Treatment Of Pediatric Brain Tumors Research Articles

2274: Demyelination in white matter after pediatric brain tumor treatment, assessed with quantitative MRI

2274: Demyelination in white matter after pediatric brain tumor treatment, assessed with quantitative MRI

CSF biomarkers of neurotoxicity in childhood cancer survivors after cranial radiotherapy or surgery.

Treatment of pediatric brain tumors is associated with potential long-term cognitive sequelae. Patients treated with craniospinal irradiation for posterior fossa tumors are at high risk. New biomarkers that could help to differentiate treatment effects from other causes of cognitive dysfunction would be valuable in tailoring optimal survivorship care. Biomarkers that reflect biological mechanisms behind treatment-associated cognitive decline would also be important in the evaluation of future treatment regimens for pediatric brain or skull base tumors. In this biomarker-finding study, 10 adult survivors of pediatric medulloblastoma, skull base tumors, and posterior fossa low-grade glioma underwent study specific lumbar puncture at a minimum of 17 years following treatment. We analyzed cerebrospinal fluid biomarkers reflecting neuron and astrocyte integrity, amyloid metabolism, inflammation, extracellular matrix, synaptic integrity, and blood-brain barrier function. The values were compared with biomarker levels in healthy controls of comparable age. Biomarkers reflecting neuronal injury (neurofilament light chain protein), astrocyte injury or activation (glial fibrillary acidic protein) as well as inflammation (YKL-40) were significantly elevated in cancer survivors compared to controls. Biomarkers reflecting amyloid metabolism showed a pattern of decrease in patients treated for medulloblastoma. The results suggest a potential chronic low-grade neurodegeneration and astrocyte activation in patients treated for pediatric brain or skull base tumors. Protein biomarkers of CNS disease could potentially be used to increase our understanding of the contribution from different tumor treatments with regard to long-term symptoms in cancer patients.

MDB-52. MYC-DRIVEN PEDIATRIC BRAIN TUMORS SHARE A COMMON PHOTORECEPTOR IDENTITY

Abstract Mouse models serve as invaluable tools for improving the understanding and treatment of pediatric brain tumors. We recently published a highly aggressive MYC-driven brain tumor model (GMYC), which exhibits approximately 70% penetrance. Our transcription profiling indicates that GMYC tumors accurately resemble human Group 3 medulloblastoma (MB-G3). Interestingly, a strong photoreceptor program was activated in the tumor model. This is commonly upregulated in MB-G3 but also in pineoblastoma (PB), another malignant pediatric brain tumor. CRX, a transcription factor critical for pineal cell development is also a master regulator for MB-G3 maintenance. By studying early tumor initiation using Crx-lineage tracing and scRNA-seq, we confirmed that GMYC tumors originate from early pinealocytes. Exome sequencing of GMYC tumors further confirmed mutations of epigenetic regulators commonly reported in either PB or MB. To investigate tumor development from photoreceptor-positive progenitors in the developing brain, we performed Crx-lineage tracing with tamoxifen injections, confirming that Crx-positive cells exist in pineal gland progenitors. However, Crx-traced cells also marked granule neurons in the flocculonodular lobe of the cerebellum, which is the suggested site of MB-G3 origin arising from the developing rhombic lip. To investigate if the Myc oncogene can generate different types of pediatric brain tumors in Crx-positive cells, an XMYCT58A-Tomato mouse model was established by crossing Crx-CreERT2; LSL-MycT58A and Rosa26LSL-tdTomato strains. Here, MycT58A was turned on with tamoxifen injection after birth and tumor development followed using the tdTomato reporter. XMYCT58A-Tomato mice developed brain tumors from both the pineal gland and cerebellum after 2-6 months. Histologically, tumors were non-glial (GFAP-, Olig2-), showed neuronal activity (Neurod1+), and stained positive for photoreceptor identity markers (CRX+, OTX2+) similar to both MB-G3 and PB-MYC. Collectively, our data suggest that both MYC-driven MB-G3 and PB-MYC originate from photoreceptor-positive cells, which has implications for developing novel treatments targeting these devastating childhood malignancies.

QOL-24. TREATMENT- AND TIME-RELATED IMPACT ON LONG-TERM NEUROCOGNITIVE OUTCOMES IN ADULT SURVIVORS OF A PEDIATRIC BRAIN TUMOR

Abstract Treatment for pediatric brain tumors has been associated with the risk of developing long-term neurocognitive impairment. However, it is not well understood which neurocognitive profiles exist within this population. We investigated neurocognitive functioning (NF) in survivors in early adulthood and aimed to assess the impact of radiotherapy dose (RTD) and time since treatment (TxT) on NF. Forty-six survivors of pediatric brain tumors (mean age 23.99±4.71, mean age at diagnosis 9.29±4.54) performed an extensive neurocognitive test battery resulting in intelligence (n=5), memory (n=2), and language (n=3) scores. NF in long-term survivors was compared to sex-, age-, and education-matched controls, and between the different treatment strategies (surgery-only n=19, chemotherapy n=8, radiotherapy n=11, or chemo-radiotherapy n=8). Furthermore, relation between max-RTD (range 40.28 – 61.61 Gy) as well as TxT and NF was assessed. Three ANCOVA models were tested, and false discovery rate (FDR) was applied. For all scales and domain scores, survivors scored lower compared to controls. Scores were significant lower on full scale intelligence (pfdr< 0.001), verbal comprehension (pfdr< 0.001), working memory (pfdr= 0.003), perceptual reasoning (pfdr< 0.001), processing speed (pfdr< 0.001), spoken word comprehension (pfdr= 0.001), and semantic word generation (pfdr= 0.036) compared to controls. NF was not significantly different between the different treatments, nor did the association with max-RTD reach significance. TxT was associated with verbal comprehension and spoken word comprehension; albeit significance was not retained after FDR correction. In this study, the overall survivor cohort scored lower on multiple cognitive outcomes. More detailed analysis of various risk factors might further elucidate the different neurocognitive profiles for this population. Furthermore, more detailed analysis of RTD distributions and affected brain structures may provide greater insight on the impact of radiotherapy on NF.

QOL-43. COMPARISON OF SOCIAL DETERMINANTS OF HEALTH MEASURES ON IQ AND ACADEMIC OUTCOMES IN PEDIATRIC BRAIN TUMORS

Abstract BACKGROUND Treatment for pediatric brain tumors impacts IQ and academic achievement; fewer studies have examined the role of social determinants of health (SDoH). To date, studies have primarily focused on family-based SDoH such as insurance type or parental education as predictors of cognition. Limited studies have examined community factors, though our work highlighted the role of education quality on IQ and academics in pediatric brain tumors. To our knowledge, no study has examined the predictive value of family and community-based SDoH. METHODS Participants included 151 pediatric brain tumor patients (M age at diagnosis=8.82) seen for a clinical neuropsychological evaluation (M age at evaluation=13.71). IQ was obtained from age-appropriate intelligence measures (WISC>6 years, DAS-II<6 years); untimed reading and math calculation were examined via WIAT/KTEA/WJ subtests. Family-based SDoH included insurance type (public, private) and maternal education (<high school degree, some college, >college degree). Community-based SDoH included the Area Deprivation Index (ADI) and Education, Health-Environment, and Social-Economic indices from the Childhood Opportunity Index (COI). Multiple regressions examined variance in IQ, reading, and math accounted for by each of the SDoH measures, after controlling for treatment exposures using the Neurological Predictor Scale (NPS). RESULTS Insurance [β=-.302, t(151)=-4.00; p<001] and Education [β=.235, t(151)=3.14; p=.002] accounted for 14.9% and 19.7% of the IQ variance, respectively. Education also accounted for 12.8% of the reading variance (β=.304, t(109)=3.40; p<.001). Both the Education [β=.570, t(107)=3.41; p<.001] and Social-Economic [β=-.381, t(107)=-2.28; p=.03] indices accounted for 7.7% and 11.3% of the math calculation variance, respectively. CONCLUSIONS Community, particularly those related to education and social & economic resources, and family factors (e.g., insurance status) were associated with IQ and academic performance. Findings indicate the importance of investigating both family and community factors that may contribute to outcomes in pediatric brain tumors.

Targeting Histone 3 Variants Epigenetic Landscape and Inhibitory Immune Checkpoints: An Option for Paediatric Brain Tumours Therapy.

Despite little progress in survival rates with regular therapies, which do not provide complete care for curing pediatric brain tumors (PBTs), there is an urgent need for novel strategies to overcome the toxic effects of conventional therapies to treat PBTs. The co-inhibitory immune checkpoint molecules, e.g., CTLA-4, PD-1/PD-L1, etc., and epigenetic alterations in histone variants, e.g., H3K27me3 that help in immune evasion at tumor microenvironment have not gained much attention in PBTs treatment. However, key epigenetic mechanistic alterations, such as acetylation, methylation, phosphorylation, sumoylation, poly (ADP)-ribosylation, and ubiquitination in histone protein, are greatly acknowledged. The crucial checkpoints in pediatric brain tumors are cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PDL1), OX-2 membrane glycoprotein (CD200), and indoleamine 2,3-dioxygenase (IDO). This review covers the state of knowledge on the role of multiple co-inhibitory immunological checkpoint proteins and histone epigenetic alterations in different cancers. We further discuss the processes behind these checkpoints, cell signalling, the current scenario of clinical and preclinical research and potential futuristic opportunities for immunotherapies in the treatment of pediatric brain tumors. Conclusively, this article further discusses the possibilities of these interventions to be used for better therapy options.

The development of fatigue after treatment for pediatric brain tumors does not differ between tumor locations.

Children and adolescents treated for a brain tumor suffer from more fatigue than survivors of other types of childhood cancer. As tumor location might be predictive of fatigue, our aim was to investigate the longitudinal development of fatigue in children with brain tumors and risk factors for fatigue separately for different tumor locations. Fatigue was assessed 1235 times for 425 participants. Self-report versions of PedsQL Multidimensional Fatigue Scale were used to repeatedly assess fatigue from the end of treatment up to 8years later. Mixed models were used to analyze fatigue over time and determinants separately for infratentorial (N=205), supratentorial hemispheric (N=91), and supratentorial midline tumors (N=129). Cognitive fatigue worsened with time, while sleep-rest and general fatigue first decreased and then increased. There was no difference in fatigue between the tumor locations, but the risk factors differed when stratified by location. Radiotherapy was associated with more fatigue for infratentorial tumors, and centralization of care was associated with less fatigue for the supratentorial midline tumors. For supratentorial hemispheric tumors, female sex was associated with more fatigue. Higher parental education was associated with less fatigue regardless of tumor location. The development of fatigue seems to be more related to sociodemographic and treatment variables than to tumor location. Healthcare providers need to be aware that fatigue may develop in the years following end of treatment, and that patients with a low/middle educational family background might be more vulnerable and in need of targeted support.

Multimodal imaging with magnetization transfer and diffusion tensor imaging reveals evidence of myelin damage in children and youth treated for a brain tumor.

The microstructural damage underlying compromise of white matter following treatment for pediatric brain tumors is unclear. We use multimodal imaging employing advanced diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) MRI methods to examine chronic microstructural damage to white matter in children and adolescents treated for pediatric brain tumor. Notably, MTI may be more sensitive to macromolecular content, including myelin, than DTI. Fifty patients treated for brain tumors (18 treated with surgery ± chemotherapy and 32 treated with surgery followed by cranial-spinal radiation; time from diagnosis to scan ~6 years) and 45 matched healthy children completed both MTI and DTI scans. Voxelwise and region-of-interest approaches were employed to compare white matter microstructure metrics (magnetization transfer ratio (MTR); DTI- fractional anisotropy [FA], radial diffusivity [RD], axial diffusivity [AD], mean diffusivity [MD]) between patients and healthy controls. MTR was decreased across multiple white matter tracts in patients when compared to healthy children, P < .001. These differences were observed for both patients treated with radiation and those treated with only surgery, P < .001. We also found that children and adolescents treated for brain tumors exhibit decreased FA and increased RD/AD/MD compared to their healthy counterparts in several white matter regions, Ps < .02. Finally, we observed that MTR and DTI metrics were related to multiple white matter tracts in patients, Ps < .01, but not healthy control children. Our findings provide evidence that the white matter damage observed in patients years after treatment of pediatric posterior fossa tumors, likely reflects myelin disruption.

18 Executive Dysfunction Following Treatment for Pediatric Low Grade Brain Tumors: Increased Risk Associated with Infratentorial Tumor Location

Objective:Treatment for pediatric brain tumors (PBTs) is associated with neurocognitive risk, including declines in IQ, executive function, and visual motor processing. Low grade tumors require less intensive treatment (i.e., focal radiotherapy (RT) or surgical resection alone), and have been associated with more favorable cognitive outcomes. However, these patients remain at risk of cognitive problems, which may present differently depending on tumor location. Executive functioning (EF), in particular, has been broadly associated with both frontal-subcortical networks (supratentorial) and the cerebellum (infratentorial). The current study examined intellectual functioning, executive functioning (set-shifting and inhibition), and visual motor skills in patients who were treated for low-grade tumors located in either the supratentorial or infratentorial region.Participants and Methods:Participants were survivors (age 8-18) previously treated with focal proton RT or surgery alone for infratentorial (n=21) or supratentorial (n=34) low grade glioma (83.6%) or low grade glioneuronal tumors (16.4%). Survivors &gt;2.5 years post-treatment completed cognitive testing (WISC-IV/WAIS-IV; D-KEFS Verbal Fluency (VF), Color-Word Interference (CW), Trail Making Test (TM); Beery Visual-Motor Integration). We compared outcomes between infratentorial and supratentorial groups using analysis of covariance (ANCOVA). Demographic and clinical variables were compared using Welch’s t-tests. ANCOVAs were adjusted for age at evaluation, age at treatment, and history of posterior fossa syndrome due to significant or marginally significant differences between groups.Results:Tumor groups did not significantly differ with respect to sex (49.0% male), length of follow-up (M 4.4 years), or treatment type (74.5% surgery alone, 25.5% proton RT). Marginally significant group differences were found for age at evaluation (infratentorial M = 12.4y, supratentorial M = 14.1y, p = .054) and age at treatment (infratentorial M = 7.9y, supratentorial M = 9.7y, p =.074). Posterior fossa syndrome only occurred with infratentorial tumors (n=5, p = .003). Adjusting for covariates, the supratentorial group exhibited significantly superior performance on a measure of inhibition and set-shifting (CW Switching Time (t(32) = -2.05, p=.048, n2 =.11). There was a marginal group difference in the same direction on CW Inhibition Time (t(32 = -1.77, p = .086, n2 =.08). On the other hand, the supratentorial group showed significantly lower working memory than the infratentorial group (t(50) = 2.45, p = .018, n2 = .11), and trends toward lower verbal reasoning (t(50)=1.96, p = .056, n2 = .07) and full-scale IQ (t(50)=1.73, p = .090, n2 = .055). No other group differences were identified across intellectual, EF, and visualmotor measures.Conclusions:Infratentorial tumor location was associated with weaker switching and inhibition performance, while supratentorial tumor location was associated with lower performance on intellectual measures, particularly working memory. These findings suggest that even with relatively conservative treatment (i.e., focal proton RT or surgery alone), there remains neurocognitive risk in children treated for low-grade brain tumors. Moreover, tumor location may predict distinct patterns of long-term neurocognitive outcomes, depending on which brain networks are involved.

Memantine for Pediatric Patients Receiving Cranial Irradiation: A Pilot Study

While memantine has become standard in certain adults receiving brain RT to decrease the cognitive impacts of RT, it is unknown whether pediatric patients can take and tolerate memantine or experience benefit. In this prospective single-arm feasibility study, we hypothesized pediatric patients receiving brain RT would tolerate memantine with good treatment adherence. Patients aged 4-18 years with a primary CNS malignancy (excluding WHO Grade IV astrocytoma and glioblastoma) receiving intracranial RT were eligible. A 6-month course of memantine was given during and after RT. Dosing began once daily at 5 mg with up-titration in 5 mg increments over 4 weeks to a weight-based maximum (0.4 mg/kg to the closest 5 mg), not to exceed 10 mg BID. To reduce patient and clinical research associate (CRA) burden, medication adherence was tracked via the Medisafe Pill and Reminder application which study staff helped install on the patient or parent's smart phone. A paper pill diary was provided for those unable to use the app. The primary endpoint was to achieve 80% adherence rate to memantine in 80% of patients measured 1-month post-RT. Eighteen patients (14 male and 4 female, median age 11.5 years (range: 4-18)) were enrolled from 2020-2022. The study closed early after enrolling 18 of 20 planned patients to avoid competing with the phase III randomized Children's Oncology Group (COG) study AACL2031. One patient withdrew for cognition-altering substance-use, leaving 17 patients with data available for analysis. Histologies included germ cell tumor (n = 6), craniopharyngioma (n = 3), choroid plexus papilloma (n = 2), ependymoma (n = 2), glial/astrocytoma (n = 2), medulloblastoma (n = 1), and meningioma (n = 1). Thirteen had surgery, and 9 received chemotherapy. Eight received craniospinal irradiation (CSI). Median RT dose was 54 Gy (range 36-59.4) in 30 fractions (range: 20-33). At data freeze, all 17 had passed the 1-month post-RT time point. One patient discontinued memantine after a single dose due to nausea. Pill-reports were available for 14 of the remaining 16; two patients did not complete digital pill logs. For those with complete logs, all adherence rates were above 80%, with a median of 99.32% pill completion rate (range: 92.67-100). Seven (50%) took 100% of prescribed doses. Irrespective of adherence for the 2 unavailable for evaluation, the primary endpoint was still achieved. Grade 1 toxicities included headache (n = 6, 35%) and constipation (n = 1, 6%); there were no grade 2+ toxicities. At last follow-up, 15/16 have completed the full 6-month memantine course. Secondary endpoints including neurocognitive evaluations have not yet been met and will be the subject of future reports. Memantine is a feasible and well-tolerated addition to multi-modality treatment for pediatric brain tumors. Secondary endpoints of this study and results of the ongoing COG study are awaited to define the value of memantine in this population.

Neurosurgical treatment of pediatric brain tumors - results from a single center multidisciplinary setup

ObjectiveThe challenge of pediatric brain tumor surgery is given due to a relative low prevalence but high heterogeneity in age, localization, and pathology. Improvements of long-term overall survival rates were achieved during the past decades stressing the importance of a multidisciplinary decision process guided by a national treatment protocol. We reviewed the entire spectrum of pediatric brain tumor surgeries from the perspective of an interdisciplinary pediatric neuro-oncology center in Germany.MethodsEvery patient who underwent brain tumor surgery from January 2010 to June 2017 in our Pediatric Neurosurgery department was retrospectively included and evaluated regarding the course of treatment. Perioperative data such as tumor localization, timing of surgery, extent of resection, neuropathological diagnosis, transfusion rates, oncologic and radiation therapy, and neurological follow-up including morbidity and mortality were evaluated.ResultsTwo hundred ninety-three pediatric brain tumor patients were applicable (age: 8.28 ± 5.62 years, 1.22:1.0 m:f). A total of 531 tumor surgical interventions was performed within these patients (457 tumor resections, 74 tumor biopsies; mean interventions per patient 1.8 ± 1.2). Due to a critical neurologic status, 32 operations (6%) were performed on the day of admission. In 65.2% of all cases, tumor were approached supratentorially. Most frequent diagnoses of the cases were glial tumors (47.8%) and embryonal tumors (17.6%). Preoperative planned extent of resection was achieved in 92.7%. Pre- and postoperative neurologic deficits resolved completely in 30.7%, whereas symptom regressed in 28.6% of surgical interventions. New postoperative neurologic deficit was observed in 10.7%, which resolved or improved in 80% of these cases during 30 days. The mortality rate was 1%.ConclusionWe outlined the center perspective of a specialized pediatric neuro-oncological center describing the heterogeneous distribution of cases regarding age-related prevalence, tumor localization, and biology, which requires a high multidisciplinary expertise. The study contributes to define challenges in treating pediatric brain tumors and to develop quality indicators for pediatric neuro-oncological surgery. We assume that an adequate volume load of patients within a interdisciplinary infrastructure is warranted to aim for effective treatment and decent quality of life for the majority of long-term surviving pediatric tumor patients.

IMMU-11. PRECLINICAL HIGH-RISK PEDIATRIC BRAIN TUMOR MODELS FOR IMMUNOTHERAPY: HURDLES AND THE WAY FORWARD

Abstract Despite recent therapeutic advancements in the treatment of pediatric brain tumors, high-risk brain tumors (pHRBT) remain the leading cause of cancer-related deaths in children. In recent years, immunotherapy has become a viable treatment option for several cancers including brain tumors. However, several factors have limited the use of immunotherapy in the treatment of pHRBT. For example, an "immunologically cold" tumor environment has been predominantly implicated in the failure of checkpoint inhibitors (ICIs) as monotherapy in pHRBT. Nevertheless, priming the effects of ICIs with epigenetic modulators through a process called “viral mimicry” that induces the expression of human endogenous retroviruses has the potential to enhance immunotherapy by sparking a T-cell mediated immune response. However, the inadequate understanding of the limitations of the preclinical models has prevented the development of efficient immunotherapy strategies for pHRBT. Although several studies and reviews have compiled some limitations of the available models, a hands-on experience using preclinical models for ICIs testing has not been fully communicated. Here, we share our bedside to bench experience with syngeneic and humanized mouse models of DIPG, ATRT, and medulloblastoma using ICIs therapy in conjunction with an epigenetic alteration. We will present and discuss the limitations of mouse models for the development of immunotherapies for pHRBT. For instance, our results indicated that the baseline levels of MHC-I expression in patients’ DIPG tumors were comparable to matched normal tissue. However, these levels were significantly lower in mouse DIPG tumors. To compensate for this difference, we treated mice with IFN-γ in combination with an epigenetic modulator. Surprisingly, the addition of INF-γ had a negative effect on animal overall survival compared to the treatment with the epigenetic modulator alone. Together, our experience demonstrated the importance of suitability assessment of current models for developing and translating successful immunotherapy strategies to treat pHRBT.

OUTC-03. IMPACT OF TREATMENT EXPOSURES AND SOCIOECONOMIC STATUS ON NEUROCOGNITIVE PERFORMANCE IN CHILDREN WITH BRAIN TUMORS

Abstract PURPOSE To investigate the impact of treatment exposures and socioeconomic status on neurocognitive performance in children with brain tumors. METHODS Eligible patients included those diagnosed with a brain tumor at &amp;lt;22 years of age with ≥ 1 neurocognitive assessment. Neurocognitive impairment was defined as performance 1.5 standard deviations below the normative mean using age standardized measures of intellectual function. Neurocognitive outcomes included Wechsler indices of full-scale intelligent quotient (IQ), working memory (WM), and processing speed (PS). Neurocognitive decline was defined as a negative slope. Logistic regression identified variables associated with neurocognitive impairment. Longitudinal data was analyzed using linear mixed models. RESULTS Eligible patients (n=152) had a mean neurocognitive follow-up of 50.2 months and median age at diagnosis of 9.6 years. PS was most frequently impaired in patients (37.5%) followed by IQ (20.6%) and WM (16.5%). Patients with public insurance had eight-fold increased odds of impaired IQ compared to those with private insurance (Odds Ratio [OR]: 7.59, p&amp;lt;0.001). Patients treated with CSI had eight-fold increased odds of impaired IQ (OR: 7.86, p=0.003) and almost six-fold increased odds of impaired WM (OR: 5.66, p=0.028) compared to those treated without RT. After accounting for age, change in IQ was associated with chemotherapy use (slope: -0.45 points/year with chemotherapy vs. 0.71 points/year without chemotherapy, p=0.012). Patients treated with both chemotherapy and RT demonstrated the greatest decline whereas those treated without either demonstrated no decline in any of the neurocognitive measures. CONCLUSION After treatment for pediatric brain tumors, public insurance, an indicator of low socioeconomic status, was associated with impairment in IQ with a large effect size similar to that of CSI. Chemotherapy was associated with decline in IQ with a small effect size. Combined chemotherapy and RT had additive effects on neurocognitive decline in IQ, WM, and PS.

Carbon Dots in Treatment of Pediatric Brain Tumors: Past, Present, and Future Directions.

Pediatric brain tumors remain a significant source of morbidity and mortality. Though developments have been made in treating these malignancies, the blood-brain barrier, intra- and inter-tumoral heterogeneity, and therapeutic toxicity pose challenges to improving outcomes. Varying types of nanoparticles, including metallic, organic, and micellar molecules of varying structures and compositions, have been investigated as a potential therapy to circumvent some of these inherent challenges. Carbon dots (CDs) have recently gained popularity as a novel nanoparticle with theranostic properties. This carbon-based modality is highly modifiable, allowing for conjugation to drugs, as well as tumor-specific ligands in an effort to more effectively target cancerous cells and reduce peripheral toxicity. CDs are being studied pre-clinically. The ClinicalTrials.gov site was queried using the search terms: brain tumor and nanoparticle, liposome, micelle, dendrimer, quantum dot, or carbon dot. At the time of this review, 36 studies were found, 6 of which included pediatric patients. Two of the six studies investigated nanoparticle drug formulations, whereas the other four studies were on varying liposomal nanoparticle formulations for the treatment of pediatric brain tumors. Here, we reviewed the context of CDs within the broader realm of nanoparticles, their development, promising pre-clinical potential, and proposed future translational utility.

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

Primary malignant brain tumors are the most common solid neoplasm in childhood. Despite recent advances, many children affected by aggressive or metastatic brain tumors still present poor prognosis, therefore the development of more effective therapies is urgent. Cancer stem cells (CSCs) have been discovered and isolated in both pediatric and adult patients with brain tumors (e.g., medulloblastoma, gliomas and ependymoma). CSCs are a small clonal population of cancer cells responsible for brain tumor initiation, maintenance and progression, displaying resistance to conventional anticancer therapies. CSCs are characterized by a specific repertoire of surface markers and intracellular specific pathways. These unique features of CSCs biology offer the opportunity to build therapeutic approaches to specifically target these cells in the complex tumor bulk. Treatment of pediatric brain tumors with classical chemotherapeutic regimen poses challenges both for tumor location and for the presence of the blood-brain barrier (BBB). Lastly, the application of chemotherapy to a developing brain is followed by long-term sequelae, especially on cognitive abilities. Novel avenues are emerging in the therapeutic panorama taking advantage of nanomedicine. In this review we will summarize nanoparticle-based approaches and the efficacy that NPs have intrinsically demonstrated and how they are also decorated by biomolecules. Furthermore, we propose novel cargoes together with recent advances in nanoparticle design/synthesis with the final aim to specifically target the insidious CSCs population in the tumor bulk.

Past, present and future of Focused Ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting

Diffuse Intrinsic Pontine Glioma (DIPG), now known as Diffuse Midline Glioma (DMG) is a devastating pediatric brain tumor with limited treatment options and a very poor prognosis. Despite more than 250 clinical trials aimed to treat children diagnosed with DMG, no curative therapies currently exist for this patient population. A major obstacle has been the intact blood brain barrier (BBB) which prevents most therapeutics from crossing into the tumor bed. Focused Ultrasound (FUS) is an emerging, noninvasive medical technology which has been shown in both preclinical and clinical research to disrupt the blood brain barrier safely and temporarily. FUS blood brain barrier opening has been studied in combination with chemotherapies in preclinical DMG models, and this technology is now being investigated in clinical trials for the treatment of pediatric brain tumors. Focused ultrasound has additional mechanisms of action, including sonodynamic therapy and radiation sensitization, that hold promise as future DMG therapies as well. This paper, largely based off the proceedings from a workshop held by the Focused Ultrasound Foundation in October of 2021, summarizes the current state of the field of focused ultrasound for DIPG/DMG, including preclinical, technical, and clinical summaries in addition to recommended next steps for continued advancement of the game changing technology of Focused Ultrasound.

Advances in the Treatment of Pediatric Brain Tumors.

Pediatric brain tumors are the most common solid malignancies in children. Advances in the treatment of pediatric brain tumors have come in the form of imaging, biopsy, surgical techniques, and molecular profiling. This has led the way for targeted therapies and immunotherapy to be assessed in clinical trials for the most common types of pediatric brain tumors. Here we review the latest efforts and challenges in targeted molecular therapy, immunotherapy, and newer modalities such as laser interstitial thermal therapy.

Immunotherapy for the treatment of pediatric brain tumors: a narrative review.

The goal of this narrative review is to report and summarize the completed pediatric immunotherapy clinical trials for primary CNS tumors. Pediatric central nervous system (CNS) tumors are the most common cause of pediatric solid cancer in children aged 0 to 14 years and the leading cause of cancer mortality. Survival rates for some pediatric brain tumors have improved, however, there remains a large portion of pediatric brain tumors with poor survival outcomes despite advances in treatment. Cancer immunotherapy is a growing field that has shown promise in the treatment of pediatric brain tumors that have historically shown a poor response to treatment. This narrative review provides a summary and discussion of the published literature focused on treating pediatric brain tumors with immunotherapy. MEDLINE via PubMed, Embase and Scopus via Elsevier were searched. The search utilized a combination of keywords and subject headings to include pediatrics, brain tumors, and immunotherapies. Manuscripts included in the analysis included completed clinical studies using any immunotherapy intervention with a patient population that consisted of at least half pediatric patients (<18 years) with primary CNS tumors. Conference abstracts were excluded as well as studies that did not include completed safety or primary outcome results. Search results returned 1,494 articles. Screening titles and abstracts resulted in 180 articles for full text review. Of the 180 articles, 18 were included for analysis. Another two articles were ultimately included after review of references and inclusion of newly published articles, for a total of 20 included articles. Immunotherapies included dendritic cell vaccines, oncolytic virotherapy/viral immunotherapy, chimeric antigen receptor (CAR) T-cell therapy, peptide vaccines, immunomodulatory agents, and others. In this review, 20 published articles were highlighted which use immunotherapy in the treatment of primary pediatric brain tumors. To date, most of the studies published utilizing immunotherapy were phase I and pilot studies focused primarily on establishing safety and maximum dose-tolerance and toxicity while monitoring survival endpoints. With established efficacy and toxicity profiles, future trials may progress to further understanding the overall survival and quality of life benefits to pediatric patients with primary brain tumors.

EPCT-07. Updated report on the pilot study of using MRI-guided laser heat ablation to induce disruption of the peritumoral blood brain barrier to enhance deliver and efficacy of treatment of pediatric brain tumors

Abstract BACKGROUND: MRI-guided laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive surgery useful for managing unresectable brain tumors. LITT disrupts the blood brain barrier (BBB) and facilitates chemotherapy delivery. We report the toxicity and outcome for pediatric brain tumors treated on a pilot trial of LITT and chemotherapy. The primary objectives were to quantify peritumoral BBB disruption following LITT and evaluate toxicity and efficacy. METHODS: The trial had two arms, A: patients with newly diagnosed gliomas underwent LITT followed by standard of care management, and B: patients with relapsed malignant brain tumors received 6 weeks of weekly doxorubicin post-LITT followed by maintenance etoposide. RESULTS: Between 2015 – 2018, six patients were enrolled: five on arm A (four with low-grade gliomas, one with high-grade glioma), one on Arm B with progressive anaplastic astrocytoma. All patients tolerated the procedure well; four experienced a transient hemiparesis post-LITT. The Arm B patient progressed and died of disease 2 months and 22 months post-LITT, respectively. The HGG patient received standard therapy and remains without disease progression 44 months post-LITT. One patient with LGG required additional treatment for disease progression 14 months post-LITT. Two patients with LGGs did not require additional therapy, now 51 and 41 months post-LITT. One patient was alive 24 weeks post-LITT and subsequently lost to follow-up. Peritumoral BBB disruption was analyzed in two ways: serum abundance of brain-derived proteins and MRI Dynamic contrast enhancement (DCE). Neuron-specific enolase were measurable in the serum of all patients, using ELISA up to 84 days post-LITT. DCE 2 weeks post-LITT demonstrated increased enhancement and FLAIR signal, consistent with BBB disruption and vasogenic edema. This effect was evident up to 4 months post-procedure. CONCLUSION: LITT is safe in children with brain tumors and can be combined with chemotherapy. DCE and serum brain-derived proteins can measure BBB disruption.

PATH-07. Diagnostic and therapeutic value of cerebrospinal fluid biopsy in pediatric brain tumors

BACKGROUND: The application of cerebrospinal fluid (CSF) biopsy in brain tumors is valuable. This paper further explores the diagnostic and therapeutic value of CSF biopsy in pediatric brain tumors. METHODS: In this study, children with primary brain tumor aged ≤18 years old in Guangdong Sanjiu Brain Hospital were enrolled．CSF next-generation sequencing (NGS) tests were required for all included patients. The genetic mutations in these children were analyzed. RESULTS: A total of 12 pediatric brain tumors who underwent CSF NGS were included in this study. 9 patients were brainstem glioma and 3 were pilocytic astrocytoma. The mutated genes were detected in 67% (8/12) patients by CSF NGS. In brainstem glioma, the rate was 67% (6/9), and the most common genes were H3F3A (5/6, 83%) and TP53 (5/6, 83%). Other detected genes included EGFR, CDK4 and NF2. H3F3A mutation is of great significance for the diagnosis and treatment of brainstem glioma, and CDK4 and EGFR are valuable for the treatment. In pilocytic astrocytoma, the deteaction rate was 67% (2/3), and the genes included KIAA1549-BRAF fusion, FGFR1 and PTPN11 mutations. KIAA1549-BRAF fusion is of great value in the diagnosis and treatment of pilocytic astrocytoma, and FGFR is valuable in the treatment. CONCLUSIONS: Fluid biopsy of CSF for pediatric brain tumors may be an important supplement to histological diagnosis, especially when histopathology is not available. The results are significant for the diagnosis and treatment of pediatric brain tumors.