A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors.

Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability in H3.3 mutant pHGG, and opens new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme polynucleotide kinase 3'-phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.

Brain Tumor Imaging in Adolescents and Young Adults: 2021 WHO Updates for Molecular-based Tumor Types.

Published in 2021, the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) introduced new molecular criteria for tumor types that commonly occur in either pediatric or adult age groups. Adolescents and young adults (AYAs) are at the intersection of adult and pediatric care, and both pediatric-type and adult-type CNS tumors occur at that age. Mortality rates for AYAs with CNS tumors have increased by 0.6% per year for males and 1% per year for females from 2007 to 2016. To best serve patients, it is crucial that both pediatric and adult radiologists who interpret neuroimages are familiar with the various pediatric- and adult-type brain tumors and their typical imaging morphologic characteristics. Gliomas account for approximately 80% of all malignant CNS tumors in the AYA age group, with the most common types observed being diffuse astrocytic and glioneuronal tumors. Ependymomas and medulloblastomas also occur in the AYA population but are seen less frequently. Importantly, biologic behavior and progression of distinct molecular subgroups of brain tumors differ across ages. This review discusses newly added or revised gliomas in the fifth edition of the CNS WHO classification, as well as other CNS tumor types common in the AYA population.

Targeting the RAS/MAPK pathway in children with glioma.

PURPOSE: Pediatric gliomas are the most common brain tumor in children, encompassing both low-grade glioma (pLGG) and high-grade glioma (pHGG). Alterations in the RAS/MAPK pathway are the driver event in the majority of pLGG and account for a subset of pHGG. Identification of these alterations has resulted in the transition to targeted therapy as a treatment option. RESULTS: In pLGG, multiple trials have demonstrated superior outcomes using targeted therapy compared to traditional chemotherapy regimens. This has transformed care for these patients over the past decade with targeted therapy moving into front-line treatment regimens in certain scenarios. Despite these advances, novel targeted therapy approaches continue to present unique challenges to patient care, including optimal duration of therapy, distinct toxicity profiles and the unknown potential impact on the natural history of disease. While targeted therapy has revolutionized treatment of pLGG, additional questions remain in regard to pHGG including the role of targeted therapy in combination with other treatments, such as chemotherapy/radiation, and mechanisms of resistance. These developments are promising treatment options for pediatrics gliomas, enabling a move towards precision medicine. CONCLUSION: Herein, we review the role of RAS/MAPK targeted therapy for treatment of pediatric glioma along with the current controversies and outstanding questions.

Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Increased confidence of radiomics facilitating pretherapeutic differentiation of BRAF-altered pediatric low-grade glioma.

OBJECTIVES: Currently, the BRAF status of pediatric low-grade glioma (pLGG) patients is determined through a biopsy. We established a nomogram to predict BRAF status non-invasively using clinical and radiomic factors. Additionally, we assessed an advanced thresholding method to provide only high-confidence predictions for the molecular subtype. Finally, we tested whether radiomic features provide additional predictive information for this classification task, beyond that which is embedded in the location of the tumor. METHODS: Random forest (RF) models were trained on radiomic and clinical features both separately and together, to evaluate the utility of each feature set. Instead of using the traditional single threshold technique to convert the model outputs to class predictions, we implemented a double threshold mechanism that accounted for uncertainty. Additionally, a linear model was trained and depicted graphically as a nomogram. RESULTS: The combined RF (AUC: 0.925) outperformed the RFs trained on radiomic (AUC: 0.863) or clinical (AUC: 0.889) features alone. The linear model had a comparable AUC (0.916), despite its lower complexity. Traditional thresholding produced an accuracy of 84.5%, while the double threshold approach yielded 92.2% accuracy on the 80.7% of patients with the highest confidence predictions. CONCLUSION: Models that included radiomic features outperformed, underscoring their importance for the prediction of BRAF status. A linear model performed similarly to RF but with the added benefit that it can be visualized as a nomogram, improving the explainability of the model. The double threshold technique was able to identify uncertain predictions, enhancing the clinical utility of the model. CLINICAL RELEVANCE STATEMENT: Radiomic features and tumor location are both predictive of BRAF status in pLGG patients. We show that they contain complementary information and depict the optimal model as a nomogram, which can be used as a non-invasive alternative to biopsy. KEY POINTS: • Radiomic features provide additional predictive information for the determination of the molecular subtype of pediatric low-grade gliomas patients, beyond what is embedded in the location of the tumor, which has an established relationship with genetic status. • An advanced thresholding method can help to distinguish cases where machine learning models have a high chance of being (in)correct, improving the utility of these models. • A simple linear model performs similarly to a more powerful random forest model at classifying the molecular subtype of pediatric low-grade gliomas but has the added benefit that it can be converted into a nomogram, which may facilitate clinical implementation by improving the explainability of the model.

Spinal Atypical Teratoid Rhabdoid Tumor in a 14-Year-old Child With Down Syndrome: A Case Report.

Individuals with 21 trisomy or Down syndrome (DS) are known to have an increased risk of acute leukemia, while they rarely develop solid or central nervous system (CNS) tumors. Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive CNS-WHO grade 4 neoplasm, which has never been reported in association with Down syndrome. We present a case study of a 14-year-old female with Down syndrome, diagnosed with intradural-extramedullary spinal ATRT. The chief complaints included bilateral lower limb weakness, constipation, and urinary incontinence for 2 weeks. Surgery was scheduled, and a biopsy was taken. The histopathology, immunohistochemistry, and molecular analysis confirmed the diagnosis of the ATRT-MYC/group 2B subgroup. This report highlights the challenges of managing a patient with complex medical conditions. Moreover, it adds to the existing literature on CNS tumors in patients with Down syndrome.

Very Long-term Survivorship in Pediatric DIPG: Case Report and Review of the Literature.

Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

The in vivo Interaction Landscape of Histones H3.1 and H3.3.

Chromatin structure, transcription, DNA replication, and repair are regulated via locus-specific incorporation of histone variants and posttranslational modifications that guide effector chromatin-binding proteins. Here we report unbiased, quantitative interactomes for the replication-coupled (H3.1) and replication-independent (H3.3) histone H3 variants based on BioID proximity labeling, which allows interactions in intact, living cells to be detected. Along with a significant proportion of previously reported interactions detected by affinity purification followed by mass spectrometry, three quarters of the 608 histone-associated proteins that we identified are new, uncharacterized histone associations. The data reveal important biological nuances not captured by traditional biochemical means. For example, we found that the chromatin assembly factor-1 histone chaperone not only deposits the replication-coupled H3.1 histone variant during S-phase but also associates with H3.3 throughout the cell cycle in vivo. We also identified other variant-specific associations, such as with transcription factors, chromatin regulators, and with the mitotic machinery. Our proximity-based analysis is thus a rich resource that extends the H3 interactome and reveals new sets of variant-specific associations.

Molecular markers for pediatric low-grade glioma.

Over the past decade, our understanding of the molecular drivers of pediatric low-grade glioma (PLGG) has expanded dramatically. These tumors are predominantly driven by RAS/MAPK pathway activating alterations (fusions and point mutations), most frequently in BRAF, FGFR1, and NF1. Furthermore, additional second hits in tumor suppressor genes (TP53, ATRX, CDKN2A) can portend more aggressive behaviour. Accordingly, comprehensive molecular profiling-specifically genetic sequencing, often plus copy number profiling-has become critical for guiding the diagnosis and management of PLGG. In this review, we discuss the most important genetic alterations that inform on classification and prognosis of PLGG, highlighting their diagnostic and therapeutic relevance.

Pediatric-type low-grade gliomas in adolescents and young adults-challenges and emerging paradigms.

Pediatric-type low-grade glioma (PLGG) encompasses a heterogeneous group of WHO grade 1 or 2 tumors and is the most common central nervous system tumor found in children. PLGG extends beyond pediatrics, into adolescents and young adults (AYA, ages 15-40). PLGG represents 25% of all gliomas diagnosed in AYA with differences in tumor location and molecular alterations compared to children, resulting in improved outcome for AYAs. Long-term outcome is excellent, though patients may suffer significant morbidity depending on tumor location. There are differences in treatment practices with radiation used to treat PLGG in AYAs more often than in children. Most PLGG in AYA harbor an alteration in the RAS/MAPK pathway, with limited insight into response to targeted therapy in this age group. This review discusses the epidemiology, current therapeutic approaches, and challenges in the management of PLGG in AYA.

Understanding diffuse leptomeningeal glioneuronal tumors.

INTODUCTION: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances. METHODS: This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted. RESULTS: DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts. CONCLUSION: Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms.

MRI-Based End-To-End Pediatric Low-Grade Glioma Segmentation and Classification.

Purpose: MRI-based radiomics models can predict genetic markers in pediatric low-grade glioma (pLGG). These models usually require tumour segmentation, which is tedious and time consuming if done manually. We propose a deep learning (DL) model to automate tumour segmentation and build an end-to-end radiomics-based pipeline for pLGG classification. Methods: The proposed architecture is a 2-step U-Net based DL network. The first U-Net is trained on downsampled images to locate the tumour. The second U-Net is trained using image patches centred around the located tumour to produce more refined segmentations. The segmented tumour is then fed into a radiomics-based model to predict the genetic marker of the tumour. Results: Our segmentation model achieved a correlation value of over 80% for all volume-related radiomic features and an average Dice score of .795 in test cases. Feeding the auto-segmentation results into a radiomics model resulted in a mean area under the ROC curve (AUC) of .843, with 95% confidence interval (CI) [.78-.906] and .730, with 95% CI [.671-.789] on the test set for 2-class (BRAF V600E mutation BRAF fusion) and 3-class (BRAF V600E mutation BRAF fusion and Other) classification, respectively. This result was comparable to the AUC of .874, 95% CI [.829-.919] and .758, 95% CI [.724-.792] for the radiomics model trained and tested on the manual segmentations in 2-class and 3-class classification scenarios, respectively. Conclusion: The proposed end-to-end pipeline for pLGG segmentation and classification produced results comparable to manual segmentation when it was used for a radiomics-based genetic marker prediction model.

Maternal and childhood medical history and the risk of childhood brain tumours: a case-control study in Ontario, Canada.

BACKGROUND: Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child's early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs. METHODS: The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0-15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child's demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times. RESULTS: Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17-6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35-21.63) and 24-month (OR 6.04, 95% CI 2.06-17.70) lead time before diagnosis. No associations for other medications were found. CONCLUSIONS: This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted.

Using comprehensive genomic and functional analyses for resolving genotype-phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.

Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges.

Malignant transformation of adult-onset pilocytic astrocytoma to diffuse leptomeningeal glioneuronal tumor within the thoracic spine: a case report and review of the literature.

We describe a 31-year-old male who presented with progressive myelopathy from a thoracic pilocytic astrocytoma (PA). Following multiple recurrences and resections, 10 years after his index surgery, pathology revealed diffuse leptomeningeal glioneuronal tumor (DLGNT) with high-grade features. We discuss his clinical course, management, histopathological findings, and present a comprehensive review of spinal PA undergoing malignant transformation in adults and adult-onset spinal DLGNT. To our knowledge, we present the first reported case of adult-onset spinal PA malignant transformation to DLGNT. Our case adds to the paucity of clinical data characterizing such transformations and highlights the importance of developing novel management paradigms.

Radiomic Features Based on MRI Predict Progression-Free Survival in Pediatric Diffuse Midline Glioma/Diffuse Intrinsic Pontine Glioma.

Purpose: Biopsy-based assessment of H3 K27 M status helps in predicting survival, but biopsy is usually limited to unusual presentations and clinical trials. We aimed to evaluate whether radiomics can serve as prognostic marker to stratify diffuse intrinsic pontine glioma (DIPG) subsets. Methods: In this retrospective study, diagnostic brain MRIs of children with DIPG were analyzed. Radiomic features were extracted from tumor segmentations and data were split into training/testing sets (80:20). A conditional survival forest model was applied to predict progression-free survival (PFS) using training data. The trained model was validated on the test data, and concordances were calculated for PFS. Experiments were repeated 100 times using randomized versions of the respective percentage of the training/test data. Results: A total of 89 patients were identified (48 females, 53.9%). Median age at time of diagnosis was 6.64 years (range: 1-16.9 years) and median PFS was 8 months (range: 1-84 months). Molecular data were available for 26 patients (29.2%) (1 wild type, 3 K27M-H3.1, 22 K27M-H3.3). Radiomic features of FLAIR and nonenhanced T1-weighted sequences were predictive of PFS. The best FLAIR radiomics model yielded a concordance of .87 [95% CI: .86-.88] at 4 months PFS. The best T1-weighted radiomics model yielded a concordance of .82 [95% CI: .8-.84] at 4 months PFS. The best combined FLAIR + T1-weighted radiomics model yielded a concordance of .74 [95% CI: .71-.77] at 3 months PFS. The predominant predictive radiomic feature matrix was gray-level size-zone. Conclusion: MRI-based radiomics may predict progression-free survival in pediatric diffuse midline glioma/diffuse intrinsic pontine glioma.

Pakistan National Guidelines for Pediatric High-Grade Gliomas.

Pediatric high-grade glioma (pHGG) is highly malignant central nervous system tumor and constitute 10% of the pediatric gliomas. Effective treatment needs a functioning multi-disciplinary team including pediatric neuro oncologist, neurosurgeon, neuroradiologist, neuropathologist and radiation oncologist. Despite surgical resection, radiotherapy and chemotherapy, most HGG will recur resulting in early death. A significant proportion of HGG occurs in context of cancer predisposition syndromes like Constitutional Mismatch Repair Deficiency (CMMRD) also known as Biallelic Mismatch Repair Deficiency (bMMRD) characterized by high mutational burden. The incidence of HGG with CMMRD is one per million patients. bMMRD is caused by homozygous germline mutations in one of the four Mis Match Repair (MMR) genes (PMS2, MLH1, MSH2, and MSH6). The use of TMZ is now avoided in CMMRD related HGG due to its limited response and known ability to increase the accumulation of somatic mutations in these patients, increasing the risk of secondary tumors. HGG should be managed under the care of multidisciplinary team to receive optimum treatment. This is particularly important for low middle-income countries (LMIC) with limited resources like Pakistan.