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Chirag G Patil,
Miriam Nuño,
Adam Elramsisy,
Debraj Mukherjee,
Christine Carico,
Jocelynn Dantis,
Jethro Hu, John S Yu,
Xuemo Fan,
Keith L Black,
Serguei I Bannykh
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ABSTRACT: We investigated whether high levels of activated mitogen-activated protein kinase (p-MAPK) were associated with poor survival among patients with newly diagnosed glioblastoma during the temozolomide era. Nuclear p-MAPK expression of 108 patients with GBM was quantified and categorized in the following levels: low (0%-10%), medium (11%-40%), and high (41%-100%). Independent predictors of overall survival were determined using a multivariate Cox proportional hazards model. Our study included 108 patients with newly diagnosed GBM. Median age was 65 years, and 74% had high Karnofsky performance status (KPS ≥ 80). Median overall survival among all patients was 19.5 months. Activated MAPK expression levels of <10%, 11%-40%, and ≥41% were observed in 33 (30.6%), 37 (34.3%), and 38 (35.2%) patients, respectively. Median survival for low, medium, and high p-MAPK expression was 32.4, 18.2, and 12.5 months, respectively. Multivariate analysis showed 2.4-times hazard of death among patients with intermediate p-MAPK than low p-MAPK expression (hazard ratio [HR], 2.4; P = .02); high-expression patients were 3.9 times more likely to die, compared with patients with low p-MAPK (HR, 3.9; P = .007). Patients aged ≥65 years (HR, 2.8; P = .002) with KPS < 80 (HR, 3.1; P = .0003) and biopsy or partial resection (HR, 1.9; P = .02) had higher hazard of death. MGMT and PTEN expression were not associated with survival differences. This study provides quantitative means of evaluating p-MAPK in patients with GBM. It confirms the significant and independent prognostic relevance of p-MAPK in predicting survival of patients with GBM treated in the temozolomide era and highlights the need for therapies targeting the p-MAPK oncogenic pathway.
Neuro-Oncology 10/2012; · 5.72 Impact Factor
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ABSTRACT: Object The prognosis of patients with glioblastoma who present with multifocal disease is not well documented. The objective of this study was to determine whether multifocal disease on initial presentation is associated with worse survival. Methods The authors retrospectively reviewed records of 368 patients with newly diagnosed glioblastoma and identified 47 patients with multifocal tumors. Each patient with a multifocal tumor was then matched with a patient with a solitary glioblastoma on the basis of age, Karnofsky Performance Scale (KPS) score, and extent of resection, using a propensity score matching methodology. Radiation and temozolomide treatments were also well matched between the 2 cohorts. Kaplan-Meier estimates and log-rank tests were used to compare patient survival. Results The incidence of multifocal tumors was 12.8% (47/368). The median age of patients with multifocal tumors was 61 years, 76.6% had KPS scores ≥ 70, and 87.2% underwent either a biopsy or partial resection of their tumors. The 47 patients with multifocal tumors were almost perfectly matched on the basis of age (p = 0.97), extent of resection (p = 1.0), and KPS score (p = 0.80) compared with 47 patients with a solitary glioblastoma. Age (>65 years), partial resection or biopsy, and low KPS score (<70) were associated with worse median survival within the multifocal group. In the multifocal group, 19 patients experienced tumor progression on postradiation therapy MRI, compared with 11 patients (26.8%) with tumor progression in the unifocal group (p = 0.08). Patients with multifocal tumors experienced a significantly shorter median overall survival of 6 months (95% CI 4-10 months), compared with the 11-month median survival (95% CI 10-19 months) of the matched solitary glioblastoma group (p = 0.02, log-rank test). Two-year survival rates were 4.3% for patients with multifocal tumors and 29.0% for the unifocal cohort. Patients with newly diagnosed multifocal tumors were found to have an almost 2-fold increase in the hazard of death compared with patients with solitary glioblastoma (hazard ratio 1.8, 95% CI 1.1-3.1; p = 0.02). Tumor samples were analyzed for expression of phosphorylated mitogen-activated protein kinase, phosphatase and tensin homolog, O(6)-methylguanine-DNA methyltransferase, laminin β1 and β2, as well as epidermal growth factor receptor amplification, and no significant differences in expression profile between the multifocal and solitary glioblastoma groups was found. Conclusions Patients with newly diagnosed multifocal glioblastoma on presentation experience significantly worse survival than patients with solitary glioblastoma. Patients with multifocal tumors continue to pose a therapeutic challenge in the temozolomide era and magnify the challenges faced while treating patients with malignant gliomas.
Journal of Neurosurgery 08/2012; 117(4):705-11. · 2.96 Impact Factor
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ABSTRACT: Race and gender disparities in outcomes have been documented in many cancers. Our study evaluated the role of race, gender, and tumor primary site in predicting in-hospital mortality, discharge disposition, and complications among patients with brain metastases.
Using Nationwide Inpatient Sample (NIS) data from 1998 to 2007, we evaluated in-patient outcomes of brain metastases patients who underwent a craniotomy in U.S. hospitals. Univariate and multivariate analyses were used to assess the effect of patient/tumor characteristics in predicting the proposed outcomes.
NIS estimated 78,170 patients with metastatic brain tumors underwent craniotomy between 1998 and 2007 in the United States. Median age was 59.2 years, 52.1 % were women, and 6.4 % were black. In-hospital mortality rate was 2.2 % with an average length of stay of 7.6 days. Black patients had significantly higher morbidity and nonroutine discharges than whites/others (p < .0001). Black women had almost twice the mortality (3.4 vs 1.8 %, p < .0001), a higher complication rate (24.6 vs 18.8 %, p < .0001), longer hospital stays (10.0 vs 7.3 days, p < .0001), and more nonroutine discharges (45.1 vs 36.8 %, p < .0001), compared with white/other women. Tumor histology was a significant predictor of outcomes, with female lung cancer patients having the highest odds of mortality and primary gastrointestinal tumors having the highest number of complications.
Evidence of race and gender disparities in outcomes were found in black patients, especially in black females who underwent surgical resection for brain metastases. These findings highlight an opportunity to reduce the gap of outcome disparities in brain metastasis patients.
Annals of Surgical Oncology 05/2012; 19(8):2657-63. · 4.17 Impact Factor
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Christine Carico,
Miriam Nuño,
Debraj Mukherjee,
Adam Elramsisy,
Jocelynn Dantis,
Jethro Hu,
Jeremy Rudnick, John S Yu,
Keith L Black,
Serguei I Bannykh,
Chirag G Patil
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ABSTRACT: Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed.
Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age, extent of resection, Karnofsky performance scale (KPS), and treatment on overall survival.
Sixty-five percent of patients were men with median age of 63 years, and 70% had KPS≥80. Most patients (81%) received standard treatment (temozolomide with concurrent radiation). A total of 72 (47%) patients had retained PTEN expression. Median overall survival (OS) was 19.1 months (95% CI: 15.0-22.5). Median survival of 20.0 months (95% CI: 15.0-25.5) and 18.2 months (95% CI: 13.0-25.7) was observed in PTEN retained and PTEN loss patients, respectively (p = .71). PTEN loss patients were also found to have amplifications of EGFR gene more frequently than patients with retained PTEN (70.8% vs. 47.8%, p = .01). Multivariate analysis showed that older age (HR 1.64, CI: 1.02-2.63, p = .04), low KPS (HR 3.57, CI: 2.20-5.79, p<.0001), and lack of standard treatment (HR 3.98, CI: 2.38-6.65, p<.0001) yielded worse survival. PTEN loss was not prognostic of overall survival (HR 1.31, CI: 0.85-2.03, p = .22).
Loss of expression of PTEN does not confer poor overall survival in the temozolomide era. These findings imply a complex and non-linear molecular relationship between PTEN, its regulators and effectors in the tumorigenesis of glioblastoma. Additionally, there is evidence that temozolomide may be more effective in eradicating GBM cancer cells with PTEN loss and hence, level the outcomes between the PTEN retained and loss groups.
PLoS ONE 01/2012; 7(3):e33684. · 4.09 Impact Factor
