bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-24. TESTOSTERONE FUNCTIONS AS A TUMOR SUPPRESSOR IN GLIOBLASTOMA
Authors: Lee Juyeun , Silver Daniel , Chung Yoon-Mi , Sharifi Nima , Lathia Justin 
Published: November 2022

Abstract
A sex difference in the incidence and outcome of patients with glioblastoma (GBM), the most common primary malignant brain tumor, has been well established, as male patients experience a worse prognosis. However, the contribution of sex hormones to anti-tumor immunity has not been fully explored. To test this, we orthotopically implanted syngeneic mouse GBM cells into male mice after castration or sham surgery to assess survival differences. Castrated immune-competent mice succumbed to tumors significantly faster than the sham surgery group, and this was rescued by exogenous testosterone administration. This finding was further corroborated by that blockade of androgen signaling using enzalutamide reproduced the effect of castration with shortened survival. In contrast, castration on immunocompromised mice, NSG and RAG1KO, resulted in no survival difference compared to sham animals, suggesting a role for immune system. Flow cytometry analysis of tumor-infiltrating immune cells revealed decreased cytokine production in T and NK cells from castrated mice, while no difference was found in immune cell infiltration. Flank tumor experiments suggested brain-specific regulation of T cell recruitment, as tumor growth was delayed in castrated mice with increased infiltration of CD8+ T cell. It is noted that decreased cytokine production in T cells and NK cells was observed in tumor as well as lymph nodes from flank tumor model. Surprisingly, mass spectrometry of serum revealed upregulated levels of circulating corticosterone in castrated mice regardless of tumor presence, suggesting that castration may induce systemic immunosuppression and regulate T cell infiltration to brain via upregulation of glucocorticoids. Taken together, our data demonstrate that testosterone regulates T cell immunity, possibly via glucocorticoids, and ultimately affects GBM tumor growth. Given the decreased level of testosterone in aged males with higher risk of GBM, these findings further suggest the potential therapeutic intervention of testosterone in GBM.
IMMU-28. THE INTRA-TUMORAL SPATIAL HETEROGENEITY OF T CELL ANTIGENS IN GLIOBLASTOMA: AN INTEGRATED MULTI-OMICS APPROACH
Authors: Medici Gioele , Wacker Marcel , Dubbelaar Marissa , Schwitalla Carolin , Hanssen Friederike , Schulz Daniel , Vasella Flavio , Rushing Elisabeth , Bauer Jens , Bodenmiller Bernd , Rammensee Hans-Georg , Regli Luca , Walz Juliane , Weller Michael , Neidert Marian 
Published: November 2022

Abstract
This study investigates the intratumoral heterogeneity of T cell antigen presentation in 15 newly diagnosed glioblastoma patients. Our multi-omics approach includes mass spectrometry-based immunopeptidome analysis, next-generation sequencing (whole-exome and RNA sequencing), and imaging mass cytometry performed on biopsies deriving from the necrotic core (NEC), the gadolinium contrast-enhancing region (T1), and the peritumoral infiltrating zone (INF, 5-ALA positive). A total of 24493 unique HLA class I and 17394 unique HLA class II peptides were identified. Comparative profiling of peptides from our study and a benign tissue database (in-house; n = 429 donors combined with HLA ligand atlas (https://hla-ligand-atlas.org)) revealed that 20% of HLA class I ligands are glioblastoma exclusive. Of these ligands, 21%, 21%, and 15% were exclusively presented in the INF, T1, or NEC zone, respectively. Here, we focused on the INF-specific antigens as this zone is likely to remain after tumor resection and gives rise to glioblastoma recurrence. Interestingly, two INF-specific HLA ligands showed a frequency presentation of 45% in our patient cohort. One ligand originated from BAALC (Brain and acute leukemia cytoplasmic protein) and one from NCAN (Neurocan core protein), which are both known to be glioblastoma-associated proteins. Immunogenicity of pre-selected candidate antigens was assessed with autologous expanded T cells and revealed a set of novel promising targets for immunotherapy. Integrated RNA/DNA sequencing also enabled the identification of neoepitopes deriving from tumor- and region-specific mutations. Furthermore, imaging mass cytometry contributed to investigating the immune compartment of the tumor microenvironment in high dimensionality and spatial resolution. In conclusion, our approach characterized the intra-tumoral regional heterogeneity of both infiltrating immune cells and tumor antigens. This multi-omics spatial atlas of the immune landscape can be used for the informed design of immunotherapy strategies against glioblastoma.
IMMU-31. PROTEASOME REARRANGED PEPTIDES ARE A NOVEL SOURCE OF ANTIGENS FOR THE PEPTIDE VACCINE IMMUNOTHERAPY OF GLIOBLASTOMAS
Authors: Fidanza Mario , Gupta Puja , Shanker Varun , Wong Nicollette , Skirboll Stephen , Lim Michael , Wong Albert 
Published: November 2022

Abstract
pepVIII, an anticancer vaccine targeting EGFRvIII, has been tested in several trials for glioblastoma including ACT IV. a randomized Phase III trial for newly diagnosed patients. While results from ACT IV were equivocal, available data suggests the elimination of EGFRvIII was not robust. Despite its essential role in antigen presentation, enhancing proteasomal processing is an unexploited strategy for improving vaccines. We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti–PD-1 therapy cured 45% of the Y6-pepVIII–vaccinated mice but was ineffective for pepVIII-treated mice. LC-MS/MS analysis of proteasome-digested pepVIII and Y6-pepVIII revealed that most fragments were similar but more abundant inY6-pepVIII digests and 77% resulted from proteasome-catalyzed peptide splicing (PCPS). We identified 10 peptides that bound human and murine MHC class I. Nine were PCPS products and only one peptide was colinear with EGFRvIII, indicating that PCPS fragments may be a component of MHC class I recognition. Despite not being colinear with EGFRvIII, two of three PCPS products tested were capable of increasing survival when administered independently as vaccines. We hypothesize that the immune response to a vaccine represents the collective contribution from multiple PCPS and linear products. Our work suggests a strategy to increase proteasomal processing of a vaccine that results in an augmented immune response and enhanced survival in mice.
IMMU-35. TREM2 RESTRAINS ANTI-TUMOR CELL ACTIVITY OF MYELOID CELLS IN GLIOBLASTOMA
Authors: Sun Rui , Khan Saad , Luo Jingqin , McCornack Colin , Chen Yun , Jiang Haowu , Mao Diane D , Yang Alicia , Liu Qin , Petti Allegra , Holtzman David , Kim Albert 
Published: November 2022

Abstract
Tumor-associated myeloid cell populations occupy a major part of the glioblastoma (GBM) tumor microenvironment (TME). The prevailing view is that myeloid cells in the TME are immunosuppressive and promote GBM tumor progression. However, myeloid cells have the functional plasticity to either restrict or support tumor cell growth. TREM2 has been shown to alter the myeloid cell landscape in cancers arising in the body and plays important roles in brain microglial function in neurodegenerative diseases. But the role of TREM2 in the GBM TME and specifically in myeloid cell function has not been examined. Here we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors, and that high TREM2 expression is associated with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased tumoricidal capacity in vitro using patient-derived glioblastoma stem cells and mouse glioblastoma cells. Accordingly, we found TREM2 in myeloid cells restricts proinflammatory polarization in both LPS-induced innate and IFNγ-induced adaptive immunity in vitro, mainly through the inhibition of NFκB and MAPK p38 signaling pathways. Orthotopic injection of mouse glioblastoma cells into TREM2 knockout mice increased animal survival compared to littermate wildtype mice. In addition, co-implantation of TREM2 knockdown macrophages or microglia with mouse glioblastoma cells in brains of immunocompetent mice increased animal survival compared to co-implantation of control myeloid cells or injection of tumor cells alone, suggesting an important role for TREM2 in myeloid cells in GBM growth in vivo. Together, these data indicate that TREM2 operates by restricting the anti-tumor and proinflammatory function of myeloid cells in GBM and that inhibition of the TREM2 pathway may represent a potential therapeutic strategy for these patients.
IMMU-36. EVALUATION OF TUMOR DERIVED SERPINA3N IN EXPERIMENTAL GLIOBLASTOMA
Authors: Wolf Delaney , Ayasoufi Katayoun , Zheng Jiaying , Tritz Zachariah , Jin Fang , Hansen Michael , Johnson Aaron 
Published: November 2022

Abstract
Glioblastoma (GBM) is an incurable brain cancer which is associated with severe peripheral immune suppression. Using experimental GBM, we recently determined that peripheral immunosuppression involves thymic atrophy, stunted T cell proliferation, and release of circulating factors that inhibit immune responses. RNA sequencing and proteomic studies have determined that transcripts and protein levels of Serpina3n are upregulated in the brain and serum of GBM patients and correlates with poor prognosis. We determined Serpina3n is a highly upregulated gene in the brain and the thymus of glioma-bearing mice using RNA sequencing technologies. Proteomic analysis of serum from glioma-bearing mice identified an upregulation of pathways associated with the extracellular expression of Serpina3n. We therefore sought to determine the role of Serpina3n in peripheral immunosuppression in GL261 glioma harboring wild type and Serpina3n knockout mice. Glioma implantation in Serpina3n knockout mice resulted in similar survival and peripheral immunosuppression compared to controls. Western blotting experiments confirmed that Serpina3n is expressed and secreted by GL261 gliomas isolated from WT and Serpina3n knockout mouse brains. Together this data suggests that tumor-derived, but not host derived, Serpina3n needs to be evaluated as a putative factor associated with peripheral immunosuppression.
INNV-02. MULTIFOCAL, DURABLE AND PATHOLOGICALLY-CONFIRMED BRAIN METASTASIS COMPLETE RESPONSE TO TRASTUZUMAB DERUXTECAN
Authors: Tosi Umberto , Moss Nelson , Santomasso Bianca , Beal Kathryn , Modi Shanu 
Published: November 2022

Abstract
Antibody-based conjugates (ADCs) have transformed the treatment of Her2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to differential activity of macromolecules across the blood-brain and blood-brain tumor barriers. Trastuzumab deruxtecan (T-DXd), a high-payload ADC, was recently found to improve the progression-free survival of Her2+ breast cancer patients compared with prior-generation trastuzumab emtansine, prompting us to evaluate this agent in a woman with CNS-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent (and previously-irradiated) lesions were subsequently biopsy-proven to represent treatment effect. Response was durable through 7 months of treatment, with subsequent recurrence in the setting of treatment holiday; partial response was observed with drug rechallenge. Drug discontinuation was ultimately required due to concern for pulmonary toxicity. Our case suggests T-DXd is active in Her2+ breast cancer brain metastases and supports further prospective evaluation in randomized clinical trials.
INNV-05. CO-OCCURRENCES OF A HIGH-GRADE GLIOMA WITH CAVERNOUS MALFORMATIONS AND PATHOGENIC VARIANTS IN PDCD10 AND SMARCA4
Authors: Damodharan Sudarshawn , Glanz Hannah , Smith-Simmer Kelcy , Helgager Jeffrey , Puccetti Diane 
Published: November 2022

Abstract

INTRODUCTION
The co-occurrence of multiple disease processes can make for more challenging diagnoses. Here we report an unusual case of a patient found to have an IDH1-mutant high-grade glioma along with multiple cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. Case Description: A 17-year-old female presented with left arm paresthesia and weakness along with persistent headaches within the frontal and occipital regions that progressed in intensity to include nausea and emesis. A fast sequence magnetic resonance imaging (MRI) of her head was obtained that revealed the presence of multiple bilateral cystic lesions suspicious for cavernomas with the most notable lesion in the right parietal lobe. Ophthalmology consultation revealed grade III papilledema bilaterally. A full brain MRI with and without contrast was obtained and demonstrated a right anterior parietal lobe lesion with associated mass effect, as well as multiple bilateral supratentorial and left cerebellar cavernous malformations. The patient underwent tumor debulking of her dominant lesion. Pathology revealed an IDH1 mutant diffuse astrocytoma, WHO grade 3. Germline genetic testing was pursued which revealed a PDCD10 pathogenic variant consistent with familial cerebral cavernous malformation syndrome and a likely pathogenic variant in SMARCA4. Treatment of her high-grade-glioma included radiation therapy followed by maintenance oral temozolomide.

DISCUSSION
This case illustrates the unusual co-occurrences of a high-grade glioma with familial cavernous malformation syndrome and germline pathogenic variants in PDCD10 and SMARCA4. Our patient continues to do well clinically, but because of her now significant risk of developing ovarian cancer she has elected to undergo a prophylactic bilateral salpingo-oophorectomy. Recognition of abnormal genetic results is critical in the setting of multiple disease processes and can play a crucial role in the on-going care for a patient.
INNV-09. IMPACT OF MOLECULAR MARKERS ON TREATMENT OUTCOME OF GLIOBLASTOMA PATIENTS TREATED WITH CONCURRENT TUMOR-TREATING FIELDS (TTF) AND CHEMORADIATION: SECONDARY ANALYSIS OF SPARE TRIAL
Authors: Cappelli Louis , Kayne Allison , Poiset Spencer , Niazi Muneeb , Ali Ayesha , Alnahhas Iyad , Shi Wenyin 
Published: November 2022

Abstract

OBJECTIVES
SPARE trial (Scalp-sparing radiation with concurrent temozolomide and tumor treating fields; NCT03477110) is a single-arm pilot study that evaluated the safety and feasibility of concurrent TTF with chemoradiation for adult patients with newly diagnosed GBM. The current study is a secondary analysis evaluating the impact of molecular markers (PTEN, TP53, EGFR, and TERT) on overall survival (OS) and progression-free survival (PFS) of the patients in the trial.

METHODS
Molecular markers of histologically-confirmed, IDH-wildtype GBM patients age ≥ 18 years old with a KPS ≥ 60 who received concurrent chemoradiation and TTF followed by maintenance TMZ + TTF were evaluated. Molecular profile was evaluated with next-generation sequencing. Impact of mutations in PTEN, TP53, EGFR, and TERT on OS and PFS was evaluated using a multivariable backward model.

RESULTS
A total of 30 patients were enrolled in the SPARE trial, and 1 patient with IDH-mutant was excluded from the current analysis. All patients underwent concurrent TTF and chemoradiation. The median age is 58 and KPS was 90. 9 patients had methylated MGMT promotor. 14 patients were found to have PTEN mutation, 9 patients with EGFR, 7 with TP53 mutation, and 23 patients with TERT mutated. MGMT methylation remained statistically significant for an increased OS (p=0.032; HR 7.18). TERT mutation had a statistically significant improvement in PFS (P=0.003) and OS (p=0.012). However, neither EGFR, TP53, nor PTEN showed any association of PFS or OS for patients who received concurrent TTF and CRT.

CONCLUSIONS
In this secondary analysis, patients with MGMT methylation showed better PFS and OS as expected. Neither EGRF, TP53, or PTEN mutation showed any association with PFS or OS. Patients with TERT mutant showed improved OS of patients treated with concurrent TTF with chemoradiation. A TERT mutation may be a new molecular biomarker in the described treatment approach.
INNV-12. REPRODUCIBLE REDUCTIONS OF CONTRAST-ENHANCED TUMOR VOLUMES IN TWO END-STAGE RECURRENT GLIOBLASTOMA PATIENTS WITH IN-HOME ONCOMAGNETIC MONOTHERAPY
Authors: Helekar Santosh , Baskin David 
Published: November 2022

Abstract
A spinning oscillating magnetic field-generating device called the Oncomagnetic device selectively kills glioblastoma (GBM) cells. It produced &gt; 30% shrinkage of a recurrent GBM tumor in an end-stage patient after &lt; 5 weeks of Oncomagnetic treatment (OMT). We have now reproduced this treatment response with additional insights into device effectiveness in two more such patients undergoing compassionate use OMT. We provided OMT to a 55-year-old man with massive recurrent tumor regrowth and a 79-year-old woman with multifocal recurrent GBM showing rapid progression, with leptomeningeal spread in both cases. Both had failed standard of care chemoradiotherapy and in the former case had not tolerated Optune treatment. They received one 2-hour, two 2-hour and three 2-hour OMTs per day in the clinic on the first three days under the supervision of the treating physician. 3 2-hour daily treatments were continued subsequently at home. The first patient received a steroid drug along with OMT to control cerebral edema from the start. In the second patient it was added after 14 days while also reducing OMT to 2 hours a day because of significant evidence of edema. MRI scans were done periodically to assess the treatment response. Both patients tolerated OMT well with no serious adverse effects – for 7 months in the first patient, including four 2-hour treatments for the last 5 months, and for 2 months in the second patient. Their last MRI scans at Day 146 and Day 42 showed &gt; 35% and &gt; 91% reduction, respectively, in contrast-enhanced tumor volume compared to pre-OMT scans. A modified treatment response assessment mapping analysis showed substantial reductions in both necrotic and active tumor volumes. These findings strongly support the observations in our published single patient case report and provide firm grounds for proposing in-home OMT monotherapy as a safe and effective noninvasive treatment for GBM.
INNV-14. PROSPECTIVE SURGICAL STUDY ON THE FEASIBILITY OF SEMI-AUTOMATED TISSUE COLLECTION, STABILIZATION, PRESERVATION, AND SITE TRANSFER IN GLIOBLASTOMA - IMPROVING UNDERSTANDING OF IMMUNE LANDSCAPE OF TUMOR
Authors: Mohammadi Alireza , Grabowski Matthew , Watson Dionysios , Lauko Adam , Lathia Justin , Ahluwalia Manmeet 
Published: November 2022

Abstract

INTRODUCTION
Despite advances in targeted therapy and immunotherapy of many cancers, glioblastoma outcome is still suboptimal in part due to heterogeneity of tumor. Standard surgical approach for glioblastoma is to remove the enhancing tumor and adjuvant treatment used to treat residual infiltrative tumor in non-enhancing surgical wall. We evaluated samples from both areas using advanced techniques of intraoperative resecting, collecting and biologically preserving viable fresh tissue for evaluation of immune landscape and special genomics of tumor.

METHODS
20 patients with glioblastoma enrolled in the study. Before removal of tumor, 3 different samples from central core, enhancing rim and non-enhancing portion of tumor were obtained using navigation assisted NICO Myriad. Fresh tissue was collected separately by an intraopertive Automated Tissue Preservation System (ATPS) and promptly prepare in iced-cold container for laboratory evaluation of tumor tissue viability, bio-banking and flow-cytometric analysis.

RESULTS
Average age was 65 years-old and 11 patients were female (55%). No adverse event was observed and on average, sampling added 10 minutes to surgical time. Flow-cytometry showed that non-enhancing portion of glioblastoma compared to enhancing tumor has less immune cells and different abundance of multiple subsets including lower CD8:CD4 ratio and more abundant of CD4 memory T-cells. However there remain activated/exhausted T-cells and suppressive myeloid cells in the non-enhancing tumor. Tissue is sent for micro-RNA analysis and next-generation sequencing as well.

CONCLUSION
Taken together, navigation assisted sampling and semi-automated tissue collection, stabilization, and preservation using ATPS is a safe and feasible technique to obtain viable cells for evaluation of heterogeneity of glioblastoma, especially for non-enhancing portion of tumor. This information can be used developing next-generation therapy. Initial results of flow-cytometry showed overall decreased leukocyte infiltration, with underrepresentation of selected immune cell subsets in non-enhancing tumor compared to enhancing portion. Further studies regarding micro-RNA analysis and next-generation sequencing are underway.
INNV-15. MANAGEMENT AND LONG-TERM OUTCOMES OF ADULTS WITH MEDULLOBLASTOMA
Authors: Neth Bryan , Raghunathan Aditya , Kizilbash Sani , Uhm Joon , Breen William , Johnson Derek , Daniels David , Sener Ugur , Carabenciov Ivan , Campian Jian , Mahajan Anita , Ruff Michael 
Published: November 2022

Abstract

INTRODUCTION
Medulloblastomas (MB) are embryonal tumors arising in the cerebellum, predominantly affecting pediatric patients. Recognition of molecularly defined subgroups has advanced management. Factors influencing the prognosis and management of adult MB patients remain poorly understood.

METHODS
We retrospectively reviewed our experience with adult (&gt; 18 years at initial diagnosis) MB patients, diagnosed between 1992-2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (Log-rank test assessing for group differences) were performed for univariate survival analysis with cox regression used for multivariate (subgroup, age, gender, disseminated disease, extent of resection) analyses.

RESULTS
Our cohort included 76 adult MB patients (62% male), with a median age of 31.7 years (range: 18-66) at diagnosis, and median follow-up of 7.7 years (range: 0.6-26.9). 58 patients had sufficient tissue for molecular characterization by immunohistochemistry and corresponded to the SHH-activated (n=37; 64%), non-WNT/non-SHH (n=12; 21%), WNT-activated (n=9; 15%) subgroups. At initial diagnosis, all patients underwent radiotherapy, with 97% (n=66) receiving craniospinal irradiation with a boost either to the posterior fossa (75%) or tumor bed (22%); and underwent gross total resection (n=51; 67%) and chemotherapy (n=56; 75%). Median overall survival (OS) for the whole cohort was 14.8 years (93% 2-year OS; 86% 5-year OS; 64% 10-year OS) and was longer for younger patients (&lt; 30: &gt; 15.4 years, &gt; 30: 9.9 years; Log-rank p&lt; 0.001). No significant OS difference was identified by MB molecular subgroup (SHH, TP53-wt: 14 years, WNT: 11.4 years, non-WNT/non-SHH: &gt; 14.8 years; Log-rank p=0.1167) or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses.

DISCUSSION
We report one of the largest retrospective cohorts in adult MB patients with molecular subtyping. Survival and molecular subgroup frequencies were similar to previous reports. Survival was longer for younger patients and was not significantly different by MB molecular subgroup or extent of resection.