Medical Specialties Commons^™

Results Of The Simultaneous Combination Of Ponatinib And Blinatumomab In Philadelphia Chromosome-Positive All, Hagop Kantarjian, Nicholas J Short, Fadi G Haddad, Nitin Jain, Xuelin Huang, Guillermo Montalban-Bravo, Rashmi Kanagal-Shamanna, Tapan M Kadia, Naval Daver, Kelly Chien, Yesid Alvarado, Guillermo Garcia-Manero, Ghayas C Issa, Rebecca Garris, Cedric Nasnas, Lewis Nasr, Farhad Ravandi, Elias Jabbour

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.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate …

Protocol For Monitoring Clonal Hematopoiesis In Transgenic Mouse Models Using Multispectral Imaging, Priyanka Khanna, Lauren B Ostermann, Shayaun Khazaei, Ran Zhao, Michael Andreeff, Rasoul Pourebrahim

Faculty, Staff and Student Publications

Clonal hematopoiesis involves the clonal expansion of hematopoietic cells, potentially progressing into hematological malignancies. Here, we present a protocol for the development and characterization of two mouse models designed to simulate clonal hematopoiesis and acute myeloid leukemia. We describe steps for model generation, monitoring clonal expansion, harvesting, fixation, and staining of bone marrow and spleen tissues. We specifically focus on the visualization and analysis of p53 mutant clonal expansions, providing a comprehensive protocol for studying these phenomena in mouse models. For complete details on the use and execution of this protocol, please refer to Pourebrahim et al.

Protocol For Culturing Patient-Derived Organoids Of Cervical Cancer, Rui Wang, Timothy Harris, Dalissa Negrón-Figueroa, David Lo, Allison Judge, D'Shaunique Walters, Bo Jiang, Lauren E Colbert

Faculty, Staff and Student Publications

Herein, we present a protocol for culturing patient-derived organoids (PDOs) of cervical cancer that includes workflows for tumor biopsy/resection tissue and cytobrush-sampled cells. We describe steps for PDO culture initiation, including rinsing, gentle dissociation, Lymphoprep separation, and cell assessment, as well as seeding cells from surgical and cytobrush tissue digestion. We then provide guidance on PDO maintenance and passage and techniques for producing conditioned medium. Overall, this protocol serves as a valuable guide for establishing and maintaining cervical cancer PDOs. For complete details on the use and execution of this protocol, please refer to Colbert et al.

Author Correction: Single-Cell And Spatial Proteo-Transcriptomic Profiling Reveals Immune Infiltration Heterogeneity Associated With Neuroendocrine Features In Small Cell Lung Cancer, Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Lungevity Panshi Initiative Consortium, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen

Faculty, Staff and Student Publications

No abstract provided.

Deuterated Water Labeling In Ibrutinib-Treated Patients With Cll: Leukemia Cell Kinetics Correlate With Ighv, Zap-70, And Mrd, Ekaterina Kim, Shih-Shih Chen, Mariela Sivina, Hyunsoo Hwang, Xuelin Huang, Alessandra Ferrajoli, Nitin Jain, William G Wierda, Dominik Wodarz, Nicholas Chiorazzi, Jan A Burger

Faculty, Staff and Student Publications

Deuterated (“heavy”) water labeling in patients with chronic lymphocytic leukemia (CLL) demonstrates that IGHV unmutated and ZAP-70+ patients have higher blood and tissue CLL death rates on ibrutinib therapy, resulting in lower measurable residual disease levels with long-term ibrutinib treatment. This trial was registered at www.clinicaltrials.gov as #NCT01752426.

The Proteomics Of T-Cell And Early T-Cell Precursor (Etp) Acute Lymphocytic Leukemia: Prognostic Patterns In Adult And Pediatric-Etp All, Fieke W Hoff, Lourdes Sriraja, Yihua Qiu, Gaye N Jenkins, David T Teachey, Brent Wood, Meenakshi Devidas, Shaina Shockley, Mignon L Loh, Evangelia Petsalaki, Steven M Kornblau, Terzah M Horton

Faculty, Staff and Student Publications

Background: The 5-year overall survival (OS) rates of T-cell lymphocytic leukemia (T-ALL) are better for children (>90%) compared to adults (~57%). The early T-cell precursor (ETP) T-ALL subtype is prognostically unfavorable in adults, but less significant in pediatric T-ALL, and the diagnosis and prognosis of "near"-ETP is controversial. We compared protein and RNA expression patterns in pediatric and adult T-ALL to identify prognostic subgroups, and to further characterize ETP and near-ETP T-ALL in both age groups.

Methods: Protein expression was assessed using RPPA methodology for 321 target proteins in 361 T-ALL patient samples from 292 pediatrics and 69 adults, …

Enhancer Reprogramming Underlies Therapeutic Utility Of A Smarca2 Degrader In Smarca4 Mutant Cancer, Sasikumar Kotagiri, Nicholas Blazanin, Yuanxin Xi, Yanyan Han, Md Qudratullah, Xiaobing Liang, Yawen Wang, Poonam Pandey, Hira Mazhar, Truong Nguyen Lam, Anand Kamal Singh, Jing Wang, Yonathan Lissanu

Faculty, Staff and Student Publications

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes …

Functional Properties Of Corticothalamic Circuits Targeting Paraventricular Thalamic Neurons, Guillermo Aquino-Miranda, Dounya Jalloul, Xu O Zhang, Sa Li, Gilbert J Kirouac, Michael Beierlein, Fabricio H Do Monte

Faculty, Staff and Student Publications

Corticothalamic projections to sensorimotor thalamic nuclei show modest firing rates and serve to modulate the activity of thalamic relay neurons. By contrast, here we find that high-order corticothalamic projections from the prelimbic (PL) cortex to the anterior paraventricular thalamic nucleus (aPVT) maintain high-frequency activity and evoke strong synaptic excitation of aPVT neurons in rats. In a significant fraction of aPVT cells, such high-frequency excitation of PL-aPVT projections leads to a rapid decay of action potential amplitudes, followed by a depolarization block (DB) that strongly limits aPVT maximum firing rates, thereby regulating both defensive and appetitive behaviors in a frequency-dependent manner. …

Transcriptomic Clustering Of Chronic Lymphocytic Leukemia: Molecular Subtypes Based On Bruton’S Tyrosine Kinase Expression Levels, Gorkem Kismali, Ganiraju Manyam, Nitin Jain, Cristina Ivan, Betty Lamothe, Mary L Ayres, Lakesla R Iles, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples …

Comparison Of Vendor-Pretrained And Custom-Trained Deep Learning Segmentation Models For Head-And-Neck, Breast, And Prostate Cancers, Xinru Chen, Yao Zhao, Hana Baroudi, Mohammad D El Basha, Aji Daniel, Skylar S Gay, Cenji Yu, He Wang, Jack Phan, Seungtaek L Choi, Chelain R Goodman, Xiaodong Zhang, Joshua S Niedzielski, Sanjay S Shete, Laurence E Court, Zhongxing Liao, Fredrik Löfman, Peter A Balter, Jinzhong Yang

Faculty, Staff and Student Publications

Background/objectives: We assessed the influence of local patients and clinical characteristics on the performance of commercial deep learning (DL) segmentation models for head-and-neck (HN), breast, and prostate cancers.

Methods: Clinical computed tomography (CT) scans and clinically approved contours of 210 patients (53 HN, 49 left breast, 55 right breast, and 53 prostate cancer) were used to train and validate segmentation models integrated within a vendor-supplied DL training toolkit and to assess the performance of both vendor-pretrained and custom-trained models. Four custom models (HN, left breast, right breast, and prostate) were trained and validated with 30 (training)/5 (validation) HN, 34/5 left …

Characterization Of An Inorganic Powder-Based Scintillation Detector Under A Uhdr Electron Beam, Daline Tho, Sam Beddar

Faculty, Staff and Student Publications

(1) Background: Ultra-high dose rate (UHDR) radiation therapy needs a reliable dosimetry solution and scintillation detectors are promising candidates. In this study, we characterized an inorganic powder-based scintillation detector under a 9 MeV UHDR electron beam. (2) Methods: A mixture of ZnS:Ag powder and optic glue was coupled to an 8 m Eska GH-4001-P polymethyl methacrylate (PMMA) optical fiber. We evaluated the dependence of the detector on dose per pulse (DPP), pulse repetition frequency (PRF), and pulse width (PW). Additionally, we determined the stability and the reproducibility of the detector. (3) Results: The signal ratio between the PMMA clear optical …

Characterization Of An Inorganic Powder-Based Scintillation Detector Under A Uhdr Electron Beam, Daline Tho, Sam Beddar

Faculty, Staff and Student Publications

Background: Ultra-high dose rate (UHDR) radiation therapy needs a reliable dosimetry solution and scintillation detectors are promising candidates. In this study, we characterized an inorganic powder-based scintillation detector under a 9 MeV UHDR electron beam.

Methods: A mixture of ZnS:Ag powder and optic glue was coupled to an 8 m Eska GH-4001-P polymethyl methacrylate (PMMA) optical fiber. We evaluated the dependence of the detector on dose per pulse (DPP), pulse repetition frequency (PRF), and pulse width (PW). Additionally, we determined the stability and the reproducibility of the detector.

Results: The signal ratio between the PMMA clear optical fiber and the …

Utility Of Colposcopy For The Screening And Management Of Cervical Cancer In Africa: A Cross-Sectional Analysis Of Providers’ Training And Practices, Joël Fokom Domgue, Issimouha Dille, Freddy Gnangnon, Sharon Kapambwe, Celine Bouchard, Nomonde Mbatani, Elodie Gauroy, Nathalie Ledaga Ambounda, Robert Yu, Fatoumata Sidibe, Joseph Kamgno, Bangaly Traore, Pierre-Marie Tebeu, Gregory Halle-Ekane, Mohenou Isidore Diomande, Jean-Marie Dangou, Fabrice Lecuru, Isaac Adewole, Marie Plante, Partha Basu, Sanjay Shete

Faculty, Staff and Student Publications

Introduction: Cervical cancer is a public health issue in Africa with devastating socioeconomic consequences due to the lack of organized screening programs. The success of screening programs depends on the appropriate investigation and management of women who test positive for screening. Colposcopic assessment following positive screening results is a noteworthy issue in Africa. This study aimed to assess the utilization of colposcopy by providers in the region.

Methods: A cross-sectional study was conducted in 2021-2022 among healthcare providers involved in cervical cancer prevention activities in Africa. They were invited to report prior colposcopy training, whether they performed colposcopy and the …

A Statistical Approach For Systematic Identification Of Transition Cells From Scrna-Seq Data, Yuanxin Wang, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Ziyi Li, Ken Chen

Faculty, Staff and Student Publications

Decoding cellular state transitions is crucial for understanding complex biological processes in development and disease. While recent advancements in single-cell RNA sequencing (scRNA-seq) offer insights into cellular trajectories, existing tools primarily study expressional rather than regulatory state shifts. We present CellTran, a statistical approach utilizing paired-gene expression correlations to detect transition cells from scRNA-seq data without explicitly resolving gene regulatory networks. Applying our approach to various contexts, including tissue regeneration, embryonic development, preinvasive lesions, and humoral responses post-vaccination, reveals transition cells and their distinct gene expression profiles. Our study sheds light on the underlying molecular mechanisms driving cellular state transitions, …

Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation For B-Lineage Acute Lymphoblastic Leukemia, Yuanxin Wang, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Ziyi Li, Ken Chen

Faculty, Staff and Student Publications

Decoding cellular state transitions is crucial for understanding complex biological processes in development and disease. While recent advancements in single-cell RNA sequencing (scRNA-seq) offer insights into cellular trajectories, existing tools primarily study expressional rather than regulatory state shifts. We present CellTran, a statistical approach utilizing paired-gene expression correlations to detect transition cells from scRNA-seq data without explicitly resolving gene regulatory networks. Applying our approach to various contexts, including tissue regeneration, embryonic development, preinvasive lesions, and humoral responses post-vaccination, reveals transition cells and their distinct gene expression profiles. Our study sheds light on the underlying molecular mechanisms driving cellular state transitions, …

Detection Of Kmt2a Partial Tandem Duplication By Optical Genome Mapping In Myeloid Neoplasms: Associated Cytogenetics, Gene Mutations, Treatment Responses, And Patient Outcomes, Qing Wei, Shimin Hu, Jie Xu, Sanam Loghavi, Naval Daver, Gokce A Toruner, Wei Wang, L Jeffrey Medeiros, Guilin Tang

Faculty, Staff and Student Publications

KMT2A partial tandem duplication (PTD) involves intragenic KMT2A duplications and has been associated with poorer prognosis. In this study, we evaluated KMT2A PTD in 1277 patients with hematological malignancies using optical genome mapping (OGM). KMT2A PTD was detected in 35 patients with acute myeloid leukemia (AML) (7%), 5 patients with myelodysplastic syndrome (MDS) (2.2%), and 5 patients with chronic myelomonocytic leukemia (CMML) (7.1%). The PTDs varied in size, region, and copy number. An Archer RNA fusion assay confirmed KMT2A PTD in all 25 patients tested: 15 spanning exons 2 to 8 and 10 spanning exons 2 to 10. Most patients …

Turn On The Lights! Building The Evidence Base To Inform Cancer Of Sexual And Gender Minority Groups, Shine Chang

Faculty, Staff and Student Publications

No abstract provided.

The American Cancer Society National Lung Cancer Roundtable Strategic Plan: Advancing Comprehensive Biomarker Testing In Non-Small Cell Lung Cancer, Adam H Fox, Raymond U Osarogiagbon, Farhood Farjah, James R Jett, Bruce E Johnson, M Patricia Rivera, Robert A Smith, Ignacio I Wistuba, Gerard A Silvestri

Faculty, Staff and Student Publications

Comprehensive biomarker testing is a crucial requirement for the optimal treatment of advanced-stage non-small cell lung cancer (NSCLC), with emerging relevance in the adjuvant treatment setting. To advance its goal of ensuring optimal therapy for persons diagnosed with lung cancer, the American Cancer Society National Lung Cancer Roundtable (ACS NLCRT) held The Summit on Optimizing Lung Cancer Biomarkers in Practice in September 2020 to align its partners toward the goal of ensuring comprehensive biomarker testing for all eligible patients with NSCLC. The ACS NLCRT's Strategic Plan for Advancing Comprehensive Biomarker Testing in NSCLC, a product of the summit, comprises actions …

The American Cancer Society National Lung Cancer Roundtable Strategic Plan: Methods For Improving Turnaround Time Of Comprehensive Biomarker Testing In Non-Small Cell Lung Cancer, Sinchita Roy-Chowdhuri, Haresh Mani, Adam H Fox, Anne Tsao, Lynette M Sholl, Farhood Farjah, Bruce E Johnson, Raymond U Osarogiagbon, M Patricia Rivera, Gerard A Silvestri, Robert A Smith, Ignacio I Wistuba

Faculty, Staff and Student Publications

Comprehensive biomarker testing for patients with non-small cell lung cancer is critical for selecting appropriate targeted therapy or immunotherapy. Ensuring timely ordering, processing, and reporting is key to optimizing patient outcomes. However, various factors can prevent or delay patients from being offered the option of treatment selection based on comprehensive biomarker testing. These factors include problems with access to testing, tissue adequacy, turnaround time, and health insurance coverage and billing practices. Turnaround time depends on several logistical and tissue handling factors, which involve institutional policies, processes, resources, testing methodology, and testing algorithms that vary across different practices. In this article, …

Preoperative Detection Of Extraprostatic Tumor Extension In Patients With Primary Prostate Cancer Utilizing [68ga]Ga-Psma-11 Pet/Mri, Clemens P Spielvogel, Jing Ning, Kilian Kluge, David Haberl, Gabriel Wasinger, Josef Yu, Holger Einspieler, Laszlo Papp, Bernhard Grubmüller, Shahrokh F Shariat, Pascal A T Baltzer, Paola Clauser, Markus Hartenbach, Lukas Kenner, Marcus Hacker, Alexander R Haug, Sazan Rasul

Faculty, Staff and Student Publications

Objectives: Radical prostatectomy (RP) is a common intervention in patients with localized prostate cancer (PCa), with nerve-sparing RP recommended to reduce adverse effects on patient quality of life. Accurate pre-operative detection of extraprostatic extension (EPE) remains challenging, often leading to the application of suboptimal treatment. The aim of this study was to enhance pre-operative EPE detection through multimodal data integration using explainable machine learning (ML).

Methods: Patients with newly diagnosed PCa who underwent [68Ga]Ga-PSMA-11 PET/MRI and subsequent RP were recruited retrospectively from two time ranges for training, cross-validation, and independent validation. The presence of EPE was measured from post-surgical histopathology …

The 2024 Nobel Prize In Physiology Or Medicine: Microrna Takes Center Stage, George A Calin, Florent Hubé, Michael R Ladomery, Nicholas Delihas, Manuela Ferracin, Laura Poliseno, Luca Agnelli, Suresh K Alahari, Ai-Ming Yu, Xiao-Bo Zhong

Faculty, Staff and Student Publications

The Non-coding Journal Editorial Board Members would like to congratulate Victor Ambros and Gary Ruvkun, who were jointly awarded the 2024 Nobel Prize in Physiology or Medicine for their groundbreaking discovery of microRNAs and the role of microRNAs in post-transcriptional gene regulation, uncovering a previously unknown layer of gene control in eukaryotes [...].

Staphylococcus Epidermidis St2 Strains Associated With Bloodstream Infections Contain A Unique Mobile Genetic Element Encoding A Plasmin Inhibitor, Amy A Gomez, Clara Kjerfve, Minseo Choi, Wen Liu, Kelly Churion, Sheila Thomas, Holger Rohde, Sam Shelburne, Jon T Skare, Magnus Hook, Srishtee Arora

Faculty, Staff and Student Publications

Staphylococcus epidermidis, a common commensal bacterium, is a leading cause of nosocomial catheter-associated bloodstream infections. S. epidermidis sequence type 2 (ST2) is specifically recognized globally for causing invasive disease. In this study, we identified a novel putative integrated conjugative element, pICE-Sepi-ST2, unique to the genomes of S. epidermidis ST2. Our investigation identified pICE-Sepi-ST2 in all ST2 isolates from bloodstream infections. Meanwhile, ST2 isolates from other infection sources, such as catheters, prosthetic joints, and fracture fixations, showed variable pICE-Sepi-ST2 prevalence. pICE-Sepi-ST2 encodes two putative cell wall anchored proteins that we have designated SesX and SesY. Biochemical characterization of SesY revealed …

Micrornas: Where Brilliance, Perseverance, And Ambition Converged, Rares Drula, George A Calin

Faculty, Staff and Student Publications

Victor Ambros at the University of Massachusetts Medical School and Gary Ruvkun at Harvard University were awarded the 2024 Nobel Prize in Medicine and Physiology for the discovery of microRNAs. This “groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans” (1). This is a well-deserved and highly anticipated recognition for a seminal discovery published 31 years ago in back-to-back Cell publications (2, 3). This landmark finding changed the way we understand gene expression regulation among most multicellular organisms (4) and had …

An Empirical Model Of Carbon-Ion Relative Biological Effectiveness Based On The Linear Correlation Between Radiosensitivity To Photons And Carbon Ions, David B Flint, Scott J Bright, Conor Mcfadden, Teruaki Konishi, David K J Martinus, Mandira Manandhar, Mariam Ben Kacem, Lawrence Bronk, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Objective.To develop an empirical model to predict carbon ion (C-ion) relative biological effectiveness (RBE).Approach.We used published cell survival data comprising 360 cell line/energy combinations to characterize the linear energy transfer (LET) dependence of cell radiosensitivity parameters describing the dose required to achieve a given survival level, e.g. 5% (D5%), which are linearly correlated between photon and C-ion radiations. Based on the LET response of the metrics D5%and D37%, we constructed a model containing four free parameters that predicts cells' linear quadratic model (LQM) survival curve parameters for C-ions,αCandβC, from the reference LQM parameters …

Oncologic Outcomes In Patients With Localized, Primary Head And Neck Synovial Sarcoma, Riddhi R Patel, Vancheswaran Gopalakrishnan, Behrang Amini, Alexander J Lazar, Patrick P Lin, Robert S Benjamin, Andrew J Bishop, Ryan P Goepfert, Dejka M Araujo

Faculty, Staff and Student Publications

Background: this study aims to evaluate the survival outcomes of patients suffering from head and neck synovial sarcoma (HNSS), especially in relation to patients with a localized disease at diagnosis.

Methods: this retrospective chart review includes 57 patients diagnosed with primary HNSS between 1981 and 2020 who presented with a localized disease at diagnosis. Overall survival (OS) from diagnosis, local recurrence-free survival (LRFS), and metastasis-free survival (MFS) from the end of the primary tumor treatment are estimated. The Kaplan-Meier method, the log-rank test, and the Cox proportional hazards regression are used.

Results: the 5-year OS, LRFS, and MFS are estimated …

Automated Segmentation Of Mri White Matter Hyperintensities In 8421 Patients With Acute Ischemic Stroke, Hosung Kim, Wi-Sun Ryu, Dawid Schellingerhout, Jonghyeok Park, Jinyong Chung, Sang-Wuk Jeong, Dong-Seok Gwak, Beom Joon Kim, Joon-Tae Kim, Keun-Sik Hong, Kyung Bok Lee, Tai Hwan Park, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Byung-Chul Lee, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Man Seok Park, Hee-Joon Bae, Dong-Eog Kim

Faculty, Staff and Student Publications

Background and purpose: To date, only a few small studies have attempted deep learning-based automatic segmentation of white matter hyperintensity (WMH) lesions in patients with cerebral infarction; this issue is complicated because stroke-related lesions can obscure WMH borders. We developed and validated deep learning algorithms to segment WMH lesions accurately in patients with cerebral infarction using multisite data sets involving 8421 patients with acute ischemic stroke.

Materials and methods: We included 8421 patients with stroke from 9 centers in Korea. 2D UNet and squeeze-and-excitation (SE)-UNet models were trained using 2408 FLAIR MRIs from 3 hospitals and validated using 6013 FLAIR …

Additional Expression Of T-Cell Engager In Clinically Tested Oncolytic Adeno-Immunotherapy Redirects Tumor-Infiltrated, Irrelevant T Cells Against Cancer Cells To Enhance Antitumor Immunity, Daisuke Morita, Amanda Rosewell Shaw, Greyson Biegert, Caroline Porter, Mae Woods, Spyridoula Vasileiou, Bora Lim, Masataka Suzuki

Faculty, Staff and Student Publications

Background: Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested "Armed" OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T …

Mutation- And Mrd-Informed Treatments For Transplant-Ineligible Patients, Curtis A Lachowiez, Courtney D Dinardo

Faculty, Staff and Student Publications

The ongoing development of molecularly targeted therapies in addition to the new standard of care combination of azacitidine and venetoclax (AZA-VEN) has transformed the prognostic outlook for older, transplant-ineligible patients with acute myeloid leukemia (AML). While conventional treatments, such as standard anthracycline and cytarabine- based chemotherapy or hypomethylating agent (HMA) monotherapy, are associated with a generally poor prognosis in this patient population, the use of these novel regimens can result in long-lasting, durable remissions in select patient subgroups. Furthermore, the simultaneous discovery of resistance mechanisms to targeted therapies and AZA-VEN has enabled the identification of patient subgroups with inferior outcomes, …

Clonal Landscape And Clinical Outcomes Of Telomere Biology Disorders: Somatic Rescue And Cancer Mutations, Fernanda Gutierrez-Rodrigues, Emma M Groarke, Natthakan Thongon, Juan Jose Rodriguez-Sevilla, Luiz Fernando B Catto, Marena R Niewisch, Ruba Shalhoub, Lisa J Mcreynolds, Diego V Clé, Bhavisha A Patel, Xiaoyang Ma, Dalton Hironaka, Flávia S Donaires, Nina Spitofsky, Barbara A Santana, Tsung-Po Lai, Lemlem Alemu, Sachiko Kajigaya, Ivana Darden, Weiyin Zhou, Paul V Browne, Subrata Paul, Justin Lack, David J Young, Courtney D Dinardo, Abraham Aviv, Feiyang Ma, Michel Michels De Oliveira, Ana Paula De Azambuja, Cynthia E Dunbar, Malgorzata Olszewska, Emmanuel Olivier, Eirini P Papapetrou, Neelam Giri, Blanche P Alter, Carmem Bonfim, Colin O Wu, Guillermo Garcia-Manero, Sharon A Savage, Neal S Young, Simona Colla, Rodrigo T Calado

Faculty, Staff and Student Publications

Telomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, …

Integrative Multi-Omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes In Ovarian Cancer, Spencer R Rosario, Mark D Long, Shanmuga Chilakapati, Eduardo Cortes Gomez, Sebastiano Battaglia, Prashant K Singh, Jianmin Wang, Katy Wang, Kristopher Attwood, Suzanne M Hess, A J Robert Mcgray, Kunle Odunsi, Brahm H Segal, Gyorgy Paragh, Song Liu, Jennifer A Wargo, Emese Zsiros

Faculty, Staff and Student Publications

Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We …