Proton beam therapy in a patient with secondary glioblastoma (32 years after postoperative irradiation of medulloblastoma): case report and literature review.

OBJECTIVE: This report details the experience of a patient who developed a second primary glioblastoma (GB), offering insights into the treatment process and reviewing relevant literature. CASE PRESENTATION: A male patient, who was diagnosed with medulloblastoma at age 9, received treatment with cobalt-60 craniospinal irradiation (CSI) (36 Gy/20 fractions) and a tumor bed boost (total of 56 Gy). After 32 years, at age 41, an MRI revealed a space-occupying mass in the left cerebellar hemisphere. Surgical resection was performed, and postoperative pathology confirmed a diagnosis of radiation-induced glioblastoma (RIGB). Given the history of irradiation and the current tolerability of brainstem doses, proton beam therapy (PBT) combined with Temozolomide (75 mg/m2) was chosen. The treatment plan included 60 Gy on the gross tumor bed and 54 Gy on the clinical target volume, delivered in 30 fractions. The patient underwent regular follow-up and achieved a complete response. CLINICAL DISCUSSION: For childhood cancer survivors, the development of a second primary tumor significantly impacts prognosis. RIGB is a rare form of secondary tumor with distinct molecular characteristics compared to primary GB and recurrent secondary GB. Molecular markers such as IDH and MGMT status can help differentiate between primary GB, recurrent secondary GB, and radiation-induced secondary GB in patients with a history of prior radiation therapy. Surgical resection remains a primary treatment option, while PBT is preferred for postoperative treatment due to its superior protection of normal tissues and the ability to deliver high-dose irradiation. CONCLUSION: RIGB is a rare second primary tumor that requires strategic molecular profiling and individualized management. Proton beam therapy provides effective high-dose irradiation in the postoperative phase and is the preferred treatment option for such cases.

Treatment Continuity and Bone Marrow Suppression in Whole-Brain and Whole-Spinal Cord Radiotherapy for Medulloblastoma Patients.

Background: This study investigated the factors influencing treatment continuity and bone marrow suppression in whole-brain and whole-spinal cord radiotherapy for medulloblastoma, providing a clinical reference for mitigating the impact of hematological suppression on radiotherapy continuity. Methods: A retrospective analysis was conducted on patients with medulloblastoma who underwent craniospinal irradiation (CSI) radiotherapy at our hospital between August 2019 and December 2023. According to the inclusion and exclusion criteria, a total of 87 patients were enrolled. The bone marrow suppression status, clinical data, and radiotherapy dose data of the enrolled patients were recorded, and correlation analyses were performed. Based on the correlation results, further group comparisons were subsequently conducted. Results: Overall, 22.99% (20 out of 87) of the patients experienced treatment interruption (median duration, 6.5 [5, 8] days), typically during the 12th (7.5, 14.75) radiotherapy session. Treatment continuity was weakly correlated with age and treatment modality, and the timing of interruptions was weakly correlated with dosage and treatment modality. Bone marrow suppression severity was weakly correlated with age, body mass index (BMI), and treatment modality. Treatment modality and age were found to be independent predictors of treatment continuity and the degree of bone marrow suppression, respectively. Subgroup comparisons revealed differences in the severity of bone marrow suppression, grade of hematological toxicity, and timing of interruption depending on the treatment modality, dosage, and sex (P < .05). Conclusions: Timely monitoring of hematological changes, especially in the middle and posterior segments after radiotherapy, is crucial. Treatment with helical tomotherapy, male sex, younger age, and lower BMI during radiotherapy are indicators of greater clinical attention.

Systematic transcriptomic analysis of childhood medulloblastoma identifies N6- methyladenosine-dependent lncRNA signatures associated with molecular subtype, immune cell infiltration, and prognosis.

Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

Functional MRI Assessment of Brain Activity Patterns Associated with Reading in Medulloblastoma Survivors.

Medulloblastoma, a malignant brain tumor primarily affecting children, poses significant challenges to patients and clinicians due to its complex treatment and potential long-term cognitive consequences. While recent advancements in treatment have significantly improved survival rates, survivors often face cognitive impairments, particularly in reading, impacting their quality of life. According to the double deficit theory, reading impairments are caused by deficits in one or both of two independent reading-related functions: phonological awareness and rapid visual naming. This longitudinal study investigates neurofunctional changes related to reading in medulloblastoma survivors in comparison to controls using functional MRI acquired during rapid automatized naming tasks over three annual visits. Support vector machine classification of functional MRI data reveals a progressive divergence in brain activity patterns between medulloblastoma survivors and healthy controls over time, suggesting delayed effects of cancer treatment on brain function. Alterations in brain regions involved in visual processing and orthographic recognition during rapid naming tasks imply disruptions in the ventral visual pathway associated with normal orthographic processing. These alterations are correlated with performance in tasks involving sound awareness, reading fluency, and word attack. These findings underscore the dynamic nature of post-treatment neurofunctional alterations and the importance of early identification and intervention to address cognitive deficits in survivors.

Geometric target margin strategy of proton craniospinal irradiation for pediatric medulloblastoma.

In proton craniospinal irradiation (CSI) for skeletally immature pediatric patients, a treatment plan should be developed to ensure that the dose is uniformly delivered to all vertebrae, considering the effects on bone growth balance. The technical (t) clinical target volume (CTV) is conventionally set by manually expanding the CTV from the entire intracranial space and thecal sac, based on the physician's experience. However, there are differences in contouring methods among physicians. Therefore, we aimed to propose a new geometric target margin strategy. Nine pediatric patients with medulloblastoma who underwent proton CSI were enrolled. We measured the following water equivalent lengths for each vertebra in each patient: body surface to the dorsal spinal canal, vertebral limbus, ventral spinal canal and spinous processes. A simulated tCTV (stCTV) was created by assigning geometric margins to the spinal canal using the measurement results such that the vertebral limb and dose distribution coincided with a margin assigned to account for the uncertainty of the proton beam range. The stCTV with a growth factor (correlation between body surface area and age) and tCTV were compared and evaluated. The median values of each index for cervical, thoracic and lumber spine were: the Hausdorff distance, 9.14, 9.84 and 9.77 mm; mean distance-to-agreement, 3.26, 2.65 and 2.64 mm; Dice coefficient, 0.84, 0.81 and 0.82 and Jaccard coefficient, 0.50, 0.60 and 0.62, respectively. The geometric target margin setting method used in this study was useful for creating an stCTV to ensure consistent and uniform planning.

Consensus guidelines for the management of posterior fossa tumour for low- and middle-income countries.

The posterior fossa is a limited compartment therefore lesions compressing its structures can result in devastating outcomes. It can cause significant neurological deficit due to mass effect on critical structures and hydrocephalus. Due to the nature of the infratentorial region, urgent surgical intervention is often the first-line option. Surgical neuro-oncologists guide patients and caregivers through the course of this disease and to inform them about the various options for management and long-term outcome optimisation. There is currently conflicting data; however, institutional experiences can guide us towards achieving improvements in surgical outcomes and quality of life. Advances in molecular classifications coupled with highdose radiation treatment improve our capacity for improving overall survival in these patients. Common childhood tumours are ependymomas, medulloblastomas, and juvenile pilocytic astrocytomas, while adults often present with metastases, and less commonly, cerebellar haemangioblastomas and gliomas. This paper outlines management strategies with consideration for multidisciplinary care and resourcelimited settings.

Consensus guidelines for the management of pediatric medulloblastoma in low and middle-income countries.

The management of medulloblastoma, a pediatric brain tumor, has evolved significantly with the advent of genomic subgrouping, yet morbidity and mortality remain high in LMICs like Pakistan due to inadequate multidisciplinary care infrastructure. This paper aims to establish evidence-based guidelines tailored to the constraints of such countries. An expert panel comprising neuro-oncologists, neurosurgeons, radiologists, radiation oncologists, neuropathologists, and pediatricians collaborated to develop these guidelines, considering the specific challenges of pediatric brain tumor care in Pakistan. The recommendations cover various aspects of medulloblastoma treatment, including pre-surgical workup, neurosurgery, neuropathology, chemotherapy, radiation therapy, and supportive care. They offer both minimum required and additional optional protocols for more advanced centers, ensuring comprehensive patient management with attention to complications and complexities encountered in Pakistan. The paper's consensus guidelines strive for uniformity in healthcare delivery and address significant gaps in diagnosis, treatment, and follow-up of pediatric medulloblastoma patients.

Medulloblastoma in a 13-Year-Old Female: A Comprehensive Case Report.

The majority of children's brain cancers are posterior fossa tumours, which include brainstem gliomas, medulloblastomas (MBs), juvenile pilocytic astrocytomas, and ependymomas. This report details a 13-year-old female presenting with headache, nausea, and ataxia. With typical magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) results, the MRI indicated a solid lesion in the fourth ventricle, producing obstructive hydrocephalus. Pilocytic astrocytoma, ependymoma, MB, and other conditions are examples of differential diagnoses. In addition to underscoring the need for early intervention to enhance prognosis and outcomes for paediatric patients with posterior fossa tumours, the case highlights the vital role that sophisticated imaging plays in early detection and therapy.

Tenovin-6 exhibits inhibitory effects on the growth of Sonic Hedgehog (SHH) medulloblastoma, as evidenced by both in vitro and in vivo studies.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Within MB, tumors driven by the Sonic Hedgehog (SHH) pathway represent the most heterogeneous subtype, known as SHH subtype medulloblastoma (SHH-MB). Tenovin-6, a recognized p53 activator, has been demonstrated to inhibit autophagy and modulate sirtuin activity, underscoring its potential as a novel therapeutic agent across various malignancies. However, its efficacy in treating SHH-MB remains unexplored. This study aims to investigate the inhibitory effects of tenovin-6 on SHH-MB and elucidate its underlying signaling pathways. We assessed the impact of tenovin-6 on cell proliferation through the CCK-8 and colony formation assays. The scratch and transwell invasion assays were utilized to evaluate the drug's effects on metastasis. Apoptosis and reactive oxygen species (ROS) levels were measured using flow cytometry. Potential signaling pathways were identified via transcriptomics and quantitative PCR (qPCR). Our in vivo studies involved a mouse xenograft model to explore tenovin-6's anticancer efficacy against SHH-MB. The findings indicate that tenovin-6 not only inhibits cell proliferation and metastasis in SHH-MB cell lines but also promotes apoptosis, which is closely linked to its proliferation-inhibiting properties. Additionally, animal experiments confirmed that tenovin-6 suppresses MB growth in vivo. We discovered that tenovin-6 reduces intracellular ROS levels and inhibits autophagy in SHH-MB by disrupting the fusion of autophagosomes with lysosomes, likely through inducing autophagosome formation.

Arrested development: the dysfunctional life history of medulloblastoma.

Medulloblastoma is a heterogeneous embryonal tumor of the cerebellum comprised of four distinct molecular subgroups that differ in their developmental origins, genomic landscapes, clinical presentation, and survival. Recent characterization of the human fetal cerebellum at single-cell resolution has propelled unprecedented insights into the cellular origins of medulloblastoma subgroups, including those underlying previously elusive groups 3 and 4. In this review, the molecular pathogenesis of medulloblastoma is examined through the lens of cerebellar development. In addition, we discuss how enhanced understanding of medulloblastoma origins has the potential to refine disease modeling for the advancement of treatment and outcomes.

The Proteasome and Cul3-Dependent Protein Ubiquitination Is Required for Gli Protein-Mediated Activation of Gene Expression in the Hedgehog Pathway.

Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin-proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway.

Enhancing targeted therapy by combining PI3K and AKT inhibitors with or without cisplatin or vincristine in medulloblastoma cell lines in vitro.

AIM: Despite current intensive therapy, survival rates of medulloblastoma (MB) greatly vary according to molecular subgroup, so new therapies are needed. Recently, we showed that combining phosphoinositide 3-kinase (PI3K), fibroblast growth factor receptor and cyclin-dependent-kinase-4/6 inhibitors (BYL719, JNJ-42756493 and PD-0332991, respectively) or poly (ADP-ribose) polymerase (PARP) and WEE-1 inhibitors (BMN673 and MK1775 respectively) had synergistic effects on MB. Here, in continuation, we investigated the effects of single and combined administrations of PI3K and AKT inhibitors, with/without cisplatin or vincristine on adherent or suspension cultures of different MB subgroups as well as in a spheroid culture of one MB line. MATERIAL AND METHODS: MB cell lines DAOY, UW228-3, D425, Med8A, and D283 were treated with single and combined administrations of BYL719, AZD5363, cisplatin or vincristine and followed for viability, cell confluence, cytotoxicity, and cell migration. DAOY was also tested as a spheroid culture. KEY FINDINGS: Single BYL719, AZD5363, cisplatin, or vincristine administrations gave dose-dependent responses with regard to inhibition of viability and cell confluence. Combining AZD5363 with BYL719, cisplatin or vincristine resulted in synergistic effects with regard to inhibition of viability in all cell lines, and confluence and migration in all tested cell lines. The administration of single and combined treatments to DAOY spheroids produced largely similar effects. SIGNIFICANCE: This study provides pre-clinical evidence that AKT inhibitors combined with PI3K inhibitors, cisplatin, or vincristine exhibit additive/synergistic anti-MB activity, and lower doses could be used. The latter also applied to one MB line grown as spheroids, further supporting their future potential use.

Direct Administration of Chemotherapy and Other Agents into the Fourth Ventricle to Treat Recurrent Malignant Brain Tumors in Children.

Direct administration of chemotherapy and other agents into the fourth ventricle of the brain is a novel approach to treating recurrent malignant posterior fossa brain tumors in children. Candidates for this treatment approach include patients with recurrent medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor, and potentially other neoplasms that originate in the fourth ventricle or elsewhere in the posterior fossa. In this chapter, the authors first explain the rationale for considering fourth ventricular drug infusions in patients with recurrent malignant posterior fossa tumors. We then summarize the results of translational experiments conducted in piglets and non-human primates that demonstrated safety and favorable pharmacokinetics. These translational experiments led to several pilot human clinical trials, and the results of these trials are reviewed. Finally, currently open clinical trials testing infusion of various agents into the fourth ventricle are discussed, and thoughts about potential future directions are shared.

AB051. Multiple meningiomas developed outside the radiation field after cranial irradiation: a case report.

BACKGROUND: Cranial irradiation has well-known long-term side effects, including radiation-induced neoplasms and vasculopathy. This report describes a case of aggressive and rapid-growing multiple meningiomas developed outside the radiation field after the treatment of medulloblastoma. CASE DESCRIPTION: A 6-year-old boy underwent surgery (gross total resection) and radiotherapy (19.8 Gy for posterior fossa only) against medulloblastoma in the 4th ventricle. The patient could not receive further craniospinal irradiation because of ventriculoperitoneal shunt-related complications. Eighteen years after the radiotherapy, the first meningioma developed in the right temporal convexity, without recurrence of medulloblastoma. It was left untreated because it was asymptomatic. Three years later, the meningioma grew from 0.6 to 6.3 cm3 in volume and another large meningioma (22.1 cm3) developed in the left temporal convexity with additional small meningioma in the right frontal convexity. The left large temporal meningioma showed aggressive nature invading the adjacent temporal bone and temporalis muscle. It was completely resected and the histology revealed as transitional meningioma with 2% of Ki-67. Another new meningioma was identified on the right cerebellar convexity three years post-craniotomy. Subsequent follow-up indicated a progressive increase in the tumor size and gamma knife radiosurgery was performed with right frontal convexity small meningioma. The patient is currently under ongoing surveillance through follow-up assessments. CONCLUSIONS: For patients who received radiotherapy at a young age, clinicians should consider the possibility of secondary neoplasm development even outside the radiation field. Careful imaging follow-up and surgical management are warranted because of the aggressive nature of secondary tumors even though benign in histology.

Rodent models of tumours of the central nervous system.

Modelling of human diseases is an essential component of biomedical research, to understand their pathogenesis and ultimately, develop therapeutic approaches. Here, we will describe models of tumours of the central nervous system, with focus on intrinsic CNS tumours. Model systems for brain tumours were established as early as the 1920s, using chemical carcinogenesis, and a systematic analysis of different carcinogens, with a more refined histological analysis followed in the 1950s and 1960s. Alternative approaches at the time used retroviral carcinogenesis, allowing a more topical, organ-centred delivery. Most of the neoplasms arising from this approach were high-grade gliomas. Whilst these experimental approaches did not directly demonstrate a cell of origin, the localisation and growth pattern of the tumours already pointed to an origin in the neurogenic zones of the brain. In the 1980s, expression of oncogenes in transgenic models allowed a more targeted approach by expressing the transgene under tissue-specific promoters, whilst the constitutive inactivation of tumour suppressor genes ('knock out')-often resulted in embryonic lethality. This limitation was elegantly solved by engineering the Cre-lox system, allowing for a promoter-specific, and often also time-controlled gene inactivation. More recently, the use of the CRISPR Cas9 technology has significantly increased experimental flexibility of gene expression or gene inactivation and thus added increased value of rodent models for the study of pathogenesis and establishing preclinical models.

Long-term outcome of the Milano-HART strategy for high-risk medulloblastoma, including the impact of molecular subtype.

BACKGROUND: We applied the strategy for M+ medulloblastoma across all high-risk subgroups, including LC/A histology, TP53 mutations, MYC/MYCN amplification. METHODS: Patients over 3-years-old received,after surgery,staging and histo-biological analysis,sequential high-dose-methotrexate(HD-MTX),high-dose-etoposide(HD-VP16),high-dose-cyclophosphamide(HD-Cyclo),high-dose-carboplatin(HD-Carbo).Hyperfractionated-accelerated-radiotherapy-craniospinal(HART-CSI),administered in twice daily 1.3 Gy-fractions reached a total dose tailored to the patients' age and pre-radiation response to chemotherapy(CT): 31.2 Gy if under 10-years-old and complete response(CR) or partial response(PR) obtained or absence of metastatic disease,39 Gy in other/older patients.Boosts to posterior fossa/residual metastatic(M+) deposits were given up to a total dose of 60 Gy/9 Gy,respectively,but avoided if metastatic nodules were very big or patients very young.Two courses of high-dose-thiotepa were delivered in case of not CR/PR after pre-radiotherapy(RT) phase and in all M0 patients either - pre/post HART.Subgrouping was performed where tissue was available. RESULTS: Eighy-nine patients were enrolled,median age 8.8 years,median follow up 136 months.Overall-survival(OS) and event-free-survival(EFS) at 5/15 years were 75.9/66.5% and 68.2/65.3%, respectively;5/28 fatal events were not related to relapse(three developed secondary malignancies).Sex,age less than 10 years,histological subtype,presence of MYC/MYCN amplification,reduction in CSI dose,omission of RT-boosts,implementation of myeloablative therapy,presence/absence of metastases did not impact prognosis.Patients progressing after pre-HART CT(14/89) and stable-disease(SD)+PD after HART(10/89) negatively affected outcome(P<0.001).Subgrouping in 66/89 patients' samples demonstrated a significantly worse EFS for patients with Sonic Hedgehog(SHH)-tumors(#15, 2 with constitutional TP53-mutations) vs. group 3 and 4(15 and 29 patients, respectively, group3/4 in 7).Patients younger than 10 received lower CSI doses if stratified according to CT response. CONCLUSIONS: This strategy, partly adopted in the ongoing SIOPE protocol,confirmed improved EFS and OS over previously reported outcomes in all high-risk categories;SHH tumors appeared the most aggressive.

Use of Neuroendoscopy in Combination Treatment of a Three-Year-Old Patient With Primary Disseminated Medulloblastoma: A Case Report.

A three-year-four-month-old boy with primary disseminated medulloblastoma M3 stage and secondary occlusive hydrocephalus underwent an endoscopic triventriculocisternostomy (ETVC) and tumor biopsy, followed by ventriculoperitoneal shunt (VPS) placement due to ETVC failure. The treatment regimen, which included intensive induction chemotherapy, proton beam therapy (PBT), and maintenance chemotherapy, led to significant clinical improvement and a complete radiological response. Four years post-treatment, the child remains in remission, illustrating the effectiveness of a multimodal approach in managing complex cases of medulloblastoma in pediatric patients.

A Case Report on Radiation-Induced Cerebral Vasculopathy in a Long-Term Survivor of Childhood Medulloblastoma.

This case report discusses a patient diagnosed with radiation-induced cerebral vasculopathy who presented after cerebral irradiation of metastatic medulloblastoma to raise awareness of radiation-induced cerebral vasculopathy. Because radiation therapy has revolutionized treatment for children with brain cancers, radiation-induced vasculopathy is becoming ever more prominent, and its recognition is crucial to implementing early treatment strategies to improve patient outcomes. Currently, medical management is poorly defined, largely unexamined, and poorly studied. Because the clinical features of this disease are nonspecific, radiation-induced cerebral vasculopathy remains a diagnosis of exclusion and an essential addition to the differential diagnosis. Discussion regarding standardized treatment, screening, and guidelines is necessary to improve treatment and survival.