Genetic Phenomena Commons^™

A Novel Sensitivity Maximization At A Given Specificity Method For Binary Classifications, Seyyed Mahmood Ghasemi, Chunhui Gu, Johannes F Fahrmann, Samir Hanash, Kim-Anh Do, Ehsan Irajizad

Faculty, Staff and Student Publications

In the cancer early detection field, logistic regression (LR) is a frequently used approach to establish a combination rule that differentiates cancer from noncancer. However, the application of LR relies on a maximum likelihood approach, which may not yield optimal combination rules for maximizing sensitivity at a clinically desirable specificity and vice versa. In this article, we have developed an improved regression framework, sensitivity maximization at a given specificity (SMAGS), for binary classification that finds the linear decision rule, yielding the maximum sensitivity for a given specificity or the maximum specificity for a given sensitivity. We additionally expand the framework …

Diet-Enhanced Lrg1 Expression Promotes Insulin Hypersecretion And Er Stress In Pancreatic Beta Cells, Desirae D Morales, Jiyoon Ryu, Cong Wei, Jason T Hadley, Maia R Smith, Juan C Lopez-Alvarenga, Ravindranath Duggirala, Jane L Lynch, Feng Liu, Lily Q Dong

Faculty, Staff and Student Publications

Aims/hypothesis: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells.

Methods: Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects …

Systems Neuroimmunology: Current Bottlenecks, Research Priorities And Future Directions, Harini Iyer, Christophe Benoist, Staci D Bilbo, Lisa M Boulanger, Michael D Burton, Aleksandra Deczkowska, Mélanie G Gareau, Peter M Grace, Javier E Irazoqui, Susanna Rosi, Irene Salinas, Anne Schaefer, Caroline L Sokol, Dionna W Williams, Robyn S Klein

Faculty, Staff and Student Publications

Strategies to advance the field of neuroimmunology by embracing its complexity via inclusion of its multidisciplinary properties were discussed at a meeting in Cold Spring Harbor. Attendees proposed fostering of open communications and funding of collaborations across disciplines, and the recognition that our understanding of the neuroimmune system requires interdisciplinary science.

Molecular Testing For The World Health Organization Classification Of Central Nervous System Tumors: A Review, Craig Horbinski, David A Solomon, Rimas V Lukas, Roger J Packer, Priscilla Brastianos, Matija Snuderl, Susan Chang, Maryam Fouladi, Joanna J Phillips, Burt Nabors, Daniel J Brat, Jason T Huse, Kenneth Aldape, Jann N Sarkaria, Matthias Holdhoff, Terry C Burns, Katherine B Peters, Ingo K Mellinghoff, David Arons, Evanthia Galanis

Faculty, Staff and Student Publications

Importance: Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify …

Safety And Antitumor Activity Of A Novel Acd25 Treg Depleter Rg6292 As A Single Agent And In Combination With Atezolizumab In Patients With Solid Tumors, Valentina Gambardella, Michael Ong, Maria E Rodriguez-Ruiz, Jean-Pascal Machiels, Miguel F Sanmamed, Anna Spreafico, Stephen J Luen, Rachel Galot, Bernard Doger De Spéville, Emiliano Calvo, Aung Naing, Samira Curdt, Theresa Maria Kolben, Eva Rossmann, Tamara Tanos, Kevin Smart, Maria Amann, Yuying Xie, Linxinyu Xu, Enrique Gomez Alcaide, Nicolas Städler, Nicole Justies, Christophe Boetsch, Vaios Karanikas, Gabriel Schnetzler, Kristoffer S Rohrberg

Faculty, Staff and Student Publications

Purpose: Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.

Patients and methods: Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). …

Ensartinib For Advanced Or Metastatic Non-Small-Cell Lung Cancer With Met Exon 14 Skipping Mutations (Embrace): A Multi-Center, Single-Arm, Phase 2 Trial, Yang Xia, Panwen Tian, Mo Zhou, Jun Zhao, Yang Jin, Xiuzhen Li, Da Miao, Yuefei Lu, Wanting Xu, Yongchang Zhang, Xiuning Le, Wen Li

Faculty, Staff and Student Publications

Background: MET exon14 skipping mutations (METex14) is an established actionable driver oncogene of non-small-cell lung cancer (NSCLC). While ensartinib is a known second-generation tyrosine kinase inhibitor with primary activity against ALK translocation, it is also classified as a type Ia MET inhibitor. We have previously shown anti-tumor activity against METex14 positive NSCLC both in vivo and in vitro. The EMBRACE trial aims to evaluate the clinical efficacy and safety of ensartinib for treatment of METex14 positive NSCLC.

Methods: This is a multicenter single arm phase II investigator-initiated study that enrolled METex14 positive lung cancer …

Medical Image Segmentation Assisted With Clinical Inputs Via Language Encoder In A Deep Learning Framework, Hengrui Zhao, Biling Wang, Deepkumar Mistry, Jing Wang, Michael Dohopolski, Weiguo Lu, Dan Nguyen

Faculty, Staff and Student Publications

Introduction: Auto-segmentation of tumor volumes and organs at risk (OARs) is a critical step in cancer radiotherapy treatment planning, where rapid, precise adjustments to treatment plans are required to match the patient anatomy. Although auto-segmentation has been clinically accepted for most OARs, auto-segmentation of tumor volumes, particularly clinical target volumes (CTVs), remains a challenge. This difficulty arises because images alone are often insufficient to capture the necessary information for accurate delineation of microscopic tumor invasion invisible on the image itself.

Methods: We propose a deep learning-based medical image segmentation framework designed to mimic the clinical process of delineating CTVs and …

American Association Of Physicists In Medicine (Aapm) Chapter Climate Check: Mixed Methods Analysis Of Survey Responses, Ashley J Cetnar, Ghada Aldosary, Meghan C Koo, Holly Lincoln, Angélica Pérez-Andújar, Samantha J Simiele

Faculty, Staff and Student Publications

Introduction: The American Association of Physicists in Medicine (AAPM) recently shared results and recommendations from its first Equity, Diversity, and Inclusion (EDI) Climate Survey, which was designed to assess the climate at the workplace, the AAPM organization, and the AAPM regional chapter level. This work further explores the status of EDI at the regional chapter level.

Methods: AAPM's EDI Survey was distributed to 5500 members and had a response rate of 25%. In the survey, three open-ended comment boxes were provided for feedback, including one for regional AAPM members. Sixty-four percent of respondents indicated they were part of a regional …

In Pursuit Of Ki-Rads: Toward A Single, Evidence-Based Imaging Classification Of Renal Masses, Stuart G Silverman, Ivan Pedrosa, Nicola Schieda, Vitaly Margulis, Payal Kapur

Faculty, Staff and Student Publications

Despite the successful application of Imaging Reporting and Data Systems to improve the radiologic description and management of disease in many organs, one does not yet exist for the kidney. Instead, the radiologic approach to the kidney has focused on the Bosniak classification system, which is based on imaging characteristics for cystic renal masses, and detecting macroscopic fat within solid renal masses. Radiologically, cystic and solid renal masses are categorized and evaluated separately because of historical precedent, differences in appearance at imaging, and differences in biologic behavior. However, the World Health Organization classification of renal neoplasms does not support such …

Wmh Contributions To Cognitive Impairment: Rationale And Design Of The Diverse Vcid Study, Charles Decarli, Kumar B Rajan, Lee-Way Jin, Jason Hinman, David K Johnson, Myriam Fornage

Faculty, Staff and Student Publications

As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter …

Diagnostic Pearls And Pitfalls In The Interpretation Of Small Biopsies And Frozen Sections Of The Pancreatobiliary Tract, Huamin Wang, Olca Basturk

Faculty, Staff and Student Publications

No abstract provided.

Difference-Makers For Collecting Sexual Orientation And Gender Identity Data In Oncology Settings, Mandi L Pratt-Chapman, Edward J Miech, Megan A Mullins, Shine Chang, Gwendolyn P Quinn, Matthew B Schabath

Faculty, Staff and Student Publications

Purpose: The purpose of this analysis was to identify key difference-making conditions that distinguish oncology institutions that collect sexual orientation and gender identity (SOGI) data across a sample of American Society of Clinical Oncology (ASCO) members.

Methods: From October to November 2020, an anonymous 54-item web-based survey was distributed to ASCO members. Coincidence analysis was used to identify difference-making conditions for the collection of SOGI data.

Results: ASCO members' responses to just three items consistently distinguished practices that reported collecting both SO and GI data (n = 25) from those who did not (n = 20): (1)."Do you ask your …

Predicting Chemotherapy Responsiveness In Gastric Cancer Through Machine Learning Analysis Of Genome, Immune, And Neutrophil Signatures, Shota Sasagawa, Yoshitaka Honma, Xinxin Peng, Kazuhiro Maejima, Koji Nagaoka, Ayako Oosawa, Yuki Okawa, Han Liang, Kazuhiro Kakimi, Yasuhide Yamada, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Background: Gastric cancer is a major oncological challenge, ranking highly among causes of cancer-related mortality worldwide. This study was initiated to address the variability in patient responses to combination chemotherapy, highlighting the need for personalized treatment strategies based on genomic data.

Methods: We analyzed whole-genome and RNA sequences from biopsy specimens of 65 advanced gastric cancer patients before their chemotherapy treatment. Using machine learning techniques, we developed a model with 123 omics features, such as immune signatures and copy number variations, to predict their chemotherapy outcomes.

Results: The model demonstrated a prediction accuracy of 70-80% in forecasting chemotherapy responses in …

Safety And Efficacy Of Dtx401, An Aav8-Mediated Liver-Directed Gene Therapy, In Adults With Glycogen Storage Disease Type I A (Gsdia), David A Weinstein, Terry G Derks, David F Rodriguez-Buritica, Ayesha Ahmad, María-Luz Couce, Rebecca Riba-Wolman, Julieta Bonvin Sallago, Katalin M Ross, Melanie M Van Der Klauw, Foekje De Boer, Caroline Van Der Schaaf, Heather Saavedra, Miguel Martínez-Olmos, Elvis Atanga, Asad Hosseini, Deepali Mitragotri, Eric Crombez

Faculty, Staff and Student Publications

Glycogen storage disease type Ia (GSDIa) is a rare, life‐threatening, inherited carbohydrate metabolism disorder caused by glucose‐6‐phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno‐associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open‐label, phase 1/2, dose‐escalation, 52‐week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × …

A Predictive Chromatin Architecture Nexus Regulates Transcription And Dna Damage Repair, Audesh Bhat, Sonali Bhan, Aindrila Kabiraj, Raj K Pandita, Keneth S Ramos, Shreya Sopori, Arti Dhar, Shruti Pandita, Rakesh Kumar, Chandrima Das, John A Tainer, Tej K Pandita

Faculty, Staff and Student Publications

Genomes are blueprints of life essential for an organism's survival, propagation, and evolutionary adaptation. Eukaryotic genomes comprise of DNA, core histones, and several other nonhistone proteins, packaged into chromatin in the tiny confines of nucleus. Chromatin structural organization restricts transcription factors to access DNA, permitting binding only after specific chromatin remodeling events. The fundamental processes in living cells, including transcription, replication, repair, and recombination, are thus regulated by chromatin structure through ATP-dependent remodeling, histone variant incorporation, and various covalent histone modifications including phosphorylation, acetylation, and ubiquitination. These modifications, particularly involving histone variant H2AX, furthermore play crucial roles in DNA damage …

Resolving Tissue Complexity By Multimodal Spatial Omics Modeling With Miso, Kyle Coleman, Amelia Schroeder, Melanie Loth, Daiwei Zhang, Jeong Hwan Park, Niklas Blank, Xuyu Qian, Jianfeng Chen, Jiahui Jiang, Hanying Yan, Laith Z Samarah, Jean R Clemenceau, Inyeop Jang, Minji Kim, Isabel Barnfather, Joshua D Rabinowitz, Yanxiang Deng, Edward B Lee, Alexander Lazar, Jianjun Gao, Emma E Furth, Tae Hyun Hwang, Linghua Wang, Christoph A Thaiss, Jian Hu, Mingyao Li

Faculty, Staff and Student Publications

Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multi-modal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with sub-cellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets. MISO (MultI-modal Spatial Omics) is a versatile algorithm for feature extraction and clustering, capable of integrating multiple modalities from diverse spatial omics experiments with high spatial resolution. Its effectiveness is …

Guidelines For Minimal Reporting Requirements, Design And Interpretation Of Experiments Involving The Use Of Eukaryotic Dual Gene Expression Reporters (Mindr), Gary Loughran, Dmitry E Andreev, Ilya M Terenin, Olivier Namy, Martin Mikl, C Joel Mcmanus, John F Atkins, Christopher S Fraser, Zoya Ignatova, Shintaro Iwasaki, Joanna Kufel, Ola Larsson, Sebastian A Leidel, Alexander S Mankin, Marco Mariotti, Marvin E Tanenbaum, Ivan Topisirovic, Nora Vázquez-Laslop, Gabriela Viero, Neva Caliskan, Yiwen Chen, Patricia L Clark, Jonathan D Dinman, Philip J Farabaugh, Wendy V Gilbert, Pavel Ivanov, Jeffrey S Kieft, Oliver Mühlemann, Matthew S Sachs, Ivan N Shatsky, Nahum Sonenberg, Anna-Lena Steckelberg, Anne E Willis, Michael T Woodside, Leos Shivaya Valasek, Sergey E Dmitriev, Pavel V Baranov

Faculty, Staff and Student Publications

Dual reporters encoding two distinct proteins within the same mRNA have had a crucial role in identifying and characterizing unconventional mechanisms of eukaryotic translation. These mechanisms include initiation via internal ribosomal entry sites (IRESs), ribosomal frameshifting, stop codon readthrough and reinitiation. This design enables the expression of one reporter to be influenced by the specific mechanism under investigation, while the other reporter serves as an internal control. However, challenges arise when intervening test sequences are placed between these two reporters. Such sequences can inadvertently impact the expression or function of either reporter, independent of translation-related changes, potentially biasing the results. …

Clinical Use Of Gafchromic Ebt4 Film For In Vivo Dosimetry For Total Body Irradiation, Emily Draeger, Fada Guan, Min-Young Lee, Dae Yup Han, William Donahue

Faculty, Staff and Student Publications

Purpose: In vivo dosimetry is a common requirement to validate dose accuracy/uniformity in total body irradiation (TBI). Several detectors can be used for in vivo dosimetry, including thermoluminescent dosimeters (TLDs), diodes, ion chambers, optically stimulated luminescent dosimeters (OSLDs), and film. TLDs are well established for use in vivo but required expertise and clinical system availability may make them impractical for multifractionated TBI. OSLDs offer quick readout, but recalls have restricted their use. The purpose of this work was to validate the newly available Gafchromic EBT4 film for TBI in vivo dosimetry.

Methods: Film calibration curves were created under standard conditions …

Development And Characterization Of Orthotopic Patient-Derived Xenograft Models Of Peritoneal Metastatic Mucinous Appendiceal Adenocarcinoma, Ichiaki Ito, Vinay K Pattalachinti, Abdelrahman Mg Yousef, Saikat Chowdhury, Mohammad M Fanaeian, Betul Beyza Gunes, Emma R Salle, Mohammad A Zeineddine, Shuangxi Ji, Ruonan Li, Wenyi Wang, Beth A Helmink, Melissa W Taggart, Michael G White, Keith F Fournier, Natalie W Fowlkes, John Paul Shen

Faculty, Staff and Student Publications

Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous group of tumors for which few preclinical models exist. The lack of preclinical models of AA has hindered drug development and is a major factor in why AA remains without a single FDA-approved systemic treatment.

Materials and methods: Tumors from 16 patients with appendiceal neoplasms (15 AA and one HAMN) were implanted into flank and peritoneal cavity of immunodeficient mice leading to the successful establishment of 3 AAPDX models. Histological, immunohistochemical, genetic, and transcriptomic comparison of patient and PDX tumors were performed.

Results: Higher tumor grade, peritoneal implantation, and RAS/RAF mutation …

Seq-Scope: Repurposing Illumina Sequencing Flow Cells For High-Resolution Spatial Transcriptomics, Yongsung Kim, Weiqiu Cheng, Chun-Seok Cho, Yongha Hwang, Yichen Si, Mitchell Schrank, Angelo Anacleto, Jingyue Xi, Myungjin Kim, Ellen Pedersen, Olivia I Koues, Thomas Wilson, Changhee Lee, Goo Jun, Hyun Min Kang, Jun Hee Lee

Faculty, Staff and Student Publications

Spatial transcriptomics technologies aim to advance gene expression studies by profiling the entire transcriptome with intact spatial information from a single histological slide. However, the application of spatial transcriptomics is limited by low resolution, limited transcript coverage, complex procedures, poor scalability and high costs of initial setup and/or individual experiments. Seq-Scope repurposes the Illumina sequencing platform for high-resolution, high-content spatial transcriptome analysis, overcoming these limitations. It offers submicrometer resolution, high capture efficiency, rapid turnaround time and precise annotation of histopathology at a much lower cost than commercial alternatives. This protocol details the implementation of Seq-Scope with an Illumina NovaSeq 6000 …

Psychometric Evaluation Of The Scleroderma Skin Questionnaire: A Novel Patient-Reported Outcome For Skin Disease In Patients With Systemic Sclerosis, Jeong Min Yu, John M Vanburen, Angela Child, Jessica S Alvey, Lisa A Mandl, Shervin Assassi, Flavia V Castelino, Lorinda Chung, Luke Evnin, Tracy M Frech, Faye N Hant, Laura K Hummers, Dinesh Khanna, Kimberly S Lakin, Dorota Lebiedz-Odrobina, Yiming Luo, Ashima Makol, Jerry A Molitor, Duncan F Moore, Carrie Richardson, Nora Sandorfi, Ami A Shah, Ankoor Shah, Victoria K Shanmugam, Brian Skaug, Virginia D Steen, Elizabeth R Volkmann, Jessica K Gordon

Faculty, Staff and Student Publications

Objective: We aimed to evaluate the psychometric properties of the Scleroderma Skin Questionnaire (SSQ), a novel patient-reported outcome (PRO) to assess systemic sclerosis (SSc)-related skin symptoms.

Methods: Participants were recruited from the SSc Collaborative National Quality and Efficacy Registry (CONQUER). Internal consistency was determined using Cronbach α and McDonald ω total (ωt). The correlation of the SSQ was assessed with the modified Rodnan skin score (mRSS), physician global assessment (PGA), Scleroderma Health Assessment Questionnaire, 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29), and patient global assessment to assess criterion, convergent, and divergent validity. Correlations were also assessed between patients' self-reported recall …

An Antibody-Toxin Conjugate Targeting Cd47 Linked To The Bacterial Toxin Listeriolysin O For Cancer Immunotherapy, Benjamin R Schrank, Yifan Wang, Annette Wu, Nhat Tran, Daeyong Lee, Kristin Huntoon, Jonghoon Ha, Yifan Ma, Adam J Grippin, Seong Dong Jeong, Abin Antony, Mengyu Chang, Minjeong Kang, Thomas D Gallup, Albert C Koong, Jing Li, Kyuson Yun, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Antigen-presenting cells phagocytose tumor cells and subsequently cross-present tumor-derived antigens. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-toxin conjugate (ATC) that targets the 'don't eat me' signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes cancer cell phagocytosis by macrophages followed by LLO release and activation to form pores on phagolysosomal membranes that enhance antigen cross-presentation of tumor-derived peptides and activate cytosolic immune sensors. CD47-LLO treatment in vivo significantly …

Proceedings Of The National Cancer Institute Workshop On Combining Immunotherapy With Radiotherapy: Challenges And Opportunities For Clinical Translation, Zachary S Morris, Sandra Demaria, Arta M Monjazeb, Silvia C Formenti, Ralph R Weichselbaum, Heiko Enderling, Joshua D Brody, Heather M Mcgee, Michele Mondini, Michael S Kent, Kristina H Young, Lorenzo Galluzzi, Sana D Karam, Willemijn S M E Theelen, Joe Y Chang, Mai Anh Huynh, Adi Daib, Sean Pitroda, Caroline Chung, Raphael Serre, Clemens Grassberger, Jie Deng, Quaovi H Sodji, Anthony T Nguyen, Ravi B Patel, Simone Krebs, Anusha Kalbasi, Caroline Kerr, Claire Vanpouille-Box, Logan Vick, Todd A Aguilera, Irene M Ong, Fernanda Herrera, Hari Menon, Deedee Smart, Jalal Ahmed, Robyn D Gartrell, Christina L Roland, Fatemeh Fekrmandi, Binita Chakraborty, Eric H Bent, Tracy J Berg, Alan Hutson, Samir Khleif, Andrew G Sikora, Lawrence Fong

Faculty, Staff and Student Publications

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and …

Cd147 Mediates The Metabolic Reprogramming Of Cancer Associated Fibroblasts Induced By Evs Released By Differentiating Cancer Stem Cells, Filomena Colella, Federica Calapà, Giulia Artemi, Erica Pazzaglia, Rita Colonna, Giacomo Lazzarino, Micol Eleonora Fiori, Ruggero De Maria, Sara Lucchisani, Giannicola Genovese, Luigi Perelli, Barbara Tavazzi, Alessandro Sgambato, Donatella Lucchetti

Faculty, Staff and Student Publications

Several reports have demonstrated that CD147, an N-glycosylated protein that is exchanged by cells in soluble form or through small extracellular vesicles (sEVs), can promote cancer progression. However, its activity related to EVs in colorectal cancer (CRC) is still not fully understood. Previously, we showed that sEV secretion during CRC stem cell (CR-CSCs) differentiation is partially controlled by CD147, and that CD147-expressing sEVs (sEVs-CD147) activate a signalling cascade in recipient cells, inducing molecular invasive features in CR-CSCs. In the present study, we demonstrated that sEVs-CD147 increase the expression of myofibroblast and activation markers in cancer-associated fibroblasts (CAF). In sEVs-CD147-activated CAF, …

Rhabdoid Tumor Of The Kidney And Soft Tissues: Results From National Wilms Tumor Study-5 And Children's Oncology Group Study Aren0321, James I Geller, Lindsay A Renfro, Paul E Grundy, Elizabeth J Perlman, John A Kalapurakal, Jackie Biegel, Anne B Warwick, Arnold Paulino, Elizabeth A Mullen, Najat C Daw, Fredric A Hoffer, Zelig Tochner, Kenneth Gow, Eric Gratias, Deborah A Ward, James R Anderson, Conrad V Fernandez, Jeffrey S Dome

Faculty, Staff and Student Publications

Purpose: National Wilms Tumor Study-5 (NWTS-5) and AREN0321 evaluated the outcomes of children with rhabdoid tumor of the kidney (RTK) and malignant rhabdoid tumor of soft tissues (MRT).

Patients and methods: Eligible patients with RTK were enrolled prospectively on NWTS-5 (1995-2002) and treated with carboplatin and etoposide alternating with cyclophosphamide (Regimen RTK). Patients with RTK or MRT were enrolled on AREN0321 (2005-2012) and received vincristine, doxorubicin, and cyclophosphamide alternating with carboplatin, cyclophosphamide, and etoposide (Regimens UH-1 or dose-reduced Revised UH-1). We report event-free survival (EFS) and overall survival (OS) from each study.

Results: Thirty patients received Regimen RTK on NWTS-5; …

Imgn853 Induces Autophagic Cell Death In Combination Therapy For Ovarian Cancer, Anca Chelariu-Raicu, Thanh Chung Vu, Sujanitha Umamaheswaran, Elaine Stur, Pahul Hanjra, Min Hu, Barrett C Lawson, Jinsong Liu, Anil K Sood, Yunfei Wen

Faculty, Staff and Student Publications

FOLR1 is heterogeneously overexpressed in epithelial ovarian cancer. We examined the combined effects of the anti-FOLR1 antibody-drug conjugate (IMGN853) with other drugs, including topotecan, anti-VEGF-A antibody, and olaparib. These findings could contribute to the continued development of IMGN853 in the treatment of ovarian cancer.

A Neoantigen Vaccine Generates Antitumour Immunity In Renal Cell Carcinoma, David A Braun, Giorgia Moranzoni, Vipheaviny Chea, Bradley A Mcgregor, Eryn Blass, Allison P Vanasse, Juliet Forman, Alexander B Afeyan, Nicholas R Schindler, Yiwen Liu, Shuqiang Li, Jackson Southard, Steven L Chang, Michelle S Hirsch, Nicole R Leboeuf, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Keerthi Shetty, Susan Klaeger, Siranush Sarkizova, Christina B Pedersen, Matthew Mossanen, Isabel Carulli, Anna Tarren, Joseph Duke-Cohan, Alexis A Howard, J Bryan Iorgulescu, Bohoon Shim, Jeremy M Simon, Sabina Signoretti, Jon C Aster, Liudmila Elagina, Steven A Carr, Ignaty Leshchiner, Gad Getz, Stacey Gabriel, Nir Hacohen, Lars R Olsen, Giacomo Oliveira, Donna S Neuberg, Kenneth J Livak, Sachet A Shukla, Edward F Fritsch, Catherine J Wu, Derin B Keskin, Patrick A Ott, Toni K Choueiri

Faculty, Staff and Student Publications

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 …

An Inducible Foxl2-Dependent Mouse Model Of Ovarian Adult Type Granulosa Cell Tumor, Jian Li, Thomas Welte, Katherine Calzoncinth, Veena K Vuttaradhi, Allison L Brodsky, Manu M Sebastian, Charles V Kingsley, R Tyler Hillman

Faculty, Staff and Student Publications

Background: Adult-type granulosa cell tumors (AGCTs) are rare ovarian sex cord/stromal tumors with near-universal hotspot mutations in FOXL2 (c.C402G; p.Cys134Trp). Progress in the treatment of relapsed AGCT has been hindered by the lack of high-fidelity FOXL2-based mouse models. To address this critical unmet need, we created and validated a genetically engineered inducible mouse model of the human FOXL2 mutation that recapitulates the key features of the human disease.

Methods: Gene targeting in embryonic stem cells was used to introduce a Cre-inducible Foxl2C130W allele (mouse equivalent of the human oncogenic mutation) into the endogenous mouse Foxl2 locus. Animals with the Foxl2C130W-FLEx …

Encorafenib, Cetuximab And Chemotherapy In Braf-Mutant Colorectal Cancer: A Randomized Phase 3 Trial, Scott Kopetz, Takayuki Yoshino, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Jayesh Desai, Rona Yaeger, Timothy S Maughan, Elena Beyzarov, Xiaoxi Zhang, Graham Ferrier, Xiaosong Zhang, Josep Tabernero

Faculty, Staff and Student Publications

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, …

Bevacizumab Beyond Progression: Impact Of Subsequent Bevacizumab Re-Treatment In Patients With Ovarian, Fallopian Tube, And Peritoneal Cancer After Progression, Amma Asare, Rebecca Ann Previs, Daniel Spinosa, Bryan Fellman, Amelia L Scott, May Mahmoud, Jean Hansen Siedel, Lauren Cobb, Pamela T Soliman, Anil K Sood, Robert L Coleman, Angeles Alvarez Secord, Shannon N Westin

Faculty, Staff and Student Publications

Background: This study evaluated whether patients with epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) who are immediately re-treated with bevacizumab derive benefit after disease progression on a bevacizumab-containing regimen.

Methods: This multi-institutional, retrospective study compared patients with high grade non-mucinous epithelial OC who received bevacizumab followed directly by another bevacizumab-containing treatment regimen to patients who received bevacizumab followed by a regimen that did not contain bevacizumab (or received no further treatment). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier product-limit estimator and modeled via Cox proportional hazards regression.

Results: Among 226 patients with OC …