Alfred T. Ogden

Glial Progenitors in Adult White Matter Are Driven to Form Malignant Gliomas by Platelet-Derived Growth Factor-Expressing Retroviruses

To test the gliomagenic potential of adult glial progenitors, we infected adult rat white matter with a retrovirus that expresses high levels of PDGF and green fluorescent protein (GFP). Tumors that closely resembled human glioblastomas formed in 100% of the animals by 14 d postinfection. Surprisingly, the tumors were composed of a heterogeneous population of cells, <20% of which expressed the retroviral reporter gene (GFP). The vast majority of both GFP+ and GFP– tumor cells expressed markers of glial progenitors. Thus, the tumors arose from the massive expansion of both infected and uninfected glial progenitors, suggesting that PDGF was driving tumor formation via autocrine and paracrine stimulation of glial progenitor cells. To explore this possibility further, we coinjected a retrovirus expressing PDGF-IRES-DsRed with a control retrovirus expressing only GFP. The resulting tumors contained a mixture of red cells (PDGF-expressing/tumor-initiating cells) and green cells (recruited progenitors). Both populations were highly proliferative and infiltrative. In contrast, when the control GFP retrovirus was injected alone, the animals never formed tumors and the majority of infected cells differentiated along the oligodendrocyte lineage. Together, these results reveal that adult white matter progenitors not only have the capacity to give rise to gliomas, but resident progenitors are recruited to proliferate within the mitogenic environment of the tumor and in this way contribute significantly to the heterogeneous mass of cells that compose a malignant glioma.

Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline.

MEDICAL MANAGEMENT OF cerebral edema and elevated intracranial pressure (ICP) is a critical component of perioperative care in neurosurgical practice. Traumatic brain injury, arterial infarction, venous hypertension/infarction, intracerebral hemorrhage, subarachnoid hemorrhage, tumor progression, and postoperative edema can all generate clinical situations in which ICP management is a critical determinant of patient outcomes. Although osmotic agents are among the most fundamental tools to control ICP, prospective data to establish clear guidelines on their use are lacking. Hypertonic saline is emerging as an alternative to mannitol. Early data suggest that indications for each agent may ultimately depend on ICP etiology.

Surgical Strategies for Treating Patients with Pineal Region Tumors

Optimal management of pineal region tumors depends on securing an accurate histologic diagnosis to facilitate management customized to the nuances of specific pathologies. As an initial step, surgical intervention by either stereotactic biopsy or open surgery is necessary to obtain tissue for pathologic examination. Stereotactic biopsy has the benefit of relative ease and minimal morbidity but is associated with greater likelihood of diagnostic inaccuracy compared to open surgery where more extensive tissue sampling is possible.The role of surgical debulking in the management of pineal tumors is clearly defined for some tumors but is less evident for others. Among the one third of pineal tumors that are benign or low grade, complete surgical resection is achievable and constitutes optimal management with excellent long-term recurrence-free survival. The benefits of aggressive surgical resection among malignant tumors are less clear but several studies have correlated degree of tumor removal with improved outcome.Advances in technology, surgical technique, and post-operative care have minimized surgical complications, however all surgical procedures in the pineal region, including both stereotactic biopsy and open surgery, are potentially hazardous. Advanced judgment, experience, and expertise are necessary to achieve rates of success sufficient to justify aggressive management. Management strategies using stereotactic biopsy, endoscopy, and radiosurgery can also provide favorable outcomes in some cases. Selective incorporation of these innovations can be expected to improve the already highly favorable outcome for all pineal region tumors.

A biomechanical evaluation of graded posterior element removal for treatment of lumbar stenosis: comparison of a minimally invasive approach with two standard laminectomy techniques.

Study Design. A validated finite element model of the intact lumbar spine (L1–S1) was modified to study the biomechanical changes as a result of surgical alteration for treatment of stenosis at L3–L4 and L4–L5 using 2 established techniques and 1 new minimally invasive technique. Objective. To investigate the impact of graded posterior element removal associated with new surgical techniques on postoperative segmental motion and loading in the annulus. Summary of Background Data. Several studies have shown that laminectomy increases and produces segmental instability unless fusion is performed. However, no data exist comparing the biomechanical impact of completely preserving the contralateral anatomy and what effect this has compared to traditional approaches. Methods. The effect of graded removal of posterior elements because of iatrogenic change associated with the 3 approaches was investigated using an 800 N compressive preload using the follower load technique and application of 8 Nm flexion, 6 Nm extension, 4 Nm torsion, and 6 Nm lateral bending moments. Results. This study shows that removal of posterior elements for treatment of stenosis at L3–L4 and L4–L5 results in increased flexion-extension and axial rotation at the surgical site. This study also shows that the segmental motion following a traditional laminectomy is greater than the minimally invasive approach in flexion, extension, left and right axial rotation. Moderate preservation of the posterior elements which occurs in the intralaminar approach generates greater segmental motion that the minimally invasive approach in extension, left and right axial rotation. Conclusion. Minimization of bone and ligament removal associated with minimally invasive procedures results in greater preservation of the normal motion of the lumbar spine after surgery. This study suggests that preservation of the posterior spinal elements associated with minimally invasive surgery could minimize the risk of developing de novo postoperative changes in spinal alignment and/or acceleration of facet and disc degeneration.

OBESITY AND SELF-REPORTED OUTCOME AFTER MINIMALLY INVASIVE LUMBAR SPINAL FUSION SURGERY

OBJECTIVEMany patients undergoing lumbar spine fusion are overweight or obese. The relationship between body habitus and outcome after lumbar spine fusion surgery is not well defined. METHODSWe analyzed a prospectively maintained database of self-reported pain and quality of life measures, including Visual Analog Scale pain score, Short Form 36, and Oswestry Disability Index. We selected patients undergoing minimally invasive transforaminal lumbar interbody fusion between September 2002 and June 2006 at a single institution. We used linear regression models and mixed-effects linear models to examine the relationships between body habitus and self-reported outcomes. RESULTSThe analysis identified 110 patients meeting the study criteria, with a median follow-up period of 14.8 months. The mean age was 56 years, mean height was 169 cm, and mean weight was 82.2 kg. The mean body mass index (BMI) was 28.7 kg/m2; 31% of patients were overweight (BMI, 25–29.9), and 32% of patients were obese (BMI, >30). Linear regression analysis did not identify a correlation between weight or BMI and pre- and postsurgery changes in any of the outcome measures. The significant findings observed in the mixed-effects linear models were that the changing patterns of Short Form 36 Body Pain subscale and Short Form 36 Vitality subscale varied significantly by category of BMI (P = 0.01 and P = 0.002, respectively), but not significantly if continuous BMI was used (P = 0.53 and P = 0.46, respectively). BMI correlated marginally with estimated blood loss (P = 0.08), but not operative time, length of hospital stay, or complications. CONCLUSIONAmong this cohort of minimally invasive lumbar fusion patients, body habitus measured by BMI, weight, or height did not have a significant relationship with most self-reported outcome measures, operative time, length of hospital stay, or complications. Obesity should not be considered a contraindication to minimally invasive lumbar spinal fusion surgery.

Preferential In Situ CD4+CD56+ T Cell Activation and Expansion within Human Glioblastoma

Recent evidence suggests that suppression of the cellular immune response is often attributable to populations of functionally distinct T cells that act to down-regulate Ag-specific effector T cells. Using flow cytometry, we evaluated tumor-infiltrating lymphocytes (TIL) from patients undergoing neurosurgical resection of glioblastoma multiforme (GBM), metastatic lung carcinoma, and meningioma for markers known to be expressed on immunoregulatory T cells. Ex vivo phenotypic characteristics, cellular proliferation, and cytokine expression patterns were compared between T cell subsets found in the PBMC and within TIL from fresh tumor samples. Interestingly, nearly half of all T cells infiltrating GBM specimens were CD56+ T cells, while much smaller percentages of similar cells were identified within metastatic lung tumors and meningiomas. CD56+ T cells identified within GBM were not canonical, or “invariant,” NKT cells, as they demonstrated diverse TCR expression, a primarily CD4 single-positive phenotype, and lack of CD1d reactivity. The percentage of CD56+ T cells exhibiting evidence of proliferation within GBM was 3- to 4-fold higher than the proportion of proliferating CD56− T cells from these lesions. In addition, direct ex vivo analysis of cytokine expression by TIL from GBM demonstrated significant numbers of IL-4/IL-13 positive cells, cytokines that are integral in the cell-mediated repression of tumor immunity in experimental models. We propose that GBM has a unique capacity to recruit and activate CD4+CD56+ T cells, a population that has not been previously described within human tumors.

Biomechanical comparison of traditional and minimally invasive intradural tumor exposures using finite element analysis.

BACKGROUND Minimally invasive approaches to intradural pathology have evolved in part in an effort to reduce approach related destabilization of the spine. No biomechanical data exist however evaluating the effects of traditional and minimally invasive exposures. METHODS A finite element model of the lumbar spine was generated, and a simulated open laminectomy and a modified hemilaminectomy at L4 were performed. Forces were applied to assess changes in flexion, extension, axial rotation, and lateral bending. FINDINGS Open laminectomy produced much greater changes in extension, flexion, and axial rotation than the modified hemilaminectomy from the intact. Lateral bending was similarly unaffected for both exposures. INTERPRETATION The results suggest that a minimally invasive hemilaminar exposure preserves the structural integrity of the lumbar spine and minimizes alterations to segmental motion postoperatively.

Defective receptor expression and dendritic cell differentiation of monocytes in glioblastomas.

OBJECTIVE:Better characterization of the changes that occur in the circulating monocytes of patients with glioblastoma has become more important recently as monocyte-derived dendritic cells are used as adjuvants in the development of glioma vaccines. This study seeks to develop understanding of the phenotypic changes that occur in circulating monocytes of patients with intracranial cancer and to assess the ability of these cells to differentiate into mature dendritic cells. METHODS:Monocyte expression levels of HLA-ABC, HLA-DR, CD86, ICAM-1, TNFRII, and GMCSFR were compared between three cohorts: patients with intracranial glioblastoma (n = 15), patients with intracranial metastases (n = 9), and a group of healthy controls (n = 10). Monocytes were then tested for their ability to differentiate into mature dentritic cells based on morphology, CD83 expression and high levels of co-stimulatory molecules. RESULTS:Comprehensive analysis of monocyte receptor expression demonstrated significantly reduced HLA-ABC, HLA-DR, CD86, ICAM-1, and TNFRII in patients with glioblastoma but not in patients with intracranial metastases compared with a group of healthy controls. GMCSFR expression was significantly reduced in both patients with glioblastoma and intracranial metastases. Additionally, the monocytes of patients with glioblastoma showed a reduced capacity to differentiate into mature dendritic cells as identified by CD83 expression, receptor expression, and morphology. CONCLUSION:Peripheral monocytes are phenotypically altered in the setting of glioblastoma and display a reduced functional capacity to differentiate into mature dendritic cells.

OPERATIVE MANAGEMENT OF SPINAL HEMANGIOBLASTOMA

HEMANGIOBLASTOMAS OCCUR IN 2% to 15% of reported series of intramedullary spinal cord tumors. They are benign, highly vascular tumors that can be cured with surgical resection. Complete removal of these tumors with low morbidity is possible with current microneurosurgical techniques and a thorough understanding of the typical relationship of the tumor to adjacent neural structures. We describe our experience with 16 intramedullary and 2 lumbosacral nerve root hemangioblastomas and review the relevant published literature. A detailed discussion of the operative technique is provided along with an operative video. Three illustrative cases are used to demonstrate clinical considerations that can arise with these tumors, including surgery during pregnancy, symptoms related to syrinx or syringomyelia, and postoperative consequences of neurological deficits.

Minimally invasive posterior thoracic fusion

Thoracic spine fusion may be indicated in the surgical treatment of a wide range of pathologies, including trauma, deformity, tumor, and infection. Conventional open procedures for surgical treatment of thoracic spine disease can be associated with significant approach-related morbidity, which has motivated the development of minimally invasive approaches. Thoracoscopy and, later, video-assisted thoracoscopic surgery were developed to address diseases of the thoracic cavity and subsequently adapted for thoracic spine surgery. Although video-assisted thoracoscopic surgery has been used to treat a variety of thoracic spine diseases, its relatively steep learning curve and high rate of pulmonary complications have limited its widespread use. These limitations have motivated the development of minimally invasive posterior approaches to address thoracic spine pathology without the added risk of morbidity involved in surgically entering the chest. Many of these advances are ongoing and represent the forefront of minimally invasive spine surgery. As these techniques are developed and applied, it will be important to assess their equivalence or superiority in comparison with standard open techniques using prospective trials. In this paper the authors focus on minimally invasive posterior thoracic procedures that include fusion, and provide a review of the current literature, a discussion of future pathways for development, and case examples. The topic is divided by pathology into sections including trauma, deformity, spinal column tumors, and osteomyelitis.