Prognostic relevance and validation of ARPC1A in the progression of low-grade glioma.

Low-grade glioma (LGG) is a grade II-III glioma accompanied by distinct clinical and molecular characteristics and the studies related to its prognosis are still unclear. The objective of this study is to explore the involvement of mitochondrial-related genes SLBP, COMMD7, LSM4, TOMM34, RPP40, FKBP1A, ARPC1A, and TBCA for the prognosis of LGG. We detected differences in the expression of some of the genes by analyzing the bioinformatics dataset and combining it with RT-PCR experiments. Subsequently, a nomogram was constructed and validated for the clinical relevance of risk factors such as age, WHO grade, IDH mutation status, Ch.1p19q co-deletion status, and high and low expression of ARPC1A to predict the 1-, 3-, 5-year overall survival and prognostic relevance of ARPC1A. Gene set enrichment analysis was performed for the relevant datasets pertinent to the expression of ARPC1A to elucidate the cancer-promoting pathways involved in the LGG through KEGG and GO analysis. Transfection assays, CCK-8 assays, and flow cytometry were used to determine the proliferation rate, and apoptosis rate of the HS683 and SW1783 cell lines respectively. Western blotting was used to examine the involvement of the cancer-promoting activity of ARPC1A through MAPK signaling. In this study, the prognostic value of ARPC1A in LGG was found by bioinformatics analysis combined with experimental approach analysis and may be a significant independent risk factor. ARPC1A fosters a higher LGG proliferation rate that may control the MAP kinase signaling and could be a prominent biomarker for LGG. Future studies are warranted to explore its clinical implications.

Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas: accumulated experience from 4 centers.

PURPOSE: Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children and achieving complete resection (CR) in pLGG is the most important prognostic factor. There are multiple intraoperative tools to optimize the extent of resection (EOR). This article investigates and discusses the role of intraoperative ultrasound (iUS) and intraoperative magnetic resonance imaging (iMRI) in the surgical treatment of pLGG. METHODS: The tumor registries at Tuebingen, Rome and Pretoria were searched for pLGG with the use of iUS and data on EOR. The tumor registries at Liverpool and Tuebingen were searched for pLGG with the use of iMRI where preoperative CR was the surgical intent. Different iUS and iMRI machines were used in the 4 centers. RESULTS: We included 111 operations which used iUS and 182 operations using iMRI. Both modalities facilitated intended CR in hemispheric supra- and infratentorial location in almost all cases. In more deep-seated tumor location like supratentorial midline tumors, iMRI has advantages over iUS to visualize residual tumor. Functional limitations limiting CR arising from eloquent involved or neighboring brain tissue apply to both modalities in the same way. In the long-term follow-up, both iUS and iMRI show that achieving a complete resection on intraoperative imaging significantly lowers recurrence of disease (chi-square test, p < 0.01). CONCLUSION: iUS and iMRI have specific pros and cons, but both have been proven to improve achieving CR in pLGG. Due to advances in image quality, cost- and time-efficiency, and efforts to improve the user interface, iUS has emerged as the most accessible surgical adjunct to date to aid and guide tumor resection. Since the EOR has the most important effect on long-term outcome and disease control of pLGG in most locations, we strongly recommend taking all possible efforts to use iUS in any surgery, independent of intended resection extent and iMRI if locally available.

Longitudinal assessment of quality of life, neurocognition, and psychopathology in patients with low-grade glioma on first-line temozolomide: A feasibility study.

Background: The treatment timing and choice after neurosurgical resection in patients with newly diagnosed diffuse low-grade glioma (DLGG) remain controversial. Indeed, the effect of such treatments must be balanced with the possible side effects. This study evaluated the feasibility of longitudinal exhaustive quality of life (QoL) and neuropsychological assessments in patients with DLGG receiving first-line temozolomide. Methods: QoL, neurocognition, and psychological disorders were assessed prospectively until disease progression, using testing, clinician-reported, and self-reported questionnaires. The primary endpoint was the participation and adherence to this complete assessment at Baseline (before temozolomide initiation), months 6 and 12 of treatment, and month 6 post-treatment. The QoL and neuropsychological changes over time also were described. Results: Twenty-six of the twenty-nine eligible patients were enrolled (participation rate: 89.7%, 95% CI: 72.6-97.8). The adherence rate was 95.7% (95% CI: 78.1-99.9; n = 23 because 3 patients progressed in the first 12 months of treatment). Up to month 6 post-treatment, QoL and fatigue remained stable (EORTC QLQC30 and BN20, MFI-20); some specific symptoms were transitory. Both subjective (FACT-Cog) and objective (Z-scores of neurocognitive tests) neurocognitive outcomes remained stable or tended to improve. The percentage of patients with severe depression (BDI-II), anxiety (STAI-Y), or anger (STAXI-II) was stable over time. Conclusions: This prospective study demonstrated the feasibility of an exhaustive and longitudinal evaluation of QoL, neurocognition, and psychological disorders, with high acceptability by patients with DLGG undergoing chemotherapy. First-line temozolomide seems to have limited short-term effects on QoL and neurocognition. These findings must be confirmed in the long term and in a larger cohort.

Identification of TNFAIP6 as a reliable prognostic indicator of low-grade glioma.

Glioma is the most common primary malignant tumor in the brain, characterizing by high disability rate and high recurrence rate. Although low-grade glioma (LGG) has a relative benign biological behavior, the prognosis of LGG patients still varies greatly. Glioma stem cells (GSCs) are considered as the chief offenders of glioma cell proliferation, invasion and resistance to therapies. Our study screened a series of glioma stem cell-related genes (GSCRG) based on mDNAsi and WCGNA, and finally established a reliable single-gene prognostic model through 101 combinations of 10 machine learning methods. Our result suggested that the expression level of TNFAIP6 is negatively correlated with the prognosis of LGG patients, which may be the result of pro-cancer signaling pathways activation and immunosuppression. In general, this study revealed that TNFAIP6 is a robust and valuable prognostic factor in LGG, and may be a new target for LGG treatment.

Translation and validation of the Neurological Assessment in Neuro-Oncology scale to Brazilian Portuguese.

Introduction: The Neurological Assessment for Neuro-Oncology (NANO) scale was elaborated to assess neurologic function in integration with radiological criteria to evaluate neuro-oncological patients in clinical setting and enable the standardization of neurological assessment in clinical trials. The objective of this study is the translation to Brazilian Portuguese and transcultural adaptation of NANO scale in patients with the diagnosis of glioblastoma, brain metastasis and low-grade glioma. Methods: Patients with diagnosis of glioblastoma, brain metastasis, and low-grade glioma were prospectively evaluated between July 2019 and July 2021. The process of translating and cross-culturally adapting the NANO scale included: translation from English to Portuguese, synthesis and initial revision by an expert committee, back-translation from Portuguese to English, a second revision by the expert committee, and the application of the NANO scale. Regarding the reliability of the NANO scale, Cronbach's alpha was employed to measure the internal consistency of all scale items and assess the impact of item deletion. Additionally, Spearman's correlation test was used to evaluate the convergent validity between the NANO scale and Karnofsky Performance Scale (KPS). Results: One hundred and seventy-four patients were evaluated. A statistically significant inverse relation (p < 0.001) between KPS and NANO scale was founded. The Cronbach's alpha values founded for NANO scale were 0.803 for glioblastoma, 0.643 for brain metastasis, and 0.482 for low grade glioma. Discussion: The NANO scale Brazilian Portuguese version proves to be reproducible and valid to evaluate neuro-oncological patients with glioblastoma and brain metastasis, presenting a strong correlation with KPS scale. Further studies are warranted to assess the validity and reliability of the scale in patients diagnosed with low-grade glioma.

Second-look surgery in postoperative pediatric low-grade glioma.

OBJECTIVE: To review the literature on second-look surgery in pediatric low-grade gliomas (LGG) with a view to presenting both sides of the picture of re-exploration. METHODS: Collection of material from recent literature on pediatric LGG. This was a retrospective review of these publications. RESULTS: There are a number of publications recommending second-look surgery in selected cases, provided morbidity of the second surgery is minimum, and indeed some in which there is improvement in the neurodeficit after the second resection. CONCLUSION: There seems a fair balance of articles recommending and dissuading the practice of second-look surgery, but in our limited experience we have found it useful in selected patients.

Dissecting the Natural Patterns of Progression and Senescence in Pediatric Low-Grade Glioma: From Cellular Mechanisms to Clinical Implications.

Pediatric low-grade gliomas (PLGGs) comprise a heterogeneous set of low-grade glial and glioneuronal tumors, collectively representing the most frequent CNS tumors of childhood and adolescence. Despite excellent overall survival rates, the chronic nature of the disease bears a high risk of long-term disease- and therapy-related morbidity in affected patients. Recent in-depth molecular profiling and studies of the genetic landscape of PLGGs led to the discovery of the paramount role of frequent upregulation of RAS/MAPK and mTOR signaling in tumorigenesis and progression of these tumors. Beyond, the subsequent unveiling of RAS/MAPK-driven oncogene-induced senescence in these tumors may shape the understanding of the molecular mechanisms determining the versatile progression patterns of PLGGs, potentially providing a promising target for novel therapies. Recent in vitro and in vivo studies moreover indicate a strong dependence of PLGG formation and growth on the tumor microenvironment. In this work, we provide an overview of the current understanding of the multilayered cellular mechanisms and clinical factors determining the natural progression patterns and the characteristic biological behavior of these tumors, aiming to provide a foundation for advanced stratification for the management of these tumors within a multimodal treatment approach.

Deconstructing Intratumoral Heterogeneity through Multiomic and Multiscale Analysis of Serial Sections.

Tumors may contain billions of cells, including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that are consistently expressed by astrocytoma truncal clones, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors.

Analysis of glutathione Stransferase mu class 5 gene methylation as a prognostic indicator in low-grade gliomas.

BACKGROUND: Low-grade gliomas (LGG) are a variety of brain tumors that show different clinical outcomes. The methylation of the GSTM5 gene has been noted in the development of LGG, however, its prognostic importance remains uncertain. OBJECTIVE: The objective of this study was to examine the correlation between GSTM5 DNA methylation and clinical outcomes in individuals diagnosed with LGG. METHODS: Analysis of GSTM5 methylation levels in LGG samples was conducted using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. The overall survival based on GSTM5 methylation status was evaluated using Kaplan-Meier curves. The DNA methylation heatmap for particular CpG sites in the GSTM5 gene was visualized using the "pheatmap" R package. RESULTS: The study analyzed that LGG tumors had higher levels of GSTM5 methylation than normal tissues. There was an inverse relationship discovered between GSTM5 expression and methylation. LGG patients with hypermethylation of GSTM5 promoter experienced a positive outcome. Age, grade, and GSTM5 methylation were determined as independent prognostic factors in LGG through both univariate and multivariate Cox regression analyses. CONCLUSION: Methylation of GSTM5 DNA, specifically at certain CpG sites, is linked to a positive outlook in patients with LGG. Utilizing the "pheatmap" R package to visualize GSTM5 methylation patterns offers important information for identifying prognostic markers and therapeutic targets in low-grade gliomas.

A systematic review and meta-analysis informing the role of adjuvant radiotherapy (RT) in Grade 2 and 3 oligodendroglioma.

BACKGROUND AND PURPOSE: Evidence and clinical guidelines support the use of adjuvant RT in high-risk low-grade gliomas. However, patients with oligodendroglioma have a more indolent disease course and delaying or avoiding RT is often considered to reduce treatment-related toxicities. As the optimal adjuvant management for oligodendroglioma is unclear, we aimed to assess the effect of adjuvant RT on overall survival (OS) and progression-free survival (PFS). METHODS: MEDLINE, EMBASE, CENTRAL and CINAHL were searched from January 1990 to February 2023 for studies comparing adjuvant RT versus no adjuvant RT for patients with oligodendroglioma. RESULTS: This review found 17 eligible studies including 14 comparative retrospective studies and 3 randomized controlled trials. Using random-effects model, the results suggested that adjuvant RT improved OS by 28 % (HR 0.72, 95 % CI (0.56-0.93), I2 = 86 %), and PFS by 48 % (HR 0.52, (95 % CI 0.40-0.66), I2 = 48 %) compared to patients without adjuvant RT. Subgroup analysis showed that upfront adjuvant RT improved OS and PFS compared to salvage RT. There were no significant differences in OS and PFS between adjuvant RT versus adjuvant chemotherapy. There was improvement in PFS but not OS for adjuvant chemoradiotherapy versus adjuvant chemotherapy alone. Adjuvant RT improved OS in WHO Grade 3 but not WHO Grade 2 oligodendroglioma. CONCLUSION: Overall, adjuvant RT improved OS and PFS in patients with oligodendroglioma. In patients with low-risk features (e.g. Grade 2, gross total resection), alternative approaches and individualization of management such as adjuvant chemotherapy alone may be reasonable considering the lack of survival benefit. Future efforts should prospectively investigate these treatment regimens on molecularly-classified oligodendroglioma patients (defined by presence of IDH mutation and 1p/19q co-deletion), balancing between maximizing survival outcomes and reducing RT-related toxicities.

Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era.

While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.

Diffuse low-grade glioma: What is the optimal linear measure to assess tumor growth?

Background: Radiological follow-up of diffuse low-grade gliomas (LGGs) growth is challenging. Approximative visual assessment still predominates over objective quantification due to the complexity of the pathology. The infiltrating character, diffuse borders and presence of surgical cavities demand LGG-based linear measurement rules to efficiently and precisely assess LGG evolution over time. Methods: We compared optimized 1D, 2D, and 3D linear measurements with manual volume segmentation as a reference to assess LGG tumor growth in 36 patients with LGG (340 magnetic resonance imaging scans), using the clinically important mean tumor diameter (MTD) and the velocity diameter expansion (VDE). LGG-specific progression thresholds were established using the high-grade gliomas-based RECIST, Macdonald, and RANO criteria, comparing the sensitivity to identify progression/non-progression for each linear method compared to the ground truth established by the manual segmentation. Results: 3D linear volume approximation correlated strongly with manually segmented volume. It also showed the highest sensitivity for progression detection. The MTD showed a comparable result, whereas the VDE highlighted that caution is warranted in the case of small tumors with multiple residues. Novel LGG-specific progression thresholds, or the critical change in estimated tumor volume, were increased for the 3D (from 40% to 52%) and 2D methods (from 25% to 33%) and decreased for the 1D method (from 20% to 16%). Using the 3D method allowed a ~5-minute time gain. Conclusions: While manual volumetric assessment remains the gold standard for calculating growth rate, the 3D linear method is the best time-efficient standardized alternative for radiological evaluation of LGGs in routine use.

Canadian Consensus for Treatment of BRAF V600E Mutated Pediatric and AYA Gliomas.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Applications of machine learning to MR imaging of pediatric low-grade gliomas.

INTRODUCTION: Machine learning (ML) shows promise for the automation of routine tasks related to the treatment of pediatric low-grade gliomas (pLGG) such as tumor grading, typing, and segmentation. Moreover, it has been shown that ML can identify crucial information from medical images that is otherwise currently unattainable. For example, ML appears to be capable of preoperatively identifying the underlying genetic status of pLGG. METHODS: In this chapter, we reviewed, to the best of our knowledge, all published works that have used ML techniques for the imaging-based evaluation of pLGGs. Additionally, we aimed to provide some context on what it will take to go from the exploratory studies we reviewed to clinically deployed models. RESULTS: Multiple studies have demonstrated that ML can accurately grade, type, and segment and detect the genetic status of pLGGs. We compared the approaches used between the different studies and observed a high degree of variability throughout the methodologies. Standardization and cooperation between the numerous groups working on these approaches will be key to accelerating the clinical deployment of these models. CONCLUSION: The studies reviewed in this chapter detail the potential for ML techniques to transform the treatment of pLGG. However, there are still challenges that need to be overcome prior to clinical deployment.

Transcallosal Retroforniceal Transchoroidal Approach: To the Posterior Third Ventricle and Beyond.

BACKGROUND: The transcallosal retroforniceal transchoroidal approach represents an advanced neurosurgical technique that allows access to lesions located within the posterior third ventricle and mesencephalon. It relies on a comprehensive understanding of microsurgical anatomy and embryology, integrating modern neurosurgical operative techniques to minimize retraction and injury to the normal neuronal structures. METHODS: We report the cases of two patients undergoing treatment via this approach, one presenting with a thalamic cavernoma and the other with cystic low-grade glioma of the midbrain. RESULTS: In these 2 cases, the decision to use the transcallosal approach was mainly due to improved trajectory, gravitational retraction of the hemisphere, and improved delivery of the lesion into the operative field by gravity alone. CONCLUSION: Through a detailed description of the surgical approach and anatomy, we illustrate the feasibility of the transcallosal retroforniceal transchoroidal approach for accessing lesions located deeply in the brain.

Intramedullary pediatric low-grade glioma of the spine.

PURPOSE: Pediatric intramedullary spinal cord low-grade gliomas (pLGGs) are rare diagnoses among central nervous system (CNS) tumors in the pediatric population. The classic presentation of the patients includes some degree of neurologic deficit, although many times the symptoms are vague which leads to delayed diagnosis. MATERIAL AND METHODS: The first step in the diagnosis includes special parameters in spinal imaging, particularly magnetic resonance imaging (MRI), and surgical resection remains the cornerstone for both diagnosis and treatment. Yet, recent years advancement in molecular and genetic understanding of CNS tumors allows for better adjustment of the treatment and follow-up regimens. Based on postoperative status, adjuvant therapy may provide additional therapeutic advantage for some types of tumors. CONCLUSION: Ultimately, patients have a very promising prognosis when treated appropriately in most of the cases of pediatric spinal cord LGG with continued advances arising. This manuscript summarizes the most contemporary evidence regarding clinical and treatment features of intramedullary pLGGs.

Adaption of neurosurgical resection patterns for pediatric low-grade glioma spanning two decades-Report from the German LGG-studies 1996-2018.

INTRODUCTION: Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. PATIENTS AND METHODS: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age. RESULTS: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. CONCLUSIONS: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.

Pediatric-type diffuse low-grade gliomas.

The World Health Organization's 5th edition classification of Central Nervous System (CNS) tumors differentiates diffuse gliomas into adult and pediatric variants. Pediatric-type diffuse low-grade gliomas (pDLGGs) are distinct from adult gliomas in their molecular characteristics, biological behavior, clinical progression, and prognosis. Various molecular alterations identified in pDLGGs are crucial for treatment. There are four distinct entities of pDLGGs. All four of these tumor subtypes exhibit diffuse growth and share overlapping histopathological and imaging characteristics. Molecular analysis is essential for differentiating these lesions.

Immunotherapy for pediatric low-grade gliomas.

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor types affecting children. Although gross-total resection remains the treatment of choice, many tumors are not amenable to complete removal, because they either involve midline structures, such as the optic chiasm or hypothalamus, and are not conducive to aggressive resection, or have diffuse biological features and blend with the surrounding brain. Historically, radiation therapy was used as the second-line option for disease control, but with the recognition that this often led to adverse long-term sequelae, particularly in young children, conventional chemotherapy assumed a greater role in initial therapy for unresectable tumors. A variety of agents demonstrated activity, but long-term disease control was suboptimal, with more than 50% of tumors exhibiting disease progression within 5 years. More recently, it has been recognized that a high percentage of these tumors in children exhibit constitutive activation of the mitogen-activated protein kinase (MAPK) pathway because of BRAF translocations or mutations, NFI mutations, or a host of other anomalies that converged on MAPK. This led to phase 1, 2, and 3 trials that explored the activity of blocking this signaling pathway, and the efficacy of this approach compared to conventional chemotherapy. Despite initial promise of these strategies, not all children tolerate this therapy, and many tumors resume growth once MAPK inhibition is stopped, raising concern that long-term and potentially life-long treatment will be required to maintain tumor control, even among responders. This observation has led to interest in other treatments, such as immunotherapy, that may delay or avoid the need for additional treatments. This chapter will summarize the place of immunotherapy in the current armamentarium for these tumors and discuss prior results and future options to improve disease control, with a focus on our prior efforts and experience in this field.

Higher YAP1 Levels Are Associated With Shorter Survival of Patients With Low Grade Astrocytoma.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is one of the most lethal types of brain cancer with a median survival of only 12 months due to its aggressiveness and lack of effective treatment options. Astrocytomas and oligodendrogliomas are classified as low-grade gliomas (LGG) and have the potential to progress into secondary GBM. YAP1 and TAZ are transcriptional co-activators of the hippo pathway and play an important role in tumorigenesis by controlling cell proliferation and differentiation. The aim of this study was to analyze whether YAP1 and TAZ influence the survival in patients with astrocytoma and oligodendroglioma. PATIENTS AND METHODS: A total of 22 patient samples of astrocytoma and 11 samples of oligodendroglioma were analyzed using real-time PCR. We utilized open-access data from The Cancer Genome Atlas (TCGA) focusing on "brain lower grade glioma". mRNA expression rates were used to validate our findings on survival analysis. RESULTS: Expression of YAP1 was twice as high in astrocytoma than in oligodendroglioma, whereas there was no difference in TAZ. In oligodendrogliomas, the expression of TAZ was higher in relapsed than in primary tumors. Patients with astrocytoma having a high YAP1 expression had a significantly shorter overall survival than patients with lower expression (median survival 161 vs. 86 months, p=0.0248). These findings were validated with survival analysis of TCGA data. CONCLUSION: High YAP1 expression shows a high correlation with poorer overall survival in LGG. YAP1 has higher levels of expression in astrocytomas than in oligodendrogliomas.