Neoplasms Commons^™

The Short- And Long-Term Readmission Of Four Major Categories Of Digestive System Cancers: Does Obesity Or Metabolic Disorder Matter?, Yan Li, Xiaoqin Wu, Yongfeng Song, Peipei Wang, Bofei Zhang, Bingzhou Guo, Ziwei Liu, Yafei Wu, Shanshan Shao, Yiping Cheng, Honglin Guo, Xiude Fan, Jiajun Zhao

Faculty, Staff and Student Publications

Purpose: Patients with digestive system cancers (DSCs) are at a high risk for hospitalizations; however, the risk factors for readmission remain unknown. Here, we established a retrospective cohort study to assess the association between metabolic obesity phenotypes and readmission risks of DSC.

Experimental design: A total of 142,753 and 74,566 patients at index hospitalization were ultimately selected from the Nationwide Readmissions Database (NRD) 2018 to establish the 30-day and 180-day readmission cohorts, respectively. The study population was classified into four groups: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO). Multivariate Cox …

Targeted Exome-Based Predictors Of Patterns Of Progression Of Colorectal Liver Metastasis After Percutaneous Thermal Ablation, Iwan Paolucci, Yuan-Mao Lin, Yoshikuni Kawaguchi, Harufumi Maki, A Kyle Jones, Marco Calandri, Scott Kopetz, Timothy E Newhook, Kristy K Brock, Jean-Nicolas Vauthey, Bruno C Odisio

Faculty, Staff and Student Publications

BACKGROUND: Percutaneous thermal ablation is a curative-intent locoregional therapy (LRT) for selected patients with unresectable colorectal liver metastasis (CLM). Several factors have been identified that contribute to local tumour control after ablation. However, factors contributing to disease progression outside the ablation zone after ablation are poorly understood.

METHODS: In this retrospective study, using next-generation sequencing, we identified genetic biomarkers associated with different patterns of progression following thermal ablation of CLM.

RESULTS: A total of 191 ablation naïve patients between January 2011 and March 2020 were included in the analysis, and 101 had genomic profiling available. Alterations in the TGFβ pathway …

Autologous T Cell Therapy For Mage-A4+ Solid Cancers In Hla-A*02+ Patients: A Phase 1 Trial, David S Hong, Brian A Van Tine, Swethajit Biswas, Cheryl Mcalpine, Melissa L Johnson, Anthony J Olszanski, Jeffrey M Clarke, Dejka Araujo, George R Blumenschein, Partow Kebriaei, Quan Lin, Alex J Tipping, Joseph P Sanderson, Ruoxi Wang, Trupti Trivedi, Thejo Annareddy, Jane Bai, Stavros Rafail, Amy Sun, Lilliam Fernandes, Jean-Marc Navenot, Frederic D Bushman, John K Everett, Derin Karadeniz, Robyn Broad, Martin Isabelle, Revashnee Naidoo, Natalie Bath, Gareth Betts, Zohar Wolchinsky, Dzmitry G Batrakou, Erin Van Winkle, Erica Elefant, Armin Ghobadi, Amanda Cashen, Anne Grand'maison, Philip Mccarthy, Paula M Fracasso, Elliot Norry, Dennis Williams, Mihaela Druta, David A Liebner, Kunle Odunsi, Marcus O Butler

Faculty, Staff and Student Publications

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced …

Stem Cell Theory Of Cancer: Origin Of Metastasis And Sub-Clonality, Shi-Ming Tu, Cesar Moran, William Norton, Niki M Zacharias

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Metastasis may be the secret weapon cancer uses to dominate and subjugate, to persist and prevail. However, it is no longer a secret when we realize that a stem cell has the same ways and means to fulfill its own omnipotence and accomplish its own omnipresence… and when we realize that a cancer cell has its own version of stem-ness origin and stem-like nature. In this perspective, we discuss whether stem-ness enables metastasis or mutations drive metastasis. We ponder about low-grade versus high-grade tumors and about primary versus metastatic tumors. We wonder about stochasticity and hierarchy in the genesis and …

Clinical Significance Of Glycolytic Metabolic Activity In Hepatocellular Carcinoma, Joann Jung, Sowon Park, Yeonwoo Jang, Sung-Hwan Lee, Yun Seong Jeong, Sun Young Yim, Ju-Seog Lee

Faculty, Staff and Student Publications

High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor …

Anti-Cancer Mechanisms Of Action Of Therapeutic Alternating Electric Fields (Tumor Treating Fields [Ttfields]), Shadi Shams, Chirag B Patel

Faculty, Staff and Student Publications

Despite improved survival outcomes across many cancer types, the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer. Invariably in these cancers, the control achieved by time-limited interventions such as traditional surgical resection, radiation therapy, and chemotherapy is short-lived. A new form of anti-cancer therapy called therapeutic alternating electric fields (AEFs) or tumor treating fields (TTFields) has been shown, either by itself or in combination with chemotherapy, to have anti-cancer effects that translate to improved survival outcomes in patients. Although the pre-clinical and clinical data are promising, the mechanisms of TTFields are not fully elucidated. Many …

Concurrent Mutations In Sf3b1 And Phf6 In Myeloid Neoplasms, Zhuang Zuo, L Jeffrey Medeiros, Sofia Garces, Mark J Routbort, Chi Young Ok, Sanam Loghavi, Rashmi Kanagal-Shamanna, Fatima Zahra Jelloul, Guillermo Garcia-Manero, Kelly S Chien, Keyur P Patel, Rajyalakshmi Luthra, C Cameron Yin

Faculty, Staff and Student Publications

It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the …

Neoadjuvant Chemotherapy Is Associated With Altered Immune Cell Infiltration And An Anti-Tumorigenic Microenvironment In Resected Pancreatic Cancer, Andressa Dias Costa, Sara A Väyrynen, Akhil Chawla, Jinming Zhang, Juha P Väyrynen, Mai Chan Lau, Hannah L Williams, Chen Yuan, Vicente Morales-Oyarvide, Dalia Elganainy, Harshabad Singh, James M Cleary, Kimberly Perez, Kimmie Ng, William Freed-Pastor, Joseph D Mancias, Stephanie K Dougan, Jiping Wang, Douglas A Rubinson, Richard F Dunne, Margaret M Kozak, Lauren Brais, Emma Reilly, Thomas Clancy, David C Linehan, Daniel T Chang, Aram F Hezel, Albert C Koong, Andrew J Aguirre, Brian M Wolpin, Jonathan A Nowak

Faculty, Staff and Student Publications

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood.

DESIGN: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient …

Radiomics In Abdominopelvic Solid-Organ Oncologic Imaging: Current Status, Xiaoyang Liu, Mohamed G Elbanan, Antonio Luna, Masoom A Haider, Andrew D Smith, Carl F Sabottke, Bradley M Spieler, Baris Turkbey, David Fuentes, Ahmed Moawad, Serageldin Kamel, Natally Horvat, Khaled M Elsayes

Faculty, Staff and Student Publications

Radiomics is the process of extraction of high-throughput quantitative imaging features from medical images. These features represent noninvasive quantitative biomarkers that go beyond the traditional imaging features visible to the human eye. This article first reviews the steps of the radiomics pipeline, including image acquisition, ROI selection and image segmentation, image preprocessing, feature extraction, feature selection, and model development and application. Current evidence for the application of radiomics in abdominopelvic solid-organ cancers is then reviewed. Applications including diagnosis, subtype determination, treatment response assessment, and outcome prediction are explored within the context of hepatobiliary and pancreatic cancer, renal cell carcinoma, prostate …

Genomic Profiling For Clinical Decision Making In Myeloid Neoplasms And Acute Leukemia, Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D Dinardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M Ross, Michael Savona, Akiko Shimamura, Radek C Skoda, Francesc Solé, Richard M Stone, Ayalew Tefferi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola

Faculty, Staff and Student Publications

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome …

Preclinical Evaluation Of Combination Nemtabrutinib And Venetoclax In Chronic Lymphocytic Leukemia, Elizabeth M Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A Rogers, John C Byrd, Jennifer A Woyach

Faculty, Staff and Student Publications

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and …

Dll3 As An Emerging Target For The Treatment Of Neuroendocrine Neoplasms, James Yao, Emily Bergsland, Rahul Aggarwal, Ana Aparicio, Himisha Beltran, Judy S Crabtree, Christine L Hann, Toni Ibrahim, Lauren A Byers, Hironobu Sasano, John Umejiego, Marianne Pavel

Faculty, Staff and Student Publications

INTRODUCTION: Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis.

METHODS: This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the …

International Delphi Consensus Guidelines For Follow-Up After Prophylactic Total Gastrectomy: The Life After Prophylactic Total Gastrectomy (Lag-Tg) Study, Geoffrey Roberts, Patrick R Benusiglio, Tanya Bisseling, Daniel Coit, Jeremy L Davis, Sam Grimes, Theresa A Guise, Richard Hardwick, Kirsty Harris, Paul Furman Mansfield, Jeremy Rossaak, Karen Chelcun Schreiber, Peter P Stanich, Vivian E Strong, Pardeep Kaurah

Faculty, Staff and Student Publications

BACKGROUND: Prophylactic total gastrectomy (PTG) remains the only means of preventing gastric cancer for people with genetic mutations predisposing to Hereditary Diffuse Gastric Cancer (HDGC), mainly in the CDH1 gene. The small but growing cohort of people undergoing PTG at a young age are expected to have a life-expectancy close to the general population, however, knowledge of the long-term effects of, and monitoring requirements after, PTG is limited. This study aims to define the standard of care for follow-up after PTG.

METHODS: Through a combination of literature review and two-round Delphi consensus of major HDGC/PTG units and physicians, and patient …

Advances In Understanding Cancer-Associated Neurogenesis And Its Implications On The Neuroimmune Axis In Cancer, Ismail Yaman, Didem Ağaç Çobanoğlu, Tongxin Xie, Yi Ye, Moran Amit

Faculty, Staff and Student Publications

Nerves and immunologic mediators play pivotal roles in body homeostasis by interacting with each other through diverse mechanisms. The spread of nerves in the tumor microenvironment increases tumor cell proliferation and disease progression, and this correlates with poor patient outcomes. The effects of sympathetic and parasympathetic nerves on cancer regulation are being investigated. Recent findings demonstrate the possibility of developing therapeutic strategies that target the tumor microenvironment and its components such as immune cells, neurotransmitters, and extracellular vesicles. Therefore, examining and understanding the mechanisms and pathways associated with the sympathetic and parasympathetic nervous systems, neurotransmitters, cancer-derived mediators and their interactions …

Outcomes Of Gynecologic Cancer Surgery During The Covid-19 Pandemic: An International, Multicenter, Prospective Covidsurg-Gynecologic Oncology Cancer Study, Christina Fotopoulou, Tabassum Khan, Juraj Bracinik, James Glasbey, Nadeem Abu-Rustum, Luis Chiva, Anna Fagotti, Keiichi Fujiwara, Rahel Ghebre, Murat Gutelkin, Thomas O Konney, Joseph Ng, Rene Pareja, Rajkumar Kottayasamy Seenivasagam, Jalid Sehouli, Shylasree T S Surappa, Aneel Bhangu, Elaine Leung, Sudha Sundar

Faculty, Staff and Student Publications

BACKGROUND: The CovidSurg-Cancer Consortium aimed to explore the impact of COVID-19 in surgical patients and services for solid cancers at the start of the pandemic. The CovidSurg-Gynecologic Oncology Cancer subgroup was particularly concerned about the magnitude of adverse outcomes caused by the disrupted surgical gynecologic cancer care during the COVID-19 pandemic, which are currently unclear.

OBJECTIVE: This study aimed to evaluate the changes in care and short-term outcomes of surgical patients with gynecologic cancers during the COVID-19 pandemic. We hypothesized that the COVID-19 pandemic had led to a delay in surgical cancer care, especially in patients who required more extensive …

Differential Integrated Stress Response And Asparagine Production Drive Symbiosis And Therapy Resistance Of Pancreatic Adenocarcinoma Cells, Christopher J Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A Jiménez, Amy Mccarthy, Nina G Steele, Samuel A Kerk, Hanna S Hong, Lin Lin, Fiona V Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K Beutel, Rima Singh, Barbara S Nelson, Fran Van Den Bergh, Abigail S Krall, Peter J Mullen, Li Zhang, Sandeep Batra, Jennifer P Morton, Ben Z Stanger, Heather R Christofk, Michelle A Digman, Daniel A Beard, Andrea Viale, Ji Zhang, Howard C Crawford, Marina Pasca Di Magliano, Claus Jorgensen, Costas A Lyssiotis

Faculty, Staff and Student Publications

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive …

Tumor Microenvironment: Barrier Or Opportunity Towards Effective Cancer Therapy, Aadhya Tiwari, Rakesh Trivedi, Shiaw-Yih Lin

Faculty, Staff and Student Publications

Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis of tumor. With the advent of 3D culture and advanced bioinformatic methodologies, it is now possible to study TME's individual components and their interplay at higher resolution. Deeper understanding of the immune cell's diversity, stromal constituents, repertoire profiling, neoantigen prediction of TMEs has provided the opportunity to explore the spatial and temporal regulation of immune therapeutic interventions. The variation of TME composition among patients plays an important role in determining responders and non-responders towards cancer immunotherapy. Therefore, there could be a …

First-In-Human Study Of An Ox40 (Ivuxolimab) And 4-1bb (Utomilumab) Agonistic Antibody Combination In Patients With Advanced Solid Tumors, Omid Hamid, Alberto A Chiappori, John A Thompson, Toshihiko Doi, Siwen Hu-Lieskovan, Ferry A L M Eskens, Willeke Ros, Adi Diab, Jean-Philippe Spano, Naiyer A Rizvi, Jeffrey S Wasser, Eric Angevin, Patrick A Ott, Alison Forgie, Wenjing Yang, Cen Guo, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

Background: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.

Methods: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every …

Nerve Density And Neuronal Biomarkers In Cancer, Shahrukh R Ali, Madeleine Jordan, Priyadharsini Nagarajan, Moran Amit

Faculty, Staff and Student Publications

Certain histologic characteristics of neurons, novel neuronal biomarkers, and nerve density are emerging as important diagnostic and prognostic tools in several cancers. The tumor microenvironment has long been known to promote tumor development via promoting angiogenesis and cellular proliferation, but new evidence has shown that neural proliferation and invasion in the tumor microenvironment may also enable tumor growth. Specific neuronal components in peripheral nerves and their localization in certain tumor sites have been identified and associated with tumor aggressiveness. In addition, dense neural innervation has been shown to promote tumorigenesis. In this review, we will summarize the histological components of …

The Hect Family Of E3 Ubiquitin Ligases And Pten, Min Sup Song, Pier Paolo Pandolfi

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Members of the HECT family of E3 ubiquitin ligases have emerged as prominent regulators of PTEN function, subcellular localization and levels. In turn this unfolding regulatory network is allowing for the identification of genes directly involved in both tumorigenesis at large and cancer susceptibility syndromes. While the complexity of this regulatory network is still being unraveled, these new findings are paving the way for novel therapeutic modalities for cancer prevention and therapy as well as for other diseases. Here we will review the signal transduction and therapeutic implications of the cross-talk between HECT family members and PTEN.

Synthetic Essentiality Of Tryptophan 2,3-Dioxygenase 2 In Apc-Mutated Colorectal Cancer, Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A Labella, Jing Li, Denise J Spring, Di Zhao, Y Alan Wang, Ronald A Depinho

Faculty, Staff and Student Publications

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit …

Targeting Cd123 In Blastic Plasmacytoid Dendritic Cell Neoplasm Using Allogeneic Anti-Cd123 Car T Cells, Tianyu Cai, Agnès Gouble, Kathryn L Black, Anna Skwarska, Ammar S Naqvi, Deanne Taylor, Ming Zhao, Qi Yuan, Mayumi Sugita, Qi Zhang, Roman Galetto, Stéphanie Filipe, Antonio Cavazos, Lina Han, Vinitha Kuruvilla, Helen Ma, Connie Weng, Chang-Gong Liu, Xiuping Liu, Sergej Konoplev, Jun Gu, Guilin Tang, Xiaoping Su, Gheath Al-Atrash, Stefan Ciurea, Sattva S Neelapu, Andrew A Lane, Hagop Kantarjian, Monica L Guzman, Naveen Pemmaraju, Julianne Smith, Andrei Thomas-Tikhonenko, Marina Konopleva

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN

Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable With Isolated Isochromosome 17q Represents A Distinct Clinico-Biologic Subset: A Multi-Institutional Collaborative Study From The Bone Marrow Pathology Group, Rashmi Kanagal-Shamanna, Attilio Orazi, Robert P Hasserjian, Daniel A Arber, Kaaren Reichard, Eric D Hsi, Adam Bagg, Heesun Joyce Rogers, Julia Geyer, Faezeh Darbaniyan, Kim-Anh Do, Kyle M Devins, Olga Pozdnyakova, Tracy I George, Paola Dal Cin, Patricia T Greipp, Mark J Routbort, Keyur Patel, Guillermo Garcia-Manero, Srdan Verstovsek, L Jeffrey Medeiros, Sa A Wang, Carlos Bueso-Ramos

Faculty, Staff and Student Publications

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated …

Development And Characterization Of Anti-Galectin-9 Antibodies That Protect T Cells From Galectin-9-Induced Cell Death, Riyao Yang, Linlin Sun, Ching-Fei Li, Yu-Han Wang, Weiya Xia, Boning Liu, Yu-Yi Chu, Laura Bover, Long Vien, Mien-Chie Hung

Faculty, Staff and Student Publications

Antibodies that target immune checkpoint proteins such as programmed cell death protein 1, programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 in human cancers have achieved impressive clinical success; however, a significant proportion of patients fail to respond to these treatments. Galectin-9 (Gal-9), a β-galactoside-binding protein, has been shown to induce T-cell death and facilitate immunosuppression in the tumor microenvironment by binding to immunomodulatory receptors such as T-cell immunoglobulin and mucin domain-containing molecule 3 and the innate immune receptor dectin-1, suggesting that it may have potential as a target for cancer immunotherapy. Here, we report the development of two …

Synergy Of Venetoclax And 8-Chloro-Adenosine In Aml: The Interplay Of Rrna Inhibition And Fatty Acid Metabolism, Dinh Hoa Hoang, Corey Morales, Ivan Rodriguez Rodriguez, Melissa Valerio, Jiamin Guo, Min-Hsuan Chen, Xiwei Wu, David Horne, Varsha Gandhi, Lisa S Chen, Bin Zhang, Vinod Pullarkat, Steven T Rosen, Guido Marcucci, Ralf Buettner, Le Xuan Truong Nguyen

Faculty, Staff and Student Publications

It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado …

Of Vascular Defense, Hemostasis, Cancer, And Platelet Biology: An Evolutionary Perspective, David G Menter, Vahid Afshar-Kharghan, John Paul Shen, Stephanie L Martch, Anirban Maitra, Scott Kopetz, Kenneth V Honn, Anil K Sood

Faculty, Staff and Student Publications

We have established considerable expertise in studying the role of platelets in cancer biology. From this expertise, we were keen to recognize the numerous venous-, arterial-, microvascular-, and macrovascular thrombotic events and immunologic disorders are caused by severe, acute-respiratory-syndrome coronavirus 2 (SARS-CoV-2) infections. With this offering, we explore the evolutionary connections that place platelets at the center of hemostasis, immunity, and adaptive phylogeny. Coevolutionary changes have also occurred in vertebrate viruses and their vertebrate hosts that reflect their respective evolutionary interactions. As mammals adapted from aquatic to terrestrial life and the heavy blood loss associated with placentalization-based live birth, platelets …

Loss Of Mmr And Tgfbr2 Increases The Susceptibility To Microbiota-Dependent Inflammation-Associated Colon Cancer, Elena Tosti, Ana S Almeida, Tam T T Tran, Mariel Barbachan E Silva, Pilib Ó Broin, Robert Dubin, Ken Chen, Amanda P Beck, Andrew S Mclellan, Eduardo Vilar, Aaron Golden, Paul W O'Toole, Winfried Edelmann

Faculty, Staff and Student Publications

Background and aims: Mutations in DNA mismatch repair (MMR) genes are causative in Lynch syndrome and a significant proportion of sporadic colorectal cancers (CRCs). MMR-deficient (dMMR) CRCs display increased mutation rates, with mutations frequently accumulating at short repetitive DNA sequences throughout the genome (microsatellite instability). The TGFBR2 gene is one of the most frequently mutated genes in dMMR CRCs. Therefore, we generated an animal model to study how the loss of both TGFBR2 signaling impacts dMMR-driven intestinal tumorigenesis in vivo and explore the impact of the gut microbiota.

Methods: We generated VCMsh2/Tgfbr2 mice in which Msh2loxP and Tgfbr2loxP alleles are …

Evaluating The Disparity Of Female Breast Cancer Mortality Among Racial Groups - A Spatiotemporal Analysis, Chiehwen E. Hsu, Holly Jacobson, Francisco Soto Mas

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Background The literature suggests that the distribution of female breast cancer mortality demonstrates spatial concentration. There remains a lack of studies on how the mortality burden may impact racial groups across space and over time. The present study evaluated the geographic variations in breast cancer mortality in Texas females according to three predominant racial groups (non-Hispanic White, Black, and Hispanic females) over a twelve-year period. It sought to clarify whether the spatiotemporal trend might place an uneven burden on particular racial groups, and whether the excess trend has persisted into the current decade.

Methods The Spatial Scan Statistic was employed …