Dima Suki

Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients

Object The current North American experience with minimally invasive vertebro- and kyphoplasty is largely limited to the treatment of benign osteoporotic compression fractures. The objective of this study was to assess the safety and efficacy of these procedures for painful vertebral body (VB) fractures in cancer patients. Methods The authors reviewed a consecutive group of cancer patients (21 with myeloma and 35 with other primary malignancies) undergoing vertebro- and kyphoplasty at their institution. Ninety-seven (65 vertebro- and 32 kyphoplasty) procedures were performed in 56 patients during 58 treatment sessions. The mean patient age was 62 years (+/- 13 years [standard deviation]) and the median duration of symptoms was 3.2 months. All patients suffered intractable spinal pain secondary to VB fractures. Patients noted marked or complete pain relief after 49 procedures (84%), and no change after five procedures (9%); early postoperative Visual Analog Scale (VAS) pain scores were unavailable in four patients (7%). No patient was worse after treatment. Reductions in VAS pain scores remained significant up to 1 year (p = 0.02, Wilcoxon signed-rank test). Analgesic consumption was reduced at 1 month (p = 0.03, Wilcoxon signed-rank test). Median follow-up length was 4.5 months (range 1 day-19.7 months). Asymptomatic cement leakage occurred during vertebroplasty at six (9.2%) of 65 levels; no cement extravasation was seen during kyphoplasty. There were no deaths or complications related to the procedures. The mean percentage of restored VB height by kyphoplasty was 42 +/- 21%. Conclusions Percutaneous vertebro- and kyphoplasty provided significant pain relief in a high percentage of patients, and this appeared durable over time. The absence of cement leakage-related complications may reflect the use of 1) high-viscosity cement; 2) kyphoplasty in selected cases; and 3) relatively small volume injection. Precise indications for these techniques are evolving; however, they are safe and feasible in well-selected patients with refractory spinal pain due to myeloma bone disease or metastases.

Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients

Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in ∼50% to 60% of glioblastoma multiforme tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24% to 67% of cases. We sought to determine whether glioblastoma multiforme expression of either overexpressed wild-type EGFR or the mutant EGFRvIII is an independent predictor of overall patient survival. Experimental Design: Glioblastoma multiforme patients (n = 196) underwent a ≥95% volumetric tumor resection followed by conformal radiation. Their EGFR and EGFRvIII status was determined by immunohistochemistry and survival analyses were done. Results: In our study of glioblastoma multiforme patients, 46% (n = 91) failed to express EGFR, 54% (n = 105) had overexpression of the wild-type EGFR, and 31% (n = 61) also expressed the EGFRvIII. Patients within groups expressing the EGFR, EGFRvIII, or lacking EGFR expression did not differ in age, sex, Karnofsky performance scale score, extent of tumor resection, or radiation. The median overall survival times for patients with tumors having EGFR expression absent, overexpressed only, or mutant (EGFRvIII) were 0.96, 0.98, and 1.07 years, respectively. However, for patients surviving ≥1 year, these values were 2.03, 2.02, and 1.21 years (P < 0.0001; log-rank test comparing EGFRvIII with all others). This effect remained significant in the multivariate analysis after adjustment for all other cofactors including age and Karnofsky performance scale score (rate ratio 4.34; 95% confidence interval, 2.21-8.51). Conclusions: Neither the overexpressed wild-type EGFR nor EGFRvIII was an independent predictor of median overall survival in this selected cohort of patients who underwent extensive tumor resection. However, in patients surviving ≥1 year, the expression of EGFRvIII was an independent negative prognostic indicator.

The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses

Little is known about the immune performance and interactions of CNS microglia/macrophages in glioma patients. We found that microglia/macrophages were the predominant immune cell infiltrating gliomas ( approximately 1% of total cells); others identified were myeloid dendritic cells (DCs), plasmacytoid DCs, and T cells. We isolated and analyzed the immune functions of CD11b/c+CD45+ glioma-infiltrating microglia/macrophages (GIMs) from postoperative tissue specimens of glioma patients. Although GIMs expressed substantial levels of Toll-like receptors (TLRs), they did not appear stimulated to produce pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin 1, or interleukin 6), and in vitro, lipopolysaccharides could bind TLR-4 but could not induce GIM-mediated T-cell proliferation. Despite surface major histocompatibility complex class II expression, they lacked expression of the costimulatory molecules CD86, CD80, and CD40 critical for T-cell activation. Ex vivo, we demonstrate a corresponding lack of effector/activated T cells, as glioma-infiltrating CD8+ T cells were phenotypically CD8+CD25-. By contrast, there was a prominent population of regulatory CD4 T cells (CD4+CD25+FOXP3+) infiltrating the tumor. We conclude that while GIMs may have a few intact innate immune functions, their capacity to be stimulated via TLRs, secrete cytokines, upregulate costimulatory molecules, and in turn activate antitumor effector T cells is not sufficient to initiate immune responses. Furthermore, the presence of regulatory T cells may also contribute to the lack of effective immune activation against malignant human gliomas.

Epidermal Growth Factor Receptor Variant III Status Defines Clinically Distinct Subtypes of Glioblastoma

PURPOSE The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status. PATIENTS AND METHODS The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Groups recursive partitioning analysis (RTOG-RPA) class. RESULTS The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40-negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers. CONCLUSION Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.

Prognostic Associations of Activated Mitogen-Activated Protein Kinase and Akt Pathways in Glioblastoma

Purpose: Activation of mitogen-activated protein kinase (MAPK) and members of the Akt pathway have been shown to promote cell proliferation, survival, and resistance to radiation. This study was conducted to determine whether any of these markers are associated with survival time and response to radiation in glioblastoma. Experimental Design: The expression of phosphorylated (p-)Akt, mammalian target of rapamycin (p-mTOR), p-p70S6K, and p-MAPK were assessed by immunohistochemical staining in 268 cases of newly diagnosed glioblastoma. YKL-40, a prognostic marker previously examined in these tumors, was also included in the analysis. Expression data were tested for correlations with response to radiation therapy in 131 subtotally resected cases and overall survival (in all cases). Results were validated in an analysis of 60 patients enrolled in clinical trials at a second institution. Results: Elevated p-MAPK expression was most strongly associated with poor response to radiotherapy, a finding corroborated in the validation cohort. For survival, higher expressions of p-mTOR, p-p70S6K, and p-MAPK were associated with worse outcome (all P < 0.03). YKL-40 expression was associated with the expressions of p-MAPK, p-mTOR, and p-p70S6K (all P < 0.02), with a trend toward association with p-Akt expression (P = 0.095). When known clinical variables were added to a multivariate analysis, only age, Karnofsky performance score, and p-MAPK expression emerged as independent prognostic factors. Conclusions: p-MAPK and activated members of the Akt pathway are markers of outcome in glioblastoma. Elevated expression of p-MAPK is associated with increased radiation resistance and represents an independent prognostic factor in these tumors.

The natural history of EGFR and EGFRvIII in glioblastoma patients

BackgroundThe epidermal growth factor receptor (EGFR) is over expressed in approximately 50–60% of glioblastoma (GBM) tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24–67% of cases. This study was designed to address whether over expressed EGFR or EGFRvIII is an actual independent prognostic indicator of overall survival in a uniform body of patients in whom gross total surgical resection (GTR; ≥ 95% resection) was not attempted or achieved.MethodsBiopsed or partially/subtotally resected GBM patients (N = 54) underwent adjuvant conformal radiation and chemotherapy. Their EGFR and EGFRvIII status was determined by immunohistochemistry and Kaplan-Meier estimates of overall survival were obtained.ResultsIn our study of GBM patients with less than GTR, 42.6% (n = 23) failed to express EGFR, 25.9% (n = 14) had over expression of the wild-type EGFR only and 31.5 % (n = 17) expressed the EGFRvIII. Patients within groups expressing the EGFR, EGFRvIII, or lacking EGFR expression did not differ in age, Karnofsky Performance Scale (KPS) score, extent of tumor resection. They all had received postoperative radiation and chemotherapy. The median overall survival times for patients with tumors having no EGFR expression, over expressed EGFR only, or EGFRvIII were 12.3 (95% CI, 8.04–16.56), 11.03 (95% CI, 10.18–11.89) and 14.07 (95% CI, 7.39–20.74) months, respectively, log rank test p > 0.05). Patients with tumors that over expressed the EGFR and EGFRvIII were more likely to present with ependymal spread, 21.4% and 35.3% respectively, compared to those patients whose GBM failed to express either marker, 13.0%, although the difference was not statistically significant. There was no significant difference in multifocal disease or gliomatosis cerebri among EGFR expression groups.ConclusionThe over expressed wild-type EGFR and EGFRvIII are not independent predictors of median overall survival in the cohort of patients who did not undergo extensive tumor resection.

IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection

BACKGROUND IDH1 gene mutations identify gliomas with a distinct molecular evolutionary origin. We sought to determine the impact of surgical resection on survival after controlling for IDH1 status in malignant astrocytomas-World Health Organization grade III anaplastic astrocytomas and grade IV glioblastoma. METHODS Clinical parameters including volumetric assessment of preoperative and postoperative MRI were recorded prospectively on 335 malignant astrocytoma patients: n = 128 anaplastic astrocytomas and n = 207 glioblastoma. IDH1 status was assessed by sequencing and immunohistochemistry. RESULTS IDH1 mutation was independently associated with complete resection of enhancing disease (93% complete resections among mutants vs 67% among wild-type, P < .001), indicating IDH1 mutant gliomas were more amenable to resection. The impact of residual tumor on survival differed between IDH1 wild-type and mutant tumors. Complete resection of enhancing disease among IDH1 wild-type tumors was associated with a median survival of 19.6 months versus 10.7 months for incomplete resection; however, no survival benefit was observed in association with further resection of nonenhancing disease (minimization of total tumor volume). In contrast, IDH1 mutants displayed an additional survival benefit associated with maximal resection of total tumor volume (median survival 9.75 y for >5 cc residual vs not reached for <5 cc, P = .025). CONCLUSIONS The survival benefit associated with surgical resection differs based on IDH1 genotype in malignant astrocytic gliomas. Therapeutic benefit from maximal surgical resection, including both enhancing and nonenhancing tumor, may contribute to the better prognosis observed in the IDH1 mutant subgroup. Thus, individualized surgical strategies for malignant astrocytoma may be considered based on IDH1 status.

Spinal cord ependymoma: Radical surgical resection and outcome

OBJECTIVE Several authors have noted increased neurological deficits and worsening dysesthesia in the postoperative period in patients with spinal cord ependymoma. We describe the neurological progression and pain evolution of these patients over the 1-year period after surgery. In addition, our favored method of en bloc tumor resection is illustrated, and the rate of complications, recurrence, and survival in this group of patients is addressed. METHODS We operated on 26 patients (12 male and 14 female) with low-grade spinal cord ependymomas between 1975 and 2001. The median age at diagnosis was 42 years. Tumors extended into the cervical cord in 13 patients, the thoracic cord in 7 patients, and the conus medullaris in 6 patients. Eleven patients had previous surgery and/or radiation therapy. RESULTS We achieved a gross total resection in 88% of patients, whereas 8% had a subtotal resection and 4% had a biopsy. Only 1 patient developed a recurrence over a mean follow-up period of 31 months. CONCLUSION We conclude that radical surgical resection of spinal cord ependymomas can be safely achieved in the majority of patients. A trend toward neurological improvement from a postoperative deficit can be expected between 1 and 3 months after surgery and continues up to 1 year. Postoperative dysesthesias begin to improve within 1 month of surgery and are significantly better by 1 year after surgery. The best predictor of outcome is the preoperative neurological status.

Impact of intraoperative high-field magnetic resonance imaging guidance on glioma surgery: a prospective volumetric analysis.

OBJECTIVETo determine the impact of intraoperative magnetic resonance imaging (iMRI) on the decision to proceed with additional glioma resection during surgery and to maximize extent of resection (EOR). METHODSPatients who underwent craniotomy for glioma resection with high-field iMRI guidance were prospectively evaluated between September 2006 and August 2007. Volumetric analysis and EOR were assessed with iMRI, using postcontrast T1-weighted images for tumors showing contrast enhancement and T2-weighted images for nonenhancing tumors. RESULTSForty-six patients underwent resection using iMRI guidance, with iMRI being used to evaluate the EOR in 44 patients and for reregistration in 2 patients. Surgery was terminated after iMRI in 23 patients (52%) because gross total resection was achieved or because of residual tumor infiltration in an eloquent brain region. Twenty-one patients (47%) underwent additional resection of residual tumor after iMRI. For enhancing gliomas, the median EOR increased significantly from 84% (range, 59%–97%) to 99% (range, 85%–100%) with additional tumor removal after iMRI (P < 0.001). For nonenhancing gliomas, the median EOR increased (from 63% to 80%) with additional tumor removal after iMRI, but not significantly, owing to the small sample size (7 patients). Overall, the EOR increased from 76% (range, 35%–97%) to 96% (range, 48%–100%) (P < 0.001). Gross total resection was achieved after additional tumor removal after iMRI in 15 of 21 patients (71%). Overall, 29 patients (65%) experienced gross total resection, and in 15 (52%), this was achieved with the contribution of iMRI. CONCLUSIONHigh-field iMRI is a safe and reliable technique, and its use optimizes the extent of glioma resection.

Awake craniotomy for brain tumors near eloquent cortex: Correlation of intraoperative cortical mapping with neurological outcomes in 309 consecutive patients

OBJECTIVEIntraoperative localization of cortical areas for motor and language function has been advocated to minimize postoperative neurological deficits. We report herein the results of a retrospective study of cortical mapping and subsequent clinical outcomes in a large series of patients. METHODSPatients with intracerebral tumors near and/or within eloquent cortices (n = 309) were clinically evaluated before surgery, immediately after, and 1 month and 3 months after surgery. Craniotomy was tailored to encompass tumor plus adjacent areas presumed to contain eloquent cortex. Intraoperative cortical stimulation for language, motor, and/or sensory function was performed in all patients to safely maximize surgical resection. RESULTSA gross total resection (≥95%) was obtained in 64%, and a resection of 85% or more was obtained in 77% of the procedures. Eloquent areas were identified in 65% of cases, and in that group, worsened neurological deficits were observed in 21% of patients, whereas only 9% with negative mapping sustained such deficits (P < 0.01). Intraoperative neurological deficits occurred in 64 patients (21%); of these, 25 (39%) experienced worsened neurological outcome at 1 month, whereas only 27 of 245 patients (11%) without intraoperative changes had such outcomes (P < 0.001). At 1 month, 83% overall showed improved or stable neurological status, whereas 17% had new or worse deficits; however, at 3 months, 7% of patients had a persistent neurological deficit. Extent of resection less than 95% also predicted worsening of neurological status (P < 0.025). CONCLUSIONNegative mapping of eloquent areas provides a safe margin for surgical resection with a low incidence of neurological deficits. However, identification of eloquent areas not only failed to eliminate but rather increased the risk of postoperative deficits, likely indicating close proximity of functional cortex to tumor.