Charles B. Stevenson

CXCR4 mediates the proliferation of glioblastoma progenitor cells

Increasing evidence points to a fundamental role for cancer stem cells (CSC) in the initiation and propagation of many tumors. As such, in the context of glioblastoma multiforme (GBM), the development of treatment strategies specifically targeted towards CSC-like populations may hold significant therapeutic promise. To this end, we now report that the cell surface chemokine receptor, CXCR4, a known mediator of cancer cell proliferation and invasion, is overexpressed in primary glioblastoma progenitor cells versus corresponding differentiated tumor cells. Furthermore, administration of CXCL12, the only known ligand for CXCR4, stimulates a specific and significant proliferative response in progenitors but not differentiated tumor cells. Taken together, these results implicate an important role for the CXCR4 signaling mechanism in glioma CSC biology and point to the therapeutic potential of targeting this pathway in patients with GBM.

Tethered cord syndrome: a review of the literature from embryology to adult presentation

Tethered cord syndrome (TCS) is a clinical condition of various origins that arises from tension on the spinal cord. Radiographic findings may include the conus medullaris in a lower than normal position, fatty infiltration of the filum terminale, lipomyelomeningocele, myelomeningocele, myelocystocele, meningocele, split cord malformations, dermal sinus, anorectal malformations, and intraspinal tumors. The clinical constellation of signs and symptoms associated with TCS may include dermatologic, urological, gastrointestinal, neurological, and orthopedic findings. The current review focuses on TCS by age group of the more common causes of the condition, including myelomeningocele, lipomyelomeningocele, as well as the adult presentation of occult TCS. Pertinent review of the neuroembryology and normal anatomical position of the conus medullaris is included.

CXCR4 Expression is Elevated in Glioblastoma Multiforme and Correlates with an Increase in Intensity and Extent of Peritumoral T2-weighted Magnetic Resonance Imaging Signal Abnormalities

OBJECTIVEWith the objective of investigating the utility of CXCR4, a chemokine receptor known to mediate glioma cell invasiveness, as a molecular marker for peritumoral disease extent in high-grade gliomas, we sought to characterize the expression profile of CXCR4 in a large panel of tumor samples and determine whether CXCR4 expression levels within glioblastoma multiforme might correlate with radiological evidence of a more extensive disease process. METHODSFreshly resected tumor tissue samples were processed for immunohistochemical and quantitative polymerase chain reaction analyses to identify and quantify expression levels of CXCR4 and its corresponding ligand CXCL12. T1 postcontrast and T2-weighted magnetic resonance imaging brain scans were used to generate voxel signal intensity histograms that were quantitatively analyzed to determine the extent and intensity of peritumoral signal abnormality as a marker of disseminated disease in the brain. RESULTSCXCR4 expression was markedly elevated in Grade III and IV tumors compared with Grade II gliomas. Significantly, when patients with glioblastoma multiforme were segregated into two groups based on CXCR4 expression level, we observed a statistically significant increase in the intensity and extent of peritumoral magnetic resonance imaging signal abnormalities associated with CXCR4 high-expressing gliomas. CONCLUSIONOur data confirm that high-grade gliomas robustly express CXCR4 and demonstrate a correlative relationship between expression levels of the CXCR4 receptor and the magnetic resonance imaging-based finding of a diffuse and more extensive disease process in the brain. CXCR4 expression status may, therefore, prove useful as a marker of disseminated disease in patients with glioblastoma multiforme.

C-1 lateral mass screw fixation in children with atlantoaxial instability: case series and technical report.

Study Design Retrospective cohort study. Objective To evaluate the feasibility, safety, and efficacy of incorporating C-1 lateral mass screws into fusion constructs in children with atlantoaxial instability. Summary of Background Data The operative treatment of atlantoaxial instability varies widely based on anatomy, patient age, and surgeon preference. The modified Harms construct, consisting of polyaxial C-1 lateral mass screws together with C-2 pedicle or pars screws and rods, has shown satisfactory fusion rates and minimal incidence of complications in adult patients. However, its utility in the pediatric population remains unproven, largely because of the technical challenges and risks inherent in placing C-1 lateral mass screws in children with immature bone quality, extensive anatomical variability, and smaller osseous structures. Methods We retrospectively reviewed the records of all pediatric patients with atlantoaxial instability treated surgically, with a fusion construct incorporating C-1 lateral mass screws, at our institution between July 1, 2005 and June 30, 2008. Eight patients were identified and their relevant clinical data were abstracted from the medical record. Results All patients had C-1 lateral mass screws placed as part of a fixation construct. Six cases used C-2 pedicle screws and 2 cases used C-3 lateral mass screw fixation for the inferior portion of the construct. There were 6 female and 2 male patients. Age at the time of the surgery ranged from 5 to 13 years (mean 9 y), and follow-up ranged from 11 to 38 months (mean 23 mo). No C-2 nerve root was sacrificed in any patient. There were no intraoperative or postoperative complications, including neurological injury, vascular injury, or hardware-related complications. Successful fusion was documented with dynamic cervical spine radiography in all cases. Conclusions C-1 lateral mass screw placement is generally feasible and safe in pediatric patients. With a nearly 2-year average follow-up, C1-2 rigid screw/rod fixation has proven to be an effective treatment modality for pediatric atlantoaxial instability in our series.

Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas

Children with high-grade glioma, including diffuse intrinsic pontine glioma (DIPG), have a poor prognosis despite multimodal therapy. Identifying novel therapeutic targets is critical to improve their outcome. We evaluated prognostic roles of telomere maintenance mechanisms in children with HGG, including DIPG. A multi-institutional retrospective study was conducted involving 50 flash-frozen HGG (35 non-brainstem; 15 DIPG) tumors from 45 children (30 non-brainstem; 15 DIPG). Telomerase activity, expression of hTERT mRNA (encoding telomerase catalytic component) and TERC (telomerase RNA template) and alternative lengthening of telomeres (ALT) mechanism were assayed. Cox Proportional Hazard regression analyses assessed association of clinical and pathological variables, TERC and hTERT levels, telomerase activity, and ALT use with progression-free or overall survival (OS). High TERC and hTERT expression was detected in 13/28 non-brainstem HGG samples as compared to non-neoplastic controls. High TERC and hTERT expression was identified in 13/15 and 11/15 DIPG samples, respectively, compared to controls. Evidence of ALT was noted in 3/11 DIPG and 10/19 non-brainstem HGG specimens. ALT and telomerase use were identified in 4/19 non-brainstem HGG and 2/11 DIPG specimens. In multivariable analyses, increased TERC and hTERT levels were associated with worse OS in patients with non-brainstem HGG, after controlling for tumor grade or resection extent. Children with HGG and DIPG, have increased hTERT and TERC expression. In children with non-brainstem HGG, increased TERC and hTERT expression levels are associated with a worse OS, making telomerase a promising potential therapeutic target in pediatric HGG.

CT-based, fiducial-free frameless stereotaxy for difficult ventriculoperitoneal shunt insertion: experience in 26 consecutive patients.

Background:Patients with small or dysmorphic ventricles requiring ventriculoperitoneal shunt (VPS) insertion for hydrocephalus can be challenging. The ‘freehand’ technique does not always provide for accurate catheter insertion, particularly in patients with slit ventricles, complex hydrocephalus or displaced ventricles. Consequently, many surgeons use stereotaxy for assistance. We have employed a frameless stereotactic technique, obviating the need for fiducials or preoperative MRI, for difficult ventricular catheter placement over the past 1.5 years with excellent results. We describe our experience with frameless stereotactic VPS insertion. Methods:We retrospectively reviewed the charts of 26 patients who underwent frameless stereotactic VPS insertion. All patients had preoperative CT scans using a navigation protocol and were registered into the Stealth Station via the face tracer program. Catheters were inserted using the Medtronic frameless trajectory guide kit. We recorded demographic data, operative time, complications and follow-up. Results:The mean patient age was 31 years. The average operative time was 46 min. There were 3 complications. The average follow-up was 5 months. Twenty-one patients had postoperative imaging, with 20 having excellent catheter positioning. Conclusions:Our results confirm that frameless stereotactic VPS without fiducial marker placement is a feasible technique for catheter insertion in patients who have small/dysmorphic ventricles. In experienced hands, there is negligible added operative time and a low complication rate.

T2 detection of tumor invasion within segmented components of glioblastoma multiforme

To use T2‐weighted images to detect tumor invasion when comparing normal individuals to groups of gliomablastoma multiforme (GBM) patients with varying levels of CXCR4, a chemokine receptor that promotes tumor migration.

Senescence associated with the over-replication of a mitochondrial retroplasmid in Neurospora crassa

Abstract Mitochondrial DNA rearrangements and deletions are a prevailing feature of filamentous fungal cultures that undergo senescence. In Neurospora spp., strains containing the Mauriceville and Varkud mitochondrial retroplasmids routinely senesce at elevated temperatures, a process that is initiated by the integration of variant forms of the plasmids into the mitochondrial genome. Here, we describe a strain that is phenotypically distinguishable from previously characterized senescent strains and show that senescence can occur in the absence of plasmid integration and associated alterations in mitochondrial DNA. The MS4416 strain contains a unique variant of the Mauriceville retroplasmid, and undergoes senescence at highly predictable frequencies at 37°, 25° and 18 °C. Decline in vegetative growth rate correlates with increased levels of the variant plasmid and alterations in the synthesis of mitochondrially encoded proteins, suggesting that plasmid over-replication interferes with mitochondrial translation. We also report the isolation of a mutant strain that escapes senescence yet still maintains high levels of the variant plasmid. Its ability to tolerate a growth-suppressive retroplasmid suggests that there are mechanisms in Neurospora which compensate for the deleterious effects that plasmid over-replication has on mitochondrial function.

Cystic degeneration of the cerebellar tonsils in pediatric patients with Chiari Type I malformation.

OBJECT The operative indications and treatment algorithms for pediatric patients with Chiari Type I malformation (CM-I) vary widely. When an intradural approach and duraplasty are thought necessary at the time of surgery, neurosurgeons may elect to fulgurate or resect a portion of the cerebellar tonsils. Histological analyses of cerebellar tonsils resected during decompression in pediatric patients with CM-I have revealed multiple abnormal findings including extensive ischemic and degenerative changes. The authors describe an interesting phenomenon of cystic degeneration in the distal ends of the cerebellar tonsils in children undergoing operative treatment of CM-I. METHODS The authors reviewed the clinical database of 440 pediatric patients who underwent surgical decompression for CM-I performed by a single surgeon. The clinical course, preoperative MR imaging and intraoperative ultrasound characteristics, and histological findings in 3 children found to have tonsillar cystic degeneration were analyzed and detailed. RESULTS Cystic changes were subtle but uniformly evident on preoperative MR imaging and were more readily apparent on intraoperative ultrasonography. In each patient, the tonsillar cyst was resected. Histological examination revealed areas of cystic degenerative change characterized by distortion of the normal cerebellar architecture with absent Purkinje and internal granular cell layers. All children experienced improvement in their symptoms, without complication, postoperatively. CONCLUSIONS Cystic degeneration of the tonsils in pediatric patients with CM-I is an uncommon pathological process most likely resulting from long-standing and excessive compression. Based on their experience, the authors advocate expeditious surgical treatment, including intradural exploration and capacious duraplasty, for patients in whom there is evidence of this phenomenon on preoperative imaging.

December 2006: 31-year-old woman with hemiparesis.

© 2007 The Authors Journal Compilation