tbuckley/cabot-search huggingface dataset:
RARE-32. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG (PLNTY): GENETIC ANALYSIS CONFIRMS FREQUENT MAPK PATHWAY ACTIVATION
Authors: Cristiane Ida, Derek Johnson, Thomas Kollmeyer, DongKun Kim, Timothy Kaufmann, Benjamin Kipp, Robert Jenkins, Caterina Giannini
Journal: Neuro-Oncology (2019)

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and genetic MAPK pathway activation through alterations such as BRAF V600E mutation, and FGFR2-KIAA1598/CTNNA3 and FGFR3-TACC3 fusions. We report the molecular profiling of PLNTY in 9 patients, 7 female: 2 male, median age at diagnosis of 16 years (range, 5–34). All tumors were supratentorial with diagnostic morphological features of PLNTY including oligodendroglioma-like areas and strong diffuse CD34 immunostaining. Four (of 9; 44%) tumors were positive for BRAF V600E immunostain, indicating the presence of a BRAF V600E mutation. The 6 cases evaluated for IDH status were negative by IDH1-R132H immunostain (n=5; 3 BRAF V600E-negative and 2 BRAF V600E-positive) or by NGS (n=1; BRAF V600E-negative). Oncoscan chromosomal microarray performed in 5 BRAF V600E-negative tumors showed recurrent copy number changes including gain of whole chromosomes 5, 7, 8, 9, 12, 18, 19, 20, 21 and X, and loss of chromosomes 1, 2, 10q, 13, 22 and Xq. The 10q losses (n=2) were highly suggestive of an FGFR2-KIAA1598 and of a potentially novel FGFR2 underlying fusion event in one case each. Custom targeted neuro-oncology DNA and RNA NGS panel performed in 2 cases revealed a fusion similar to fusions previously reported in pilocytic astrocytoma: one with a KIAA1549-BRAF (exon 15-exon 9) fusion associated with a 7q34 ~785 kilobase deletion rather than the characteristic ~2 megabase duplication seen in pilocytic astrocytoma, and another with a QKI-NTRK2 (exon 6-exon 15) fusion associated with a 9q21 ~191 kilobase duplication disrupting NTRK2. The KIAA1549-BRAF fusion-positive case also had a TP53 mutation with loss of whole chromosome 17, suggesting TP53 complete inactivation. This study confirms that PLNTY is a low-grade neuroepithelial tumor with frequent MAPK pathway activation and expands the spectrum of MAPK activating alterations observed in PLNTY.
Knowledge Transfer between Artificial Neural Networks for Different Multicolor Flow Cytometry Protocols Improves Classification Performance for Rare B-Cell Neoplasm Subtypes
Authors: Nanditha Mallesh, Max Zhao, Franz Elsner, Hannes Lueling, Richard Schabath, Claudia Haferlach, Torsten Haferlach, Peter Krawitz, Wolfgang Kern
Journal: Blood (2019)
RTHP-22. EDEMA PROGRESSION DURING MRI-GUIDED GLIOBLASTOMA RADIOTHERAPY
Authors: Sarah Dooley, Ricardo LLorente, Kolton Jones, John Ford, Eric Mellon
Journal: Neuro-Oncology (2019)

Abstract PURPOSE Despite the common finding of pseudoprogression or true progression one month after primary chemoradiotherapy for glioblastoma, there are few studies evaluating brain MRI changes that occur during concurrent chemotherapy and radiotherapy (RT). With the first generation combination MRI-RT device, daily predominantly T2-weighted MRIs are obtained of glioblastoma during RT. We quantified how many patients had significant MRI detectable volumetric changes through the six week course of primary chemoradiotherapy. This is of particular importance since glioblastoma RT is only planned at the beginning of therapy and not commonly re-planned for changes during therapy. METHODS We retrospectively reviewed the daily set-up imaging of 8 patients at our institution who received RT for glioblastoma using the Cobalt-60 MRI-RT system. Patients received standard chemoradiation at 60 Gy in 30 fractions with temozolomide per EORTC22981/26981. We contoured the abnormality on the initial ViewRay setup scan and the set-up scan for fraction 30. After rigid fusion of the contours of the initial setup MRI and fraction 30 MRI, the volumes were compared. RESULTS Of the 8 patients, 3 patients (37.5%) demonstrated edema expansion greater than 5 mm. The maximum distances of T2-weighted abnormality volume growth for these patients were 1.0 cm, 1.5 cm, and 4.1 cm. These findings were correlated with the post-treatment diagnostic MRIs at 3–4 weeks which demonstrated similar FLAIR abnormalities and expansion in T1 with gadolinium contrast volumes within these areas of the radiotherapy fields (pseudoprogression vs. true progression). CONCLUSION Review of MRIs obtained by daily MRI-RT for glioblastoma indicates that 3 of 8 patients had over 5 mm of change in T2-weighted dimensions from beginning to end of radiotherapy. Groups using limited CTV margins for treatment planning should be aware that MRI volumes could significantly increase during radiotherapy.
NIMG-07. LACUNARITY AND FRACTAL DIMENSION ACT AS PRETREATMENT IMAGING BIOMARKERS FOR SURVIVAL IN GLIOBLASTOMA PATIENTS
Authors: Lee Curtin, Paula Whitmire, Haylye White, Maciej Mrugala, Leland Hu, Kristin Swanson
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of only 15 months with standard of care treatment. Lacunarity, a quantitative morphological measure of how shapes fill space, and fractal dimension, another morphological measure of the complexity of pixel arrangement, of segmented necrotic regions on gadolinium-enhanced T1 weighted (T1gd) MRI have previously been shown to distinguish both overall survival (OS) and progression free survival (PFS) in GBM (n = 95). In our larger patient cohort (n = 389), we sought to validate or refute previously published results connecting morphological metrics and patient survival. We identified pretreatment necrotic regions of our retrospective first-diagnosis GBM patient cohort using segmented T1gd MRI enhancing regions. We calculated lacunarity and fractal dimension across all T1gd MRI slices with enhancing tumor, and used the median lacunarity and fractal dimension values for our analysis. We find that a lacunarity threshold can significantly distinguish OS (14 months vs 19 months median, log-rank p = 0.015, n = 389) and a fractal dimension threshold can significantly distinguish PFS (8 months vs 11 months median, log-rank p = 0.015, n = 123). We believe that morphological metrics such as lacunarity and fractal dimension could play a role in standard-of-care prognostic considerations at tumor presentation. This link between morphological and survival metrics could be driven by underlying biological phenomena or microenvironmental factors that should be further explored.
UK Single Institution Experience of Mastocytosis: Guy's and St Thomas' NHS Foundation Trust
Authors: Clare Oni, Mufaddal Moonim, Joana Desterro, Clive Grattan, Natalia Curto-Garcia, Claire Woodley, Monika Ciesielska, Deimante Drasutyte, Yvonne Francis, Jennifer O'Sullivan, Thompson Olaoni, Anna Green, Miki Yurina, Mark Ong, Nick C.P. Cross, Donal P. McLornan, Deepti Radia
Journal: Blood (2019)
Risk Factors for Progression to Blast Phase and Outcome in 589 Patients with Myelofibrosis Treated with Ruxolitinib: Real-World Evidence
Authors: Francesca Palandri, Massimo Breccia, Mario Tiribelli, Nicola Polverelli, Giulia Benevolo, Alessia Tieghi, Gianni Binotto, Massimiliano Bonifacio, Bruno Martino, Alessandra Iurlo, Elena Maria Elli, Elisabetta Abruzzese, Micaela Bergamaschi, Nicola Sgherza, Francesco Cavazzini, Monica Crugnola, Costanza Bosi, Alessandro Isidori, Florian H. Heidel, Uros Markovic, Giuseppe Auteri, Lucia Catani, Roberto Latagliata, Davide Griguolo, Katia Codeluppi, Daniele Cattaneo, Malgorzata Monika Trawinska, Daniela Bartoletti, Mauro Krampera, Gianpietro Semenzato, Roberto Massimo Lemoli, Antonio Cuneo, Michele Cavo, Nicola Vianelli, Giuseppe A. Palumbo
Journal: Blood (2019)
Locum oncologist is struck off for failing to arrange cancer treatments
Authors: Clare Dyer
Journal: BMJ (2019)

A locum consultant who repeatedly failed to follow through after assuring patients with cancer that he would arrange their treatment has been struck off the UK medical register.

Leopold Reinecke, who qualified in South Africa in 1969, was found to have given inadequate treatment or made inappropriate or incorrect statements in the cases of 11 patients while working as a locum consultant clinical oncologist at two trusts, North Cumbria University Hospital NHS Trust and …
Ankylosing Spondylitis and Chronic Inflammatory Lesions of the Intestines
Authors: V. L. Steinberg, G. Storey
Journal: BMJ (1957)

A case of poisoning as a result of the ingestion of an alcoholic podophyllum extract is described.The resulting toxic effects comprised an initial severe disturbance of consciousness followed by a state of con- fusion, and a fairly severe type of peripheral neuropathy.A substantial amount of recovery of function had occurred at the end of six months after ingestion of the podophyllin, but a residual neurological deficit was still evident at the end of 16 months.The mode of action and probable effects of the podo- phyllum extract are discussed briefly.We thank Mr. J. B.
Is 4400 Steps per Day the New 10 000 Steps per Day?—Reply
Authors: I-Min Lee, Eric J. Shiroma
Journal: JAMA Internal Medicine (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Phase Ib of Copanlisib in Combination with Ibrutinib in Recurrent/Refractory Primary CNS Lymphoma (PCNSL)
Authors: Christian Grommes, Igor Gavrilovic, Alexandra M Miller, Jacqueline B Stone, Thomas Kaley, Juli T Madzsar, Alyssa Schumpp, Brittany T Butler, Lauren Schaff, Ingo K Mellinghoff
Journal: Blood (2019)
MNGI-02. FEATURES OF TUMOR TEXTURE INFLUENCE SURGERY AND OUTCOME IN INTRACRANIAL MENINGIOMA
Authors: Thomas Sauvigny, Franz Ricklefs, Lena Hoffmann, Raphael Schwarz, Till Burkhardt, Manfred Westphal, Nils Ole Schmidt
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVE Texture-related factors such as consistency, vascularity and adherence vary considerably in meningioma and are thought to be linked with surgical resectability and morbidity. However, data analyzing the true impact of meningioma texture on the surgical management is sparse. METHODS Patients with intracranial meningioma treated between 08/2014-04/2018 were prospectively collected for demographics and surgical treatment with related morbidity and extend of resection (EOR). Tumor characteristics were reported by the surgeon using a standardized questionnaire including items such as tumor rigidity, homogeneity, vascularization and adherence to surrounding neurovascular structure and analyzed for their impact on EOR and neurological outcome using multivariate regression analyses. RESULTS 296 patients (214 female (72.3%) with intracranial meningiomas were included with a mean age of 60.4 years. 23% of patients had a transient and 6.1% permanent neurological deficits and three patients (1.1%) died. The occurrence of a neurological deficit was associated with duration of surgery (p = 0.013) and tumor adherence to neurovascular structures (p = 0.014). Similar associations were observed in subgroup analyses of different tumor localizations (e.g. convexity and skull base). With regard to EOR, the tumor adherence (p &lt; 0.001) and recurrent surgery (p = 0.001) were found as independent predictors for subtotal resection. Noteworthy, the tumor rigidity had no significant impact on the morbidity or EOR. CONCLUSION Our analysis supports the notion that tumor texture has an impact on the surgical management of meningioma and provides sound data that tumor adherence is a significant factor influencing neurological outcome and EOR. In contrast, the influence of tumor rigidity has less impact than previously thought. Preoperative prediction of tumor texture is therefore required for optimized risk assessment.
Hypovitaminosis D Is Prevalent in Patients with Renal AL Amyloidosis and Associated with Non-t(11;14)
Authors: Eli Muchtar, Matthew T. Drake, Angela Dispenzieri, Martha Q. Lacy, Francis K. Buadi, David Dingli, Suzanne R. Hayman, Prashant Kapoor, Nelson Leung, Dragan Jevremovic, Amie Fonder, Miriam A. Hobbs, Yi L. Hwa, Wilson I Gonsalves, Rahma M Warsame, Taxiarchis Kourelis, Stephen J Russell, John A. Lust, Ronald S. Go, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar, Morie A Gertz
Journal: Blood (2019)
Acute Myeloid Leukemia with High Risk Features: Routine Central Nervous System Evaluation May be Beneficial
Authors: Meera Yogarajah, William J Hogan, Naseema Gangat, Dong Chen, Rong He, Hassan B. Alkhateeb, Mithun Vinod Shah, Mrinal M Patnaik, Michelle A Elliott, Mark Litzow, Aref Al-Kali, Animesh Pardanani, Ayalew Tefferi, Kebede H. Begna
Journal: Blood (2019)
Spontaneous Remission of Secondary Acute Lymphoblastic Leukemia Associated with Lenalidomide Therapy for Multiple Myeloma
Authors: Arjun Lakshman, Cai Chen, Kayla Parr, Sarah McGregor, Sara Monaghan, Steven H. Swerdlow, Warren D Shlomchik, Mounzer Agha, Sawa Ito
Journal: Blood (2019)
The Role of UAF1 in the Fanconi Anemia Pathway Regulation of Homologous Recombination-Mediated Genome Maintenance
Authors: Fengshan Liang, Simonne Longerich, Caroline Tang, Olga Buzovestsky, Yong Xiong, David Maranon, Claudia Wiese, Adam Miller, Patrick Sung, Gary M. Kupfer
Journal: Blood (2016)
Interim Circulating Tumor DNA As a Prognostic Biomarker in the Setting of Interim PET-Based Adaptive Therapy for DLBCL
Authors: Charles Macaulay, Stefan Alig, David M. Kurtz, Michael C. Jin, Stephen Opat, Joanne Soo, Brian Sworder, Mark S. Hertzberg, Maher K. Gandhi, Maximilian Diehn, Ash A. Alizadeh
Journal: Blood (2019)
Off-Target HLA Cross-Reactivity By (Third Party) Virus-Specific T Cells Is Surprisingly Affected By HLA Restriction and HLA Background but Not By Virus Specificity
Authors: Wesley Huisman, Didier A.T. Leboux, Lieve E. van der Maarel, Lois Hageman, Derk Amsen, Fred Falkenburg, Inge Jedema
Journal: Blood (2019)
Polatuzumab Vedotin Plus Bendamustine with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase Ib/II Randomized Study
Authors: Laurie H Sehn, Matthew J Matasar, Christopher R. Flowers, Manali Kamdar, Andrew K McMillan, Mark Hertzberg, Sarit Assouline, Tae Min Kim, Won Seog Kim, Muhit Ozcan, Brandon Croft, Jamie Hirata, Ji Cheng, Grace Ku, Alex F. Herrera
Journal: Blood (2019)
Clinical Significance of KIR Genotype in Patients with Methotrexate-Associated Lymphoproliferative Disorders
Authors: Norina Tanaka, Aya Watanabe, Suguru Honda, Mitsuko Kobayashi, Yan-Hua Wang, Yuki Iizuka, Michiko Ryuzaki, Midori Ishiyama, Akihito Shinohara, Hiroshi Kazama, Shotaro Hagiwara, Kentaro Yoshinaga, Katsunori Ikari, Masayuki Shiseki, Masayoshi Harigai, Junji Tanaka
Journal: Blood (2019)
High Residual Allelic Burden Increases Leukemic Transformation Irrespective of Clinical Response in Patients with Lower Risk Myelodysplastic Syndrome Treated with Azacitidine
Authors: Joon Ho Moon, Hee Jeong Cho, Dong Won Baek, Sang Kyun Sohn, Jae-Sook Ahn, Seo-Yeon Ahn, Seunghyun Choi, Kyoung Ha Kim, Taehyung Kim, Zhaolei Zhang, Hyeoung-Joon Kim, Dennis Dong Hwan Kim
Journal: Blood (2019)
Targeting of Integrin α4/VCAM-1 with AVA4746 Modulates the Redox-Status and Metabolism in ALL and Angiogenesis
Authors: Ruan Yongsheng, Enzi Jiang, Hye Na Kim, Heather Ogana, Mo Yang, Deepa Bhojwani, Alan S. Wayne, Yong-Mi Kim
Journal: Blood (2019)
Fto Promotes Extramedullary Progression of Multiple Myeloma By Regulation of HSF1 through m6a RNA Methylation
Authors: Aoshuang Xu, Jiasi Zhang, Liping Zuo, Jian Xu, Xuejiao Yin, Qianwen Cheng, Yuyang Zhang, Lei Chen, Fei Zhao, Fengjuan Fan, Yu Hu, Chunyan Sun
Journal: Blood (2019)
Development of Predictive Biomarker and Optimal Treatment Strategy with FLT3 Inhibitors in Acute Myeloid Leukemia
Authors: Jeong Hui Kim, Yasuhiko Harada, Yuichi Ishikawa, Naomi Kawashima, Marie Nakashima, Yoko Ushijima, Takahiro Nishiyama, Tatsunori Goto, Nobuaki Fukushima, Rika Kihara, Tomohiro Kajiguchi, Koichi Watamoto, Akio Kohno, Kunio Kitamura, Yukiyasu Ozawa, Hitoshi Kiyoi
Journal: Blood (2019)
Hyperparathyroidism and Cancer
Authors: C. E. Dent, L. C. A. Watson
Journal: BMJ (1964)

Mesothelioma-OwenMEDICALJOURNATS with these fibres.On the other hand, Cartier (1952) mentioned two cases of diffuse mesothelioma from a Canadian chrysotile nmine.It is clear that evidence of exposure to asbestos may assist in the diagnostic of diffuse mesothelioma and that a careful occupational history should be obtained in cases of prolonged chest pain or recurrent pleural effusion of obscure origin.The presence of hyaluronic acid in serous effusions is said to provide confirmatory evidence, and a simple screening test is available for the detection of this substance (Wagner et al. (1962).No pleural or peritoneal fluids have been available for examination in this series. SummarySeventeen cases of diffuse mesothelioma occurring in the M~rseyside area were investigated and evidence was sought of exposure to asbestos dust.An account is given of the clinical features of diffuse meso- tt elioma, and in 12 cases the pathological findings at post- mortem ixaini nation are described.Difficulties Cf histological diagnosis are discussed and the histological appearance of the tumours described.Exposure to asbestos had occurred in 14 (82 00) of the 17 cases examined, and asbestos bodies were seen in seven out of 10 specimens of lung tissue examined.It is concluded that exposure to asbestos is a major factor in the causation of diffuse mesothelioma.
Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis
Authors: Christina D. Camell, Patrick Günther, Aileen Lee, Emily L. Goldberg, Olga Spadaro, Yun-Hee Youm, Andrzej Bartke, Gene B. Hubbard, Yuji Ikeno, Nancy H. Ruddle, Joachim Schultze, Vishwa Deep Dixit
Journal: Cell Metabolism (2019)
PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia
Authors: Laury Poulain, Adrien Grenier, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Rudy Birsen, Sarah Mouche, Justine Decroocq, Fetta Mazed, Benoit Viollet, Patrick Auberger, Pierre Sujobert, Didier Bouscary, Jean-Emmanuel Sarry, Jerome Tamburini
Journal: Blood (2019)
Patient Experience of Chimeric Antigen Receptor (CAR)-T Cell Therapy Vs. Stem Cell Transplant: Longitudinal Patient Reported Adverse Events, Cognition and Quality of Life
Authors: Surbhi Sidana, Gita Thanarajasingam, Joan Griffin, Carrie A. Thompson, Michelle Burtis, Rahma Warsame, Jonas Paludo, Andrea Cheville, Morie A Gertz, Angela Dispenzieri, Jose Villasboas, Stephen M Ansell, S. Vincent Rajkumar, Kathleen J Yost, N. Nora Bennani, Mustaqeem Siddiqui, Yi Lin, Shaji K. Kumar, Amylou C. Dueck
Journal: Blood (2019)
In Vitro-Selected Nanobody-Based Cellular Therapy Targeting CD72 for Treatment of Refractory B-Cell Malignancies
Authors: Matthew Nix, Yu-Hsiu T. Lin, Huimin Geng, Makeba Marcoulis, Paul Phojanakong, Donghui Wang, Veronica Steri, Jeffrey Whitman, Sagar Bapat, Elliot Stieglitz, Anne Deucher, Kristie L White, Byron C Hann, Arun P. Wiita
Journal: Blood (2019)
Plasmic and Plasic Αre Εxcellent Predictors of Severe ADAMTS13 Deficiency in Thrombotic Microangiopathy Patients without Secondary Causes
Authors: Eleni Gavriilaki, Evdoxia Koravou, Thomas Chatziconstantinou, Christina Kalpadakis, Maria Ximeri, Anna Christoforidou, Nikoleta Printza, Georgios Karavalakis, Maria Kaliou, Vasiliki Kalaitzidou, SOFIA Chissan, SOFIA Vakalopoulou, Tasoula Touloumenidou, Lila Papalexandri, Maria Papathanassiou, Antonia Syrigou, Maria Topalidou, Maria Liga, Alexandros Spyridonidis, Anna Kioumi, Efthymia Vlachaki, Eleni Papadaki, Panayiotis Panayiotidis, Chrysavgi Lalayanni, Ioanna Sakellari, Achilles Anagnostopoulos
Journal: Blood (2019)
High Risk of Relapse with Intermediate Dose Cytarabine for Consolidation in Young Favorable Risk AML Patients Following Induction with 7+3
Authors: Bhaskar Kolla, Nurul Aidah Abdul Halim, Zohar Sachs, Erica D. Warlick, Daniel J. Weisdorf, Fiona He, Lao Zhentang
Journal: Blood (2019)
Anti-breast cancer activity of 7-α-hydroxyfrullanolide triggered G2/M arrest and apoptotic induction of triple negative breast cancer cell line, revealed by proteomics
Authors: S. Chimplee, S. Roytrakul, P. Graidist, S. Sukrong, T. Srisawat, K. Kanokwiroon
Journal: Annals of Oncology (2019)
ADAR1 Drives Disease Progression in Multiple Myeloma By Acting Both As an RNA Editor of Specific Transcripts and As a DNA Mutator of Their Cognate Genes
Authors: Rafail Nikolaos Tasakis, Alessandro Lagana, Violetta Leshchenko, David Melnekoff, Itai Beno, Jonathan J Keats, Daniel Auclair, Deepu Madduri, Joshua Richter, Ajai Chari, Hearn Jay Cho, Sundar Jagannath, Joel Dudley, F. Nina Papavasiliou, Samir Parekh
Journal: Blood (2019)
IMMU-13. MECHANISMS OF IMMUNOLOGICAL ESCAPE DURING ADOPTIVE CELLULAR THERAPY IN HIGH GRADE GLIOMA
Authors: Tyler Wildes, Kyle Dyson, Connor Francis, Brandon Wummer, Changlin Yang, Oleg Yegorov, David Shin, Adam Grippin, Bayli Divita, Duane Mitchell, Catherine Flores
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Immunotherapy is remarkably effective, yet tumor escape is common. Herein, we investigated tumor escape after adoptive cellular therapy (ACT) in intractable glioma models. These studies revealed multiple mechanisms of escape including a shift in immunogenic tumor antigens, downregulation of MHC-I, and upregulation of checkpoint molecules. Despite these changes, we HYPOTHESIZED that a new population of escape variant-specific polyclonal T cells could be generated to target immune-escaped tumors through using tumor escape variant RNA. METHODS We studied KR158B-luc glioma-bearing mice during treatment with ACT with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. RESULTS Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of major histocompatibility complex (MHC) class I by 50%, and upregulation of checkpoint molecules. This included activated T cells and NK cells from tumor-draining lymph nodes expressing 50% and 30% PD-1 after ACT. Importantly, polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60% (24 to 33 days, p=.0003). The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon NK cells and T cells as determined by cell depletion experiments. To prevent escape from primary tumors, we combined ACT with PD-1 blockade to yield 71% long-term cures in KR158B-luc-bearing mice. CONCLUSIONS These findings suggest that the immune landscape of brain tumors is markedly different post-immunotherapy yet can still be targeted with immunotherapy.