SummaryWe collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Infant high grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histological review, methylation profiling, custom panel and genome/exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an 'intrinsic' spectrum of disease specific to the infant population. These included those with targetable MAP-kinase alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n=31), NTRK1/2/3 (n=21), ROS1 (n=9) and MET (n=4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly supports the concept that infant gliomas require a change in diagnostic practice and management.

Resection can alleviate both the seizures and the behavioral and cognitive abnormalities of hypothalamic hamartomas, but complications are frequent.

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.

The problem of providing surgical navigation using image overlays on the operative scene can be split into four main tasks-calibration of the optical system; registration of preoperative images to the patient; tracking of the display system and patient and display using a suitable visualisation scheme. To achieve a convincing result in the magnified view through the operating microscope high alignment accuracy is required. We have simulated our entire system to establish the major sources of error. We have improved each of the stages involved. The microscope calibration process has been automated. We have introduced bone-implanted markers for registration and incorporated a locking acrylic dental stent (LADS) for patient tracking and/or registration. These improvements have significantly increased the alignment accuracy of our overlays. LADS repositioning on volunteers showed a mean target registration error of 0.7mm. Phantom accuracy is 0.3-0.5mm and clinical overlay errors were 0.5-1.0mm on the bone fiducials and 0.5-4mm on target structures. We have improved the graphical representation of the stereo overlays. The resulting system provides 3D surgical navigation for microscope-assisted guided interventions (MAGI).

Summary:Purpose: Hamartomas of the hypothalamus (HH) cause an uncommon and unusual epilepsy syndrome. The condition is recognized to affect children, but the presentation in adults is not well understood. We present 19 children and adult patients with HH, including three patients whose epilepsy began in adult life. The patterns of clinical presentation, evolution of the epilepsy from childhood to adult life, and electroclinical diagnostic features are presented.Methods: Nineteen patients, both children and adults with HH and epilepsy, were evaluated clinically, with EEG, video-EEG, and magnetic resonance imaging (MRI) scanning. Seven patients underwent surgical resection of the hamartoma. Stereotactic thermocoagulation of the hamartoma was performed in two patients.Results: Gelastic seizures occurred at onset of epilepsy in 15 of 16 early-onset cases. Subsequently, multiple seizures types occurred, which then evolved to mainly partial epilepsy with tonic or complex partial seizures (five of eight adults), or became entrenched symptomatic generalized epilepsy with atypical absences, drop attacks, and secondarily generalized seizures, and cognitive impairment (three of eight adults). In the adult-onset patients, gelastic seizures were not prominent, the epilepsy was milder, and they functioned normally. Stereotactic thermocoagulation of the hamartoma resulted in improvement in seizure control in two patients.Conclusions: Gelastic seizures are not a prominent feature of epilepsy in adult patients with HH. The epilepsy associated with HH, although severe at onset, can evolve into a milder syndrome in later life. For less severely affected patients, minimally invasive alternatives to the traditionally difficult open surgical treatment should be considered.

We recommend ceftriaxone/cefotaxime and metronidazole as empiric treatment, although metronidazole may be unnecessary in many cases, with antistaphylococcal cover in cases of head trauma. Meropenem potentially would be a better choice in the immunocompromised. A prospective study of intravenous and oral treatment guided by clinical improvement is required beause 1-2 weeks of intravenous antibiotics during a total of 6 weeks may be sufficient in children.

We present a system for surgical navigation using stereo overlays in the operating microscope aligned to the operative scene. This augmented reality system provides 3D information about nearby structures and offers a significant advancement over pointer-based guidance, which provides only the location of one point and requires the surgeon to look away from the operative scene. With a previous version of this system, we demonstrated feasibility, but it became clear that to achieve convincing guidance through the magnified microscope view, a very high alignment accuracy was required. We have made progress with several aspects of the system, including automated calibration, error simulation, bone-implanted fiducials and a dental attachment for tracking. We have performed experiments to establish the visual display parameters required to perceive overlaid structures beneath the operative surface. Easy perception of real and virtual structures with the correct transparency has been demonstrated in a laboratory and through the microscope. The result is a system with a predicted accuracy of 0.9 mm and phantom errors of 0.5 mm. In clinical practice errors are 0.5–1.5 mm, rising to 2–4 mm when brain deformation occurs.