Andrew J. Martin

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

Summary We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of 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.

Nocardia farcinica brain abscess in a patient without immunocompromise

Brain abscess has an incidence of 1 per 100,000 in developed countries and a mortality rate of 10%. Cerebral infections with Nocardia farcinica have a mortality of up to 90%. Nocardial species are important pathogens in immunocompromised hosts, but infections in immunocompetent patients are extremely rare. We report a case of primary brain abscess with N. farcinica in a patient without immunosuppression, which was treated with surgery and a one-year course of oral moxifloxacin.

Pre-emptive intrathecal vancomycin therapy reduces external ventricular drain infection: a single centre retrospective case-control study

Abstract Objectives: External ventricular drain (EVD)-related infection is a significant source of morbidity in neurosurgical patients. Recently, there has been a drive to adopt new catheters with bactericidal properties to reduce infection rates. We propose that the use of standard catheters combined with pre-emptive intrathecal vancomycin (ITV) 10 mg daily provides an effective alternative. Design: Retrospective study of all patients with EVDs between 2010 and 2012, comparing infection rates in those who did and did not receive pre-emptive ITV. All EVDs were of the standard silicon catheter type. CSF infection was defined, as per Centre for Disease Control (CDC) guidelines, as clinical suspicion ± positive CSF gram stain/culture or leucocytosis. Infection rates were compared using Pearsons chi-squared test. Results: 262 EVDs were included in the study, of which 111 were managed with pre-emptive ITV. The infection rate was 2.7% in the vancomycin group and 11.9% in the control group (p<.01). There were no cases of vancomycin-resistant infection in either group. Conclusion: The use of pre-emptive ITV is associated with a significantly lower EVD infection rate. This compares favourably with those reported in the literature for bactericidal catheters.

Comparative gene expression profiling of ADAMs, MMPs, TIMPs, EMMPRIN, EGF-R and VEGFA in low grade meningioma

MMPs (matrix metalloproteinases), ADAMs (a disintegrin and metalloproteinase) and TIMPs (tissue inhibitors of metalloproteinases) are implicated in invasion and angiogenesis: both are tissue remodeling processes involving regulated proteolysis of the extracellular matrix, growth factors and their receptors. The expression of these three groups and their correlations with clinical behaviour has been reported in gliomas but a similar comprehensive study in meningiomas is lacking. In this study, we aimed to evaluate the patterns of expression of 23 MMPs, 4 TIMPs, 8 ADAMs, selective growth factors and their receptors in 17 benign meningiomas using a quantitative real-time polymerase chain reaction (qPCR). Results indicated very high gene expression of 13 proteases, inhibitors and growth factors studied: MMP2 and MMP14, TIMP-1, -2 and -3, ADAM9, 10, 12, 15 and 17, EGF-R, EMMPRIN and VEGF-A, in almost every meningioma. Expression pattern analysis showed several positive correlations between MMPs, ADAMs, TIMPs and growth factors. Furthermore, our findings suggest that expression of MMP14, ADAM9, 10, 12, 15 and 17, TIMP-2, EGF-R and EMMPRIN reflects histological subtype of meningioma such that fibroblastic subtype had the highest mRNA expression, transitional subtype was intermediate and meningothelial type had the lowest expression. In conclusion, this is the first comprehensive study characterizing gene expression of 8 ADAMs in meningiomas. These neoplasms, although by histological definition benign, have invasive potential. Taken together, the selected elevated gene expression pattern may serve to identify targets for therapeutic intervention or indicators of biological progression and recurrence.

Patent foramen ovale closure prior to surgery in the sitting position.

Abstract Previously, patent foramen ovale (PFO) was an absolute contraindication to surgery in the sitting position. We report two patients with PFO who underwent surgery in the sitting position after percutaneous PFO closure. To our knowledge this is the first report of this technique.

Isolated intracranial Rosai-Dorfman disease in a child, a case report and review of the literature.

BackgroundRosai–Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy (SHML), usually affects young adults and commonly presents with massive painless cervical lymphadenopathy. Extranodal disease is present in a third of patients, and it is recognised that this can involve the central nervous system. Intracranial RDD is rare in adults and fewer than 10 paediatric cases have been reported.CaseA 10-year-old boy with isolated intracranial RDD presents with a painless forehead mass. The management is discussed and the literature reviewed.ConclusionThis case of isolated intracranial RDD highlights the importance of considering RDD in the differential of paediatric intracranial mass lesions and outlines the diagnostic and treatment challenges faced when managing this rare condition.

Evolving traumatic cerebellar hematoma.

A 10-year-old boy fell from a tree onto concrete. When he was first assessed, he had a headache but had a normal conscious level and no neurologic signs. A cranial CT scan …

Giant Vestibular Schwannoma in a 12-Year-Old Girl

a planned staged resection via a left retromastoid craniectomy performed in the sitting position. The tumour was fi rm, fi brous and vascular with a few small areas of softening centrally. At the fi rst operation it was internally debulked down to the petrous face, with subsequent drilling of the porous acousticus and dissection of the tumour from the cranial nerves and brainstem at a second operation 2 weeks later to achieve a total resection with anatomical preservation of the facial nerve. Histology confi rmed a benign schwannoma. Post-operative left VIth, IXth and Xth cranial nerve palsies recovered by 5 months. A left VIIth cranial nerve palsy was persistent but had improved from House Brackmann grade 5 to grade 2 by 10 months. MRI at 6 months after surgery ( fi g. 2 ) showed no evidence of residual or recurrent tumour. Neurofi bromatosis type 2 (NF2) gene analysis was normal. Paediatric vestibular schwannomas are extremely rare, and have been reported primarily in children with NF2, when they are frequently bilateral. There are very few reports of unilateral acoustic schwannomas in children found not to have NF2, with less than 40 cases reported worldwide [1, 2] . These tumours have generally been large with signifi cant mass effect impairing the function of multiple cranial nerves. Careful evaluation for underlying NF2 is obligatory. A 12-year-old girl presented with 18 months of left facial twitching, 12 months of intermittent headaches, clumsiness and veering to the left, and 3 months of decreased hearing on the left side. One month before presentation she developed increasingly severe headaches and left facial numbness. She was previously well and had no relevant family history. Examination revealed bilateral papilloedema, reduced conjugate upgaze, a partial left lateral gaze palsy, coarse horizontal nystagmus, reduced left facial sensation, mild left-sided lower motor neurone facial weakness and left-sided ataxia. There were no neurocutaneous features. MRI demonstrated a 6.5 ! 6 ! 5-cm extra-axial mass in the left cerebellopontine angle with marked displacement of the brainstem and compression of the IVth ventricle to produce triventricular hydrocephalus ( fi g. 1 a–d). The left internal acoustic meatus was widened and fi lled with tumour, which extended across the midline and inferiorly to the foramen magnum. There was heterogeneous enhancement, with central irregular low signal on enhanced T 1 images. There was no calcifi cation on CT ( fi g. 1 e). The radiological differential diagnosis included meningioma, extra-axial PNET, ependymoma, atypical teratoid rhabdoid tumour, vestibular schwannoma or malignant nerve sheath tumour. The patient was commenced on steroids and an external ventricular drain placed. Subsequently she underwent

Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells

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.Genomic and functional analysis of intratumor heterogeneity in pediatric glioma uncovers early clonal divergence and stable spontaneous cooperation between subclonal populations throughout tumor evolution.

A proposed link between spinal epidural lipomatosis, prostate cancer and androgen deprivation therapy:

We present a patient with prostate cancer with vertebral metastases who developed spastic paraparesis secondary to spinal epidural lipomatosis (SEL) after receiving androgen deprivation therapy (ADT). We propose a link between ADT, metastatic prostate cancer and SEL.