Prognostic impact of CD133 mRNA expression in 48 glioblastoma patients treated with concomitant radiochemotherapy: a prospective patient cohort at a single institution.

BACKGROUND: Cancer stem cells are thought to represent the population of tumorigenic cells responsible for tumor development. The CD133 antigen has been described as a putative stem cell marker in malignant brain tumor that could identify such a tumorigenic population in a subset of glioblastoma. To date, the correlation between CD133 expression in primary glioblastoma and patient prognosis is not clearly established. To address this question we investigated the relationship between CD133 mRNA expression and patient outcome in a glioblastoma patient cohort. MATERIALS AND METHODS: The quantitative expression of CD133 stem cell antigen mRNA using real-time QRT-PCR was assessed in a cohort of 48 consecutive primary glioblastoma patients treated by chemoradiation with temozolomide. RESULTS: On multivariate survival analysis, high CD133 mRNA expression was a significant (P = 0.007) prognostic factor for adverse progression-free and overall survival independent of extent of resection (P = 0.012) and MGMT methylation status (P = 0.002). Patient age was also an independent prognosticator of overall survival (P = 0.037). Furthermore, according to the conjoined expression of CD133 mRNA and MGMT status, the patients were categorized into 3 groups with homogenous prognosis. CONCLUSIONS: These findings constitute conclusive evidence that the measurement of the mRNA expression of CD133 stem cell antigen actually impacts the survival of GBM patients.

IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients.

Mutations in the gene encoding isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have recently been identified in a large proportion of glial tumors of the CNS, but their mechanistic role in tumor development remains unclear. Here, we assessed the actual impact of IDH1 and IDH2 mutations in patients harboring WHO grade II and III gliomas. We sequenced IDH1 at codon 132 and IDH2 at codon 172 in 33 patients with WHO grade II and III gliomas who benefited from a preoperative (18)F-FDG positron emission tomography (PET). Immunohistochemical expression of Hypoxia Inducible Factor-1alpha (HIF-1α), Carbonic Anhydrase IX (CAIX), Glucose Transporter 1 (GLUT1) and Caspase 3 active form (CASP3) along with the R132HIDH1 mutation was assessed in all cases as well as 1p/19q deletion status and p53 expression. HIF-1α expression was found in 15% of IDH-mutated compared to 7.7% of IDH-nonmutated tumors (P = 0.954). Also, GLUT-1 positive staining was found in 5% of IDH-mutated and in 7.1% of IDH-nonmutated tumors (P = 0.794). Finally, CA-IX expression was found in 15% of IDH-mutated and in 7.7% of IDH-nonmutated tumors (P = 0.484). The combined expression of these three hypoxic markers was found in two WHO grade III tumors, one of which was IDH-mutated whereas the other was IDH-nonmutated (P = 0.794). In IDH-mutated tumors, the median SUVmax ratio was 2.24 versus 2.15 in IDH-nonmutated tumors (P = 0.775). Together, these data question the actual relationship between IDH mutation status and in vivo hypoxic biomarkers expression in WHO grade II and III gliomas.

Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred?

Whole brain radiotherapy (WBRT) has been increasingly omitted as the first treatment of primary central nervous system lymphoma (PCNSL) because of neurotoxicity risks. However, neurotoxicity risks are lower in young (<60 years) patients; deferring WBRT may not be necessary and may compromise disease control. To investigate this question, we report a consecutive series of young (<60 years) PCNSL patients uniformly treated with a response-adjusted approach, with WBRT omitted in patients with chemosensitive disease. Treatment started with induction chemotherapy consisting of methotrexate (3 g/m(2)), CCNU, procarbazine, methylprednisolone and intrathecal methotrexate, cytarabine, and methylprednisolone. Patients achieving complete response (CR) received five additional chemotherapy cycles and no further treatment. Patients with less than CR were treated on an individual basis, typically with WBRT or high-dose chemotherapy (HDC) with stem cell rescue. Sixty-four patients were included (median age: 47; median KPS: 70). Median progression-free survival (PFS) was 12 months; median overall survival (OS) was 63 months (median follow-up: 108 months). Objective response after induction was 87% (CR: 54%; PR: 33%). To date, salvage WBRT has been given to a total of 27 patients and HDC to 29. Neurotoxicity developed in five patients (none in patients treated with chemotherapy only). Deferring WBRT in chemosensitive patients seems to compromise PFS but not OS. Neurotoxicity was reduced but not eliminated, as salvage WBRT was frequently required. HDC and WBRT were effective salvage treatments. As the objective of treatment in this population is a cure, withholding WBRT may not be the best strategy and deserves further investigation. Ongoing studies are investigating whether upfront treatment with HDC can replace WBRT in this setting.

Infratentorial ependymomas: prognostic factors and outcome analysis in a multi-center retrospective series of 106 adult patients.

OBJECT: This study was undertaken to analyze outcomes and to assess the prognostic impact of age, location, surgery, radiotherapy (RT), and histopathology in a series of adult infratentorial ependymomas. METHODS: This was a retrospective study of a population of 106 adult patients with infratentorial ependymomas diagnosed between 1990 and 2004. A central pathological review of all cases was performed. Grading was according to the WHO and Marseille's neograding classifications. RESULTS: The series consisted of 58 males (54.7%) and 48 females (45.3%) in the age range of 18-82 years. Using the WHO classification, 88 patients (83.0%) had grade II and 18 patients (17.0%) grade III ependymomas. Using the Marseille's neograding system, 91 patients were low-grade and 15 high-grade. Gross total resection was achieved in 66 patients (62.3%). Thirty-seven patients (35.0%) received adjuvant RT. The 5- and 10-year overall survival rates for the entire cohort were 86.1% and 80.5%, respectively. On multivariate analysis, a preoperative Karnofski performance status score > 80, no recessus lateral extension and a low histological grade (Marseille's grading) were associated with a longer overall survival. The 5- and 10-year progression-free survival rates for the entire cohort were 70.8% and 57.7%, respectively. On multivariate analysis, no recessus lateral extension, gross total resection and a low histological grade (Marseille's grading) were associated with a longer progression-free survival. Adjuvant RT was significantly associated with a better overall and progression-free survival in incompletely resected WHO grade II ependymomas. CONCLUSIONS: This study highlights the key role of histology in the clinical outcome and the fact that gross total resection is a main prognostic factor and the treatment of choice for posterior fossa ependymomas. The use of adjuvant RT in patients with incompletely resected WHO grade II ependymomas appears beneficial, but its effect on high-grade tumors remains to be determined.

Multicentric French study on adult intracranial ependymomas: prognostic factors analysis and therapeutic considerations from a cohort of 152 patients.

Ependymomas account for 2% of all intracranial tumours in adults. Considerable controversy continues to exist with regard to their prognostic factors and therapeutic management due to the rarity and the heterogeneity of series reported so far. The authors report a retrospective study of a homogenous population of 152 adult patients harbouring intracranial ependymomas from 24 French Neurosurgical Centres between 1990 and 2004. All clinico-radiological and follow-up data were analysed and a central pathologic review was performed by two confirmed neuropathologists. The 5- and 10-year overall survival rates were 84.8 and 76.5%, respectively; the 5- and 10-year progression-free survival rates were 63.5 and 52.8%, respectively. On multivariate analysis, overall survival rates were associated with histological grade (P < 0.001), extent of surgery (P = 0.006), patient age (P = 0.004) and patient Karnofski performance status (P = 0.03). The multivariate analysis also revealed that the risk of recurrence was associated with high histological grade (P < 0.001), incomplete resection (P < 0.001) and Karnofski performance status < or = 80 (P = 0.04). The impact of radiotherapy was found to be beneficial for incompletely resected low-grade ependymomas and to a lesser extent for completely removed high-grade tumours. In association with Karnofski performance status and extent of surgery, histological grade is a major prognostic factor in adult intracranial ependymomas. The application of a simple and reproducible grading scheme using objective anaplastic criteria seems useful practically and clinically applicable. The role of adjuvant radiotherapy for patients with incompletely resected low-grade ependymomas seems to be beneficial but remains to be addressed for high-grade tumours.

Adult intracranial WHO grade II ependymomas: long-term outcome and prognostic factor analysis in a series of 114 patients.

Ependymomas account for 2% of all intracranial tumors in adults. Considerable controversy continues to exist with regard to their prognostic factors and therapeutic management due to the rarity and the heterogeneity of series reported so far. The authors report a retrospective study of a homogenous population of 114 adult patients harboring WHO grade II intracranial ependymomas from 32 French Neurosurgical Centers between 1990 and 2004. All clinico-radiological and follow-up data were analyzed, and a central pathologic review was performed by two confirmed neuropathologists. The 5- and 10-year overall survival (OS) rates were 86.1% and 81.0%, respectively; the 5- and 10-year progression-free survival (PFS) rates were 74.6% and 58.9%, respectively. On multivariate analysis, the OS rates were associated with preoperative KPS score (P = .027), extent of surgery (P = .008), and tumor location (supratentorial vs infratentorial, P = .012). The multivariate analysis also revealed that the risk of recurrence was associated with incomplete resection (P = .001) and supratentotrial location (P = .038). Moreover, adjuvant radiotherapy (RT) for patients with incompletely resected tumors is responsible for a significant improvement of both overall (P = .005) and progression-free (P = .002) survival. This study clearly supports the major prognostic impact of the extent of surgery in WHO grade II. Interestingly, tumor location also seems to have an actual impact on both OS and PFS. Finally, the prognostic impact of RT was found to be beneficial for incompletely resected tumors.

Prognostic impact of O6-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort.

BACKGROUND: O(6)-methylguanine-DNA methyltransferase (MGMT) is a key enzyme in the DNA repair process after alkylating agent action. Epigenetic silencing of the MGMT gene by promoter methylation has been associated with longer survival in patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. In this study, the authors evaluated the prognostic value of different biomarkers in recurrent GBM and analyzed the changes in MGMT status between primary tumors and recurrent tumors. METHODS: Twenty-two patients who had recurrent GBM and who underwent surgery with carmustine wafer implantation were enrolled prospectively between 2005 and 2007. The authors investigated the correlation between MGMT silencing in the tumor at recurrence and survival taking into account other clinically recognized prognostic factors. MGMT status was determined by using methylation-specific polymerase chain reaction analysis, a high-throughput quantitative methylation assay, and immunohistochemistry. In addition, expression analyses of human mutL homolog 1, human mutS homolog 2, and tumor necrosis factor alpha-induced protein 3 at recurrence were conducted with regard to their prognostic impact. RESULTS: The median progression-free survival (PFS) and overall survival (OS) rates after recurrence were 3.6 months and 9.9 months, respectively, and the 6-month PFS rate after recurrence was 27.2%. On multivariate analysis, only age (P=.04) and MGMT promoter hypermethylation at recurrence, as determined by MethyLight technology (P=.0012) and methylation-specific polymerase chain reaction (MSP) analysis (P=.004), were correlated with better PFS. On multivariate analysis, only MGMT promoter hypermethylation at recurrence, as determined by using MethyLight technology (P=.019) and MSP analysis (P=.046), was associated with better OS. CONCLUSIONS: MGMT methylation status was an important prognostic factor in patients with recurrent GBM who underwent surgery plus carmustine wafer implantation; therefore, it was useful in predicting the outcome of GBM therapy at recurrence.

Supratentorial ependymomas: prognostic factors and outcome analysis in a retrospective series of 46 adult patients.

BACKGROUND: Ependymomas account for 2% of all intracranial tumors in adults. Supratentorial ependymomas are less common than their infratentorial counterparts. To the authors' knowledge to date, the predictive values of surgery, histology, and patient-related prognostic factors for these tumors remain unresolved. The authors report a series of adult patients with supratentorial ependymomas to characterize the roles of surgery and histology in tumor control. METHODS: The authors retrospectively studied a homogenous population of 46 adult patients who had supratentorial ependymomas from 24 French neurosurgical centers between 1990 and 2004. All clinicoradiologic and follow-up data were analyzed, and a central pathologic review was performed by 2 certified neuropathologists. RESULTS: The mean (+/-standard error) 5- and 10-year overall survival rates for the entire population were 57.1% +/- 8.7% and 41.8% +/- 9.9%, respectively. The 5- and 10-year progression-free survival rates for the entire cohort were of 33.8% +/- 8.1% and 25.4 +/- 8%, respectively. On both univariate and multivariate analysis, age <55 years, greater extent of surgery, and lower histologic grade were associated with longer overall and progression-free survival. However, longer progression-free survival but was not considered a candidate variable for the multivariate model, because data were available for only 34 of 46 patients. CONCLUSIONS: In association with age and extent of surgery, histologic grade was identified as a major prognostic factor in adult supratentorial ependymomas. The application of a simple and reproducible grading scheme using objective anaplastic criteria appeared to be both useful practically and clinically applicable. The role of adjuvant radiotherapy for patients with incompletely resected, low-grade ependymomas needs to be investigated further.