Summary Medulloblastoma, the most common malignant pediatric brain tumour, is currently treated with non-specific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, prior attempts to identify targets for therapy have been underpowered due to small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of the Parkinson’s disease gene SNCAIP, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1 that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGFβ signaling in Group 3, and NF-κB signaling in Group 4 suggest future avenues for rational, targeted therapy.

This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

The mechanisms previously proposed for the progression of syringomyelia associated with Chiari I malformation of the cerebellar tonsils are controversial, leave many clinical observations unexplained, and underlie the prevalence of different operations currently used as initial treatment. To explore the mechanism of syringomyelia progression in this setting, the authors used anatomical and dynamic (phase-contrast and phase-contrast cine) magnetic resonance (MR) imaging, and intraoperative ultrasonography to examine the anatomy and dynamics of movement of the cerebellar tonsils, the wall of the spinal cord surrounding the syrinx, and the movement of cerebrospinal fluid (CSF) and syrinx fluid at rest, during the respiratory and cardiac cycles, and during Valsalva maneuver in seven affected patients. In all patients the cerebellar tonsils occluded the subarachnoid space at the level of the foramen magnum. Syringomyelia extended from the cervical to the lower thoracic segment of the spinal cord. No patient had evidence of a patent communication between the fourth ventricle and the syrinx on anatomical MR images, dynamic MR images, or intraoperative ultrasound studies. Dynamic MR images of three patients revealed abrupt downward movement of the spinal CSF and the syrinx fluid during systole and upward movement during diastole, but limited movement of CSF across the foramen magnum during the cardiac cycle. Intraoperative ultrasound studies demonstrated abrupt downward movement of the cerebellar tonsils during systole that was synchronous with sudden constriction of the spinal cord and syrinx. Decompression of the foramen magnum was achieved via suboccipital craniectomy, laminectomy of C-1 and C-2, and dural grafting, leaving the arachnoid intact. Immediately after surgery, the pulsatile downward thrust of the tonsils and constriction of the spinal cord and syrinx disappeared. Syringomyelia resolved within 1 to 6 months after surgery in all patients. Observations by the authors suggest the following previously unrecognized mechanism for progression of syringomyelia associated with occlusion of the subarachnoid space at the foramen magnum. The brain expands as it fills with blood during systole, imparting a systolic pressure wave to the intracranial CSF that is accommodated in normal subjects by sudden movement of CSF from the basal cisterns to the upper portion of the spinal canal. With obstruction to rapid movement of CSF at the foramen magnum, the cerebellar tonsils, which plug the subarachnoid space posteriorly, move downward with each systolic pulse, acting as a piston on the partially isolated spinal CSF and producing a systolic pressure wave in the spinal CSF that acts on the surface of the spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)