Dosimetric impact of adding non-coplanar arcs for scalp-avoidance whole-brain irradiation with volumetric-modulated arc radiotherapy on scalp dose reduction in pediatric patients with medulloblastomas.

PURPOSE: We performed scalp-avoidance whole-brain irradiation with volumetric-modulated arc therapy (SAWB-VMAT) as a component of craniospinal irradiation. In SAWB-VMAT with two coplanar arcs, radiation oncologists and medical physicists sometimes experience difficulty in reducing the dose to the scalp to below the cut-off equivalent dose in 2 Gy per fraction (assuming α/ß = 2) to 50% (EQD50%scalp ). To investigate the advantage of adding coplanar or non-coplanar arcs in reducing the dose to the scalp in SAWB-VMAT, we conducted a planning study to compare the EQD50%scalp , the dose to other organs at risk (OARs), and target coverage in VMAT with two coplanar arcs (Co2arcVMAT), VMAT with three coplanar arcs (Co3arcVMAT), and VMAT with two coplanar and two non-coplanar arcs (NcVMAT). METHODS: Co2arcVMAT, Co3arcVMAT, and NcVMAT plans were created for 10 pediatric patients with medulloblastoma. The planned target volume (PTV) included the regions of the whole brain, cervical spinal cord, cerebrospinal fluid space, and intervertebral foramen. The EQD50%scalp was evaluated separately for four areas (top, back, left, and right) in each case. The prescribed dose for the PTV was 35.2 Gy in 22 fractions. RESULTS: The median EQD50%scalp of the top area was 21.9 , 22.1 , and 18.3 Gy for Co2arcVMAT, Co3arcVMAT, and NcVMAT, respectively. The EQD50%scalp of the top area was significantly reduced in NcVMAT compared to those in Co2arcVMAT and Co3arcVMAT (p < 0.05). The median EQD50%scalp of the top area for NcVMAT was < 19.9 Gy, which is the cut-off dose for severe permanent alopecia. There were no significant differences in EQD50%scalp in the three other areas, the dose to other OARs, or the dose coverage of PTV among the three techniques. CONCLUSION: NcVMAT could reduce the EQD50%scalp of the top area below the cut-off dose of 19.9 Gy. NcVMAT appears to be a promising treatment technique for SAWB-VMAT.

Targeting Angiogenic Factors for the Treatment of Medulloblastoma.

OPINION STATEMENT: Medulloblastoma (MB) is the most frequent pediatric brain tumor. Despite conventional therapy, MB patients have high mortality and morbidity rates mainly due to the incomplete understanding of the molecular and cellular processes involved in development of this cancer. Similar to other solid tumors, MB demonstrated high endothelial cell proliferation and angiogenic activity, wherein new blood vessels arise from the pre-existing vasculature, a process named angiogenesis. MB angiogenesis is considered a hallmark for MB development, progression, and metastasis emphasizing its potential target for antitumor therapy. However, angiogenesis is tightly regulated by a set of angiogenic factors making it a complex process to be targeted. Although agents targeting these factors and their receptors are early in development, the potential for their targeting may translate into improvement in the clinical care for MB patients. In this review, we focus on the most potent angiogenic factors and their corresponding receptors, highlighting their basic properties and expression in MB. We describe their contribution to MB tumorigenesis and angiogenesis and the potential therapeutic targeting of these factors.

Immunosuppression in Medulloblastoma: Insights into Cancer Immunity and Immunotherapy.

OPINION STATEMENT: Medulloblastoma (MB) is the most common pediatric brain malignancy, with a 5-year overall survival (OS) rate of around 65%. The conventional MB treatment, comprising surgical resection followed by irradiation and adjuvant chemotherapy, often leads to impairment in normal body functions and poor quality of life, especially with the increased risk of recurrence and subsequent development of secondary malignancies. The development and progression of MB are facilitated by a variety of immune-evading mechanisms such as the secretion of immunosuppressive molecules, activation of immunosuppressive cells, inhibition of immune checkpoint molecules, impairment of adhesive molecules, downregulation of the major histocompatibility complex (MHC) molecules, protection against apoptosis, and activation of immunosuppressive pathways. Understanding the tumor-immune relationship in MB is crucial for effective development of immune-based therapeutic strategies. In this comprehensive review, we discuss the immunological aspect of the brain, focusing on the current knowledge tackling the mechanisms of MB immune suppression and evasion. We also highlight several key immunotherapeutic approaches developed to date for the treatment of MB.

Drug Repurposing in Medulloblastoma: Challenges and Recommendations.

OPINION STATEMENT: Medulloblastoma is the most frequently diagnosed primary malignant brain tumor among children. Currently available therapeutic strategies are based on surgical resection, chemotherapy, and/or radiotherapy. However, majority of patients quickly develop therapeutic resistance and are often left with long-term therapy-related side effects and sequelae. Therefore, there remains a dire need to develop more effective therapeutics to overcome the acquired resistance to currently available therapies. Unfortunately, the process of developing novel anti-neoplastic drugs from bench to bedside is highly time-consuming and very expensive. A wide range of drugs that are already in clinical use for treating non-cancerous diseases might commonly target tumor-associated signaling pathways as well and hence be of interest in treating different cancers. This is referred to as drug repurposing or repositioning. In medulloblastoma, drug repurposing has recently gained a remarkable interest as an alternative therapy to overcome therapy resistance, wherein existing non-tumor drugs are being tested for their potential anti-neoplastic effects outside the scope of their original use.

Challenges in the Diagnosis of Medulloblastoma Recurrence at an Unusual Site in a Patient With Prader-Willi Syndrome.

Medulloblastoma is the most common malignant pediatric brain tumor. Survival rates range between 50% and 80% depending on histology and other biologic features, metastases, and treatment approach. Prader-Willi syndrome (PWS) is a genetically inherited disorder characterized by dysmorphic features, mental retardation, obesity, and hypogonadism among other features. We describe a 10.5-year-old girl with PWS and previous standard-risk medulloblastoma that relapsed in the pons 3 years after the end of treatment. Diagnosis of relapse was delayed by a preceding varicella infection, an initial clinical/radiologic response to steroids and the unusual location, and was confirmed with a stereotactic biopsy. Second-line therapy was commenced, however, the patient rapidly deteriorated and died. This is the first report of medulloblastoma in a patient with PWS.

Updates on Management of Adult Medulloblastoma.

OPINION STATEMENT: Medulloblastoma (MB) is a malignant embryonal tumor of the posterior fossa and is the most common type of brain cancer in pediatric patients. In contrast, adult MB is very rare with an incidence of 0.6 per million per year and mostly affects young adults below the age of 40. Recent molecular analyses of pediatric and adult MB have classified these tumors into at least four individual molecular subgroups (SHH, WNT, group 3, and group 4) with distinct demographics, histology, and prognosis. The discrete biological composition of these tumors likely explains the marked heterogeneity in responses seen to conventional therapies such as radiation and cytotoxic chemotherapies. Given the low incidence of adult MB, prospective studies are challenging and scarce, and management guidelines are largely derived from the pediatric MB patient population and retrospective data. However, adult MB is clinically and molecularly distinct from pediatric MB and a comprehensive review of published literature on adult MB highlighting their differences is warranted. Here, we review the management of adult MB focusing on recent studies exploring the effectiveness of upfront chemotherapy, clinical trials in the context of molecular subgroup-specific therapies, and the potential role of immunotherapy in treating this disease.

[Meduloblastoma and recurrent meningioma in association with colonic polyposis: an unusual presentation of Turcot syndrome]. / Meduloblastoma y meningioma recidivante asociados a poliposis colónica: una presentación inusual del síndrome de Turcot.

Turcot syndrome is an association of primary neuroepithelial tumors of the central nervous system with adenomatous polyposis coli. It is a genetic disorder, with two forms; In type I, glioblastomas are usually associated with hereditary nonpolyposis colorectal cancer (HNPC or Lynch). In Type II, medulloblastomas are often associated with familial adenomatous polyposis coli (classical or attenuated). This patient had a medulloblastoma at seven years of age, then 20 years later developed a meningioma which recurred several times. At 36 years old he presented with anemia after digestive bleeding, and an adenomatous polyposis coli with high grade dysplasia was found at colonoscopy. As far as we know, this is the first case of Turcot syndrome described in our country.

First evidence of genotype-phenotype correlations in Gorlin syndrome.

BACKGROUND: Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS. METHODS: We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1-61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. RESULTS: Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). CONCLUSION: We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant.

The postirradiation incidence of cavernous angioma is higher in patients with childhood pineoblastoma or primitive neuroectodermal tumors than medulloblastoma.

PURPOSE: The purpose of this study is to investigate the incidence of cavernous angioma (CVA) in long-term survivors of childhood embryonal tumors treated by cranial irradiation. MATERIALS AND METHODS: Between 1990 and 2012, we treated 25 patients (13 males, 12 females) with embryonal tumors (17 medulloblastomas, 5 primitive neuroectodermal tumors (PNET), 3 pineoblastomas) with craniospinal irradiation. Follow-up ranged from 15.5 to 289.9 months, the irradiation dose to the whole neural axis from 18 to 36 Gy, and the total local dose from 49.6 to 60 Gy. All patients underwent follow-up magnetic resonance imaging (MRI) studies at least once a year, and the diagnosis of posttreatment CVA was based solely on MRI findings. RESULTS: At the time of this writing, 18 were alive and free of the recurrence of the original disease or the development of secondary neoplasms other than CVA; another 2 were alive with medulloblastoma or diffuse astrocytoma. Posttreatment, 14 patients developed CVAs in the course of a median of 56.7 months; 13 of these presented with multiple CVAs. Patients who underwent radiation therapy (RT) at an age younger than 6 years developed multiple CVAs significantly earlier than those treated at a later age (p = 0.0110). Patients with PNET or pineoblastoma developed Zabramski type 1 and 2 CVA significantly earlier than did medulloblastoma patients (p = 0.0042). CONCLUSION: We attribute the high rate of post-RT CVA in our long-term follow-up study of pediatric patients to the delivery of cranial irradiation for embryonal tumors, especially PNET and pineoblastoma, and recommend the regular, long-term follow-up of patients whose embryonal tumors were treated by cranial irradiation.

Rubinstein-Taybi syndrome predisposing to non-WNT, non-SHH, group 3 medulloblastoma.

Medulloblastomas (MB) are classified in four subgroups: the well defined WNT and Sonic Hedgehog (SHH) subgroups, and the less defined groups 3 and 4. They occasionally occur in the context of a cancer predisposition syndrome. While germline APC mutations predispose to WNT MB, germline mutations in SUFU, PTCH1, and TP53 predispose to SHH tumors. We report on a child with a Rubinstein-Taybi syndrome (RTS) due to a germline deletion in CREBBP, who developed a MB. Biological profilings demonstrate that this tumor belongs to the group 3. RTS may therefore be the first predisposition syndrome identified for non-WNT/non-SHH MB.

The biologic era of childhood medulloblastoma and clues to novel therapies.

Currently, the treatment of childhood medulloblastoma (MB) is tailored to risk groups defined by clinical parameters. Growing evidence of tumoral heterogeneity is apparent as response remains varied and unpredictable based on current treatment strategies, indicating the lack of understanding of the elusive biology that drives oncogenesis of these tumors. Advances in genomic technologies are revealing newer insights into the molecular pathogenesis of MB. Utilization of the genomic machinery has enabled the definition of new molecular markers and signaling pathways, resulting in a paradigm shift in the classification of childhood MB. Recent focus into the postgenomic era has revealed varied perturbations in the epigenetic machinery in these subtypes as likely predictive biomarkers and potential therapeutic targets. Ahead lies the task and challenge in the ability to comprehensively evaluate all these data, which could provide clues to profile the next-generation clinical trials combining conventional with molecularly targeted novel therapies.

Medulloblastoma in a patient with the PTPN11 p.Thr468Met mutation.

Medulloblastoma is the commonest brain tumor in childhood and in a minority of patients is associated with an underlying genetic disorder such as Gorlin syndrome or familial adenomatous polyposis. Increased susceptibility to certain tumors, including neuroblastoma and some hematological malignancies, is recognized in disorders caused by mutations in genes encoding components of the RAS signaling pathway which include Noonan syndrome, Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome), Costello syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, and Neurofibromatosis type 1 (NF1), collectively termed RASopathies. Although an association between medulloblastoma and NF1 has been reported, this tumor has not previously been reported in other RASopathies. We present a patient with NSML caused by the recurrent PTPN11 mutation c.1403C > T (p.Thr468Met) in whom medulloblastoma was diagnosed at age 10 years. Medulloblastoma could therefore be part of the tumor spectrum associated with this disorder.

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized Controlled Trial.

Importance: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. Objective: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). Design, Setting, and Participants: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. Interventions: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. Main Outcomes and Measures: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. Results: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. Conclusions and Relevance: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT01356290.

Loss of Trp53 promotes medulloblastoma development but not skin tumorigenesis in Sufu heterozygous mutant mice.

Basal cell carcinoma of the skin typically carries genetic alterations in components of the hedgehog (HH) signaling pathway. Previously, we generated a knockout mouse with a loss-of-function mutation in suppressor of fused (Sufu), an essential repressor of the pathway downstream of Hh ligand cell surface reception. Mice heterozygous for the mutated Sufu allele develop a skin phenotype that includes lesions similar to basaloid follicular hamartomas. The purpose of the current study was to test the possibility that the simultaneous loss of the tumor suppressor gene, transformation related protein 53 (Trp53), would aggravate the Sufu skin phenotype since Trp53 loss is known to enhance the growth of other Hh-driven tumors. Consistent with previous reports, medulloblastomas and rhabdomyosarcomas developed in Sufu(+/-) ;Trp53(-/-) mice. However, the characteristic Sufu(+/-) skin phenotype was not altered in the absence of Trp53, and showed no changes in latency, multiplicity, cellular phenotype, or proliferative capacity of the basaloid lesions. This finding was both novel and intriguing and demonstrated a differential, tissue-specific sensitivity to Sufu and Trp53 tumor suppressor gene loss, which may be linked to developmental stage and the degree of proliferative activity in specific cell types.

Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency.

Inactivation of homologous recombination (HR) or nonhomologous end-joining (NHEJ) predisposes to a spectrum of tumor types. Here, we inactivated DNA double-strand break repair (DSBR) proteins, DNA Ligase IV (Lig4), Xrcc2, and Brca2, or combined Lig4/Xrcc2 during neural development using Nestin-cre. In all cases, inactivation of these repair factors, together with p53 loss, led to rapid medulloblastoma formation. Genomic analysis of these tumors showed recurring chromosome 13 alterations via chromosomal loss or translocations involving regions containing Ptch1. Sequence analysis of the remaining Ptch1 allele showed a variety of inactivating mutations in all tumors analyzed, highlighting the critical tumor suppressor function of this hedgehog-signaling regulator. We also observed genomic amplification or up-regulation of either N-Myc or cyclin D2 in all medulloblastomas. Additionally, chromosome 19, which contains Pten, was also selectively deleted in medulloblastoma arising after disruption of HR. Thus, our data highlight the preeminence of Ptch1 as a tumor suppressor in cerebellar granule cells and reveal other genomic events central to the genesis of medulloblastoma.

Radiation-induced adult medulloblastoma: a two-case report and review of the literature.

Radiation-induced medulloblastoma is an exceedingly rare phenomenon for which treatment standards have not been established. The literature suggests that these tumors are high grade with aggressive behavior. We report two cases of radiation-induced medulloblastoma which have been treated with full dose re-irradiation with curative intent. In both cases, treatment toxicity and tumor progression proved to be insurmountable obstacles. Further reports are necessary in order to fully characterize this clinical entity so that more effective therapies may be sought.

High Relative Biological Effectiveness of 2 MeV Fast Neutrons for Induction of Medulloblastoma in Ptch1+/- Mice with Radiation-specific Deletion on Chromosome 13.

Neutron radiation, a high-linear energy transfer radiation, has a high relative biological effectiveness (RBE) for various end points. The age at exposure is an important modifier of the effects of radiation, including carcinogenesis, with infants being generally more radiosensitive. Ptch1+/- mice offer a unique experimental system for assessing radiation carcinogenesis. Spontaneous development of medulloblastoma tumors occurs in nonirradiated animals that lose their Ptch1+ allele, most frequently by a loss of heterozygosity (LOH) of chromosome 13 via recombination or non-disjunction (referred to as S-type tumors). In contrast, tumors occur in irradiated Ptch1+/- mice as a result of chromosome 13 LOH with an interstitial deletion (R-type), making spontaneous and radiation-induced tumors discernible. To elucidate the influence of age on the effect of fast neutrons, we irradiated Ptch1+/- mice with neutrons (mean energy, ∼2 MeV) or γ rays on embryonic day (E)14 and E17 and on postnatal day (P)1, 4 or 10 and classified the resulting medulloblastomas based on chromosome 13 aberrations. Instead of LOH, some tumors harbored mutations in their Ptch1+ gene via a nonirradiation-associated mechanism such as duplication, insertion, base substitution or deletion with microhomology-mediated end joining; thus, these tumors were classified as S-type. The RBE regarding the induction of R-type tumors was 12.9 (8.6, 17.2), 9.6 (6.9, 12.3), 21.5 (17.2, 25.8), and 7.1 (4.7, 9.5) (mean and 95% confidence interval) for mice irradiated on E14, E17, P1 and P4, respectively, with the highest value seen during the most active development of the tissue and P10 being completely resistant. These results indicate that the developmental stage at exposure of the tissue influences the RBE of neutrons.

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes. RESULTS: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes. CONCLUSIONS: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.

3D spheroid models of paediatric SHH medulloblastoma mimic tumour biology, drug response and metastatic dissemination.

Studying medulloblastoma, the most common malignant paediatric brain tumour, requires simple yet realistic in vitro models. In this study, we optimised a robust, reliable, three-dimensional (3D) culture method for medulloblastoma able to recapitulate the spatial conformation, cell-cell and cell-matrix interactions that exist in vivo and in patient tumours. We show that, when grown under the same stem cell enriching conditions, SHH subgroup medulloblastoma cell lines established tight, highly reproducible 3D spheroids that could be maintained for weeks in culture and formed pathophysiological oxygen gradients. 3D spheroid culture also increased resistance to standard-of-care chemotherapeutic drugs compared to 2D monolayer culture. We exemplify how this model can enhance in vitro therapeutic screening approaches through dual-inhibitor studies and continual monitoring of drug response. Next, we investigated the initial stages of metastatic dissemination using brain-specific hyaluronan hydrogel matrices. RNA sequencing revealed downregulation of cell cycle genes and upregulation of cell movement genes and key fibronectin interactions in migrating cells. Analyses of these upregulated genes in patients showed that their expression correlated with early relapse and overall poor prognosis. Our 3D spheroid model is a significant improvement over current in vitro techniques, providing the medulloblastoma research community with a well-characterised and functionally relevant culture method.