tbuckley/cabot-search huggingface dataset:
IMMU-42. DUAL ACTIVATION OF THE cGAS-STING PATHWAY AND AIM2-INDUCED PYROPTOSIS BY TUMOR-TREATING FIELDS PRODUCES ANTI-TUMOR IMMUNITY IN GLIOBLASTOMA
Authors: Dongjiang Chen, Mathew Sebastian, Tarun Hutchinson, Ashley Ghiaseddin, Sonisha Warren, Annie Allen, Dan Jin, Son Le, David Tran
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES Tumor Treating Fields (TTFields) was approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed Glioblastoma (GBM) patients and resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. In many patients, a transient stage of increased peritumoral edema is often observed early during TTFields treatment, suggesting that a major component of therapeutic efficacy by TTFields may be an immune mediated process. We hypothesize that TTFields activate the immune system by triggering pyroptosis and type I Interferon (IFN) response. METHODS A panel of GBM cell lines were treated with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system. Cells were analyzed for the production of micronuclei and activation of both pyroptosis and STING pathways using immunostaining, quantitative PCR, ELISA and cytometry. Pre-treated mouse GBM cells were injected into mouse brain to monitor survive and immunophenotyping. GBM patients’ blood was collected, and PBMC were isolated and analyzed by single cell RNAseq. RESULTS TTFields resulted in a significantly higher rate of micronuclei structures released into the cytoplasm, which were co-localized with two upstream dsDNA sensors AIM2 and cGAS. TTFields-activated micronuclei-dsDNA sensor complexes led to i) induction of pyroptotic cell death, as measured by LDH release assay, and through AIM2-recruited caspase1 activation and cleavage of pyroptosis-specific Gasdermin D; and ii) activation of STING pathway leading to the increase of type I IFNs and pro-inflammatory cytokines. In mouse model, double knocking down of STING/AIM2 eliminated the tumor suppression effects caused by TTFields. TTFields pretreated wild type cells successfully elevated dendritic cell level in mouse cervical lymph nodes which can be reversed by double knocking down. CONCLUSIONS These results provide compelling evidence that TTFields induces effective anti-tumor immunity in GBM cells and patients.
DIPG-70. DISORDERED DNA METHYLATION IN DIPG UNDERLIES PHENOTYPIC PLASTICITY
Authors: Michael Koldobskiy, Ashley Tetens, Allison Martin, Charles Eberhart, Eric Raabe, John Goutsias, Andrew Feinberg
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a dismal prognosis and no effective treatment. Recent studies point to a critical role for epigenetic dysregulation in this disease. Nearly 80% of DIPGs harbor mutations in histone H3 encoding replacement of lysine 27 with methionine (K27M), leading to global loss of the repressive histone H3K27 trimethylation mark, global DNA hypomethylation, and a distinct gene expression profile. However, a static view of the epigenome fails to capture the plasticity of cancer cells and their gene expression states. Recent studies across diverse cancers have highlighted the role of epigenetic variability as a driving force in tumor evolution. Epigenetic variability may underlie the heterogeneity and phenotypic plasticity of DIPG cells and allow for the selection of cellular traits that promote survival and resistance to therapy. We have recently formalized a novel framework for analyzing variability of DNA methylation directly from whole-genome bisulfite sequencing data, allowing computation of DNA methylation entropy at precise genomic locations. Using these methods, we have shown that DIPG exhibits a markedly disordered epigenome, with increased stochasticity of DNA methylation localizing to specific regulatory elements and genes. We evaluate the responsiveness of the DIPG epigenetic landscape to pharmacologic modulation in order to modify proliferation, differentiation state, and immune signaling in DIPG cells.
Sex-Based Differences Entangling With Electronic Health Record Documentation
Authors: Jennifer Claytor, Richard W. Grant
Journal: JAMA Internal Medicine (2020)

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Exploring Potential Signals of Selection for Disordered Residues in Prokaryotic and Eukaryotic Proteins
Authors: Arup Panda, Tamir Tuller
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract Intrinsically disordered proteins (IDPs) are an important class of proteins in all domains of life for their functional importance. However, how nature has shaped the disorder potential of prokaryotic and eukaryotic proteins is still not clearly known. Randomly generated sequences are free of any selective constraints, thus these sequences are commonly used as null models. Considering different types of random protein models, here we seek to understand how the disorder potential of natural eukaryotic and prokaryotic proteins differs from random sequences. Comparing proteome-wide disorder content between real and random sequences of 12 model organisms, we noticed that eukaryotic proteins are enriched in disordered regions compared to random sequences, but in prokaryotes such regions are depleted. By analyzing the position-wise disorder profile, we show that there is a generally higher disorder near the N- and C-terminal regions of eukaryotic proteins as compared to the random models; however, either no or a weak such trend was found in prokaryotic proteins. Moreover, here we show that this preference is not caused by the amino acid or nucleotide composition at the respective sites. Instead, these regions were found to be endowed with a higher fraction of protein–protein binding sites, suggesting their functional importance. We discuss several possible explanations for this pattern, such as improving the efficiency of protein–protein interaction, ribosome movement during translation, and post-translational modification. However, further studies are needed to clearly understand the biophysical mechanisms causing the trend.
DIPG-01. REIRRADIATION PRACTICES FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Chantel Cacciotti, Kevin Liu, Daphne Haas-Kogan, Katherine Warren
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Diffuse intrinsic pontine gliomas (DIPG) are a leading cause of brain tumor deaths in children. Current standard of care includes focal radiation therapy (RT). Despite clinical improvement in the majority of patients, the effect is temporary and median survival is less than one year. The use of reirradiation and possible benefit has been reported in progressive DIPG, yet standardized approaches are lacking. We conducted an internet-based survey to assess physicians’ practices in pediatric DIPG. METHODS A 14-question REDCap survey regarding re-irradiation practices was emailed to 396 physicians identified through an International Pediatric Neuro-Oncology and Radiation-Oncology database. RESULTS Response rate was 35% overall (radiation-oncologists, 28%; pediatric oncologists, 57%). Two participants were excluded (did not treat DIPG). Participants included radiation-oncologists (62%), pediatric oncologists (7%), and pediatric neuro-oncologists (29%). Most physicians (62%) treated 1–5 DIPG patients per year, with 10% treating &amp;gt;10/year. Reirradiation was considered a treatment option in 88%. Progressive disease or worsening clinical status were the most common reasons to consider reirradiation. The majority (84%) considered reirradiation a minimum of 6 months following initial RT. Doses varied, with median total dose 24Gy (range 12–60); 2Gy/fraction (range 1–9). Concurrent use of systemic agents with reirradiation was considered in 46%, mainly with targeted agents (37%), biologics (34%), or immunotherapy (25%). One-time reirradiation was the most common practice (71%). Interestingly, 9% of respondents would not consider reirradiation. CONCLUSION Although, the vast majority of physicians agree with re-irradiation as a treatment option for DIPG the total doses varied, and further clinical trials are needed.
MODL-15. THE COMBINATION TREATMENT OF PARP INHIBITOR AND TMZ, OR DAG WILL BE PROMISING TREATMENT IN SF8628
Authors: Shigeo Ohba, Yuichi Hirose
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline glioma, H3 K27M-mutant (DMG) is a newly defined entity. The prognosis of DMG is poor. Because surgical resection is often incomplete for DMG, radiotherapy and chemotherapy are important. Temozolomide (TMZ) is an alkylating agent that adds a methyl group to DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by O6-methylguanine DNA methyltransferase (MGMT). It has been reported that most of DMG lacked MGMT promoter hypermethylation, which is thought to contribute to less effectiveness of TMZ to DMG. The purpose of the study is to explore the way to inhibit the proliferation of DMG. A DMG cell line, SF8628, was used for the experiments. SF8628 had the expression of MGMT and was revealed to be resistant to TMZ. Because N7-methylguanine and N3-methyladenine are repaired via base excision repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor combined with TMZ was considered to be effective to suppress the proliferation of SF8628. As expected, PARP inhibitor enhanced TMZ-induced cytotoxicity in SF8628. Dianhydrogalactiol (DAG) is a bifunctional DNA-targeting agent forming N7-alkylguanine and inter-strand DNA crosslinks. DAG reduced the clonogenicity of SF8628. Moreover, inhibition of homologous recombination enhanced the DAG-induced cytotoxicity in SF8629. The combination treatment of PARP inhibitor and TMZ, or DAG were revealed to be promising treatments in SF8628.
CTNI-65. COMBINED RITUXIMAB, METHOTREXATE, PROCARBAZINE, VINCRISTINE, AND CYTARABINE (R-MPV-A) TREATMENT FOR PATIENTS WITH RELAPSED PRIMARY CNS LYMPHOMA
Authors: Motoo Nagane, Nobuyoshi Sasaki, Keiichi Kobayashi, Kuniaki Saito, Daisuke Shimada, Yoshie Matsumoto, Shohei Iijima, Yuki Yamagishi, Saki Shimizu, Nobuyuki Takayama, Yoshiaki Shiokawa
Journal: Neuro-Oncology (2020)

Abstract BACKGROUNDS Standard of care for patients with primary CNS lymphoma (PCNSL) has been high-dose methotrexate (HD-MTX)-based multiagent immunochemotherapy including an induction R-MPV with consolidation whole-brain radiotherapy (WBRT) and HD-cytarabine to achieve complete remission, however, the optimal treatment for relapsed/refractory (r/r) PCNSL has not been established yet, besides the recent approval of a BTK inhibitor, tirabrutinib, in Japan. We evaluated retrospectively efficacy of R-MPV-A for r/rPCNSL. PATIENTS Histologically proven PCNSL patients treated at relapse in our institution from April 2000 to November 2019 were analyzed. Outcomes were compared between those treated with RMPVA or other regimens. RESULTS Among 148 PCNSL patients identified, 73 had at least one relapse, of whom 47 received salvage chemotherapy including 23 treated with RMPVA either at the first relapse (11) or at the second or later relapse (12). Median age/KPS of this salvage RMPVA group were 71 (42–87)/80 (40–100). Nine patients were pretreated with the first-line RMPVA. HD-cytarabine was given to 13 patients. Median number of RMPV cycles was 8 (1–4 cycles: 10; 8 cycles 13). CR/CRu were achieved in 19 (83%), response rate was 87%, while there were two PDs (9%). After median follow-up of 21.9 months, the median PFS after salvage RMPVA was 13.0 m (95%CI: 9.1–16.9), 1-year overall survival (OS) was 82%, median OS was 70.0 m (95%CI: 12.9–127.1), which were longer than those in 24 patients with salvage treatment other than RMPVA (mPFS 4.4 m, P=0.054; mOS 13.6 m, P=0.009). Among patients with salvage RMPVA, HD-cytarabine was associated with better PFS (P=0.066), and complete responses were significantly correlated with longer OS. Treatment was generally well-tolerated but there was one treatment-related death. CONCLUSIONS Salvage RMPVA at relapses was active and associated with longer survival compared with other regimens, necessitating further development of salvage regimens incorporating tirabrutinib in the future studies.
CTIM-25. ONCOLYTIC VIRUS FOR DIPG: THE CLINICAL EXPERIENCE WITH DNX-2401
Authors: Marta M Alonso, Ignacio Iñigo-Marco, Marc Garcia-Moure, Marisol González-Huarriz, Chris Jones, Alan MACKAY, Esther Hulleman, Jasper Van der Lugt, Carlos De Andrea, Maria Villalba, Ruben Hernandez, Sandra Hervás, Ibon Tamayo, Frederick Lang, Candelaria Gomez-Manzano, Juan Fueyo, Ricardo Diez-Valle, Jaime Gállego-pérez de Larraya, Sonia Tejada
Journal: Neuro-Oncology (2020)

Abstract Despite our increased understanding of Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains dismal. Recently we showed that the virus Delta-24-RGD (DNX-2401 in the clinic) was effective in preclinical models of DIPG and had the ability to trigger an antitumor immune response. These data allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. The main objective is to determine the safety, tolerability, and toxicity of DNX-2401. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. All patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 9 out of the 12 patients. The immune cell composition of the biopsies was assessed using multiplexed quantitative immunofluorescence. T cells were hardly noticeable in these tumors while macrophages were abundant. We detected increased clonal T cell diversity following treatment with virus in peripheral blood lymphocytes when compared paired pre- and post-treatment samples from the trial. In addition, we measure pre and post treatment neutralizing antibodies and its relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). Overall, the administration of DNX2401 was safe, feasible and therapeutically beneficial in a subgroup of patients. This trial constitutes a proof of principle that aids to understand the response of DIPGs to viral therapies allowing to set the bases to improve this strategy for DIPG.
Phase II clinical trial using camrelizumab combined with apatinib and chemotherapy as the first‐line treatment of advanced esophageal squamous cell carcinoma
Authors: Bo Zhang, Ling Qi, Xi Wang, Jianping Xu, Yun Liu, Lan Mu, Xingyuan Wang, Lidan Bai, Jing Huang
Journal: Cancer Communications (2020)

Abstract Background Effective therapeutic options are limited for patients with advanced esophageal squamous cell carcinoma (ESCC). The incorporation of an immune checkpoint inhibitor and a molecular anti‐angiogenic agent into the commonly adopted chemotherapy may produce synergistic effects. Therefore, we aimed to investigate the efficacy and safety of camrelizumab plus apatinib combined with chemotherapy as the first‐line treatment of advanced ESCC. Methods In this single‐arm prospective phase II trial, patients with unresectable locally advanced or recurrent/metastatic ESCC received camrelizumab 200 mg, liposomal paclitaxel 150 mg/m 2 , and nedaplatin 50 mg/m 2 on day 1, and apatinib 250 mg on days 1‐14. The treatments were repeated every 14 days for up to 9 cycles, followed by maintenance therapy with camrelizumab and apatinib. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Secondary endpoints included disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety. Results We enrolled 30 patients between August 7, 2018 and February 23, 2019. The median follow‐up was 24.98 months (95% confidence interval [CI]: 23.05‐26.16 months). The centrally assessed ORR was 80.0% (95% CI: 61.4%‐92.3%), with a median duration of response of 9.77 months (range: 1.54 to 24.82+ months). The DCR reached 96.7% (95% CI: 82.8%‐99.9%). The median PFS was 6.85 months (95% CI: 4.46‐14.20 months), and the median OS was 19.43 months (95% CI: 9.93 months – not reached). The most common grade 3‐4 treatment‐related adverse events (AEs) were leukopenia (83.3%), neutropenia (60.0%), and increased aspartate aminotransferase level (26.7%). Treatment‐related serious AEs included febrile neutropenia, leukopenia, and anorexia in one patient (3.3%), and single cases of increased blood bilirubin level (3.3%) and toxic epidermal necrolysis (3.3%). No treatment‐related deaths occurred. Conclusions Camrelizumab plus apatinib combined with liposomal paclitaxel and nedaplatin as first‐line treatment demonstrated feasible anti‐tumor activity and manageable safety in patients with advanced ESCC. Randomized trials to evaluate this new combination strategy are warranted. Trial registration This trial was registered on July 27, 2018, at ClinicalTrials.gov (identifier: NCT03603756).
OTHR-02. MULTIMODALITY TREATMENT FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM (CNS) TUMOR IN OUR INSTITUTE
Authors: Mari Sasano, Koichiro Sumi, Nobuhiro Moro, Hideki Oshima, Maiko Hirai, Hiroshi Yagasaki, Atsuo Yoshino
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The brain tumor has a highest mortality rate among childhood malignant tumors. Development of peripheral blood stem cell transplant combined chemotherapy and radiation therapy improved the survival rate of patients with pediatric brain tumor drastically late years. Because of its complicated treatment plan, neurosurgeons cannot readily manage these aggressive therapies which require minute whole body control including prevention of lethal infection due to bone marrow suppression. Even if such treatment is effective and patient survives, the aftereffects may reduce patient’s QOL. PURPOSE We report outcomes of the patients with CNS tumor after multimodality treatment. In addition, we introduce the activity contents by the in-hospital children brain tumor multi-disciplinary medical treatment team organized in March 2016. METHODS We retrospectively reviewed 29 patients (under 15 years old) diagnosed as CNS tumors with total of 43 tumor surgeries between January 2001 and December 2019. RESULTS The histopathological diagnoses were 7 germ cell tumor, 7 astrocytic tumor, 4 ependymal tumor, 4 medulloblastoma, 2 craniopharyngioma, 2 AT/RT and 3 others. The mean age at first surgery was 7.4 y.o. (range: 0.3–14.8). Both chemotherapy and radiation therapy were performed in 22 cases out of 29. There were 15 survivors (11 ambulant, 3 W/C, 1 bedridden), 12 deaths, 2 lost follow-ups. Mean follow-up period was 66 months (range: 1–206). CONCLUSION To improve outcomes, we hold on a regular basis of team meeting, discuss treatment plan, and share information. Recently, we also care issues of the patients, such as fertility and palliative medicine.
18F-FDG PET/CT Assessment of Malignant Granular Cell Tumor of the Soft Tissue
Authors: María Fernanda Lara Martínez, Alicia Díaz Silván, Olga Vilahomat Hernández, Dolores Cabello García, Ana Julia Allende Riera
Journal: Clinical Nuclear Medicine (2020)

Malignant granular cell tumor variant is rare and even more if lower extremities are involved. We present a rare case with images of 18F-FDG PET/CT showing 2 hypermetabolic lesions on the right tight with an elevated SUVmax value of 7.50 and 2 adenopathies with an SUVmax almost as high as the lesions. Histopathologic sample after complete excision confirmed malignant granular cell tumor with lymph node metastases.
DDRE-09. DEVELOPING IDO-PROTACS TO IMPROVE IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA
Authors: Lakshmi Bollu, Derek Wainwright, Lijie Zhai, Erik Ladomersky, Kristen Lauing, April Bell, Gary Schlitz
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes the essential amino acid tryptophan into kynurenine. Recent work by our group has revealed that IDO promotes tumor development and suppresses immune cell functions independent of its enzyme activity. Moreover, pharmacologic IDO enzyme inhibitors that currently serve as the only class of drugs available for targeting immunosuppressive IDO activity, fail to improve the survival of patients with GBM. Here, we developed IDO-Proteolysis Targeting Chimeras (IDO-PROTACs). PROTACs bind to a specific protein and recruit an E3 ubiquitin ligase that enhance proteasome-mediated degradation of the target protein. METHODS A library of ≥100 IDO-PROTACs were developed by joining BMS986205 (IDO binder) with a linker group to various E3-ligase ligands. Western blot analysis of PROTAC-induced IDO degradation was tested in vitro among multiple human and mouse GBM cell lines including U87, GBM6, GBM43 and GL261 along a time course ranging between 1–96 hours of treatment and at varying concentrations. The mechanism of IDO protein degradation was investigated using pharmacologic ligands that inhibit or compete with the proteasome-mediated protein degradation pathway. RESULTS Primary screening identified several IDO-PROTACs with IDO protein degradation potential. Secondary screening showed that our lead compound has a DC50 value of ~0.5µM with an ability to degrade IDO in all GBM cells analyzed, and an initial activity within 12 hours of treatment that extended for up to 96 hours. Mutating the CRBN-binding ligand, pretreatment with the ubiquitin proteasome system inhibitors MG132 or MLN4924 or using unmodified parental compound all inhibited IDO protein degradation. CONCLUSIONS This study developed an initial IDO-PROTAC technology that upon further optimization, can neutralize both IDO enzyme and non-enzyme immunosuppressive effects. When combined with other forms of immunotherapy, IDO-PROTACs have the potential to substantially enhance immunotherapeutic efficacy in patients with GBM.
The Association of Autoimmune Disease With Lung Cancer Survival
Authors: Elizabeth R. Volkmann
Journal: JAMA Network Open (2020)

Saya Jacob, MD; Kian Rahbari, BS; Kyle Tegtmeyer, BS; Jeffrey Zhao, BA; Steven Tran, BS; Irene Helenowski, PhD; Hui Zhang, PhD; Theresa Walunas, PhD; John Varga, MD; Jane Dematte, MD; Victoria Villaflor, MD