Childhood Brain Tumors Research Articles

Spatial transcriptomic analysis delineates epithelial and mesenchymal subpopulations and transition stages in childhood ependymoma.

The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant. Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data. PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA. These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression.

Childhood brain tumors: It is the child's brain that really matters.

Childhood brain tumors: It is the child's brain that really matters.

STEM CELL TRANSPLANTATION IN BRAIN TUMORS

Central nervous system (CNS) tumors are the second most common pediatric malignancies after acute leukemias and are the most common pediatric solid tumors. Although cure rates have improved with numerous technical advances in multimodal therapy, the prognosis remains poor for some high-risk histological type and for patients with residual, recurrent or disseminated disease. Radiotherapy (RT) remains an integral part of treatment for childhood brain tumors; however, the profound and irreversible sequelae of brain irradiation in the younger children are now well documented. In an effort to decrease irradiation toxicity while improving survival and quality of life in these patients, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HD-CT&autoHSCT) has been incorporated in both up-front as well as recurrent therapies. In up-front treatment, it is used in patients under the age of 3 years to delay RT or not to use RT at all. It can be used tandem non-myeloablatively in patients older than 3 years of age, after dose-intensive chemotherapy, both to shorten the neutropenic period and to give more intense chemotherapy in a shorter time when compared to conventional chemotherapy treatment approaches. AutoHSCT may also be considered after a myeloablative conditioning regimen for relapsed embryonal brain tumors, as either once or tandem, in cases with good response to salvage therapy as consolidation. In this talk, the role of autoHSCT in childhood brain tumors will be discussed by giving the results from international studies.

A Comparative Proteomic Analysis of the Cell Membrane of Histone 3 Mutated Paediatric High-Grade Gliomas in order to Identify Potential Immunotherapeutic Targets

Abstract AIMS Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome or cell surface proteins. We analysed the cell surface proteomics of H3.3 G34V and G34R mutated high-grade glioma in comparison to the H3 wild-type Glioma, to explore whether these proteins have the potential to be used as immunotherapeutic targets. METHOD We have at first isolated the cell membrane fractions from a range of patient cells carrying histone 3 mutations (G34R, G34V) relative to wild type histone 3. A comparative quantitative liquid chromatographic mass- spectrometry analyses of these cell surface membrane fractions were performed to identify specific targetable factors. RESULTS The results of these were analysed with the focus in identifying proteins that can be targeted for tumour specific immune modulation or immunotherapeutic intervention. CONCLUSION Results of these analyses will be presented.

CLIC1 and CLIC4 Ion Channel Deficiency Confers Increased Sensitivity to Tumour Treating Fields and Improved Survival in Paediatric Glioblastoma

Abstract AIMS (1) To determine if specific and unique chloride intracellular channel (CLIC) expression patterns exist in paediatric glioblastoma. (2) To assess if these expression patterns can be exploited as a treatment strategy. (3) To assess the combination of ion channel manipulation with Tumour Treating Fields (TTFields). METHOD CLIC channel expression patterns were identified via multivariate analysis of in-house and publicly available data sets and RNA sequencing of in-house patient tumour samples. siRNA depletion or inhibition via IAA94 of CLIC1 and CLIC4 was assessed using cell cycle, clonogenic, migration and proliferation assays, alone and in combination with TTFields. Whole transcriptome gene expression analysis (Human Clairom™ Array) of pGBM cells treated with TTFields was carried out. RESULTS Clinical correlation determined that CLIC4 and CLIC1 deficiency was associated with increased overall survival, with siRNA depletion propagating a reduction in the proliferation, migration and invasion of pHGG cell lines associated with cell cycle arrest. Furthermore, CLIC1 and CLIC4 deficiency exacerbated the killing capacity of TTFields, reducing clonogenic and proliferative capabilities. Whole transcriptome gene expression analysis of paediatric GBM cell lines treated with TTFields and found that cells treated with TTfields exhibited a down-regulation in CLIC1 and CLIC4 compared to untreated cells. CONCLUSION These data provide rationale that genetic, electrical, and pharmacological manipulation of ion channels can reduce the capacity of childhood brain tumours to proliferate and invade. CLIC channels may be a suitable target for combination therapy to enhance the treatment efficacy of TTfields and help bring this non-invasive therapy to paediatric patients.

Neurosurgically-Applied Chemotherapy for Childhood Brain Tumours Arising in the Posterior Fossa Using a Biodegradable Paste

Abstract AIMS This project aims to develop a local drug delivery system for treatment of childhood medulloblastoma (MB) and atypical teratoid/rhabdoid tumours (AT/RT), malignant brain neoplasms occurring in the posterior fossa for which prognoses remains poor. Our goal is to repurpose drug compounds reported as effective against MB and AT/RT, but which either cannot cross the blood-brain-barrier (BBB) or have not been assessed for localised delivery. We have developed a novel intra-cavity drug delivery system, consisting of polymer microparticles made from poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) which will be employed to release drugs over several weeks. METHOD Cell toxicity assays were undertaken using drugs of interest against an in vitro panel of relevant MB and AT/RT cell lines. PLGA/PEG paste incorporating the drugs were prepared and release kinetics assessed. RESULTS IC50 values of the drugs were assessed across all cell lines and a range of potencies were observed, with optimum conditions identified as dual treatments of PG545 (heparanse inhibitor) with CHIR99021 (glycogen synthase kinase-3 inhibitor) for MB and ribavirin (anti-viral) with CHIR99021 for AT/RT. Importantly, it was noted that the drugs retained their cytotoxicity following release from PLGA/PEG. Furthermore, release kinetics were finely tuned through careful control of the composition through addition of excipients and encapsulation of drugs in nanoparticles, and a library of formulations were prepared. CONCLUSION A local drug delivery system for MB and AT/RT has been developed and an optimum formulation, based upon in vitro cell assays and release kinetics, has been identified for in vivo efficacy studies in orthotopic models.

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma.

Simple SummaryBrainstem gliomas are deadly childhood brain tumors and new treatments are needed. The treatment meeting the standard of care is radiation therapy, but the tumors inevitably progress at some point after this treatment. One treatment strategy under preclinical investigation for brainstem gliomas is to inhibit the function of ataxia–telangiectasia mutated kinase (ATM), a master regulator of the cellular response to radiation therapy. ATM inhibition makes some tumors more sensitive to radiation therapy, but this may depend on the genetic makeup of the tumor. An important subset of brainstem gliomas harbor mutations in the PTEN gene or related genes. Here, we develop a genetically engineered mouse model of Pten-mutated brainstem glioma. We use genetic tools to test if ATM inactivation can enhance the efficacy of radiation therapy in this Pten-mutated brainstem glioma model. We find that ATM inactivation does not enhance the efficacy of radiation therapy for this model of Pten-mutated brainstem glioma. These findings indicate that PTEN mutational status should be considered in the design of inclusion criteria and correlative studies for future clinical trials of ATM inhibitors in brainstem glioma patients.Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.

Ophthalmological Findings in Youths With a Newly Diagnosed Brain Tumor

Visual impairment is an irreversible adverse effect in individuals who experienced a childhood brain tumor. Ophthalmological evaluation at diagnosis enables early detection of vision loss, decision-making about treatment, and when applicable, the timely use of visual interventions. However, awareness of visual impairment in clinical practice is suboptimal, and adherence to ophthalmological evaluation needs to be improved. To assess the prevalence and types of abnormal ophthalmological findings in youths with a newly diagnosed brain tumor. In this nationwide, prospective cohort study, youths aged 0 to 18 years with a newly diagnosed brain tumor between May 15, 2019, and August 11, 2021, were consecutively enrolled in 4 hospitals in the Netherlands, including the dedicated tertiary referral center for pediatric oncology care. A standardized and comprehensive ophthalmological examination, including orthoptic evaluation, visual acuity testing, visual field examination, and ophthalmoscopy, was performed within 4 weeks from brain tumor diagnosis. The main outcomes were prevalence and types of visual symptoms and abnormal ophthalmological findings at brain tumor diagnosis. Of 170 youths included in the study (96 [56.5%] male; median age, 8.3 years [range, 0.2-17.8 years]), 82 (48.2%) had infratentorial tumors; 53 (31.2%), supratentorial midline tumors; and 35 (20.6%), cerebral hemisphere tumors. A total of 161 patients (94.7%) underwent orthoptic evaluation (67 [41.6%] preoperatively; 94 [58.4%] postoperatively); 152 (89.4%), visual acuity testing (63 [41.4%] preoperatively; 89 [58.6%] postoperatively); 121 (71.2%), visual field examination (49 [40.4%] preoperatively; 72 [59.6%] postoperatively); and 164 (96.5%), ophthalmoscopy (82 [50.0%] preoperatively; 82 [50.0%] postoperatively). Overall, 101 youths (59.4%) presented with visual symptoms at diagnosis. Abnormal findings were found in 134 patients (78.8%) during ophthalmological examination. The most common abnormal findings were papilledema in 86 of 164 patients (52.4%) who underwent ophthalmoscopy, gaze deficits in 54 of 161 (33.5%) who underwent orthoptic evaluation, visual field defects in 32 of 114 (28.1%) with reliable visual field examination, nystagmus in 40 (24.8%) and strabismus in 32 (19.9%) of 161 who underwent orthoptic evaluation, and decreased visual acuity in 13 of 152 (8.6%) with reliable visual acuity testing. Forty-five of 69 youths (65.2%) without visual symptoms at diagnosis had ophthalmological abnormalities on examination. The results of this study suggest that there is a high prevalence of abnormal ophthalmological findings in youths at brain tumor diagnosis regardless of the presence of visual symptoms. These findings support the need of standardized ophthalmological examination and the awareness of ophthalmologists and referring oncologists, neurologists, and neurosurgeons for ophthalmological abnormalities in this patient group.

CBTRUS Statistical Report: Pediatric Brain Tumor Foundation Childhood and Adolescent Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018.

The CBTRUS Statistical Report: Pediatric Brain Tumor Foundation Childhood and Adolescent Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and other CNS tumors in children and adolescents ages 0-19 years, collected and reported by central cancer registries covering approximately 100% of the United States population. Overall, brain and other CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in children and adolescents ages 0-19 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

Pre- and postdiagnosis growth failure, adult short stature, and untreated growth hormone deficiency in radiotherapy-treated long-term survivors of childhood brain tumor.

PurposeGrowth failure is common in radiotherapy-treated long-term survivors of pediatric brain tumors, but studies on longitudinal growth in this patient group are lacking. Here, the aim was to assess the changes in growth patterns before and after brain tumor diagnosis, the adult height, and the risk factors for compromised growth. The incidence and treatment practices of growth hormone deficiency were analyzed.MethodsA cohort of 73 survivors of childhood brain tumor (median age 27.2 years, range 16.2 to 43.8 years) was studied after a median follow-up period of 20.4 years from diagnosis (IQR 14.9 to 22.9 years). Patients were treated in five university hospitals in Finland between 1970 and 2008. Growth curves, final height, and patient- and disease-related risk factors for compromised growth during different growth periods were analyzed. Laboratory analyses for IGF-1 and IGFBP-3 were performed at the follow-up.ResultsGrowth failure was evident at diagnosis, with a mean height decline of -0.6 SDS (standard deviation score) from birth (95% CI -1.15 to -0.05). Mean height SDS decline after the diagnosis was -1.09 SDS (95%CI -1.51 to -0.66). At follow-up, 37% of the study subjects (27/73) had true short stature (height < -2 SDS). The mean height deficit corrected for target height was -1.9 SDS (95% CI -1.45 to -2.40). Growth failure was associated with the age at diagnosis, corticosteroid dose, radiotherapy modality and mean dose of irradiation in the thalamic area. Low IGF-1 level (below -2.0 SDS) was found in 32% (23/72), and untreated growth hormone deficiency in 40% (29/72) of the subjects.ConclusionLongitudinal growth impairment was common in radiotherapy-treated survivors of childhood brain tumor, resulting in compromised adult height. Loss of growth potential was evident already at diagnosis and further accelerated by the treatments. At young adulthood, unrecognized growth hormone deficiency was common.

Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling

A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade gliomas (LGGs) harboring the two most common pediatric pilocytic astrocytoma-associated molecular alterations, NF1 loss and KIAA1549:BRAF fusion. Herein, we identified that hiPSC-derived neuroglial progenitor populations (neural progenitors, glial restricted progenitors and oligodendrocyte progenitors), but not terminally differentiated astrocytes, give rise to tumors retaining LGG histologic features for at least 6 months in vivo. Additionally, we demonstrated that hiPSC-LGG xenograft formation requires the absence of CD4 T cell-mediated induction of astrocytic Cxcl10 expression. Genetic Cxcl10 ablation is both necessary and sufficient for human LGG xenograft development, which additionally enables the successful long-term growth of patient-derived pediatric LGGs in vivo. Lastly, MEK inhibitor (PD0325901) treatment increased hiPSC-LGG cell apoptosis and reduced proliferation both in vitro and in vivo. Collectively, this study establishes a tractable experimental humanized platform to elucidate the pathogenesis of and potential therapeutic opportunities for childhood brain tumors.

CLRM-05 FEASIBILITY OF EVALUATING ABEMACICLIB NEUROPHARMACOKINETICS OF DIFFUSE MIDLINE GLIOMA USING INTRATUMORAL MICRODIALYSIS

INTRODUCTIONDiffuse midline gliomas are the most aggressive brain tumors of childhood and young adults, with documented 2 year survival rates of <10%. Treatment failure is due in part to the presence of the blood-brain barrier (BBB), which limits permeability of varied agents. Efforts to evaluate drug delivery across the BBB in midline gliomas have been restricted to post biopsy specimens. Intracerebral microdialysis sampling of cortical tissue has been shown to be a highly effective tool in determining neuropharmacokinetics in adult brain tumors. METHODSAll participants will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. A maximally safe surgical resection for cortical high grade glioma or stereotactic needle biopsy for midline glioma will be performed in the OR and verified by brain CT. Continuous microdialysis sampling will be obtained over the course of the next 48 hours. We propose to evaluate 5 participants. RESULTSThis is a safety and feasibility study to evaluate tumor pharmacokinetics (PK) and pharmacodynamics (PD) of abemaciclib in recurrent high grade glioma and midline glioma participants in need of surgical resection or biopsy respectively. If intratumoral or PK brain dialysate sampling concentrations are >10nmol/L, or PD findings suggest CDK inhibition (decreased expression of Rb and/or topoIIα), then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy post resection or biopsy. After every 3 cycles, repeat brain MRI’s will be obtained to evaluate treatment response and disease progression. Exploratory aims include catheter stability testing, tissue genomic sequencing and PDX modeling. CONCLUSIONWe propose a trial using clinical microdialysis, placed in diffuse midline glioma tissue post biopsy, as an experimental research tool, to assess CNS drug entry and targeted inhibition with abemaciclib. These studies will be the first of their kind focused on the dynamic nature of CNS drug delivery with the overall intent to inform future clinical therapies.

Nanomedicines and cell-based therapies for embryonal tumors of the nervous system.

Embryonal tumors of the nervous system are neoplasms predominantly affecting the pediatric population. Among the most common and aggressive ones are neuroblastoma (NB) and medulloblastoma (MB). NB is a sympathetic nervous system tumor, which is the most frequent extracranial solid pediatric cancer, usually detected in children under two. MB originates in the cerebellum and is one of the most lethal brain tumors in early childhood. Their tumorigenesis presents some similarities and both tumors often have treatment resistances and poor prognosis. High-risk (HR) patients require high dose chemotherapy cocktails associated with acute and long-term toxicities. Nanomedicine and cell therapy arise as potential solutions to improve the prognosis and quality of life of children suffering from these tumors. Indeed, nanomedicines have been demonstrated to efficiently reduce drug toxicity and improve drug efficacy. Moreover, these systems have been extensively studied in cancer research over the last few decades and an increasing number of anticancer nanocarriers for adult cancer treatment has reached the clinic. Among cell-based strategies, the clinically most advanced approach is chimeric-antigen receptor (CAR) T therapy for both pathologies, which is currently under investigation in phase I/II clinical trials. However, pediatric drug research is especially hampered due not only to ethical issues but also to the lack of efficient pre-clinical models and the inadequate design of clinical trials. This review provides an update on progress in the treatment of the main embryonal tumors of the nervous system using nanotechnology and cell-based therapies and discusses key issues behind the gap between preclinical studies and clinical trials in this specific area. Some directions to improve their translation into clinical practice and foster their development are also provided.

Bone mineral density and nutrition in long-term survivors of childhood brain tumors.

Childhood cancer survivors are at risk of unwanted late effects. The primary aim of this study was to assess bone mineral density Z-scores (BMDz) in long-term survivors of childhood medulloblastoma (MB) or central nervous system supratentorial primitive neuroectodermal tumor (CNS-PNET). Secondary aims were to describe nutrient intake, vitamin D status, physical activity and explore potential risk factors for decreased BMDz. All MB and CNS-PNET survivors treated at Oslo University Hospital from 1974 to 2013 were invited to participate in a cross-sectional study. Dual-energy x-ray absorptiometry (Lunar Prodigy) assessed BMDz lumbar spine, BMDz total body, and lean body mass. Decreased BMDz was defined as a combination of low BMDz-1 to-1.99 and very low BMDz ≤-2. Lean body mass index (LMI) was calculated by dividing lean body mass by the squared height. Nutrient intake was assessed by a 3-day food record. Serum 25(OH)D was analyzed. Physical activity was reported by a questionnaire. Descriptive statistics and multivariable Cox regression analyses were applied. Fifty survivors with a median age of 25.5 years (5.5-51.9) and a median follow-up time of 19.5 years (3.2-40.5) were included. Mean BMDz lumbar spine was-0.8 (SD 1.1, 95% CI:-1.1 to-0.4), and BMDz total body was-0.6 (SD 1.1, 95% CI:-0.9 to-0.3). Decreased BMDz was detected in 48% of the lumbar spine and 34% of the total body measurements. In all, 62% had low calcium, and 69% had low vitamin D intake. 26% of participants had serum 25(OH)D<50nmol/L, and 62% reported an inactive lifestyle. Male sex, higher age at diagnosis, and lower LMI were potential risk factors for decreased BMDz. Long-term survivors of childhood MB and CNS-PNET had decreased BMDz, and risk factors were male sex, higher age at diagnosis, and lower LMI. Inadequate calcium and vitamin D intake, an inactive lifestyle, and a high prevalence of 25(OH)D≤50nmol/L were detected.

Quantification of spatial subclonal interactions enhancing the invasive phenotype of pediatric glioma.

SummaryDiffuse midline gliomas (DMGs) are highly aggressive, incurable childhood brain tumors. They present a clinical challenge due to many factors, including heterogeneity and diffuse infiltration, complicating disease management. Recent studies have described the existence of subclonal populations that may co-operate to drive pro-tumorigenic processes such as cellular invasion. However, a precise quantification of subclonal interactions is lacking, a problem that extends to other cancers. In this study, we combine spatial computational modeling of cellular interactions during invasion with co-evolution experiments of clonally disassembled patient-derived DMG cells. We design a Bayesian inference framework to quantify spatial subclonal interactions between molecular and phenotypically distinct lineages with different patterns of invasion. We show how this approach could discriminate genuine interactions, where one clone enhanced the invasive phenotype of another, from those apparently only due to the complex dynamics of spatially restricted growth. This study provides a framework for the quantification of subclonal interactions in DMG.

Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003.

PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Patients (3-25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN). Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2-18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome. Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.

Advanced Neuroimaging Approaches to Pediatric Brain Tumors.

Simple SummaryAfter leukemias, brain tumors are the most common cancers in children, and early, accurate diagnosis is critical to improve patient outcomes. Beyond the conventional imaging methods of computed tomography (CT) and magnetic resonance imaging (MRI), advanced neuroimaging techniques capable of both structural and functional imaging are moving to the forefront to improve the early detection and differential diagnosis of tumors of the central nervous system. Here, we review recent developments in neuroimaging techniques for pediatric brain tumors. Central nervous system tumors are the most common pediatric solid tumors; they are also the most lethal. Unlike adults, childhood brain tumors are mostly primary in origin and differ in type, location and molecular signature. Tumor characteristics (incidence, location, and type) vary with age. Children present with a variety of symptoms, making early accurate diagnosis challenging. Neuroimaging is key in the initial diagnosis and monitoring of pediatric brain tumors. Conventional anatomic imaging approaches (computed tomography (CT) and magnetic resonance imaging (MRI)) are useful for tumor detection but have limited utility differentiating tumor types and grades. Advanced MRI techniques (diffusion-weighed imaging, diffusion tensor imaging, functional MRI, arterial spin labeling perfusion imaging, MR spectroscopy, and MR elastography) provide additional and improved structural and functional information. Combined with positron emission tomography (PET) and single-photon emission CT (SPECT), advanced techniques provide functional information on tumor metabolism and physiology through the use of radiotracer probes. Radiomics and radiogenomics offer promising insight into the prediction of tumor subtype, post-treatment response to treatment, and prognostication. In this paper, a brief review of pediatric brain cancers, by type, is provided with a comprehensive description of advanced imaging techniques including clinical applications that are currently utilized for the assessment and evaluation of pediatric brain tumors.

Effectiveness of internet-based behavioral activation on quality of life among young adult survivors of childhood brain tumor: a randomized controlled trial

Purpose Diagnosis and treatment of childhood brain tumor have detrimental effects on physical, neurocognitive, psychological, and social functioning that lasts into adulthood and effects quality of life (QOL). To address diminished QOL, an Internet-based behavioral activation (BA) intervention was developed. Behavioral activation aims to increase activities and behaviors likely to improve thoughts, mood, and QOL. Methods Participants included 127 young adult survivors of childhood brain tumor (SCBT) randomized into the experimental group (n= 64) or the waitlist control group (n= 63). The dependent variables included: life satisfaction, stress, and activation and were assessed with a two-way mixed analysis of variance (ANOVA). Results Results revealed a significant interaction between the intervention and time on life satisfaction, F(1, 125)=4.793, p = 0.03. There were no significant main effects over time for perceived stress and activation. Conclusions Findings offer initial evidence that BA can be delivered over the internet and that Internet-delivered BA can have a positive effect on the QOL of young adult SCBT. Internet-based BA interventions can serve as a resource for young adult SCBT who desire to boost their mood and QOL. Implications for rehabilitation Behavioral activation (BA) is aimed at increasing positively reinforcing overt behaviors that are likely to promote improved thoughts, mood, and quality of life (QOL). Results indicated study participants in the experimental group demonstrated a significant gain in life satisfaction compared to the control group after receiving the Internet-based BA intervention; and provides support that the intervention was associated with positive changes across time. Findings offer initial evidence that BA can be delivered over the internet and that Internet-delivered BA can have a positive effect on the QOL of young adult survivors of childhood brain tumor (SCBT). Internet-based BA interventions can serve as a resource for young adult SCBT who desire to boost their mood and QOL.

The Current State of Radiotherapy for Pediatric Brain Tumors: An Overview of Post-Radiotherapy Neurocognitive Decline and Outcomes.

Tumors of the central nervous system are the most common solid malignancies diagnosed in children. While common, they are also found to have some of the lowest survival rates of all malignancies. Treatment of childhood brain tumors often consists of operative gross total resection with adjuvant chemotherapy or radiotherapy. The current body of literature is largely inconclusive regarding the overall benefit of adjuvant chemo- or radiotherapy. However, it is known that both are associated with conditions that lower the quality of life in children who undergo those treatments. Chemotherapy is often associated with nausea, emesis, significant fatigue, immunosuppression, and alopecia. While radiotherapy can be effective for achieving local control, it is associated with late effects such as endocrine dysfunction, secondary malignancy, and neurocognitive decline. Advancements in radiotherapy grant both an increase in lifetime survival and an increased lifetime for survivors to contend with these late effects. In this review, the authors examined all the published literature, analyzing the results of clinical trials, case series, and technical notes on patients undergoing radiotherapy for the treatment of tumors of the central nervous system with a focus on neurocognitive decline and survival outcomes.

Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion.

Despite significant improvements in treatment and survival in paediatric cancers, outcomes for children with brain tumours remain poor. Novel therapeutic approaches are needed to improve survival and quality of survival. Extracellular arginine dependency (auxotrophy) has been recognised in several tumours as a potential therapeutic target. This dependency is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma exhibits this dependency, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. We used immunohistochemical (IHC) methods to stain for arginine pathway enzymes in paediatric high-grade glioma (pHGG), low-grade glioma (pLGG), ependymoma (EPN), and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser arginase (Arg1 and Arg2); recycling enzymes ornithine transcarbamoylase (OTC), argininosuccinate synthetase (ASS1), and argininosuccinate lyase (ASL); and the transporter SLC7A1. Deficiency of OTC, ASS1, and ASL was seen in 87.5%, 94%, and 79% of pHGG samples, respectively, consistent with an auxotrophic signature. Similar result was obtained in pLGG with 96%, 93%, and 91% of tumours being deficient in ASL, ASS1, and OTC, respectively. 79%, 88%, and 85% of MB cases were ASL, ASS1, and OTC deficient whilst ASL and OTC were deficient in 57% and 91% of EPN samples. All tumour types highly expressed SLC7A1 and Arginase, with Arg2 being the main isoform, demonstrating that they could transport and utilise arginine. Our results show that pHGG, pLGG, EPN, and MB demonstrate arginine auxotrophy based on protein expression and are likely to be susceptible to arginine depletion. Pegylated arginase (BCT-100) is currently in phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in other tumour types and IHC analysis of patient tumour samples could help identify patients likely to benefit from this treatment.