Midline pediatric high-grade astrocytomas (pHGAs) are incurable with few treatment targets identified. Most tumors harbor K27M mutations on histone 3 variants. In 40 treatment-naïve midline pHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with H3.1 K27M, while FGFR1 mutations/fusions occur in thalamic tumors associated with H3.3 K27M. Hyper-activation of the bone morphogenetic protein (BMP)/ACVR1 developmental pathway in pHGAs harbouring ACVR1 mutations led to increased phospho-SMAD1/5/8 expression and up-regulation of BMP downstream early response genes in tumour cells. Global DNA methylation profiles were significantly associated with the K27M mutation regardless of the mutant H3 variant and irrespective of tumor location, supporting its role in driving the epigenetic phenotype. This significantly expands the potential treatment targets and further justifies pre-treatment biopsy in pHGA as a means to orient therapeutic efforts in this disease.
Although cerebrospinal fluid (CSF) shunt placement is the most common procedure performed by pediatric neurosurgeons, shunts remain among the most failure-prone life-sustaining medical devices implanted in modern medical practice. This article provides an overview of the mechanisms of CSF shunt failure for the 3 most commonly employed definitive CSF shunts in the practice of pediatric neurosurgery: ventriculoperitoneal, ventriculopleural, and ventriculoatrial. The text has been partitioned into the broad modes of shunt failure: obstruction, infection, mechanical shunt failure, overdrainage, and distal catheter site-specific failures. Clinical management strategies for the various modes of shunt failure are discussed as are research efforts directed towards reducing shunt complication rates. As it is unlikely that CSF shunting will become an obsolete procedure in the foreseeable future, it is incumbent on the pediatric neurosurgery community to maintain focused efforts to improve our understanding of and management strategies for shunt failure and shunt-related morbidity.
The supracallosal medial frontal cortex can be divided into three functional domains: a ventral region with connections to the limbic system, an anterior dorsal region with connections to lateral prefrontal systems, and a posterior dorsal region with connections to lateral motor systems. Lesion and functional imaging studies implicate this medial frontal cortex in speech and language generation. The current functional magnetic resonance imaging (fMRI) study of word generation was designed to determine which of these three functional domains was substantially involved by mapping individual subjects' functional activity onto structural images of their left medial frontal cortex. Of 28 neurologically normal right-handed participants, 21 demonstrated a prominent paracingu- late sulcus (PCS), which lies in the anterior dorsal region with connections to lateral prefrontal systems. Activity increases for word generation centered in the PCS in 18 of these 21 cases. The posterior dorsal region also demonstrated significant activity in a majority of participants (16/28 cases). Activity rarely extended into the cingulate sulcus (CS) (3/21 cases) when there was a prominent PCS. If there was no prominent PCS, however, activity did extend into the CS (6/7 cases). In no case was activity present on the crest of the cingulate gyrus, which is heavily connected to the limbic system. Thus, current findings suggest that medial frontal activity during word generation reflects cognitive and motor rather than limbic system participation. The current study demonstrates that suitably designed fMRI studies can be used to determine the functional significance of anatomic variants in human cortex.
Objective To quantify the extent to which revision(s) of cerebrospinal fluid (CSF) shunt are associated with increased risk of CSF shunt infection, after adjusting for patient factors that may contribute to infection risk. Study design We used the HCRN registry to assemble a large prospective six center cohort of 1,036 children undergoing initial CSF shunt placement between April 2008 and January 2012. The primary outcome of interest was first CSF shunt infection. Data for initial CSF shunt placement and all subsequent CSF shunt revisions prior to first CSF shunt infection, where applicable, were obtained. The risk of first infection was estimated using a multivariable Cox proportional hazard model accounting for patient characteristics and CSF shunt revisions, and is reported using hazard ratios (HR) with 95% confidence intervals (CI). Results Of the 102 children who developed first infection within 12 months of placement, 33 (32%) followed one or more CSF shunt revisions. Baseline factors independently associated with risk of first infection included: gastrostomy tube (HR 2.0, 95% CI: 1.1, 3.3), age 6–12 months (HR 0.3, 95% CI: 0.1, 0.8), and prior neurosurgery (HR 0.4, 95% CI: 0.2, 0.9). After controlling for baseline factors, infection risk was most significantly associated with the need for revision (1 revision vs. none, HR 3.9, 95% CI: 2.2, 6.5; ≥2 revisions, HR 13.0, 95% CI: 6.5, 24.9). Conclusions This study quantifies the elevated risk of infection associated with shunt revisions observed in clinical practice. To reduce risk of infection risk further work should optimize revision procedures.
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