Cerebellar Mutism Syndrome and Dentato-Thalamo-Cortical Tract Disruption in Diffusion Tractography Following Surgery for Medulloblastoma.

Background Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentato-thalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS-related symptoms has not been investigated. Purpose To investigate the association between severity of CMS-related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods This retrospective case-control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma. CMS was divided into types 1 (CMS1) and 2 (CMS2). Multivariable logistic regression was used to investigate the relationship between CMS likelihood and DTCT injury. Results Overall, 82 participants with medulloblastoma (mean age, 11.0 years ± 5.2 [SD]; 53 male) and 35 healthy controls (mean age, 18.0 years ± 3.06; 18 female) were included. In participants with medulloblastoma, DTCT was absent bilaterally (AB), absent on the right side (AR), absent on the left side (AL), or present bilaterally (PB), while it was PB in all healthy controls. Odds of having CMS were associated with higher degree of DTCT damage (AB, odds ratio = 272.7 [95% CI: 269.68, 275.75; P < .001]; AR, odds ratio = 14.40 [95% CI: 2.84, 101.48; P < .001]; and AL, odds ratio = 8.55 [95% CI: 1.15, 74.14; P < .001). Left (coefficient = -0.07, χ2 = 12.4, P < .001) and right (coefficient = -0.15, χ2 = 33.82, P < .001) DTCT volumes were negatively associated with the odds of CMS. More participants with medulloblastoma with AB showed CMS1; unilateral DTCT absence prevailed in CMS2. Lower DTCT volumes correlated with more severe ataxia. Unilateral DTCT injury caused ipsilateral dysmetria; AB caused symmetric dysmetria. PB indicated better neurologic outcome. Conclusion The severity of CMS-associated mutism, ataxia, and dysmetria was associated with DTCT damage severity. DTCT damage patterns differed between CMS1 and CMS2. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Dorigatti Soldatelli and Ertl-Wagner in this issue.

[11C]-methionine positron emission tomography in the evaluation of pediatric low-grade gliomas.

Background: [11C]-Methionine positron emission tomography (PET; [11C]-MET-PET) is principally used for the evaluation of brain tumors in adults. Although amino acid PET tracers are more commonly used in the evaluation of pediatric brain tumors, data on [11C]-MET-PET imaging of pediatric low-grade gliomas (pLGG) is scarce. This study aimed to investigate the roles of [11C]-MET-PET in the evaluation of pLGGs. Methods: Eighteen patients with newly diagnosed pLGG and 26 previously treated pLGG patients underwent [11C]-MET-PET met the inclusion and exclusion criteria. Tumor-to-brain uptake ratio (TBR) and metabolic tumor volumes were assessed for diagnostic performances (newly diagnosed, 15; previously treated 26), change with therapy (newly diagnosed, 9; previously treated 7), and variability among different histology (n = 12) and molecular markers (n = 7) of pLGGs. Results: The sensitivity of [11C]-MET-PET for diagnosing pLGG, newly diagnosed, and previously treated combined was 93% for both TBRmax and TBRpeak, 76% for TBRmean, and 95% for qualitative evaluation. TBRmax showed a statistically significant reduction after treatment, while other PET parameters showed a tendency to decrease. Median TBRmax, TBRpeak, and TBRmean values were slightly higher in the BRAFV600E mutated tumors compared to the BRAF fused tumors. Median TBRmax, and TBRpeak in diffuse astrocytomas were higher compared to pilocytic astrocytomas, but median TBRmean, was slightly higher in pilocytic astrocytomas. However, formal statistical analysis was not done due to the small sample size. Conclusions: Our study shows that [11C]-MET-PET reliably characterizes new and previously treated pLGGs. Our study also shows that quantitative parameters tend to decrease with treatment, and differences may exist between various pLGG types.

Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma.

BACKGROUND: Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies. METHODS: We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated. RESULTS: Thirty-three patients (18 male; median age, 5 y) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n=10, 30%). Most tumors were in the cerebral hemispheres (n=22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3±8.3%; the 5-year overall survival (OS) rate was 96.4±4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6±15.2% (p<0.01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways. CONCLUSIONS: pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.

High-grade glioma in infants and young children is histologically, molecularly, and clinically diverse: Results from the SJYC07 trial and institutional experience.

BACKGROUND: High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking. METHODS: A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with nonprotocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and preoperative imaging were analyzed. RESULTS: Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n = 22), occurred in the youngest patients (median age = 0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI: 35.52-79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95%CI: 2.78-99.74%) for HGG (p = 0.0043, p = 0.00013). EFS and OS were not different between IHG and LGG (p = 0.95, p = 0.43). Imaging review showed IHGs are associated with circumscribed margins (p = 0.0047), hemispheric location (p = 0.0010), and intratumoral hemorrhage (p = 0.0149). CONCLUSIONS: HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.

Application of the Rotterdam postoperative cerebellar mutism syndrome prediction model in patients undergoing surgery for medulloblastoma in a single institution.

OBJECTIVE: Postoperative cerebellar mutism syndrome (CMS) develops in up to 40% of children with medulloblastoma. The Rotterdam model (RM) has been reported to predict a 66% risk of CMS in patients with a score of ≥ 100. The aim of this study was to retrospectively apply the RM to an independent cohort of patients with newly diagnosed medulloblastoma and study the applicability of the RM in predicting postoperative CMS. METHODS: Participants had to have their first tumor resection at the authors' institution and be enrolled in the SJMB12 protocol (NCT01878617). All participants underwent structured serial neurological evaluations before and then periodically after completing radiation therapy. Imaging was reviewed by the study neurologist who was blinded to CMS status when reviewing the scans and retrospectively applied RM score to each participant. RESULTS: Forty participants were included (14 females and 26 males). Four (10%) patients had CMS. The median age at tumor resection was 11.7 years (range 3.5-17.8 years). Tumor location was midline in 30 (75%), right lateral in 6 (15%), and left lateral in 4 (10%). The median Evans index was 0.3 (range 0.2-0.4), and 34 (85%) patients had an Evans index ≥ 0.3. Five participants required a ventricular shunt. The median tumor volume was 51.97 cm3 (range 20.13-180.58 cm3). Gross-total resection was achieved in 35 (87.5%) patients, near-total resection in 4 (10%), and subtotal in 1. The median RM score was 90 (range 25-145). Eighteen participants had an RM score of ≥ 100, and of these 16.7% (n = 3) had CMS. Of the 22 patients with an RM score < 100, 1 child developed CMS (4.5%, CI 0.1%-22.8%); 3 of the 18 patients with an RM score ≥ 100 developed CMS (16.7%, CI 3.6%-41.4%). The observed rate of CMS in the cohort of children with an RM score ≥ 100 was significantly lower than the observed rate in the original RM cohort (66.7%, CI 51%-80.0%, p < 0.001). A greater risk of CMS in patients with an RM score ≥ 100 could not be confirmed (p = 0.31). CONCLUSIONS: At the authors' institution, the incidence of CMS in patients who had an RM ≥ 100 was significantly lower than the RM cohort. These findings raise questions regarding generalizability of RM; however, fewer cases of CMS and a relatively small cohort limit this conclusion.

Molecular Classification Improves Therapeutic Options for Infants and Young Children With Medulloblastoma.

Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.

Phase II study of alisertib as a single agent for treating recurrent or progressive atypical teratoid/rhabdoid tumor.

BACKGROUND: Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. METHODS: We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged <22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m2 as enteric-coated tablets or 60 mg/m2 as liquid formulation) on Days 1-7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental pharmacokinetics. Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks. RESULTS: SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for >12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h). CONCLUSIONS: Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.

Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.

Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Primary cilia control translation and the cell cycle in medulloblastoma.

The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis are unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding ß-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type-specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, thereby providing new frameworks for studying cilium function in normal and pathologic conditions.

Combination of Ribociclib and Gemcitabine for the Treatment of Medulloblastoma.

Group3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3MBs. Ribociclib central nervous system (CNS) penetration was assessed by in vivo microdialysis and by IHC and gene expression studies and found to be CNS-penetrant. Tumors from mice treated with short term oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice intracranially implanted with luciferase-labeled mouse and human G3MBs. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Expression-based gene activity and cell state analysis investigated the effects of the combination after short- and long-term treatments. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell-cycle progression and DNA damage response, and an increase in the activity and expression of genes implicated in neuronal identity and neuronal differentiation. Our findings in both mouse and human patient-derived orthotopic xenograft models suggest that ribociclib and gemcitabine combination therapy warrants further investigation as a treatment strategy for children with G3MB.

Reducing Wait Time in a High-volume Pediatric Neuro-oncology Clinic by Optimizing Process Flow: A Quality Improvement Project.

Introduction: Hospital wait time (WT) influences healthcare quality and patient satisfaction. Long WTs are distressful for patients and considered substandard healthcare delivery. Pediatric hematology/oncology patients with complex medical conditions frequently need multiple appointments in a day, making their scheduling very challenging. Here, we report a quality improvement (QI) project aimed to decrease the percentage of patients waiting >30 minutes before room placement in the neuro-oncology clinic. Methods: We measured WT from when the patient reported to the clinic (or, for those arriving early, from scheduled appointment) to when the patient got an exam room. We collected data by random sampling and collected baseline data over the initial 4 weeks; generated process mapping and Pareto charts to identify reasons for delayed patient placement in rooms; and used iterative Plan-Do-Study-Act (PDSA) cycles to test interventions. We used Run charts and Shewhart charts for data analysis. Results: Our baseline data analyses showed provider and room availability as critical reasons for delayed room placement (38.4% and 30%, respectively). We also completed related PDSA improvement cycles. The median percent of patients waiting >30 minutes decreased from 21% to 13%. The median average waiting time decreased from 21 to 11 minutes. Conclusion: Using structured QI methodology, we decreased the percent of patients waiting >30 minutes before room placement and overall WTs. We developed a strategy for continuous improvement and future interventions. Furthermore, our results suggest that QI projects, which account for the complexity of hospital systems, can improve patient flow throughout the hospital.

The posterior fossa syndrome questionnaire: using science to inform practice.

INTRODUCTION: Up to 34% of patients with medulloblastoma develop posterior fossa syndrome (PFS) following brain tumor resection and have increased risk of long-term neurocognitive impairments. Lack of agreement in conceptualization and diagnosis of PFS calls for improvements in diagnostic methods. The current study aimed to describe psychometric properties of a new posterior fossa syndrome questionnaire (PFSQ). METHODS: The PFSQ was informed by prior research and developed by a multidisciplinary team with subject matter expertise. Participants (N = 164; 63.4% Male; 78.7% White; Mage at diagnosis = 10.38 years, SD = 5.09, range 3-31 years) included patients with newly diagnosed medulloblastoma enrolled in the SJMB12 clinical trial. Forty-four patients (26.8%) were classified as having PFS based on attending physician's post-surgical yes/no report. A PFSQ was completed by a neurologist within 2 weeks of coming to St. Jude Children's Research Hospital for adjuvant treatment, irrespective of suspicion for PFS. RESULTS: PFSQ items ataxia (100.00%), dysmetria (95.45%), and speech/language changes (79.55%) were most sensitive. However, ataxia (26.50%) and dysmetria (46.61%) demonstrated low specificity. Speech/language changes (81.36%), mutism (95.76%), orofacial apraxia (98.29%) and irritability (96.61%) had high specificity. A principal component analysis found four components: (1) speech/language changes, (2) apraxias (including mutism), (3) motor/oromotor, and (4) emotional lability. CONCLUSIONS: The PFSQ is a dimensional diagnostic approach that can be used to improve diagnostic consistency across clinical and research groups to help accelerate understanding of PFS etiology, identify surgical correlates of risk, predict long-term impairments, and develop targeted interventions. Additional measure validation, including correlation with symptom resolution, is required.

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG).

BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

Low-coverage whole-genome sequencing of cerebrospinal-fluid-derived cell-free DNA in brain tumor patients.

This protocol summarizes the pipeline for analysis of tumor-derived cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) using low-coverage whole-genome sequencing (lcWGS). This approach enables resolution of chromosomal and focal copy-number variations (CNVs) as oncologic signatures, particularly for patients with central nervous system tumors. Our strategy tolerates sub-nanogram cfDNA input and is thus optimized for CSF samples where cfDNA yields are typically low. Overall, the detection of tumor-specific signatures in CSF-derived cfDNA is a promising biomarker for personalization of brain-tumor therapy. For complete details on the use and execution of this protocol, please refer to Liu et al. (2021).

11C-Methionine PET for Identification of Pediatric High-Grade Glioma Recurrence.

Differentiating tumor recurrence or progression from pseudoprogression during surveillance of pediatric high-grade gliomas (PHGGs) using MRI, the primary imaging modality for evaluation of brain tumors, can be challenging. The aim of this study was to evaluate whether 11C-methionine PET, a molecular imaging technique that detects functionally active tumors, is useful for further evaluating MRI changes concerning for tumor recurrence during routine surveillance. Methods: Using 11C-methionine PET during follow-up visits, we evaluated 27 lesions in 26 patients with new or worsening MRI abnormalities for whom tumor recurrence was of concern. We performed quantitative and qualitative assessments of both 11C-methionine PET and MRI data to predict the presence of tumor recurrence. Further, to assess for an association with overall survival (OS), we plotted the time from development of the imaging changes against survival. Results: Qualitative evaluation of 11C-methionine PET achieved 100% sensitivity, 60% specificity, and 93% accuracy to correctly predict the presence of tumors in 27 new or worsening MRI abnormalities. Qualitative MRI evaluation achieved sensitivity ranging from 86% to 95%, specificity ranging from 40% to 60%, and accuracy ranging from 85% to 89%. The interobserver agreement for 11C-methionine PET assessment was 100%, whereas the interobserver agreement was only 50% for MRI (P < 0.01). Quantitative MRI and 11C-methionine PET evaluation using receiver-operating characteristics demonstrated higher specificity (80%) than did qualitative evaluations (40%-60%). Postcontrast enhancement volume, metabolic tumor volume, tumor-to-brain ratio, and presence of tumor as determined by consensus MRI assessment were inversely associated with OS. Conclusion:11C-methionine PET has slightly higher sensitivity and accuracy for correctly predicting tumor recurrence, with excellent interobserver agreement, than does MRI. Quantitative 11C-methionine PET can also predict OS. These findings suggest that 11C-methionine PET can be useful for further evaluation of MRI changes during surveillance of previously treated PHGGs.

Rare cases of medulloblastoma with hypermutation.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor of childhood and is considered a tumor with low mutational burden (~1 Mut/Mb). Therefore, though the medulloblastoma genomes have been extensively characterized in literature, reports on potential hypermutations and underlying mutagenic processes in medulloblastomas are limited. AIM: In this report, we studied the landscape of mutational burden in primary and recurrent medulloblastoma. Furthermore, we wanted to understand the differences in underlying mutagenic mechanisms in medulloblastoma with low and high mutational burdens. METHODS: Fifty-three primary and recurrent medulloblastoma genomic sequence were downloaded from the European Genome Archive as BAM files. Thirty-three cases were obtained from formalin-fixed paraffin-embedded tissues from pathology diagnostic archives of Spectrum Health and Cooperative Human Tissue Network. Somatic mutations were called using Mutect2, following best practices guidelines for Genome Analysis Toolkit V4. Mutational signatures were analyzed using deconstructSigs. RESULTS: We identified nine medulloblastoma cases with high mutational burden (>5 Mut/Mb). Of them, five cases met the criteria of hypermutation (>10Mut/Mb), two of the five tumors had canonical mutations in the POLE proof-reading domain, where a large proportion of mutations in these tumor genomes contributed to signature 10. The hypermutated cases also demonstrated mutational signatures 14, 15, and 21, indicating the role of mis match repair deficiency in their mutagenesis. Of the four known molecular subgroups in medulloblastoma-SHH, WNT, Group 3, and Group 4-both the POLE-mutated cases belonged to the SHH subgroup. This report identifies rare cases of hypermutation in medulloblastoma driven by defects in DNA repair mechanisms. CONCLUSION: Hypermutation in medulloblastoma can impact therapeutic decisions, especially at recurrence in otherwise fatal high risk SHH-medulloblastomas. A defect in DNA repair leading to SHH -medulloblastoma is yet another important mechanism that should be further investigated in the genesis of these tumors. Therefore, this report provides important scientific and clinical rationale for future research looking for incidence of hypermutation in large cohorts of medulloblastoma patients.

Circulating tumor DNA profiling for childhood brain tumors: Technical challenges and evidence for utility.

Cell-free DNA (cfDNA) profiling as liquid biopsy has proven value in adult-onset malignancies, serving as a patient-specific surrogate for residual disease and providing a non-invasive tool for serial interrogation of tumor genomics. However, its application in neoplasms of the central nervous system (CNS) has not been as extensively studied. Unique considerations and methodological challenges exist, which need to be addressed before cfDNA studies can be incorporated as a clinical assay for primary CNS diseases. Here, we review the current status of applying cfDNA analysis in patients with CNS tumors, with special attention to diagnosis in pediatric patients. Technical concerns, evidence for utility, and potential developments are discussed.