Digital Commons Network^™

Monophosphoryl Lipid A-Based Adjuvant To Promote The Immunogenicity Of Multivalent Meningococcal Polysaccharide Conjugate Vaccines, Kishore Alugupalli

Department of Microbiology and Immunology Faculty Papers

Activation of the adaptive immune system requires the engagement of costimulatory pathways in addition to B and T cell Ag receptor signaling, and adjuvants play a central role in this process. Many Gram-negative bacterial polysaccharide vaccines, including the tetravalent meningococcal conjugate vaccines (MCV4) and typhoid Vi polysaccharide vaccines, do not incorporate adjuvants. The immunogenicity of typhoid vaccines is due to the presence of associated TLR4 ligands in these vaccines. Because the immunogenicity of MCV4 is poor and requires boosters, I hypothesized that TLR4 ligands are absent in MCV4 and that incorporation of a TLR4 ligand-based adjuvant would improve their immunogenicity. …

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations In Chronic Pancreatitis: A Multicenter, Cross-Sectional Study, Kristyn Gumpper-Fedus, Kaylin Chasser, Valentina Pita-Grisanti, Molly Torok, Timothy Pfau, Thomas A Mace, Rachel M Cole, Martha A Belury, Stacey Culp, Phil A Hart, Somashekar G Krishna, Luis F Lara, Mitchell L Ramsey, William Fisher, Evan L Fogel, Chris E Forsmark, Liang Li, Stephen Pandol, Walter G Park, Jose Serrano, Stephen K Van Den Eeden, Santhi Swaroop Vege, Dhiraj Yadav, Darwin L Conwell, Zobeida Cruz-Monserrate, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Introduction: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations.

Methods: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear …

Does A Reduction In Receiving Assistance With Daily Activities Among Older Adults In Mexico Indicate An Increase In Unmet Needs Or A Decrease In Needs For Care?, Brian Downer, Rafael Samper-Ternent, Philip Cantu, Matthew Miller, Rebeca Wong

Faculty, Staff and Student Publications

OBJECTIVES: The percentage of older adults in Mexico with difficulty completing activities of daily living (ADL) who receive assistance from family appears to be decreasing. We compared 2 birth cohorts of older adults in Mexico to investigate whether this trend reflects an increase in unmet caregiving needs or a decrease in the need for care.

METHODS: We selected Mexican Health and Aging Study participants aged 60-76 in 2001 (n = 4,805) and 2018 (n = 6,494). ADL tasks were dressing, walking, bathing, getting in and out of bed, and toileting. Participants who reported difficulty with an ADL were asked if …

Potential Impact Of Annual Vaccination With Reformulated Covid-19 Vaccines: Lessons From The Us Covid-19 Scenario Modeling Hub, Sung-Mok Jung, Sara L Loo, Emily Howerton, Lucie Contamin, Claire P Smith, Erica C Carcelén, Katie Yan, Samantha J Bents, John Levander, Jessi Espino, Joseph C Lemaitre, Koji Sato, Clifton D Mckee, Alison L Hill, Matteo Chinazzi, Jessica T Davis, Kunpeng Mu, Alessandro Vespignani, Erik T Rosenstrom, Sebastian A Rodriguez-Cartes, Julie S Ivy, Maria E Mayorga, Julie L Swann, Guido España, Sean Cavany, Sean M Moore, T Alex Perkins, Shi Chen, Rajib Paul, Daniel Janies, Jean-Claude Thill, Ajitesh Srivastava, Majd Al Aawar, Kaiming Bi, Shraddha Ramdas Bandekar, Anass Bouchnita, Spencer J Fox, Lauren Ancel Meyers, Przemyslaw Porebski, Srini Venkatramanan, Aniruddha Adiga, Benjamin Hurt, Brian Klahn, Joseph Outten, Jiangzhuo Chen, Henning Mortveit, Amanda Wilson, Stefan Hoops, Parantapa Bhattacharya, Dustin Machi, Anil Vullikanti, Bryan Lewis, Madhav Marathe, Harry Hochheiser, Michael C Runge, Katriona Shea, Shaun Truelove, Cécile Viboud, Justin Lessler

Faculty, Staff and Student Publications

BACKGROUND: Coronavirus Disease 2019 (COVID-19) continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Here, we present projections of COVID-19 hospitalizations and deaths in the United States for the next 2 years under 2 plausible assumptions about immune escape (20% per year and 50% per year) and 3 possible CDC recommendations for the use of annually reformulated vaccines (no recommendation, vaccination for those aged 65 years and over, vaccination for all eligible age groups based on FDA approval).

METHODS AND FINDINGS: The COVID-19 Scenario Modeling Hub …

Does Emotional Distress Predict Worse Glycemic Control Over Time? Results From The Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness Study (Grade), Andrea L Cherrington, Ionut Bebu, Heidi Krause-Steinrauf, Claire J Hoogendoorn, Gladys Crespo-Ramos, Caroline Presley, Aanand D Naik, Ashok Balasubramanyam, Michaela R Gramzinski, Tina Killean, Valerie L Arends, Jeffrey S Gonzalez

Faculty, Staff and Student Publications

Objective: To evaluate whether baseline levels of depressive symptoms and diabetes-specific distress are associated with glycemic control in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing the metabolic effects of four common glucose-lowering medications when combined with metformin in individuals with type 2 diabetes mellitus (T2DM).

Research design and methods: The primary and secondary outcomes were defined as an HbA1c value ≥7%, subsequently confirmed, and an HbA1c value >7.5%, subsequently confirmed, respectively. Separate Cox proportional hazards models assessed the association between baseline levels of each exposure of interest (depressive symptoms measured with …

Final Report Of The Phase Ii Next/Cns-Gct-4 Trial: Gempox Followed By Marrow-Ablative Chemotherapy For Recurrent Intracranial Germ Cell Tumors, Margaret Shatara, Megan Blue, Joseph Stanek, Yin A Liu, Daniel M Prevedello, Pierre Giglio, Vinay K Puduvalli, Sharon L Gardner, Jeffrey C Allen, Kenneth K Wong, Marvin D Nelson, Floyd H Gilles, Roberta H Adams, Jasmine Pauly, Katrina O'Halloran, Ashley S Margol, Girish Dhall, Jonathan L Finlay

Faculty, Staff and Student Publications

Background: Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx).

Methods: A total of 9 patients with confirmed …

The Tudor-Knot Domain Of Kat5 Regulates Nucleosomal Substrate Acetylation, Fan Xuan, Hongwen Xuan, Mengying Huang, Wei He, Han Xu, Xiaobing Shi, Hong Wen

Faculty, Staff and Student Publications

The lysine acetyltransferase KAT5 is a pivotal enzyme responsible for catalyzing histone H4 acetylation in cells. In addition to its indispensable HAT domain, KAT5 also encompasses a conserved Tudor-knot domain at its N-terminus. However, the function of this domain remains elusive, with conflicting findings regarding its role as a histone reader. In our study, we have employed a CRISPR tiling array approach and unveiled the Tudor-knot motif as an essential domain for cell survival. The Tudor-knot domain does not bind to histone tails and is not required for KAT5's chromatin occupancy. However, its absence leads to a global reduction in …

Identifying Cancer Subtypes Based On Embryonic And Hematopoietic Stem Cell Signatures In Pan-Cancer, Jiali Lei, Jiangti Luo, Qian Liu, Xiaosheng Wang

Faculty, Staff and Student Publications

Purpose: Cancer cells with stem cell-like properties may contribute to cancer development and therapy resistance. The advancement of multi-omics technology has sparked interest in exploring cancer stemness from a multi-omics perspective. However, there is a limited number of studies that have attempted to subtype cancer by combining different types of stem cell signatures.

Methods: In this study, 10,323 cancer specimens from 33 TCGA cancer types were clustered based on the enrichment scores of six stemness gene sets, representing two types of stem cell backgrounds: embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs).

Results: We identified four subtypes of pan-cancer, …

Druggable Site Near The Upper Vestibule Determines The High Affinity And P2x3 Homotrimer Selectivity Of Sivopixant/S-600918 And Its Analogue Ddtpa, Dong-Ping Wang, Meng Zhang, Ming Li, Xiao-Na Yang, Changzhu Li, Peng Cao, Michael X Zhu, Yun Tian, Ye Yu, Yun-Tao Lei

Faculty, Staff and Student Publications

Background and purpose: The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF-219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S-600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3-(4-([3-chloro-4-isopropoxyphenyl]amino)-3-(4-methylbenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)propanoic acid (DDTPA), exhibit both high affinity …

Fear Antiviral Response Pathway Is Independent Of Interferons And Countered By Poxvirus Proteins, Emily A Rex, Dahee Seo, Sruthi Chappidi, Chelsea Pinkham, Sabrynna Brito Oliveira, Aaron Embry, David Heisler, Yang Liu, Moiz Munir, Karolin Luger, Neal M Alto, Flávio Guimarães Da Fonseca, Robert Orchard, Dustin C Hancks, Don B Gammon

Faculty, Staff and Student Publications

The human facilitates chromatin transcription (FACT) complex is a chromatin remodeller composed of human suppressor of Ty 16 homologue (hSpt16) and structure-specific recognition protein-1 subunits that regulates cellular gene expression. Whether FACT regulates host responses to infection remained unclear. We identify a FACT-mediated, interferon-independent, antiviral pathway that restricts poxvirus replication. Cell culture and bioinformatics approaches suggest that early viral gene expression triggers nuclear accumulation of SUMOylated hSpt16 subunits required for the expression of E26 transformation-specific sequence-1 (ETS-1)-a transcription factor that activates virus restriction programs. However, biochemical studies show that poxvirus-encoded A51R proteins block ETS-1 expression by outcompeting structure-specific recognition protein-1 …

Reciprocal Relationships Between Stress And Depressive Symptoms: The Essential Role Of The Nucleus Accumbens, Yizhou Ma, Peter Kochunov, Mark D Kvarta, Tara Legates, Bhim M Adhikari, Joshua Chiappelli, Andrew Van Der Vaart, Eric L Goldwaser, Heather Bruce, Kathryn S Hatch, Si Gao, Shuo Chen, Ann Summerfelt, Thomas E Nichols, L Elliot Hong

Faculty, Staff and Student Publications

BACKGROUND: Stress and depression have a reciprocal relationship, but the neural underpinnings of this reciprocity are unclear. We investigated neuroimaging phenotypes that facilitate the reciprocity between stress and depressive symptoms.

METHODS: In total, 22 195 participants (52.0% females) from the population-based UK Biobank study completed two visits (initial visit: 2006-2010, age = 55.0 ± 7.5 [40-70] years; second visit: 2014-2019; age = 62.7 ± 7.5 [44-80] years). Structural equation modeling was used to examine the longitudinal relationship between self-report stressful life events (SLEs) and depressive symptoms. Cross-sectional data were used to examine the overlap between neuroimaging correlates of SLEs and …

Rfx Transcription Factor In The Human-Associated Yeast Candida Albicans Regulates Adhesion To Oral Epithelium, Diana L Rodríguez, Elena Lindemann-Perez, J Christian Perez

Faculty, Staff and Student Publications

Adhesion to mucosal surfaces is a critical step in many bacterial and fungal infections. Here, using a mouse model of oral infection by the human fungal pathobiont Candida albicans, we report the identification of a novel regulator of C. albicans adhesion to the oral mucosa. The regulator is a member of the regulatory factor X (RFX) family of transcription factors, which control cellular processes ranging from genome integrity in model yeasts to tissue differentiation in vertebrates. Mice infected with the C. albicans rfx1 deletion mutant displayed increased fungal burden in tongues compared to animals infected with the reference strain. High-resolution …

Readiness Of Nociceptor Cell Bodies To Generate Spontaneous Activity Results From Background Activity Of Diverse Ion Channels And High Input Resistance, Jinbin Tian, Alexis G Bavencoffe, Michael X Zhu, Edgar T Walters

Faculty, Staff and Student Publications

Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia have shown that previous pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Using mouse nociceptors, we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. …

Recurrent Lymphoid And Myeloid Relapses Due To Treatment Cessations Reveal Natural History Of Ph-Positive B-All And Pose A Diagnostic Challenge, Shimin Hu, Elias J Jabbour, Collin Y Hu, Guilin Tang, Wei Wang, L Jeffrey Medeiros, Carlos Bueso-Ramos

Faculty, Staff and Student Publications

No abstract provided.

Temporal Changes In Treatment And Late Mortality And Morbidity In Adult Survivors Of Childhood Glioma: A Report From The Childhood Cancer Survivor Study, Peter M K De Blank, Katharine R Lange, Mengqi Xing, Sedigheh Mirzaei Salehabadi, Deokumar Srivastava, Tara M Brinkman, Kirsten K Ness, Kevin C Oeffinger, Joseph Neglia, Kevin R Krull, Paul C Nathan, Rebecca Howell, Lucie M Turcotte, Wendy Leisenring, Gregory T Armstrong, M Fatih Okcu, Daniel C Bowers

Faculty, Staff and Student Publications

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), …

Loss-Of-Function Mutation In Prmt9 Causes Abnormal Synapse Development By Dysregulation Of Rna Alternative Splicing, Lei Shen, Xiaokuang Ma, Yuanyuan Wang, Zhihao Wang, Yi Zhang, Hoang Quoc Hai Pham, Xiaoqun Tao, Yuehua Cui, Jing Wei, Dimitri Lin, Tharindumala Abeywanada, Swanand Hardikar, Levon Halabelian, Noah Smith, Taiping Chen, Dalia Barsyte-Lovejoy, Shenfeng Qiu, Yi Xing, Yanzhong Yang

Faculty, Staff and Student Publications

Protein arginine methyltransferase 9 (PRMT9) is a recently identified member of the PRMT family, yet its biological function remains largely unknown. Here, by characterizing an intellectual disability associated PRMT9 mutation (G189R) and establishing a Prmt9 conditional knockout (cKO) mouse model, we uncover an important function of PRMT9 in neuronal development. The G189R mutation abolishes PRMT9 methyltransferase activity and reduces its protein stability. Knockout of Prmt9 in hippocampal neurons causes alternative splicing of ~1900 genes, which likely accounts for the aberrant synapse development and impaired learning and memory in the Prmt9 cKO mice. Mechanistically, we discover a methylation-sensitive protein-RNA interaction between …

Recurrent Nontraumatic Subgaleal Hematomas In A Pediatric Patient With Sickle Cell Disease, Irtiza N Sheikh, Olayinka Okeleji, Rabya Afzal, Eliana Bonfante, Monica Kodakandla, Neethu M Menon

Faculty, Staff and Student Publications

Spontaneous subgaleal hematoma in pediatric patients with sickle cell disease (SCD) is a rare occurrence that can present with symptoms mimicking ischemic stroke, a known complication of SCD. However, unlike ischemic stroke, subgaleal hematoma is nonlethal and can be managed conservatively without major sequelae. Here, we present the case of an adolescent with SCD who presented with 2 episodes of subgaleal and epidural hematomas, 2 years apart. The latter episode occurred while on crizanlizumab, an anti-P-selectin antibody, approved for use in SCD in 2019 to reduce the number of acute pain crises. We demonstrate the diagnosis of subgaleal hematoma and …

Oral Decitabine And Cedazuridine Plus Venetoclax For Older Or Unfit Patients With Acute Myeloid Leukaemia: A Phase 2 Study, Alexandre Bazinet, Guillermo Garcia-Manero, Nicholas Short, Yesid Alvarado, Alex Bataller, Tareq Abuasab, Rabiul Islam, Kathryn Montalbano, Ghayas Issa, Abhishek Maiti, Musa Yilmaz, Nitin Jain, Lucia Masarova, Steven Kornblau, Elias Jabbour, Guillermo Montalban-Bravo, Caitlin R Rausch, Sherry Pierce, Courtney D Dinardo, Tapan Kadia, Naval Daver, Marina Konopleva, Xuelin Huang, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

Background: Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax.

Methods: This study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2-3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. …

Trajectories Of Health Care Contact Days For Patients With Stage Iv Non-Small Cell Lung Cancer, Arjun Gupta, Paul Nguyen, Danielle Kain, Andrew G Robinson, Amit A Kulkarni, David H Johnson, Carolyn J Presley, Anne H Blaes, Gabrielle B Rocque, Ishani Ganguli, Christopher M Booth, Timothy P Hanna

Faculty, Staff and Student Publications

Importance: Patients with stage IV non-small cell lung cancer (NSCLC) experience substantial morbidity and mortality. Contact days (ie, the number of days with health care contact outside the home) measure how much of a person's life is consumed by health care, yet little is known about patterns of contact days for patients with NSCLC.

Objective: To describe the trajectories of contact days in patients with stage IV NSCLC and how trajectories vary by receipt of cancer-directed treatment in routine practice.

Design, setting, and participants: A retrospective, population-based decedent cohort study was conducted in Ontario, Canada. Participants included adults aged 20 …

Efficacy And Safety Results After >35 Years Of Treatment With The Bruton’S Tyrosine Kinase Inhibitor Evobrutinib In Relapsing Multiple Sclerosis: Long-Term Follow-Up Of A Phase Ii Randomised Clinical Trial With A Cerebrospinal Fluid Sub-Study, Xavier Montalban, Karolina Piasecka-Stryczynska, Jens Kuhle, Pascal Benkert, Douglas L Arnold, Martin S Weber, Andrea Seitzinger, Hans Guehring, Jamie Shaw, Davorka Tomic, Yann Hyvert, Danielle E Harlow, Martin Dyroff, Jerry S Wolinsky

Faculty, Staff and Student Publications

BACKGROUND: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS.

OBJECTIVE: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study.

METHODS: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) …

Sting-Activating Cyclic Dinucleotide-Manganese Nanoparticles Evoke Robust Immunity Against Acute Myeloid Leukemia, Marisa E Aikins, Xiaoqi Sun, Hannah Dobson, Xingwu Zhou, Yao Xu, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults with a 5-year survival rate of 30.5%. These poor patient outcomes are attributed to tumor relapse, stemming from ineffective innate immune activation, T cell tolerance, and a lack of immunological memory. Thus, new strategies are needed to activate innate and effector immune cells and evoke long-term immunity against AML. One approach to address these issues is through Stimulator of Interferon Genes (STING) pathway activation, which produces Type I Interferons (Type I IFN) critical for innate and adaptive immune activation. Here, we report that systemic immunotherapy …

Cytogenetic And Molecular Associations With Outcomes In Higher-Risk Myelodysplastic Syndromes Treated With Hypomethylating Agents Plus Venetoclax, Alexandre Bazinet, Sai Prasad Desikan, Ziyi Li, Juan Jose Rodriguez-Sevilla, Sangeetha Venugopal, Samuel Urrutia, Guillermo Montalban-Bravo, Koji Sasaki, Kelly S Chien, Danielle Hammond, Rashmi Kanagal-Shamanna, Irene Ganan-Gomez, Tapan M Kadia, Gautam Borthakur, Courtney D Dinardo, Naval G Daver, Elias J Jabbour, Farhad Ravandi, Hagop Kantarjian, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Purpose: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood.

Experimental design: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations …

Prognostic Value Of Tumor Volume Doubling Time In Lung-Metastatic Adenoid Cystic Carcinoma, Eduardo A Dal Lago, Luana G Sousa, Zixi Yang, Camilla O Hoff, Flavia Bonini, Matthew Sawyer, Kaiwen Wang, Whitney Lewis, Kareem A Wahid, Ehab Y Hanna, Adel El-Naggar, Clifton D Fuller, Suprateek Kundu, Myrna Godoy, Renata Ferrarotto

Faculty, Staff and Student Publications

Objectives: Lung metastases in adenoid cystic carcinoma (ACC) usually have indolent growth and the optimal timing to start systemic therapy is not established. We assessed ACC lung metastasis tumor growth dynamics and compared the prognostic value of time to progression (TTP) and tumor volume doubling time (TVDT).

Methods: The study included ACC patients with ≥1 pulmonary metastasis (≥5 mm) and at least 2 chest computed tomography scans. Radiology assessment was performed from the first scan showing metastasis until treatment initiation or death. Up to 5 lung nodules per patient were segmented for TVDT calculation. To assess tumor growth rate (TGR), …

Predicting Recurrence-Free And Overall Survival For Patients With Stage Ii Melanoma: The Mia Calculator, Alexander H R Varey, Isabel Li, Mary-Ann El Sharouni, Julie Simon, Aikaterini Dedeilia, Sydney Ch'ng, Robyn P M Saw, Andrew J Spillane, Kerwin F Shannon, Thomas E Pennington, Michael Rtshiladze, Jonathan R Stretch, Omgo E Nieweg, Alexander Van Akkooi, Ryan J Sullivan, Genevieve M Boland, Jeffrey E Gershenwald, Paul J Van Diest, Richard A Scolyer, Georgina V Long, John F Thompson, Serigne N Lo

Faculty, Staff and Student Publications

Purpose: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients.

Methods: Data were extracted …

Oral Decitabine And Cedazuridine Plus Venetoclax For Older Or Unfit Patients With Acute Myeloid Leukaemia: A Phase 2 Study, Alexandre Bazinet, Guillermo Garcia-Manero, Nicholas Short, Yesid Alvarado, Alex Bataller, Tareq Abuasab, Rabiul Islam, Kathryn Montalbano, Ghayas Issa, Abhishek Maiti, Musa Yilmaz, Nitin Jain, Lucia Masarova, Steven Kornblau, Elias Jabbour, Guillermo Montalban-Bravo, Caitlin R Rausch, Sherry Pierce, Courtney D Dinardo, Tapan Kadia, Naval Daver, Marina Konopleva, Xuelin Huang, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

BACKGROUND: Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax.

METHODS: This study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2-3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. …

Cochlear Implantation After Head And Neck Radiation: A Case Series, Systematic Review, And Meta-Analysis, Jumah G Ahmad, Benjamin D Lovin, Anna Lee, Marc-Elie Nader, Paul W Gidley

Faculty, Staff and Student Publications

Objective: To determine if cochlear implant (CI) is safe and effective in patients with radiation therapy (XRT)-induced sensorineural hearing loss and to discuss considerations in this population through a retrospective cohort review, systematic review, and meta-analysis.

Databases reviewed: PubMed, Cochrane Library, and Embase.

Methods: We retrospectively reviewed all CI cases after head and neck (HN) XRT at our institution, noting intraoperative findings, postoperative complications, and hearing outcomes. Change in speech discrimination scores (SDSs) was the primary outcome measure. Systematic review was performed to identify all cases of CI after HNXRT. A meta-analysis was performed to assess SDS change.

Results: The …

Incidence And Presenting Characteristics Of Angiosarcoma In The Us, 2001-2020, Michael J Wagner, Vinod Ravi, Stephanie K Schaub, Ed Y Kim, Jeremy Sharib, Harveshp Mogal, Min Park, Michaela Tsai, Daniela Duarte-Bateman, Anthony Tufaro, Elizabeth T Loggers, Lee D Cranmer, Bonny Chau, Michael J Hassett, Juneko Grilley-Olson, Kelly G Paulson

Faculty, Staff and Student Publications

Importance: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed.

Objective: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US.

Design, setting, and participants: This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19 289 patients in …

Large-Scale Phenotyping Of Patients With Long Covid Post-Hospitalization Reveals Mechanistic Subtypes Of Disease, Felicity Liew, Claudia Efstathiou, Sara Fontanella, Matthew Richardson, Ruth Saunders, Dawid Swieboda, Jasmin K Sidhu, Stephanie Ascough, Shona C Moore, Noura Mohamed, Jose Nunag, Clara King, Olivia C Leavy, Omer Elneima, Hamish J C Mcauley, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Victoria C Harris, Linzy Houchen-Wolloff, Neil J Greening, Nazir I Lone, Matthew Thorpe, A A Roger Thompson, Sarah L Rowland-Jones, Annemarie B Docherty, James D Chalmers, Ling-Pei Ho, Alexander Horsley, Betty Raman, Krisnah Poinasamy, Michael Marks, Onn Min Kon, Luke S Howard, Daniel G Wootton, Jennifer K Quint, Thushan I De Silva, Antonia Ho, Christopher Chiu, Ewen M Harrison, William Greenhalf, J Kenneth Baillie, Malcolm G Semple, Lance Turtle, Rachael A Evans, Louise V Wain, Christopher Brightling, Ryan S Thwaites, Peter J M Openshaw, Phosp-Covid Collaborative Group, Isaric Investigators

Faculty, Staff and Student Publications

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers …

Randomized Phase 2 Trial Of Tremelimumab And Durvalumab In Combination Versus Sequentially In Recurrent Platinum-Resistant Ovarian Cancer, Emily M Hinchcliff, Anne Knisely, Naomi Adjei, Bryan Fellman, Ying Yuan, Ami Patel, Cai Xu, Shannon N Westin, Anil K Sood, Pamela T Soliman, Aaron Shafer, Nicole D Fleming, David M Gershenson, Raghunandan Vikram, Tharakeswara Bathala, David Vining, Dhakshina M Ganeshan, Karen H Lu, Charlotte C Sun, Larissa A Meyer, Amir A Jazaeri

Faculty, Staff and Student Publications

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC).

METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end …

Definitive Single Fraction Spine Stereotactic Radiosurgery For Metastatic Sarcoma: Simultaneous Integrated Boost Is Associated With High Tumor Control And Low Vertebral Fracture Risk, Mihir D Shanker, Adriana P Cavazos, Jing Li, Thomas H Beckham, Debra N Yeboa, Chenyang Wang, Mary Frances Mcaleer, Tina Marie Briere, Behrang Amini, Claudio E Tatsui, Robert Y North, Christopher A Alvarez-Breckenridge, Phillip Cem Cezayirli, Laurence D Rhines, Amol J Ghia, Andrew J Bishop

Faculty, Staff and Student Publications

Introduction: Sarcoma spinal metastases (SSM) are particularly difficult to manage given their poor response rates to chemotherapy and inherent radioresistance. We evaluated outcomes in a cohort of patients with SSM uniformly treated using single-fraction simultaneous-integrated-boost (SIB) spine stereotactic radiosurgery (SSRS).

Materials and methods: A retrospective review was conducted at a single tertiary institution treated with SSRS for SSM between April 2007-April 2023. 16-24 Gy was delivered to the GTV and 16 Gy uniformly to the CTV. Kaplan-Meier analysis was conducted to assess time to progression of disease (PD) with proportionate hazards modelling used to determine hazard ratios (HR) and respective …