Prognostic Factor In Glioblastoma Patients Research Articles

Preoperative prognostic neurologic index for glioblastoma patients receiving tumor resection.

Neurologic status is one of the major prognostic factors in glioblastoma patients; however, no consensus exists on a clinical index for predicting patient outcomes. The purpose of this study was to evaluate the correlation between neurologic deficits and clinical outcomes in glioblastoma patients, and to develop a prognostic neurologic index for identifying patients with poor outcomes. Patients receiving tumor resection with pathologically confirmed glioblastoma were retrospectively evaluated. The patients' preoperative neurologic deficits were categorized, and patients with poor overall survival (OS) were identified. Other common prognostic factors, including age, performance, imaging findings, and extent of resection, were analyzed. We evaluated 162 glioblastoma patients receiving tumor resection between February 2000 and December 2011, of whom 54 received adjuvant radiotherapy (RT) alone and 84 received concurrent chemo-RT with temozolomide. At a median follow-up of 57.6 (range 26.3-88.9)months, 26 patients had survived without loss to follow-up. We defined adverse neurologic status by using an index of combined increased intracranial pressure (IICP) and non-IICP signs. In univariate analysis, the median OS of patients with and without adverse neurologic status were 9.6 and 18.7months, respectively (p<0.001). In multivariate analyses, adverse neurologic status remained significantly associated with poor OS (hazard ratio 2.18, 95% confidence interval 1.54-3.10). Our proposed neurologic index enables significantly identifying glioblastoma patients receiving tumor resection with poor outcomes, independent of other common prognostic factors. Using the index provides a preoperative predictor of prognosis in glioblastoma patients receiving tumor resection.

Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy

The epidermal growth factor receptor vIII mutant (EGFRvIII) is found in ~50% of all EGFR-amplified glioblastomas and constitutes a tumor-specific therapeutic target. To assess molecular testing approaches and the prognostic role of EGFRvIII in patients treated according to current standards of care, we compared different EGFRvIII detection methods and correlated EGFRvIII status with outcome in a prospective patient cohort of the German Glioma Network. In total, 184 newly diagnosed glioblastoma patients were investigated for EGFR amplification and for expression of EGFR and EGFRvIII by immunohistochemistry. Further, the EGFRvIII status was additionally studied by multiplex ligation-dependent probe amplification (MLPA) analysis and reverse transcription-PCR (RT-PCR). Immunohistochemistry demonstrated EGFRvIII in 34 of 184 patients (18%). RT-PCR or MLPA analysis detected four additional EGFRvIII-positive patients. Overall, RT-PCR and immunohistochemistry were more sensitive for EGFRvIII detection than MLPA. EGFRvIII status was not associated with progression-free and overall survival. EGFRvIII also had no prognostic significance in the subgroup of patients who were free from progression after concomitant radiochemotherapy and thus would be eligible for the ongoing ACT IV EGFRvIII vaccination trial. Age, extent of resection and O⁶-methylguanine DNA methyltransferase (MGMT) promoter methylation status appeared to be less prognostic in EGFRvIII-positive patients. Thus, EGFRvIII positivity is not a major negative prognostic factor in glioblastoma patients treated according to current standards of care. Data from phase II EGFRvIII-targeted vaccination trials compare favorably with the present contemporary results, supporting the further exploration of EGVRvIII vaccination in newly diagnosed glioblastoma.

Treatment outcomes in glioblastoma patients aged 76 years or older: a multicenter retrospective cohort study

Age is one of the most important prognostic factors in glioblastoma patients, but no standard treatment has been established for elderly patients with this condition. We therefore conducted a retrospective cohort study to evaluate treatment regimens and outcomes in elderly glioblastoma patients. The study population consisted of 79 glioblastoma patients aged ≥ 76 years (median age 78.0 years; 34 men and 45 women). The median preoperative Karnofsky performance status (KPS) score was 60. Surgical procedures were classified as biopsy (31 patients, 39.2 %), <95 % resection of the tumor (21 patients, 26.9 %), and ≥ 95 % resection of the tumor (26 patients, 33.3 %). Sixty-seven patients (81.0 %) received radiotherapy and 45 patients (57.0 %) received chemotherapy. The median overall progression-free survival time was 6.8 months, and the median overall survival time was 9.8 months. Patients aged ≥ 78 years were significantly less likely to receive radiotherapy (p = 0.004). Patients with a postoperative KPS score of ≥ 60 were significantly more likely to receive maintenance chemotherapy (p = 0.008). Multivariate analyses identified two independent prognostic factors: postoperative KPS score ≥ 60 (hazard ratio [HR] = 0.531, 95 % confidence interval [CI] 0.315-0.894, p = 0.017) and temozolomide therapy (HR = 0.442, 95 % CI 0.25-0.784, p < 0.001).The findings of this study suggest that postoperative KPS score is an important prognostic factor for glioblastoma patients aged ≥ 76 years, and that these patients may benefit from temozolomide therapy.

MGMT promoter methylation in gliomas-assessment by pyrosequencing and quantitative methylation-specific PCR

BackgroundMethylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is a favorable prognostic factor in glioblastoma patients. However, reported methylation frequencies vary significantly partly due to lack of consensus in the choice of analytical method.MethodWe examined 35 low- and 99 high-grade gliomas using quantitative methylation specific PCR (qMSP) and pyrosequencing. Gene expression level of MGMT was analyzed by RT-PCR.ResultsWhen examined by qMSP, 26% of low-grade and 37% of high-grade gliomas were found to be methylated, whereas 97% of low-grade and 55% of high-grade gliomas were found methylated by pyrosequencing. The average MGMT gene expression level was significantly lower in the group of patients with a methylated promoter independent of method used for methylation detection. Primary glioblastoma patients with a methylated MGMT promoter (as evaluated by both methylation detection methods) had approximately 5 months longer median survival compared to patients with an unmethylated promoter (log-rank test; pyrosequencing P = .02, qMSP P = .06). One third of the analyzed samples had conflicting methylation results when comparing the data from the qMSP and pyrosequencing. The overall survival analysis shows that these patients have an intermediate prognosis between the groups with concordant MGMT promoter methylation results when comparing the two methods.ConclusionIn our opinion, MGMT promoter methylation analysis gives sufficient prognostic information to merit its inclusion in the standard management of patients with high-grade gliomas, and in this study pyrosequencing came across as the better analytical method.

Quantitative methylation analysis of HOXA3, 7, 9, and 10 genes in glioma: association with tumor WHO grade and clinical outcome

The purpose of this study was to determine whether specific HOXA epigenetic signatures could differentiate glioma with distinct biological, pathological, and clinical characteristics. We evaluated HOXA3, 7, 9, and 10 methylation in 63 glioma samples by MassARRAY and pyrosequencing. We demonstrated the direct statistical correlation between the level of methylation of all HOXA genes examined and WHO grading. Moreover, in glioblastoma patients, higher level of HOXA9 and HOXA10 methylation significantly correlated with increased survival probability (HOXA9-HR: 0.36, P=0.007; HOXA10-HR: 0.46, P=0.045; combined HOXA9 and 10-HR 0.28, P=0.004). This study identifies HOXA3, 7, 9, and 10 as methylation targets mainly in high-grade glioma and hypermethylation of the HOXA9 and 10 as prognostic factor in glioblastoma patients. Our data indicate that these epigenetic changes may be biomarkers of clinically different subgroups of glioma patients that could eventually benefit from personalized therapeutic strategies.

Outcome evaluation in glioblastoma patients using different ranking scores: KPS, GOS, mRS and MRC

Patient performance is an overall accepted independent prognostic factor in glioblastoma patients. Its estimation is essential for treatment planning, follow-up and clinical trials. Patient performance is mostly determined by usage of the Karnofsky Performance Score (KPS) for cancer patients. However, several other ranking scores have been developed specifically for patients with neurological diseases: Glasgow Outcome Score (GOS) for trauma patients, modified Ranking Score for stroke patients and Medical Research Council brain prognostic index (MRC) for brain tumour patients. The aims of this study were: (1) to compare these four performance scores in their ability to determine patient survival; and (2) to compare the prognostic value of performance with that of other prognostic factors. Univariate and multivariate survival analysis was used. Survival analysis revealed a high correlation to survival for all four scores. The maximum derivation of the curves was shown for the MRC and GOS. Performance had more clinical impact in determining patient survival than age and tumour resection. Differential treatment planning may need the formation of more than two patient groups. This was possible with the MRC, as well as the GOS and KPS. Forming more than three patient groups was not effective with any score.

MGMT methylation status as a prognostic factor in anaplastic astrocytomas

2052 Background: MGMT methylation status has been found to be an important prognostic factor in glioblastoma patients (pts). However, further data on the epigenetic feature are needed before its role in rare diseases such as anaplastic astrocytomas (AA) can be established. Methods: A retrospective analysis was made on a database of 139 AA pts followed prospectively from January 1995 and August 2008. We evaluated only pts who met the following inclusion criteria: age &gt;18 years; PS 0–2; histological diagnosis of AA; postoperative radiotherapy (RT) and chemotherapy (CT). MGMT status was determined with methylation specific PCR. The study aim was to evaluate the role of MGMT methylation status in AA. The log-rank test was employed to evaluate the significance of the prognostic variables. Results: 80 pts (m/f: 46/34, median age: 41 years, range: 18–71 years) were enrolled. MGMT was assessable in 71 of 80 pts (88.8%), being methylated in 30 (42.9%), and unmethylated in 41 (57.7%) pts. Median PFS was 48.6 months (95% CI: 33.7 - 63.5), being 96 months (95% CI: 29–163) and 38 months (95%CI: 18.9–57.2) in MGMT methylated and unmethylated pts, respectively (p = 0.09). At univariate analysis, complete resection (p = 0.02), age (p = 0.002), and KPS (p = 0.003) were significantly correlated with PFS. At multivariate analysis only age remains correlated with PFS (p = 0.01). Median survival (OS) was 93.7 months (95% CI: 63.5–123.8), being not reached and 77 months (95% CI: 20–134.2), in MGMT methylated and unmethylated pts, respectively (p = 0.03). MGMT methylation (p = 0.03), age (p = 0.0003), and KPS (p = 0.03) were significantly correlated with OS at univariate analysis. At multivariate analysis, age (p = 0.0002) and MGMT methylation (p = 0.01) were correlated with a better OS. Conclusions: MGMT methylation status is an independent prognostic factor together with age in AA. This datum should provide the background to improve the therapeutic index with temozolomide concurrent with and adjuvant to RT in AA. No significant financial relationships to disclose.

Correlation of molecular genetic analysis of p53, MDM2, p16, PTEN, and EGFR and survival of patients with anaplastic astrocytoma and glioblastoma.

This article reviews studies on the correlation between genetic abnormalities in malignant astrocytic tumors and patient survival. It is almost certain that alterations of PTEN on chromosome 10 represent a significant unfavorable prognostic factor in glioblastoma patients. The association of alterations in p53, MDM2, p16 or EGFR with the survival of patients with anaplastic astrocytoma or glioblastoma remains controversial. It is possible that the p16 alteration and EGFR amplification are associated with poor survival in certain groups of patients and that there might be a relationship with age. Malignant transformation of astrocytic cells are driven by the sequential acquisition of genetic alteration. Therefore, it is reasonable to subgroup gliomas by their patterns of genetic alterations. However the studies that correlated the multiple genetic alterations with survival are still limited. Further studies on large cohorts are necessary to elucidate the genetic factors that affect the prognosis and response to therapy of patients with malignant gliomas and to develop effective management strategies.