ABSTRACT
BACKGROUND: Complications of intrathecal baclofen (ITB) pump implantation for treatment of pediatric patients with spasticity and dystonia associated with cerebral palsy remain unacceptably high. To address the concern that some patients may have underlying arrested hydrocephalus, which is difficult to detect clinically because of a low baseline level of neurological function, and may contribute to the high rates of postoperative cerebrospinal fluid leak, wound breakdown, and infection associated with ITB pump implantation, the authors implemented a standardized protocol including mandatory cranial imaging and assessment of intracranial pressure (ICP) by lumbar puncture prior to ITB pump implantation. METHODS: A retrospective case series of patients considered for ITB pump implantation between September 2012 and October 2014 at Seattle Children's Hospital is presented. All patients underwent lumbar puncture under general anesthesia prior to ITB pump implantation and, if the opening pressure was greater than 21 cmH2O, ITB pump implantation was aborted and alternative management options were presented to the patient's family. RESULTS: Eighteen patients were treated during the study time period. Eight patients (44.4%) who had ICPs in excess of 21 cmH2O on initial LP were identified. Eleven patients (61.1%) ultimately underwent ITB pump implantation (9/10 in the "normal ICP" group and 2/8 in the "elevated ICP" group following ventriculoperitoneal shunt placement), without any postoperative complications. CONCLUSIONS: Given the potentially high rate of elevated ICP and arrested hydrocephalus, the authors advocate pre-implantation assessment of ICP under controlled conditions and a thoughtful consideration of the neurosurgical management options for patients with elevated ICP.
ABSTRACT
BACKGROUND: Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of great clinical importance to address invasion. We previously showed that the bHLH transcription factor TWIST1 which orchestrates carcinoma metastasis through an epithelial mesenchymal transition (EMT) is upregulated in GBM and promotes invasion of the SF767 GBM cell line in vitro. RESULTS: To further define TWIST1 functions in GBM we tested the impact of TWIST1 over-expression on invasion in vivo and its impact on gene expression. We found that TWIST1 significantly increased SNB19 and T98G cell line invasion in orthotopic xenotransplants and increased expression of genes in functional categories associated with adhesion, extracellular matrix proteins, cell motility and locomotion, cell migration and actin cytoskeleton organization. Consistent with this TWIST1 reduced cell aggregation, promoted actin cytoskeletal re-organization and enhanced migration and adhesion to fibronectin substrates. Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. Distinct from carcinoma EMT, TWIST1 did not generate an E- to N-cadherin "switch" in GBM cell lines. The clinical relevance of putative TWIST target genes SNAI2 and fibroblast activation protein alpha (FAP) identified in vitro was confirmed by their highly correlated expression with TWIST1 in 39 human tumors. The potential therapeutic importance of inhibiting TWIST1 was also shown through a decrease in cell invasion in vitro and growth of GBM stem cells. CONCLUSIONS: Together these studies demonstrated that TWIST1 enhances GBM invasion in concert with mesenchymal change not involving the canonical cadherin switch of carcinoma EMT. Given the recent recognition that mesenchymal change in GBMs is associated with increased malignancy, these findings support the potential therapeutic importance of strategies to subvert TWIST1-mediated mesenchymal change.
