Application Of A Desirability Of Outcome Ranking End Point For Complicated Urinary Tract Infection Clinical Trials, Jessica Howard-Anderson, Toshimitsu Hamasaki, Weixiao Dai, Deborah Collyar, Daniel Rubin, Sumathi Nambiar, Tori Kinamon, Carol Hill, Steven P Gelone, David Mariano, Takamichi Baba, Thomas L Holland, Sarah B Doernberg, Henry F Chambers, Vance G Fowler, Scott R Evans, Helen W Boucher

Faculty, Staff and Student Publications

BACKGROUND: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience.

METHODS: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, …

Association Of Circulating Mtdna With Cvd In Hemodialysis Patients And In Vitro Effect Of Exogenous Mtdna On Cardiac Microvascular Inflammation, Zhen Fan, Ya Feng, Li Zang, Yi Guo, Xiao-Yi Zhong

Faculty, Staff and Student Publications

BACKGROUND: Chronic kidney disease (CKD) patients sustain a fairly high prevalence of cardiovascular disease (CVD). Microvascular inflammation is an early manifestation of CVD, and the released mitochondrial DNA (MtDNA) has been proposed to be a crucial integrator of inflammatory signals. Herein, the aim of this study was to determine the relationship between CVD, microvessel, and circulating MtDNA in the settings of uremia.

METHODS: Forty-two maintenance hemodialysis (MHD) patients and 36 health controls were enrolled in this study. Plasma cell-free MtDNA was detected by TaqMan-based qPCR assay. CVD risk markers including high-sensitive C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), fibrinogen, and …

Clinical And Molecular Analyses Of Recurrent Gram-Negative Bloodstream Infections, Andrew Bock, Blake M Hanson, Felicia Ruffin, Joshua B Parsons, Lawrence P Park, Batu Sharma-Kuinkel, Michael Mohnasky, Cesar A Arias, 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 …

An Epithelial-Immune Circuit Amplifies Inflammasome And Il-6 Responses To Sars-Cov-2, Katherine C Barnett, Yuying Xie, Takanori Asakura, Dingka Song, Kaixin Liang, Sharon A Taft-Benz, Haitao Guo, Shuangshuang Yang, Kenichi Okuda, Rodney C Gilmore, Jennifer F Loome, Thomas H Oguin Iii, Gregory D Sempowski, Scott H Randell, Mark T Heise, Yu Leo Lei, Richard C Boucher, Jenny P-Y Ting

Faculty, Staff and Student Publications

Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, …

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, Gypsyamber D'Souza, Nancy A Hessol, Maarten F Schim Van Der Loeff, 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 …

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, Justin Z Amarin, Kristin L Moffitt, Mari M Nakamura, 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 …

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, Petros Nikolinakos, Patricia L Rich, Genevieve Jehl, 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 …

Production Of A Monoclonal Antibody For The Detection Of Forchlorfenuron: Application In An Indirect Enzyme-Linked Immunosorbent Assay And Immunochromatographic Strip, Xingmei Lei, A M Abd El-Aty, Lingyuan Xu, Jing Zhao, Jia Li, Song Gao, Yun Zhao, Yongxin She, Fen Jin, Jing Wang, Lufei Zheng, Maojun Jin, Bruce D Hammock

Faculty, Staff and Student Publications

In this study, a monoclonal antibody (mAb) specific to forchlorfenuron (CPPU) with high sensitivity and specificity was produced and designated (9G9). To detect CPPU in cucumber samples, an indirect enzyme-linked immunosorbent assay (ic-ELISA) and a colloidal gold nanobead immunochromatographic test strip (CGN-ICTS) were established using 9G9. The half-maximal inhibitory concentration (IC50) and the LOD for the developed ic-ELISA were determined to be 0.19 ng/mL and 0.04 ng/mL in the sample dilution buffer, respectively. The results indicate that the sensitivity of the antibodies prepared in this study (9G9 mAb) was higher than those reported in the previous literature. On the other …

Assessment Of Response To Neoadjuvant Systemic Treatment In Triple-Negative Breast Cancer Using Functional Tumor Volumes From Longitudinal Dynamic Contrast-Enhanced Mri, Bikash Panthi, Beatriz E Adrada, Rosalind P Candelaria, Mary S Guirguis, Clinton Yam, Medine Boge, Huiqin Chen, Kelly K Hunt, Lei Huo, Ken-Pin Hwang, Anil Korkut, Deanna L Lane, Huong C Le-Petross, Jessica W T Leung, Jennifer K Litton, Rania M Mohamed, Benjamin C Musall, Sanaz Pashapoor, Miral M Patel, Frances Perez, Jong Bum Son, Alastair Thompson, Vicente Valero, Peng Wei, Jason White, Zhan Xu, Lawrence Pinsky, Debu Tripathy, Wei Yang, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

Early assessment of neoadjuvant systemic therapy (NAST) response for triple-negative breast cancer (TNBC) is critical for patient care in order to avoid the unnecessary toxicity of an ineffective treatment. We assessed functional tumor volumes (FTVs) from dynamic contrast-enhanced (DCE) MRI after 2 cycles (C2) and 4 cycles (C4) of NAST as predictors of response in TNBC. A group of 100 patients with stage I-III TNBC who underwent DCE MRI at baseline, C2, and C4 were included in this study. Tumors were segmented on DCE images of 1 min and 2.5 min post-injection. FTVs were measured using the optimized percentage enhancement …

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, Maria D Iniesta, Charles S Cleeland, Larissa A Meyer

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 …

Long And Short Duration Exposures To The Selective Serotonin Reuptake Inhibitors (Ssris) Fluoxetine, Paroxetine And Sertraline At Environmentally Relevant Concentrations Lead To Adverse Effects On Zebrafish Behaviour And Reproduction, Ananda Baskaran Venkatachalam, Bailey Levesque, John C Achenbach, Jane J Pappas, Lee D Ellis

Faculty, Staff and Student Publications

Selective serotonin reuptake inhibitors (SSRIs) are currently the most prescribed class of psychotropic medications. Their increased global manufacture and use have become growing concerns for aquatic toxicologists and environmental biologists, who assess both the direct and indirect effects of substances on the environment and on human health. In order to assess the potential impact of environmentally relevant levels of SSRIs on fish development, behaviour and reproduction, we exposed juvenile and adult zebrafish to a select group of SSRIs using two separate exposure paradigms. In the first paradigm, juvenile zebrafish were exposed to Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft) or a …

3,3'-Diindolylmethane Augments 5-Fluorouracil-Inducedgrowth Suppression In Gastric Cancer Cells Through Suppression Of The Akt/Gsk-3Β And Wnt/Beta-Catenin, Cong Shan Li, Thi Van Nguyen, Ok Hee Chai, Byung Hyun Park, Ju-Seog Lee, Soo Mi Kim

Faculty, Staff and Student Publications

Gastric cancer (GC) is one of the most lethal cancers in South Korea, and it is a cancer of concern worldwide. 5-fluorouracil (5-Fu) is commonly used as the first-line therapy for advanced GC; however, its side effects often limit the dosage range and impair patients' quality of life. Due to the limitations of current chemotherapy, new anticancer therapies are urgently needed. 3,3'-diindolylmethane (DIM) has been reported to have the ability to protect against various types of cancer. Our study aimed to elucidate the anticancer effect of DIM in GC when treated with the chemotherapeutic agent 5-Fu. In our results, combined …

Factors For Poor Oral Health In Long-Term Childhood Cancer Survivors, Tushar Patni, Chun-Teh Lee, Yimei Li, Sue Kaste, Liang Zhu, Ryan Sun, Melissa M Hudson, Kirsten K Ness, 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 …

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, Daphne De Jong, Arianna Di Napoli, Dennis Hammond, 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.

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, Laura Galbraith, Kai Rakovic, Eva C Freckmann, 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 …

Spatially Resolved Single-Cell Assessment Of Pancreatic Cancer Expression Subtypes Reveals Co-Expressor Phenotypes And Extensive Intratumoral Heterogeneity, Hannah L Williams, Andressa Dias Costa, Jinming Zhang, Srivatsan Raghavan, Peter S Winter, Kevin S Kapner, Scott P Ginebaugh, Sara A Väyrynen, Juha P Väyrynen, Chen Yuan, Andrew W Navia, Junning Wang, Annan Yang, Timothy L Bosse, Radha L Kalekar, Kristen E Lowder, Mai Chan Lau, Dalia Elganainy, Vicente Morales-Oyarvide, Douglas A Rubinson, Harshabad Singh, Kimberly Perez, James M Cleary, Thomas E Clancy, Jiping Wang, Joseph D Mancias, Lauren K Brais, Emma R Hill, Margaret M Kozak, David C Linehan, Richard F Dunne, Daniel T Chang, Albert C Koong, Aram F Hezel, William C Hahn, Alex K Shalek, Andrew J Aguirre, Jonathan A Nowak, Brian M Wolpin

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed …

Immunogenetic Determinants Of Susceptibility To Head And Neck Cancer In The Million Veteran Program Cohort, Yanhong Liu, Jennifer R Kramer, Vlad C Sandulache, Robert Yu, Guojun Li, Liang Chen, Zenab I Yusuf, Yunling Shi, Saiju Pyarajan, Spyros Tsavachidis, Li Jiao, Michelle L Mierzwa, Elizabeth Chiao, Yvonne M Mowery, Andrew Shuman, Sanjay Shete, Andrew G Sikora, Donna L White

Faculty, Staff and Student Publications

Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and …

Tumor-Associated Nonmyelinating Schwann Cell-Expressed Nuclear Export Signal Mutation Of Epidermal Growth Factor Receptor Enhances Malignant Phenotypes Of Cancer Cells, Chengcao Sun, Youqiong Ye, Zhi Tan, Yuan Liu, Yajuan Li, Wei Hu, Ke Liang, Sergey D Egranov, Lisa Angela Huang, Zhao Zhang, Yaohua Zhang, Jun Yao, Tina K Nguyen, Zilong Zhao, Andrew Wu, Jeffrey R Marks, Abigail S Caudle, Aysegul A Sahin, Jianjun Gao, Seth T Gammon, David Piwnica-Worms, Jian Hu, Paul J Chiao, Dihua Yu, Mien-Chie Hung, Michael A Curran, George A Calin, Haoqiang Ying, Leng Han, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (

Association Between P2y12 Inhibitor Reloading And In-Hospital Outcomes For Patients With Non-St-Segment Elevation Acute Coronary Syndrome Already On Chronic P2y12 Receptor Inhibitors Therapy In China: Findings From The Ccc-Acs (Improving Care For Cardiovascular Disease In China-Acute Coronary Syndrome) Project, Yintang Wang, Yu Geng, Ou Zhang, Qin Xu, Yajun Xue, Boda Zhou, Ping Zhang

Faculty, Staff and Student Publications

BACKGROUND: The association between P2Y12 receptor inhibitors reloading and in-hospital outcomes in non-ST-segment elevation acute coronary syndrome (NSTEACS) patients who were on chronic P2Y12 receptor inhibitors therapy remained underdetermined.

METHODS: The Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS project) is a national registry active from November 2014 to December 2019. 4790 NSTEACS patients on chronic P2Y12 receptor inhibitors therapy were included. Cox proportional hazard models, Kaplan-Meier curves, and subgroup analyses were conducted.

RESULTS: The NSTEACS patients who received reloading of P2Y12 receptor inhibitors were younger and had fewer comorbid conditions. The reloading group had a lower risk …

Effective Treatment Of Low-Risk Acute Gvhd With Itacitinib Monotherapy, Aaron Etra, Alexandra Capellini, Amin Alousi, Monzr M Al Malki, Hannah Choe, Zachariah Defilipp, William J Hogan, Carrie L Kitko, 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 …

Hemoglobin Concentration Impacts Viscoelastic Hemostatic Assays In Icu Admitted Patients, David J Roh, Tiffany R Chang, Aditya Kumar, Devin Burke, Glenda Torres, Katherine Xu, Winni Yang, Azzurra Cottarelli, Ernest Moore, Angela Sauaia, Kirk Hansen, Angela Velazquez, Amelia Boehme, Athina Vrosgou, Shivani Ghoshal, Soojin Park, Sachin Agarwal, Jan Claassen, E Sander Connolly, Gebhard Wagener, Richard O Francis, Eldad Hod

Faculty, Staff and Student Publications

Objectives: Low hemoglobin concentration impairs clinical hemostasis across several diseases. It is unclear whether hemoglobin impacts laboratory functional coagulation assessments. We evaluated the relationship of hemoglobin concentration on viscoelastic hemostatic assays in intracerebral hemorrhage (ICH) and perioperative patients admitted to an ICU.

Design: Observational cohort study and separate in vitro laboratory study.

Setting: Multicenter tertiary referral ICUs.

Patients: Two acute ICH cohorts receiving distinct testing modalities: rotational thromboelastometry (ROTEM) and thromboelastography (TEG), and a third surgical ICU cohort receiving ROTEM were evaluated to assess the generalizability of findings across disease processes and testing platforms. A separate in vitro ROTEM laboratory …

Automated Field-In-Field Whole Brain Radiotherapy Planning, Kai Huang, Soleil Hernandez, Chenyang Wang, Callistus Nguyen, Tina Marie Briere, Carlos Cardenas, Laurence Court, Yao Xiao

Faculty, Staff and Student Publications

PURPOSE: We developed and tested an automatic field-in-field (FIF) solution for whole-brain radiotherapy (WBRT) planning that creates a homogeneous dose distribution by minimizing hotspots, resulting in clinically acceptable plans.

METHODS: A configurable auto-planning algorithm was developed to automatically generate FIF WBRT plans independent of the treatment planning system. Configurable parameters include the definition of hotspots, target volume, maximum number of subfields, and minimum number of monitor units per field. This algorithm iteratively identifies a hotspot, creates two opposing subfields, calculates the dose, and optimizes the beam weight based on user-configured constraints of dose-volume histogram coverage and least-squared cost functions. The …

Spatial Molecular And Cellular Determinants Of Stat3 Activation In Liver Fibrosis Progression In Non-Alcoholic Fatty Liver Disease, Jingjing Jiao, Jessica I Sanchez, Omar A Saldarriaga, Luisa M Solis, David J Tweardy, Dipen M Maru, Heather L Stevenson, Laura Beretta

Faculty, Staff and Student Publications

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is increasing. Individuals with NASH often develop liver fibrosis and advanced liver fibrosis is the main determinant of mortality in individuals with NASH. We and others have reported that STAT3 contributes to liver fibrosis and hepatocellular carcinoma in mice.

METHODS: Here, we explored whether STAT3 activation in hepatocyte and non-hepatocyte areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and …

Machine Learning And Acute Stroke Imaging, Sunil A Sheth, Luca Giancardo, Marco Colasurdo, Visish M Srinivasan, Arash Niktabe, Peter Kan

Faculty, Staff and Student Publications

BACKGROUND: In recent years, machine learning (ML) has had notable success in providing automated analyses of neuroimaging studies, and its role is likely to increase in the future. Thus, it is paramount for clinicians to understand these approaches, gain facility with interpreting ML results, and learn how to assess algorithm performance.

OBJECTIVE: To provide an overview of ML, present its role in acute stroke imaging, discuss methods to evaluate algorithms, and then provide an assessment of existing approaches.

METHODS: In this review, we give an overview of ML techniques commonly used in medical imaging analysis and methods to evaluate performance. …