Outcome Of Glioma Research Articles

High Intra-Tumor Transforming Growth Factor Beta 2 Level as a Predictor of Poor Treatment Outcomes in Pediatric Diffuse Intrinsic Pontine Glioma

Here, we report that tumor samples from newly diagnosed pediatric diffuse intrinsic pontine glioma (DIPG) patients express significantly higher levels of transforming growth factor beta 2 (TGFB2) messenger ribonucleic acid (mRNA) than control pons samples, which correlated with augmented expression of transcription factors that upregulate TGFB2 gene expression. Our study also demonstrated that RNA sequencing (RNAseq)-based high TGFB2 mRNA level is an indicator of poor prognosis for DIPG patients, but not for pediatric glioblastoma (GBM) patients or pediatric diffuse midline glioma (DMG) patients with tumor locations outside of the pons/brainstem. Notably, DIPG patients with high levels of TGFB2 mRNA expression in their tumor samples had significantly worse overall survival (OS) and progression-free survival (PFS). By comparison, high levels of transforming growth factor beta 3 (TGFB3) mRNA expression in tumor samples was associated with significantly better survival outcomes of DIPG patients, whereas high levels of transforming growth factor beta 1 (TGFB1) expression was not prognostic. Our study fills a significant gap in our understanding of the clinical significance of high TGFB2 expression in pediatric high-grade gliomas.

Predictive Value of Preoperative Diffusion Tensor Imaging for Evaluating Postoperative Outcomes of Supratentorial Glioma in the Motor Function Area.

This study aimed to assess the predictive value of preoperative diffusion tensor imaging (DTI) data for surgical outcomes of patients with supratentorial glioma in the motor function area. This is a retrospective study of 43 patients receiving navigation-guided surgery for histopathologically demonstrated supratentorial glioma in the motor function area. All patients underwent preoperative 3 Tesla magnetic resonance imaging examinations with conventional and DTI sequences. Data on preoperative imaging and pre- and postoperative clinical characteristics of patients were retrospectively collected. Univariate and multivariate linear regressions were applied to analyze the relationships between preoperative parameters and pre- and postoperative muscle strength and the Karnofsky Performance Status (KPS) score. Fourteen patients had low-grade gliomas and 29 had high-grade gliomas. Although the corticospinal tract (CST) score did not differ significantly between tumor grades, edema and deviation were common in low-grade gliomas (64.3%), while destroyed and infiltrated lesions were common in high-grade gliomas (58.6%). Muscle strength improved after surgery in the deviated tract group (40%) more than in the infiltrated tract group (33.3%). Two independent indices, preoperative muscle strength (p =0.000) and glioma-to-CST distance (p =0.001), were linearly related to postoperative muscle strength. The preoperative KPS score was the only indicator that affected the postoperative KPS score (p =0.000). DTI should be considered in surgical management of supratentorial gliomas in the motor function area to determine the appropriate surgical strategy and predict the nature of the tumor and postoperative motor function.

Construction of a pyroptosis-related lncRNAs signature for predicting prognosis and immunotherapy response in glioma.

Recent studies have proved that pyroptosis-related long non-coding RNAs (PRlncRNAs) are closely linked to tumor progression, prognosis, and immunity. Here, we systematically evaluated the correlation of PRlncRNAs with glioma prognosis. This study included 3 glioma cohorts (The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and Gravendeel). Through Pearson correlation analysis, PRlncRNAs were screened from these 3 cohorts. Univariate Cox regression analysis was then carried out to determine the prognostic PRlncRNAs. A pyroptosis-related lncRNAs signature (PRLS) was then built by least absolute shrinkage and selection operator and multivariate Cox analyses. We systematically evaluated the correlation of the PRLS with the prognosis, immune features, and tumor mutation burden in glioma. A total of 14 prognostic PRlncRNAs overlapped in all cohorts and were selected as candidate lncRNAs. Based on The Cancer Genome Atlas cohort, a PRLS containing 7 PRlncRNAs was built. In all cohorts, the PRLS was proved to be a good predictor of glioma prognosis, with a higher risk score related to a poorer prognosis. We observed obvious differences in the immune microenvironment, immune cell infiltration level, and immune checkpoint expression in low- and high-risk subgroups. Compared with low-risk cases, high-risk cases had lower Tumor Immune Dysfunction and Exclusion scores and greater tumor mutation burden, indicating that high-risk cases can be more sensitive to immunotherapy. A nomogram combining PRLS and clinical parameters was constructed, which showed more robust and accurate predictive power. In conclusion, the PRLS is a potentially useful indicator for predicting prognosis and response to immunotherapy in glioma. Our findings may provide a useful insight into clinically individualized treatment strategies for patients.

Impact of GAP-43, Cx43 and actin expression on the outcome and overall survival in diffuse and anaplastic gliomas

Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli, where actin forms cytoskeleton and GAP-43 mediates the axonal conus growth. We aimed to investigate the impact of GAP-43 and actin expression on overall survival (OS) as well as crucial prognostic factors. FFPE tissue of adult patients with diffuse and anaplastic gliomas, who underwent first surgery in our center between 2010 and 2019, were selected. GAP-43, Cx43 and actin expression was analyzed using immunohistochemistry and semi-quantitatively ranked. 118 patients with a median age of 46 years (IqR: 35–57) were evaluated. 48 (41%) presented with a diffuse glioma and 70 (59%) revealed anaplasia. Tumors with higher expression of GAP-43 (p = 0.024, HR = 1.71/rank) and actin (p < 0.001, HR = 2.28/rank) showed significantly reduced OS. IDH1 wildtype glioma demonstrated significantly more expression of all proteins: GAP-43 (p = 0.009), Cx43 (p = 0.003) and actin (p < 0.001). The same was confirmed for anaplasia (GAP-43 p = 0.028, actin p = 0.029), higher proliferation rate (GAP-43 p = 0.016, actin p = 0.038), contrast-enhancement in MRI (GAP-43 p = 0.023, actin p = 0.037) and age (GAP-43 p = 0.004, actin p < 0.001; Cx43 n.s. in all groups). The intercellular distant communication network in diffuse and anaplastic gliomas formed by actin and GAP-43 is associated with a negative impact on overall survival and with unfavorable prognostic features. Cx43 did not show relevant impact on OS.

Tumor-Antigen Activated Dendritic Cell Membrane-Coated Biomimetic Nanoparticles with Orchestrating Immune Responses Promote Therapeutic Efficacy against Glioma.

Immunotherapy has had a profound positive effect on certain types of cancer but has not improved the outcomes of glioma because of the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment. In this study, we developed an activated mature dendritic cell membrane (aDCM)-coated nanoplatform, rapamycin (RAPA)-loaded poly(lactic-co-glycolic acid) (PLGA), named aDCM@PLGA/RAPA, which is a simple, efficient, and individualized strategy to cross the BBB and improve the immune microenvironment precisely. In vitro cells uptake and the transwell BBB model revealed that the aDCM@PLGA/RAPA can enhance homotypic-targeting and BBB-crossing efficiently. According to the in vitro and in vivo immune response efficacy of aDCM@PLGA/RAPA, the immature dendritic cells (DCs) could be stimulated into the matured status, which leads to further activation of immune cells, such as tumor-infiltrating T cells and natural killer cells, and can induce the subsequent immune responses through direct and indirect way. The aDCM@PLGA/RAPA treatment can not only inhibit glioma growth significantly but also has favorable potential ability to induce glial differentiation in the orthotopic glioma. Moreover, the aDCM@PLGA could induce a robust CD8+ effector and therefore suppress orthotopic glioma growth in a prophylactic setup, which indicates certain tumor immunity. Overall, our work provides an effective antiglioma drug delivery system which has great potential for tumor combination immunotherapy.

Clinical features and outcomes of pediatric intracranial gliomas: results from single center's 226 cases and corroborated with SEER database.

Pediatric gliomas are the most common central nervous system (CNS) tumors in children and adolescents and show different clinical and histopathological characteristics from the adult. The prognostic factors were poorly defined in pediatric intracranial gliomas. We collected pediatric intracranial glioma cases in our institution between February 2011 and June 2022. The patient clinical data, tumor growth characteristics, treatments, and follow-up data were analyzed by Cox regression analysis to identify impact factors on the prognosis of pediatric intracranial glioma patients. To corroborate our data, an independent cohort of pediatric intracranial glioma from the Surveillance, Epidemiology, and End Results Program (SEER) database was analyzed. A total of 181 cases of pediatric low-grade glioma (PLGG) and 45 cases of pediatric high-grade glioma (PHGG) were included. In multivariate Cox regression analysis, tumor size > 59.5mm (p = 0.006) and non-gross total resection (non-GTR; subtotal resection, STR, p = 0.042; biopsy, p = 0.012) were associated with decreased overall survival (OS) in PLGG patients. In PHGG patients, only chemotherapy (p = 0.023) was associated with OS while tumor size was marginally prognostic for OS (p = 0.051). Additional independent analysis of 2734 PLGG and 741 PHGG from the SEER database corroborated that larger tumor size was associated with decreased OS in LGG (p = 0.001) and HGG (p < 0.001) patients, separately. In this study, we found that tumor size was a significant prognostic factor for the OS of PLGG patients in our series. Besides the tumor size, the extent of resection also independently impacted the prognosis of PLGG patients. While in PHGG patients, only chemotherapy was associated with improved OS and tumor size was marginally prognostic.

Role of B7 family members in glioma: Promising new targets for tumor immunotherapy.

Glioma, is a representative type of intracranial tumor among adults, usually has a weak prognosis and limited treatment options. Traditional therapies, including surgery, chemotherapy, and radiotherapy, have had little impact on patient survival time. Immunotherapies designed to target the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling pathway have successfully treated various human cancers, informing the development of similar therapies for glioma. However, anti-PD-L1 response rates remain limited in glioma patients. Thus, exploring novel checkpoints targeting additional immunomodulatory pathways for activating durable antitumor immune responses and improving glioma outcomes is needed. Researchers have identified other B7 family checkpoint molecules, including PD-L2, B7-H2, B7-H3, B7-H4, and B7-H6. The current review article evaluates the expression of all 10 reported members of the B7 family in human glioma using The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) data, as well as summarizes studies evaluating the clinical meanings and functions of B7 family molecules in gliomas. B7 family checkpoints may contribute to different immunotherapeutic management options for glioma patients.

Characterization of a lactate metabolism-related signature for evaluation of immune features and prediction prognosis in glioma.

Glioma is one of the most typical tumors in the central nervous system with a poor prognosis, and the optimal management strategy remains controversial. Lactate in the tumor microenvironment is known to promote cancer progression, but its impact on clinical outcomes of glioma is largely unknown. Glioma RNA-seq data were obtained from TCGA and GCGA databases. Lactate metabolism genes (LMGs) were then evaluated to construct an LMG model in glioma using Cox and LASSO regression. Immune cell infiltration, immune checkpoint gene expression, enriched pathways, genetic alteration, and drug sensitivity were compared within the risk subgroups. Based on the risk score and clinicopathological features, a nomogram was developed to predict prognosis in patients with glioma. Five genes (LDHA, LDHB, MRS2, SL16A1, and SL25A12) showed a good prognostic value and were used to construct an LMG-based risk score. This risk score was shown as an independent prognostic factor with good predictive power in both training and validation cohorts (p < 0.001). The LMG signature was found to be correlated with the expression of immune checkpoint genes and immune infiltration and could shape the tumor microenvironment. Genetic alteration, dysregulated metabolism, and tumorigenesis pathways could be the underlying contributing factors that affect LMG risk stratification. The patients with glioma in the LMG high-risk group showed high sensitivity to EGFR inhibitors. In addition, our nomogram model could effectively predict overall survival with an area under the curve value of 0.894. We explored the characteristics of LMGs in glioma and proposed an LMG-based signature. This prognostic model could predict the survival of patients with glioma and help clinical oncologists plan more individualized and effective therapeutic regimens.

Tumor Mutation Burden and Tumor Microenvironment as Biomarkers of Glioma Treatment Outcome and Prognosis: A Systematic Review and Meta-Analysis Protocol

Background: Gliomas are the most common solid malignant tumors of the brain; diffuse gliomas pose a remarkable conundrum on treatment strategy. WHO Grade IV (Glioblastomas) delineate a refractory resistance to treatment even with standard combination regimen therapy of surgery, chemotherapy and radiation therapy causing increased recurrence rate with a median survival of less than one year. Management of gliomas is precluded by several factors including intra and inter tumoral heterogeneity, genomic landscape and microenvironment immunosuppression ability, which spell the inflicted pathways that counteract the therapeutic interventions. This is systematic review aiming to evaluate the effect of Tumor Mutation Burden (TMB) and Tumor Microenvironment (TME) as biomarkers of treatment outcome and prognosis of gliomas. Methods and Analysis: This systematic Review and Meta-analysis will consider the PRISMA 2020 guideline correspondence. For source of literature evidence several electronic databases including EMBASE, PubMed, Cochrane Library, SCOPUS, Web of Science, Semantic Scholar and Google scholar will be searched. All non-RCTs peer reviewed original research articles addressing the prognostic role of tumor mutation burden, tumor mutation pathways, microenvironment will be included, and data will be extracted using the Ms Excel Sheets. Studies with homogeneity and low risk of bias according to NOS 4-9 will constitute a Meta-analysis for evaluating the effect of TMB, Mutation pathways and Microenvironment for treatment outcome and prognosis of glioma. Ethical Consideration and Dissemination: Ethical approval does not apply for there is no human participant involvement in this review study .The findings of this study will be disseminated at scientific conferences and the manuscript for publication will be submitted for publication to a reputable peer reviewed journal of Neurosurgery. This review was registered at PROSPERO CRD42022377829.

Institutional Patterns of Care of Diffuse Intrinsic Pontine Glioma.

Despite recent advances, the outcomes of diffuse intrinsic pontine glioma (DIPG) remain dismal. This is a retrospective study to understand the pattern of care and its impact on DIPG patients diagnosed over 5 years in a single institute. DIPGs diagnosed between 2015 and 2019 were retrospectively reviewed to understand the demographics, clinical features, patterns of care, and outcomes. The usage of steroids and response to treatment were analyzed as per the available records and criteria. The re-irradiation cohort was propensity matched with patients with a progression-free survival (PFS) >6 months treated with supportive care alone based on PFS and age as a continuous variable. Survival analysis was performed using the Kaplan-Meier method, and Cox regression model was used to identify any potential prognostic factors. One hundred and eighty-four patients were identified with demographic profiles similar to western population-based data in the literature. Of them, 42.4% were residents from outside the state of the institution. About 75.2% of patients completed their first radiotherapy treatment, of which only 5% and 6% had worsening clinical symptoms and persistent need for steroids 1 month posttreatment. On multivariate analysis, Lansky performance status <60 (P = 0.028) and cranial nerve IX and X (P = 0.026) involvement were associated with poor survival outcomes while receiving radiotherapy with better survival (P < 0.001). In the cohort of patients receiving radiotherapy, only re-irradiation (reRT) was associated with improved survival (P = 0.002). Many patient families still do not choose radiotherapy treatment, although it has a consistent and significant positive association with survival and steroid usage. reRT further improves outcomes in the selective cohorts. Involvement of cranial nerves IX and X needs improved care.

Long-term treatment outcomes of pediatric low-grade gliomas treated at a university-based hospital.

A multimodality approach is generally considered for pediatric low-grade gliomas (LGG); however, the optimal management remains uncertain. The objective of the study was to evaluate treatment outcomes of pediatric LGG, focusing on long-term survival and factors related to outcomes. A retrospective review of 77 pediatric LGG cases treated at Ramathibodi Hospital, Thailand between 2000 and 2018 was performed. The inclusion criteria were all pediatric LGG cases aged ≤ 15years. Diffuse intrinsic pontine gliomas and spinal cord tumors were excluded. The median follow-up time was 8.2years (range, 0.6-19.7). The median age at diagnosis was 6.2years (interquartile range, 3.6-11.4). Treatments modality included tumor surgery (93%), chemotherapy (40%), and radiation therapy (14%). The 10-year overall survival (OS) and 10-year progression-free survival were 94% and 59%, respectively, for the entire cohort. The 10-year OS was 100% in three subgroups of patients: pilocytic subtype, WHO grade 1 tumors, and recipient of gross total resection. After multivariable analysis, no tumor surgery had a significantly unfavorable influence on overall survival. With a multimodality approach, pediatric LGGs had excellent outcome. Gross total resection is the standard primary treatment. Chemotherapy is the alternative standard treatment in incomplete resection cases, unresectable patients, or patients with progressive disease. Radiation therapy should be reserved as a salvage treatment option because of late complications that usually affect patients' quality of life.

Australian genome-wide association study confirms higher female risk for adult glioma associated with variants in the region of CCDC26.

Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex. We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7573692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex. We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P < .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P=.0024) with the association being nominally significant for both sexes (P < .05). Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. Abetter understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment.

Varied histomorphology and clinical outcomes of FGFR3-TACC3 fusion gliomas.

Targeted therapies for driver gene fusions in cancers have yielded substantial improvements in care. Here, the authors outline a case series of 6 patients with FGFR3-TACC3 fusion in primary brain tumors ranging from polymorphous low-grade neuroepithelial tumor of the young to papillary glioneuronal tumors and glioblastoma (GBM). Previous studies indicated the FGFR3-TACC3 fusion provides survival benefit to GBM patients. Consistent with this, 2 patients with GBM had unexpectedly good outcomes and survived for 5 and 7 years, respectively. In contrast, 2 patients with initially lower graded tumors survived only 3 years and 1 year, respectively. One patient received erdafitinib, a targeted FGFR inhibitor, for 3 months at late disease recurrence and no response was seen. There were varied histomorphological features, including many cases that lacked the characteristic FGFR3-TACC3 pathology. The findings of this cohort suggest that molecular testing is justified, even for glioma cases lacking classic histopathological signatures. Currently, FGFR3-TACC3 fusion gliomas are often classified on the basis of histopathological features. However, further research is needed to examine whether IDH1/2-wild-type tumors with FGFR3-TACC3 fusion should be classified as a subtype on the basis of this molecular fusion. Because patients with IDH1/2-wild-type GBM with FGFR3-TACC3 fusion have improved survival, routine molecular testing for this mutation in patients enrolled in clinical trials and subsequent stratification may be warranted.

Activation of embryonic/germ cell-like axis links poor outcomes of gliomas

BackgroundIt is unclear which core events drive the malignant progression of gliomas. Earlier studies have revealed that the embryonic stem (ES) cell/early PGC state is associated with tumourigenicity. This study was designed to investigate the role of ES/PGC state in poor outcomes of gliomas.MethodsCrispr-Cas9 technology, RT–PCR and animal experiments were used to investigate whether PGC-like cell formation play crucial roles in the tumorigenicity of human glioma cells. Bioinformatic analysis was used to address the link between ES/PGC developmental axis and glioma overall outcomes.ResultsHere, our findings showed that germ cell-like cells were present in human gliomas and cultured glioma cells and that the formation of germ cell-like cells was essential for glioma tumours. Bioinformatic analysis showed that the mRNA levels of genes related to embryonic/germ cell development could be detected in most gliomas. Our findings showed that the activation of genes related to reprogramming or the germ cell-like state alone seemed to be insufficient to lead to a malignant prognosis, whereas increased mRNA levels of genes related to the activation of the embryonic/germ cell-like cycle (somatic PGC-EGC-like cycle and somatic parthenogenetic embryo-like cycle) were positively correlated with malignant prognoses and poor clinical outcomes of gliomas. Genes related to the embryonic/germ cell cycle alone or in combination with the WHO grade or 1p19q codeletion status could be used to subdivide gliomas with distinct clinical behaviours.ConclusionTogether, our findings indicated that a crucial role of germ cell-like cell formation in glioma initiation as well as activation of genes related with the parthenogenetic embryo-like cycle and PGC-EGC-like cycle link to the malignant prognosis and poor outcomes of gliomas, which might provide a novel way to better understand the nature of and develop targeted therapies for gliomas as well as important markers for predicting clinical outcomes in gliomas.

SURG-16. THALAMIC GLIOMAS AND THEIR SURGICAL STRATEGY: A SYSTEMATIC REVIEW

Abstract INTRODUCTION Until recent decades, thalamic gliomas had been considered largely inoperable. These lesions are deep-seated and surrounded by vital structures. However, as technology and imaging modalities have improved, so have treatment modalities. Currently, a range of surgical approaches are used, partially dependent on the location of the lesion; although no consensus has been reached regarding optimal surgical management. OBJECTIVE To conduct a systematic review of the literature to describe the current surgical outcomes of adult thalamic gliomas. METHODS Four databases were searched with keywords “‘thalamic glioma’ AND ‘surgical intervention’ OR ‘thalamic glioma’ AND ‘surgical treatment’” for articles assessing surgical techniques of adult thalamic glioma resection. Our systematic review was reported in accordance with the PRISMA guidelines. 793 full-text studies were assessed for eligibility. Ultimately, 14 studies were included. RESULTS The mean age was of 33.57 years (18-83). In 479/507 cases the surgical strategy used was described. The transcortical approach was the most utilized (37.8% of cases). The remaining cases employed transventricular (23.8%), transcallosal (22.8%), and trans-sylvian transinsular (2.92%) approaches, among others. Gross total resection (GTR), subtotal resection (STR), and partial resection were achieved in 36.7%, 47.4%, and 15.9%, respectively. New temporary postoperative deficits were observed in 57/507 patients and new permanent deficits in 56/507 patients. There were 18 total perioperative deaths reported. The degree of morbidity across approaches was recorded in just one study, where no significant difference was found. The mean overall survival of adult patients after surgery ranged from 11.5 to 27.39 months across studies. CONCLUSION There is a lack of statistically strong data that addresses which surgical approach causes less morbidity and allows a better surgical resection for thalamic gliomas. Ultimately, surgical resection of adult thalamic gliomas can increase overall survival but at the risk of operative morbidity. Transcortical approaches appear to carry a greater overall survival

NIMG-41. NON-INVASIVE TRACKING OF T-CELL RECRUITMENT TO THE TUMOR MICROENVIRONMENT IN A MURINE GLIOMA MODEL BY HIGH FIELD CELLULAR MRI

Abstract Gliomas are characterized by increased T cell exhaustion and poor T cell infiltration into the tumor as well as an overall highly immunosuppressive tumor microenvironment (TME). Response rates in preclinical glioma models and patients to promising new therapeutic approaches in the field of immunotherapies - such as checkpoint blockade, vaccines and adoptive therapy with chimeric antigen receptor (CAR) or T cell receptor (TCR)-transgenic T cells - remain heterogeneous. This demonstrates the need for non-invasive tracking of T cell recruitment to the TME in order to monitor T cell activating immunotherapies, adapt therapeutic strategies and predict treatment outcome. Iron oxide nanoparticles (NP) can be visualized non-invasively by magnetic resonance imaging (MRI) and dedicated MRI sequences such as T2* mapping. Using isolated murine T cells cultures we show that labeling of T cells with iron oxide NP as contrast agent is feasible and does not impact T cell viability and functionality as assessed by cytokine secretion and antigen-specific killing activity in vitro. We demonstrate that adoptively transferred T cells can be visualized intratumorally in a murine glioma model by high field MRI at 9.4 Tesla with high sensitivity and that T cells can be tracked non-invasively in a time course of over one week. Ongoing work assesses preclinical efficacy of adoptive T cell therapy targeting well characterized model antigens expressed in experimental gliomas using longitudinal MRI to visualize spatial and temporal T-cell dynamics in the TME. Correlative methods include immunohistochemistry, flow cytometry, tissue clearing and ultramicroscopy. We hypothesize that T cell distribution and numbers may predict therapeutic efficacy and correlate with treatment outcome in experimental gliomas.

EXTH-62. EXAMINATION OF THE TUMOR MICROENVIRONMENT OF GLIOMAS TREATED WITH VIROIMMUNOTHERAPY REVEALS THE PRODUCTION OF ONCOMETABOLITES LEADING TO IMPROVED THERAPEUTIC STRATEGIES

Abstract Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials in a small fraction of patients. To improve the response rate, it is necessary to reshape the tumor microenvironment that shields the tumor from the immune system of the patient. We engineered Delta-24-RGDOX (DNX-2440), an oncolytic adenovirus to express the T-cell activator OX40L, which triggered, in murine glioblastoma models, a dramatic reshaping of the tumor microenvironment dominated by changes in immune processes in an RNA-seq analysis of ingenuity pathways. Paradoxically, network analyses also revealed that Delta-24-RGDOX induced robust activation of the cytokine-driven immunosuppressive IDO-Kynurenine-AhR circuitry, indicating a potential mechanism of resistance of gliomas to oncolytic virotherapy. To reverse this immunosuppression, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors to treat glioma-bearing mice. The combined therapy decreased the activation of the IDO network without affecting viral activity. Flow cytometry assays revealed a decrease in the presence of the immunosuppressive cell populations, MDSCs and Tregs, which presence was higher in Delta-24-RGDOX-treated tumors. These data were further confirmed in gene set enrichment analyses. Functional co-culture studies showed that the combined therapy activated splenocytes against tumor antigens and that this activation was reversed by Kynurenine. Importantly, the combination treatment eradicated the tumors in a CD4-dependent manner and significantly prolonged the survival of glioma-bearing mice. Altogether, these studies indicate that the combination treatment promotes an adaptive immune response while decreasing the immunosuppression caused by the virus-induced IDO activation. Furthermore, our data identified the striking role of immunosuppressive pathways in the resistance of gliomas to oncolytic virotherapy. Specifically, the activity of the tumor microenvironment IDO circuitry was responsible, at least partially, for the remodeling of local immunosuppression after tumor infection. Combining molecular and immune-related therapies may improve outcomes in human gliomas treated with virotherapy.

Survival Prediction of Glioma Patients from Integrated Radiology and Pathology Images Using Machine Learning Ensemble Regression Methods

Gliomas are tumors of the central nervous system, which usually start within the glial cells of the brain or the spinal cord. These are extremely migratory and diffusive tumors, which quickly expand to the surrounding regions in the brain. There are different grades of gliomas, hinting about their growth patterns and aggressiveness and potential response to the treatment. As part of routine clinical procedure for gliomas, both radiology images (rad), such as multiparametric MR images, and digital pathology images (path) from tissue samples are acquired. Each of these data streams are used separately for prediction of the survival outcome of gliomas, however, these images provide complimentary information, which can be used in an integrated way for better prediction. There is a need to develop an image-based method that can utilise the information extracted from these imaging sequences in a synergistic way to predict patients’ outcome and to potentially assist in building comprehensive and patient-centric treatment plans. The objective of this study is to improve survival prediction outcomes of gliomas by integrating radiology and pathology imaging. Multiparametric magnetic resonance imaging (MRI), rad images, and path images of glioma patients were acquired from The Cancer Imaging Archive. Quantitative imaging features were extracted from tumor regions in rad and path images. The features were given as input to an ensemble regression machine learning pipeline, including support vector regression, AdaBoost, gradient boost, and random forest. The performance of the model was evaluated in several configurations, including leave-one-out, five-fold cross-validation, and split-train-test. Moreover, the quantitative performance evaluations were conducted separately in the complete cohort (n = 171), high-grade gliomas (HGGs), n = 75, and low-grade gliomas (LGGs), n = 96. The combined rad and path features outperformed individual feature types in all the configurations and datasets. In leave-one-out configuration, the model comprising both rad and path features was successfully validated on the complete dataset comprising HGFs and LGGs (R=0.84 p=2.2×10−16). The Kaplan–Meier curves generated on the predictions of the proposed model yielded a hazard ratio of 3.314 [95%CI:1.718−6.394], log−rank(P)=2×10−4 on combined rad and path features. Conclusion: The proposed approach emphasizes radiology experts and pathology experts’ clinical workflows by creating prognosticators upon ‘rad’ radiology images and digital pathology ‘path’ images independently, as well as combining the power of both, also through delivering integrated analysis, that can contribute to a collaborative attempt between different departments for administration of patients with gliomas.

A Head-to-Head Comparison of 18F-Fluorocholine PET/CT and Conventional MRI as Predictors of Outcome in IDH Wild-Type High-Grade Gliomas.

(1) Aim: To study the associations between imaging parameters derived from contrast-enhanced MRI (CE-MRI) and 18F-fluorocholine PET/CT and their performance as prognostic predictors in isocitrate dehydrogenase wild-type (IDH-wt) high-grade gliomas. (2) Methods: A prospective, multicenter study (FuMeGA: Functional and Metabolic Glioma Analysis) including patients with baseline CE-MRI and 18F-fluorocholine PET/CT and IDH wild-type high-grade gliomas. Clinical variables such as performance status, extent of surgery and adjuvant treatments (Stupp protocol vs others) were obtained and used to discriminate overall survival (OS) and progression-free survival (PFS) as end points. Multilesionality was assessed on the visual analysis of PET/CT and CE-MRI images. After tumor segmentation, standardized uptake value (SUV)-based variables for PET/CT and volume-based and geometrical variables for PET/CT and CE-MRI were calculated. The relationships among imaging techniques variables and their association with prognosis were evaluated using Pearson’s chi-square test and the t-test. Receiver operator characteristic, Kaplan–Meier and Cox regression were used for the survival analysis. (3) Results: 54 patients were assessed. The median PFS and OS were 5 and 11 months, respectively. Significant strong relationships between volume-dependent variables obtained from PET/CT and CE-MRI were found (r > 0.750, p < 0.05). For OS, significant associations were found with SUVmax, SUVpeak, SUVmean and sphericity (HR: 1.17, p = 0.035; HR: 1.24, p = 0.042; HR: 1.62, p = 0.040 and HR: 0.8, p = 0.022, respectively). Among clinical variables, only Stupp protocol and age showed significant associations with OS and PFS. No CE-MRI derived variables showed significant association with prognosis. In multivariate analysis, age (HR: 1.04, p = 0.002), Stupp protocol (HR: 2.81, p = 0.001), multilesionality (HR: 2.20, p = 0.013) and sphericity (HR: 0.79, p = 0.027) derived from PET/CT showed independent associations with OS. For PFS, only age (HR: 1.03, p = 0.021) and treatment protocol (HR: 2.20, p = 0.008) were significant predictors. (4) Conclusions: 18F-fluorocholine PET/CT metabolic and radiomic variables were robust prognostic predictors in patients with IDH-wt high-grade gliomas, outperforming CE-MRI derived variables.

Health-Related Quality of Life in Patients With High-Grade Glioma: A Systematic Review

Abstract AIMS Several studies have evaluated health-related quality of life (HRQoL) through patient-reported outcomes (PROs) in high-grade glioma (HGG) patients. No systematic review has summarised this increasingly important research area. METHOD Seven electronic databases were systematically searched. Primary research articles evaluating HRQoL in HGG patients through PRO assessment were included. Global, physical, mental, and social health were summarised descriptively. Risk of bias (RoB) of included studies was assessed using The Joanna Briggs Institute Critical Appraisal tool or Newcastle Ottawa Scale. Quality of study reporting was assessed using a modified ISOQOL checklist. RESULTS Twenty-six studies were included (4,451 patients): cross-sectional (n=14), longitudinal (n=12). RoB and quality of reporting were satisfactory. Ten PRO measurement instruments were identified, of which EORTC-QLQ-C30 (n=15) was utilised most frequently. Fatigue significantly impacted both physical and global health. HRQoL improved after surgery but recurrence, fatigue, and difficulties with activities of daily living were associated with worsening HRQoL. HGG patients had higher anxiety and depression scores than the general population, negatively impacting overall HRQoL. Social health was superior for patients with good supportive networks, but a majority do not return to full-time employment post-diagnosis. Long-term survivors reported improvements in their physical, social and emotional functioning over time. CONCLUSION With HGG life expectancy less than 12 months post-diagnosis, HRQoL is of paramount importance to patients. PRO assessment of HRQoL can be used to evaluate self-reported functioning and well-being in both routine practice and clinical trial settings and provide opportunities for timely intervention.