Philippe Metellus

Correlation Between O6-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide

PURPOSEnThis phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma.nnnPATIENTS AND METHODSnPatients received temozolomide (150 mg/m2/d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O6-methylguanine-DNA methyltransferase (MGMT) expression.nnnRESULTSnTwenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%).nnnCONCLUSIONnThis dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.

Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis

The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (Pxa0=xa00.031) and p53 expression (Pxa0=xa00.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, Pxa0=xa00.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratioxa0=xa040.9; 95% CI, 2.89–578.49, Pxa0=xa00.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (Pxa0=xa00.020) and that these tumors involved significantly more frequently the insula (Pxa0=xa00.004), were larger in size (>6xa0cm, Pxa0=xa00.047), displayed an infiltrative pattern on MRI (Pxa0=xa00.007) and were all p53 negative with no 1p19q deletion (Pxa0<xa010−6). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new tool to guide patient-tailored therapy.

A2B5 Cells from Human Glioblastoma have Cancer Stem Cell Properties

Glioblastomas, like other cancers, harbor small cell populations with the capability of sustaining tumor formation. These cells are referred to as cancer stem cells. We isolated cells expressing the surface marker A2B5 from three human glioblastomas (GBM) and showed that after grafting into nude mice, they generated dense and highly infiltrative tumors. Then, we extensively studied A2B5+ cells isolated from 11 human GBM. These cells display neurosphere‐like, self‐renewal, asymmetrical cell division properties and have multipotency capability. Stereotactic xenografts of dissociated A2B5+‐derived secondary spheres revealed that as few as 1000 cells produced a tumor. Moreover, flow cytometry characterization of A2B5+‐derived spheres revealed three distinct populations of cells: A2B5+/CD133+, A2B5+/CD133‐ and A2B5‐/CD133‐, with striking proportion differences among GBM. Both A2B5+/CD133+ and A2B5+/CD133‐ cell fractions displayed a high proliferative index, the potential to generate spheres and produced tumors in nude mice. Finally, we generated two green fluorescent protein‐cell lines that display—after serum induction—distinct proliferative and migratory properties, and differ in their CD133 level of expression. Taken together, our results suggest that transformed A2B5+ cells are crucial for the initiation and maintenance of GBM, although CD133 expression is more involved in determining the tumors behavior.

Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study

Immunostimulating oligodeoxynucleotides containing CpG motifs (CpG-ODN) have shown promising efficacy in cancer models when injected locally. In a phase I clinical trial, intratumoral infusions of CpG-ODN in glioblastoma (GBM) patients were well tolerated at doses up to 20 mg. This phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with recurrent GBMs. Patients with recurrent GBM occurring at least 3 months after radiotherapy, and previously treated with 1 or 2 regimens of chemotherapy received 20 mg of CpG-ODN (CpG-28) by convection-enhanced delivery. The primary endpoint was the percentage of patients without tumor progression 6 months after inclusion. Secondary endpoints were tolerance, survival, and radiological response. Thirty-four patients were enrolled in two centers between November 2004 and March 2006. Thirty-one patients received CpG-ODN treatment. The progression-free survival (PFS) at 6 months was 19%. One partial response and 3 minor responses were observed. The median overall survival was 28 weeks. Eight patients (24%) were alive 1 year after inclusion and 5 patients (15%) were alive after 2 years. Treatment was usually well tolerated. As reported previously, the most common toxicities were lymphopenia, mild fever, seizures, and transient neurological worsening. Despite a few cases showing a radiological response, CpG-28 showed modest activity on the 6-month PFS in this patient population. The molecular or clinical characteristics of a subgroup of patients that could potentially benefit from such an approach remain to be defined.

Normal pressure hydrocephalus: long-term outcome after shunt surgery

Background/objective: Little is known about the long-term clinical course and management of patients with normal pressure hydrocephalus (NPH) treated by cerebrospinal fluid (CSF) shunting. Methods: We retrospectively reviewed records of 55 patients diagnosed with idiopathic NPH (INPH) and treated with CSF shunts, all of whom were followed for more than 3 years after the original shunt surgery. At each annual follow-up visit, the patient was assessed by Folstein Mini Mental State Examination, detailed clinical evaluation of gait and assessment of headache, cognition, gait or urination, as assessed by the patient and relatives. Results: The mean duration of follow-up was 5.9±2.5 years. There was an overall sustained improvement among all symptoms. Gait showed the highest maintenance of improvement over baseline (83% at 3 years and 87% at the last analysed follow-up of 7 years), cognition showed intermediary improvement (84% and 86%, respectively), and urinary incontinence showed the least improvement (84% and 80%, respectively). Fifty-three percent of patients required shunt revisions. Indications for revision included shunt malfunction (87%), infection (10%) and change of shunt configuration (3%). Overall, 74% revisions resulted in clinical improvement. Conclusions: Clinical improvement of patients with NPH can be sustained for 5–7 years in some patients with NPH, even if shunt revision surgery is needed multiple times. With earlier diagnosis and treatment of NPH and the increasing lifespan of the ageing population, the need for long-term follow-up after shunt surgery for NPH may be greater than it was in the past. Monitoring, identification and treatment of shunt obstruction is a key management principle.

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.

O6‐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.

Brainstem metastases: management using gamma knife radiosurgery.

OBJECTIVE:Brainstem metastasis is an uncommon complication of systemic cancer, generally considered to have a highly unfavorable prognosis. Surgical risks are high and standard radiation or chemotherapy have little effect. The purpose of this study is to evaluate our experience using Gamma Knife radiosurgery (GKRS) for the management of brainstem metastasis. METHODS:Between July 1992 and March 2001, we treated 28 patients with brainstem metastasis using GKRS. Lesions were located in the pons in 17 patients, midbrain in nine, and medulla oblongata in two. At time of the radiosurgery, eight patients presented with another supratentorial metastasis. The most frequent primary tumor site was the lung (13 cases) followed by the melanoma in four cases, the kidney in two, and other locations in six. Only six patients underwent fractionated whole-brain radiation therapy. Mean marginal radiation dose for GKRS was 19.6 Gy (range, 11–30). Mean maximum diameter was 17.2 mm (range, 10–30). RESULTS:No GKRS-related morbidity was observed. Local tumor control was achieved in 92% of patients. Twenty-six patients have died. Death was related to the progression of the brainstem lesion in two cases. Mean and median survival after GKRS were 10.2 and 12 months, respectively. Follow-up periods in the two surviving patients were 12 and 13 months. CONCLUSION:The results of this small series demonstrate that GKRS can be a valuable modality for safe and effective management of brain stem metastasis. Owing to the high risk of surgical resection and low efficacy of medical treatment, radiosurgery can be proposed upfront.

Retrospective study of 77 patients harbouring lumbar synovial cysts: functional and neurological outcome.

SummaryBackground. Synovial cysts represent an uncommon and probably underestimated pathological entity of the degenerative lumbar spine. The authors report a retrospective analysis of the clinical presentation, radiological studies and operative findings in 77 patients surgically treated for symptomatic lumbar synovial cysts at their institution.n Materials and method. Between January 1992 and June 1998, a total of 77 patients presenting with symptomatic lumbar synovial cysts were operated on in the author’s department. Operative procedure, complications, results and pathological findings were correlated with preoperative assessment. There were 41 men and 36 women with an average age of 63 years (range 44–90 years).n Results. On the basis of their symptom complex on presentation, two populations were identified: patients who presented with a single radicular pain (group I = 51 patients), and patients who presented with bilateral neurogenic claudication (group II = 26 patients). Neurological examination on presentation demonstrated motor deficit (12%), sensory loss (26%) and reflex changes (35%). Degenerative disc disease and facet joint osteoarthritis was a frequent finding in patients with pre-operative MRI. Facet joint orientation was >45° in 76.6% of patients. Preoperative spondylolisthesis was found in 48% on radiological studies. All the patients were treated surgically with resection of the cyst. No fusion was performed as a first line procedure. However subsequent fusion was necessary in one patient who developed symptomatic spondylolisthesis. Mean follow-up period was of 45 months ranging from 18 to 105 months. Only one recurrence occurred during the follow-up period. An excellent or good functional outcome was seen in 97.4% of cases, and 89% of the patients with motor deficit recovered.n Conclusions. Surgical resection of lumbar synovial cysts is an effective treatment associated with very low morbidity. Synovial cysts are associated with increased grade and frequency of facet joint asteoarthritis but not with increased grade or frequency of degenerative disc disease compared with patients without cysts. In the author’s opinion, at the present time, there is no reliable criterion which allows the development of a symptomatic spinal instability to be predicted in patients with a preoperative spondylolisthesis and therefore fusion as a first line procedure is still debatable.

Biodegradable Carmustine Wafers (Gliadel) Alone or in Combination with Chemoradiotherapy: The French Experience

BackgroundCarmustine-releasing wafers (Gliadel®) have been available and reimbursed in France since 2005.MethodsA retrospective multicenter study was conducted in 26 French Departments of Neurosurgery to analyze practices of French neurosurgeons using Gliadel, compare the adverse effects and survival with those of previous phase III trials, and assess survival in patients with newly diagnosed malignant gliomas (MG) receiving Gliadel plus radiochemotherapy with temozolomide (TMZ). A total of 163 patients who received Gliadel for MG were included in this study: 83 (51%) with newly diagnosed MG and 80 (49%) with recurrent MG. In the newly diagnosed group, 51.8% of patients received radiochemotherapy with TMZ.ResultsAdverse events (AEs) emerged in 44.6% of the population, including 6% with septic abscess. The AE rate was not statistically correlated with adjuvant use of TMZ. For the newly diagnosed group, median survival was 17xa0months. Total or subtotal resection appeared to have a great impact on survival (Pxa0=xa00.016), as did treatment with adjuvant radiotherapy (Pxa0=xa00.004).For the group with recurrent MG, median survival was 7xa0months. Total or subtotal resection excision appeared to have a great impact on survival (Pxa0=xa00.002), as did preoperative Karnowsky Scale (PO-KPS) (Pxa0=xa00.012).ConclusionsSurvival rates for newly diagnosed patients were better than those reported in previous phase III trials. The combination of Gliadel and radiochemotherapy with TMZ was well tolerated and appeared to increase survival without increasing AEs.

Solitary fibrous tumors of the central nervous system: Clinicopathological and therapeutic considerations of 18 cases - Commentary

OBJECTIVEThis is a retrospective study of 18 patients harboring a solitary fibrous tumor of the central nervous system. Therapeutic management and outcome were analyzed. METHODSBetween 1999 and 2004, 18 patients harboring central nervous system solitary fibrous tumors were surgically treated at our two institutions. There were nine men and nine women. The patient ages ranged from 33 to 75 years, with a median age of 56.1 years. The locations were spinal in six cases (33.3%), the posterior fossa in six cases (33.3%), supratentorial in four cases (22.2%), and orbital in two cases (11.2%). RESULTSThe median follow-up period was 45.3 months. Gross total resection was achieved in 10 cases (55.6%); tumor recurrence or progression occurred in nine cases (50%). Incomplete surgical resection was significantly associated with recurrence (P = 0.018). On univariate analysis, extent of surgery was also associated with a longer progression-free survival (P = 0.05). No statistically significant correlation can be found between histological features and recurrence. CONCLUSIONPrognosis of solitary fibrous tumors of the central nervous system remains unclear; consequently, careful and close monitoring of patients and long-term follow-up are mandatory. Radical surgical excision seems to be a significant and reliable prognosis factor, although pathological prognostic features must be defined. In other respects, the role of postoperative radiotherapy in atypical or incompletely resected solitary fibrous tumors of the central nervous system remains to be determined and, therefore, warrants larger series with longer follow-up periods.