tbuckley/cabot-search huggingface dataset:
PATH-60. BIOINFORMATIC PROFILING IDENTIFIES THE SECRETED GLYCOPROTEIN ADAMTSL4 TO BE A POTENTIAL NOVEL IMMUNE-RELATED BIOMARKER FOR PRIMARY GLIOBLASTOMA
Authors: Kenan Zhang, Ruichao Chai, Zheng Zhao, Kuanyu Wang, Jing Chen, Tao Jiang
Journal: Neuro-Oncology (2018)

Research on immunotherapy of glioblastoma (GBM) has been increasing exponentially in recent years. As a targeted therapy, series of biomarkers have been identified in the local tumor tissue, while circulating makers which could be detected in the body fluids are still blank. ADAMTSL4, a secreted glycoprotein, was earlier found to contribute a lot in a GBM prognostic signature. We aimed to investigate the role of ADAMTSL4 at transcriptome level and its relationship with clinical practice in primary GBM. A cohort of 88 primary GBM patients with RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) was analyzed, and 168 pGBM patients from TCGA were included as validation. Multiple bioinformatic tools and predictive models were applied to investigate the ADAMTSL4-associated immune microenvironment status. We found that ADAMTSL4 was enriched in GBM, IDH wild-type and MGMT methylated groups. According to the TCGA classification scheme, ADAMTSL4 can act as a potential marker for malignant subtypes. Bioinformatical analyses revealed that ADAMTSL4 was significantly correlated to the immune processes in GBM, especially representing the infiltration of immune cells and complicated tumor microenvironment. Clinically, high expression of ADAMTSL4 was an independent indicator of poorer prognosis. The expression of ADAMTSL4 is closely related to the clinicopathologic characteristics of pGBM. Meanwhile, it plays a significantly predictive role in immune processes. For its characteristic of secreted glycoprotein, ADAMTSL4 is a promising circulating biomarker for pGBM, deserving further investigation.
IMMU-60. MAPPING TUMORAL AND IMMUNE HETEROGENEITY IN PD-1 RESPONSIVE GLIOBLASTOMA
Authors: Bojan Losic, Raymund Yong, Nicholas Akers, Ilaria Laface, Nadejda Tsankova, Robert Sebra, Sacha Gnjatic, Adilia Hormigo
Journal: Neuro-Oncology (2018)

Clonal evolution and the immune microenvironment in glioblastoma harbor critical clues to its known but poorly understood treatment resistance. To assess the potential benefit of immune checkpoint blockade (ICB) in glioblastoma it is critical to determine the immune interactions in the tumor microenvironment. We created a tumor-immune interaction map by computing the mutational and neo-epitope tumoral burden, along with the magnitude and clonality of infiltrating lymphocytes, from initial and recurrent tumor of a patient with a glioblastoma IDH1 wild type, unmethylated O6-methylguanine–DNA methyltransferase (MGMT) promoter who benefited from ICB. RNA sequencing was performed on samples from the primary and three spatial sectors of the recurrence. Data analyses included intra-tumoral gene expression including MHC-I allele-specific expression, expressed relative mutation, neo-epitope prediction, B/TCR profiling and correlation with analysis of immune cells by multiplex immunohistochemistry (MIHC). We found no evidence of hypermutation in the recurrence, a relative absence of immune infiltration in all recurrences despite the expression of a number of neo-epitope generating mutations (including a novel clonal mutation of EGFR), and compelling evidence of epigenetically driven aberrations in one sector of the recurrence. The differential tumor infiltrating lymphocyte burden observed between recurrent and primary biopsy, indicates immunosuppressive recurrent tumor microenvironment concurred by MIHC data that revealed a relative abundance of B-cell infiltrate. Neo-epitope editing (production) relative to primary is observed in 2/3 (1/3) recurrent tissues, consistent with relative somatic mutation overlap. Immune selection pressure induced from previous radiation/chemotherapy may be implicated in increased tumor heterogeneity and immune editing. Relative extended survival and response to ICB and VEGF-A inhibition can occur in IDH1 wild type, undetected MGMT and absent hypermutated phenotype GBM and warrant further studies to better determine the spectrum of response to PD-1 inhibition. Multi-regional analysis of recurrence may be give clues on failure of ICB.
Managing Clonal Hematopoiesis in Patients With Solid Tumors
Authors: Kelly L. Bolton, Nancy K. Gillis, Catherine C. Coombs, Koichi Takahashi, Ahmet Zehir, Rafael Bejar, Guillermo Garcia-Manero, Andrew Futreal, Brian C. Jensen, Luis A. Diaz, Dipti Gupta, Simon Mantha, Virginia Klimek, Elli Papaemmanuil, Ross Levine, Eric Padron
Journal: Journal of Clinical Oncology (2018)
NCMP-10. AUTOIMMUNE ENCEPHALITIS IN POST-REMISSION PINEAL GERMINOMA: A CASE REPORT.
Authors: Aaron Mochizuki, Marisa Lewis, William Yong, Noriko Salamon, Anthony Wang, Aria Fallah, Tom Davidson
Journal: Neuro-Oncology (2018)

Autoimmune encephalitis is a well-characterized complication of gonadal and extragonadal germ cell tumors (GCT), with a known culprit: anti-N-methyl-D-aspartate receptor antibodies. However, reports of autoimmune encephalitis in patients with central nervous system (CNS) GCT are rare. Here, we describe a case of progressive, severe encephalopathy of unknown etiology in a patient with history of pineal germinoma that responded to immunosuppressive therapy. An 18-year old female with history of pineal germinoma presented with a two month history of worsening confusion, short-term memory loss and nocturnal enuresis three months after achieving complete response following chemoradiotherapy. She denied fevers, headaches, ingestions or trauma. While admitted, her level of consciousness acutely deteriorated, necessitating intubation and mechanical ventilation. During this time, her exam was significant for episodic decerebrate posturing with associated dysautonomia. An extensive workup, including infectious, neoplastic and paraneoplastic testing, was nondiagnostic. An autoimmune encephalitis panel sent to a reference laboratory was negative. Electroencephalography was consistent with severe encephalopathy without evidence of seizure activity. She was treated empirically with plasma exchange, intravenous immune globulin and rituximab, demonstrating a striking return to baseline level of consciousness and extinction of dysautonomia. Nine months after rituximab treatment, she developed headaches, dizziness, diplopia and memory loss. She was treated again with rituximab and had full recovery. Autoimmune encephalitis is a known complication in cases of gonadal and extragonadal GCT, characterized by confusion, memory deficits and dysautonomia. However, little literature exists regarding this phenomenon in the genetically indistinguishable CNS GCT. Here, we describe the case of a young woman with history of pineal germinoma who presented with severe encephalopathy. Though no specific agent has yet been identified, the resolution of her symptoms after empiric treatment for autoimmune encephalitis suggests that clinicians should be cognizant of this potential complication in patients with CNS GCT.
EXTH-20. HISTONE DEACETYLASE INHIBITOR ENHANCES ONCOLYTIC HERPES SIMPLEX VIRUS THERAPY FOR MALIGNANT MENINGIOMA
Authors: Lingyang Hua, Alessandra Gartner, Juri Kiyokawa, Samuel Rabkin, Robert Martuza, Hiroaki Wakimoto
Journal: Neuro-Oncology (2018)

Malignant (anaplastic) meningioma is a minor subset of meningioma that is lethal with no effective treatment options currently. Oncolytic herpes simplex virus (oHSV) is a powerful anti-cancer modality that induces both direct cell death and anti-tumor immunity. In neuro-oncology, oHSV has been extensively studied as a promising therapeutic for malignant glioma. We recently showed that oHSV G47delta demonstrated anti-tumor activity in a preclinical model of patient-derived malignant meningioma. However, direct injections of the oHSV in the orthotopic model in mice was not curative, revealing the need of improvement in the therapeutic approach. Epigenome modulator histone deacetylase inhibitor (HDACi) is an anti-cancer agent that has been shown to cooperate with oHSV. We here show that HDACi increases anti-cancer effects of oHSV in human malignant meningioma models, IOMM-Lee (NF2 wild-type) and CH-157 (NF2 mutant). Minimally toxic, sub-micromolar concentrations of pan-HDACi, Trichostatin A and Panobinostat, substantively increased the spread of oHSVs, G47delta and MG18L, within malignant meningioma cells in vitro. The robust spread of the virus resulted in enhanced oHSV-mediated killing of target cells when infected at low multiplicity of infection (MOI). Mechanistically, HDACi increased oHSV gene expression and replication via, at least partly, modulating interferon signaling pathway. In vivo studies to determine the beneficial impact of combining systemic HDACi with local oHSV administrations are currently underway. The combination of HDACi and oHSV may be effective at controlling malignant meningioma regardless of the tumor’s NF2 status.
LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells
Authors: Ani Grigoryan, Novella Guidi, Katharina Senger, Thomas Liehr, Karin Soller, Gina Marka, Angelika Vollmer, Yolanda Markaki, Heinrich Leonhardt, Christian Buske, Daniel B. Lipka, Christoph Plass, Yi Zheng, Medhanie A. Mulaw, Hartmut Geiger, Maria Carolina Florian
Journal: Genome biology (2018)

The decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac.Here, we show that not all histone modifications display a polar localization and that a reduction in H4K16ac amount and loss of epipolarity are specific to aged HSCs. Increasing the levels of H4K16ac is not sufficient to restore polarity in aged HSCs and the restoration of HSC function. The changes in H4K16ac upon aging and rejuvenation of HSCs are correlated with a change in chromosome 11 architecture and alterations in nuclear volume and shape. Surprisingly, by taking advantage of knockout mouse models, we demonstrate that increased Cdc42 activity levels correlate with the repression of the nuclear envelope protein LaminA/C, which controls chromosome 11 distribution, H4K16ac polarity, and nuclear volume and shape in aged HSCs.Collectively, our data show that chromatin architecture changes in aged stem cells are reversible by decreasing the levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.
Letter to the Editor: Confirmation of the Optimization to Prevent the First Esophageal Variceal Bleeding?
Authors: Xinwen Yan, Ziyuan Zou, Xun Li, Xiaolong Qi
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the network meta‐analysis by Sharma et al.1 The authors compared different therapies for the first prophylaxis of esophageal variceal bleeding, based on the direct and indirect evidence, and concluded that nonselective β‐blockers (NSBBs) could be the optimization. We commend the authors for undertaking such a rigorous network meta‐analysis and would like to share our opinion on the details in methods. The authors mentioned that the network evaluating mortality had some inconsistency in the comparison of NSBBs and variceal band ligation (VBL), thus indicating that there existed biases in the research. Considering the source of inconsistency, the main assumption underpinning the transitivity of direct evidence from pairwise meta‐analysis and indirect evidence from network meta‐analysis is that there exists a common comparator between the trials.2 In the meantime, the placebo effect itself—symptom improvement after inert treatments in clinical trials—is composed of different factors, such as the natural history of a disease or fluctuation of symptoms, response biases, effects of cointerventions, or statistical phenomena.3 Doubtless, “no intervention” in VBL trials was equated with “placebo” in NSBB trials in the indirect comparison between NSBBs and VBL with the outcome of all‐cause death, irrespective of the placebo effect. This is a matter of concern because the conceptual heterogeneity could be derived from inconsistency based on the improper conducting of the indirect comparison.4 In the Bayesian network meta‐analysis, indirect evidence was compared with direct evidence from a pairwise meta‐analysis to evaluate the data credibility.2 As for the outcome of all‐cause death, the P value of the comparison between VBL and NSBBs equals 0.07, which indicates that the difference between VBL and NSBBs does not reach statistical significance according to the normal cutoff, 0.05; and there is no explicit description of the cutoff P value in this article.1 Considering the inaccurate equating of different control groups and inconsistency across indirect and direct evidence estimates derived from statistical test, results and inferences from this network meta‐analysis need to be interpreted with great caution. We suggest that a sensitivity analysis in which the control groups of “no intervention” and “placebo” are set separately into two nodes could be a supplement to this network meta‐analysis.
CBMT-26. HIGH MOBILITY GROUP AT-HOOK 2 (HMGA2) IS A PROGNOSTIC FACTOR ASSOCIATED WITH MALIGNANT PHENOTYPE IN MEDULLOBLASTOMAS
Authors: Yoshiki Arakawa, Liu Bin, Masahiro Tanji, Yohei Mineharu, Susumu Miyamoto
Journal: Neuro-Oncology (2018)

Medulloblastoma is an embryonal tumor arising in the cerebellum and its molecular mechanism has been revealed to be classified in several groups. The constitutive expression of high mobility group AT-hook 2 (HMGA2) is associated with malignant phenotype and reduced survival in some cancers. However, the clinical and biological significances of HMGA2 in medulloblastoma have not been elucidated. Here, we examined the expression, prognostic and therapeutic role of HMGA2 in medulloblastoma. HMGA1 and HMGA2 expressions were examined in 20 patients with medulloblastoma using immunohistochemical study. High expression levels of HMGA1 and HMGA2 were frequently identified in medulloblastoma tissues. In addition, high expression of HMGA2 correlated with high proliferation marker Ki-67 labeling index. High expression of HMGA2 was significantly associated with progression free survival and overall survival of patients with medulloblastoma (p=0.021 and p=0.016, respectively). To examine the function of HMGA2 expression, knock-down HMGA2 expression was applied in Daoy, D283 and D341 cells. Knock-down of HMGA2 resulted in inhibited cell proliferation, migration/invasion and enhanced apoptosis in vitro. In conclusion, HMGA2 overexpression is frequent in medulloblastoma, and its expression is related to proliferation marker and poor prognosis. These findings suggest that HMGA2 could serve as a potential target for future therapeutic strategies in medulloblastoma.
CSIG-33. ONCOLYTIC HERPES VIRUS TREATMENT INDUCED NOTCH SIGNALING VIA HSV-1 microRNA H16 AND IT INVOLVED IN TREATMENT RESISTANCE
Authors: Yoshihiro Otani, Ji Young Yoo, Tae Jin Lee, Joseph Liu, Alena Cristina Jaime-Ramirez, Balveen Kaur
Journal: Neuro-Oncology (2018)

INTRODUCTION: Glioblastomas (GBMs) are resistant to traditional therapies. Thus, the development of novel treatment strategies is urgently needed. NOTCH signaling is activated in GBM and important for mediating proliferation, angiogenesis, and resistance to therapy. In this study, we uncovered the mechanism by which oncolytic herpes simplex viruse-1 (oHSV) therapy induced NOTCH activation in the tumor microenvironment (TME). We also investigated the therapeutic benefit of combining oHSV therapy with Gamma-secretase inhibitor (GSI), a NOTCH inhibitor. Real time Q-PCR, NOTCH reporter assay, and bioluminescence mice imaging were used to test oHSV-induced NOTCH activation. Screening of HSV-1-encoded microRNAs (HSVmiRs) and genes were performed to identify the mechanism which regulates the NOTCH signaling. Intracranial glioma-bearing xenografts were used to evaluate the anti-tumor efficacy of combination of GSI and oHSV. oHSV infection induced gene expression of NOTCH ligands resulting in activation of NOTCH signaling in adjacent cells in primary GBM derived cells. This was mediated by HSV encoded miRH16. HSVmiRH16 targets and suppresses Factor Inhibitor Hif1-1 (FIH-1) expression which is known to inhibit NOTCH activation. Consistent with this both overexpression of HSVmiRH16 and knockdown of FIH-1 significantly induced NOTCH signaling. Treatment of mice bearing intracranial glioma with GSI and oHSV therapy significantly enhanced survival compared to that with monotherapy. CONCLUSION: We identified oHSV-induced NOTCH signaling activation, via HSV encoded miRH16. We further find that GSI treatment in combination with oHSV therapy demonstrated improved efficacy. To our knowledge this is the first report investigating NOTCH signaling in conjunction with oHSV therapy.
EPID-18. MALIGNANT PRIMARY BRAIN AND OTHER CENTRAL NERVOUS SYSTEM TUMOURS DIAGNOSED AMONG THE CANADIAN POPULATION FROM 2009 TO 2013
Authors: Emily Walker, Faith Davis
Journal: Neuro-Oncology (2018)

HR 0.64, 95% CI 0.54-0.76;p< 0.00001) and when AAT was combined with chemotherapy compared to chemotherapy alone (HR 0.72, 95% CI 0.66-0.77;p <0.00001).CONCLUSIONS: The use of anti-angiogenic therapy does not improve survival in newly diagnosed people with GBM, despite improved progression free survival.There is no evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent GBM.
IMMU-23. ANTIGEN-SPECIFIC EFFECTOR MEMORY CD4+ T CELLS AND CCL3 POTENTIATE DENDRITIC CELL VACCINES AND ANTITUMOR IMMUNITY
Authors: Kristen Batich, Luis Sanchez-Perez, Teilo Schaller, Xiuyu Cui, Weihua Xie, Gary Archer, Pam Norberg, David Snyder, Kendra Congdon, John Sampson
Journal: Neuro-Oncology (2018)

Efficacy of dendritic cell (DC) vaccines for glioblastoma (GBM) has been limited by suboptimal migration to draining lymph nodes. Protein antigens induce robust T cell responses that can potentiate innate antigen presenting cells such as DCs. Our previous work in patients with GBM and corroborating mouse models receiving tumor antigen-specific DCs revealed that migration and antitumor responses were significantly enhanced by CD4+ T cell memory responses to a different protein antigen, tetanus-diphtheria (Td) toxoid. Furthermore, vaccine responses were dependent on the chemokine CCL3. Here, we investigated how memory CD4+ T cells interact with cognate antigens Td and the Mycobacterium tuberculosis antigen 85B (Ag85B) to enhance responses to ovalbumin (OVA)-expressing DCs and tumors. C57BL/6 and CD4 + 85B TCR transgenic mice were used to study the effects of Td and Ag85B-specific responses on OVA-DC migration and efficacy. One day following Td and Ag85B preconditioning, there is an influx of CD4+ T cells in the skin site (p=0.002), and this is dependent on the protein antigen recall response (p=0.005). Both Td and 85B preconditioning led to locally induced CCL3 and increased migration of OVA-DCs (Td, p=0.002; Ag85B, p=0.001). Depletion of CD4+ T cells resulted in a loss of induced CCL3 as well as abrogation of increased DC migration (p=0.005). Mice with established B16/F10-OVA tumors receiving Td preconditioning demonstrated suppressed tumor growth compared to controls, which was abrogated in Ccl3-/- hosts. However, adoptive transfer of Td memory CD4+ T cells and exogenous CCL3 rescued the effect of suppressed growth (Day 21 mean tumor volumes, p=0.017). The induction of CD4+ memory responses to protein antigens can sufficiently facilitate the increased migration of tumor antigen-specific DCs and promote antitumor immunity. This axis of the adaptive immune response relies on host CCL3, which can serve as a potent immunotherapy adjuvant in future studies.
MNGI-35. SIMPSON GRADING REVISITED: SURGEONS ESTIMATION OF MENINGIOMA REMOVAL VS. POSTOPERATIVE 68GA-DOTATATE PET/CT
Authors: Moritz Ueberschaer, Franziska Vettermann, Robert Forbrig, Peter Bartenstein, Nathalie Lisa Albert, Jörg-Christian Tonn, Christian Schichor
Journal: Neuro-Oncology (2018)

The surgeons intraoperative estimation of meningioma removal (Simpson-Score, SimS) has been accepted as prognostic factor for tumor recurrence with SimS grade I and II being regarded as complete tumor removal. 68Ga-DOTATATE PET/CT has been shown to detect meningioma tissue even more sensitive and specific than MRI. We evaluate the Simpson grading within the framework of modern imaging techniques in both, a retrospective and a prospective data set. 37 adult patients with primary or recurrent WHO°I meningioma and surgical resection were retrospectively investigated. The prospective data set comprised 56 patients (59 tumors). Inclusion criteria were documented SimS, postoperative MRI and 68Ga-DOTATATE PET/CT scan. The PET parameters SUVmax, SUVmean and threshold-based biological tumor volume (BTV; SUV>2.3) were assessed by two independent experienced raters. Retrospective cohort: 4 SimS I, 4 SimS II, 4 SimS III and 25 SimS IV resections. 5/8 cases with SimS I and II presented with high tracer uptake thus indicating residual tumor (p=0,0024). Of SimS III and IV cases, all showed pathological 68Ga-DOTATATE-uptake, as expected. In the prospective data set, there were 25/59 resections classified as SimS I, 15/59 as SimS II, 5/59 SimS III and 14/59 as SimS IV. In 15/40 SimS I or II resections, PET displayed tracer uptake indicating unexpected tumor remnants (37% false negative grading in Sims I and II). 68Ga-DOTATATE-PET/CT seems to provide more specific information regarding postoperative remaining meningioma tissue compared to the surgeons estimated SimS, especially in cases judged as Simpson I and II resections. This should be taken into account for follow-up management, subsequent therapies as well as in clinical studies.