Johan Pallud

Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article.

OBJECT The spontaneous prognostic factors and optimal therapeutic strategy for WHO Grade II gliomas (GIIGs) have yet to be unanimously defined. Specifically, the role of resection is still debated, most notably because the actual amount of resection has seldom been assessed. METHODS Cases of GIIGs treated before December 2007 were extracted from a multicenter database retrospectively collected since January 1985 and prospectively collected since 1996. Inclusion criteria were a patient age ≥ 18 years at diagnosis, histological diagnosis of WHO GIIG, and MRI evaluation of tumor volume at diagnosis and after initial surgery. One thousand ninety-seven lesions were included in the analysis. The mean follow-up was 7.4 years since radiological diagnosis. Factors significant in a univariate analysis (with a p value ≤ 0.1) were included in the multivariate Cox proportional hazard regression model analysis. RESULTS At the time of radiological diagnosis, independent spontaneous factors of a poor prognosis were an age ≥ 55 years, an impaired functional status, a tumor location in a nonfrontal area, and, most of all, a larger tumor size. When the study starting point was set at the time of first treatment, independent favorable prognostic factors were limited to a smaller tumor size, an epileptic symptomatology, and a greater extent of resection. CONCLUSIONS This large series with its volumetric assessment refines the prognostic value of previously stressed clinical and radiological parameters and highlights the importance of tumor size and location. The results support additional arguments in favor of the predominant role of resection, in accordance with recently reported experiences.

Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas

A consecutive series of 143 unselected adult patients with histologically proved World Health Organization grade II gliomas was reviewed to assess the prognostic value of growth rates of mean tumor diameters on successive magnetic resonance images before treatment. There is an inverse correlation between growth rates and survival (p < 0.001; median survival at 5.16 years for a growth rate of 8mm/year or more; median survival >15.0 years for a growth rate <8mm/year). Thus, individual magnetic resonance imaging tumor growth rates should be incorporated in the planning of the initial therapeutic strategy of grade II gliomas. Ann Neurol 2006;60:380–383

Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

The mechanisms involved in the transition to an epileptic seizure remain unclear. To examine them, we used tissue slices from human subjects with mesial temporal lobe epilepsies. Ictal-like discharges were induced in the subiculum by increasing excitability along with alkalinization or low Mg2+. During the transition, distinct pre-ictal discharges emerged concurrently with interictal events. Intracranial recordings from the mesial temporal cortex of subjects with epilepsy revealed that similar discharges before seizures were restricted to seizure onset sites. In vitro, pre-ictal events spread faster and had larger amplitudes than interictal discharges and had a distinct initiation site. These events depended on glutamatergic mechanisms and were preceded by pyramidal cell firing, whereas interneuron firing preceded interictal events that depended on both glutamatergic and depolarizing GABAergic transmission. Once established, recurrence of these pre-ictal discharges triggered seizures. Thus, the subiculum supports seizure generation, and the transition to seizure involves an emergent glutamatergic population activity.

Epileptic seizures in diffuse low-grade gliomas in adults

Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.

Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities

Background: Imaging determinations of the spatial extent of diffuse low-grade gliomas (DLGGs) are of paramount importance in evaluating the risk-to-benefit ratio of surgical resection. However, it is not clear how accurately preoperative conventional MRI can delineate DLGGs. Methods: We report a retrospective histologic and imaging correlation study in 16 adult patients who underwent serial stereotactic biopsies for the diagnosis of untreated supratentorial well-defined and non–contrast-enhanced DLGG, in whom biopsy samples were taken within and beyond (OutBSs) MRI-defined abnormalities. Results: Thirty-seven OutBSs that extended from 10 to 26 mm beyond MRI-defined abnormalities were studied. Immunostaining revealed MIB-1–positive cells (i.e., cycling cells) in all but 2 of the OutBSs. None of the MIB-1–positive cells coexpressed glial fibrillary acidic protein, and all of them coexpressed OLIG2. MIB-1–positive cells were cycling isolated tumor cells, because 1) their morphologic characteristics reflected those of tumor cells, 2) the number of MIB-1–positive cells per square centimeter was significantly higher than that of controls, 3) the number of MIB-1–positive cells per square centimeter was positively correlated with the tumor growth fraction (p = 0.012), and 4) the number of MIB-1–positive cells per square centimeter in OutBSs decreased with distance from the tumor (p = 0.003). Conclusions: This study demonstrates, using a multiscale correlative approach, that conventional MRI underestimates the actual spatial extent of diffuse low-grade gliomas (DLGGs), even when they are well delineated. These results suggest that an extended resection of a margin beyond MRI-defined abnormalities, whenever feasible in noneloquent brain areas, might improve the outcome of DLGGs.

Natural history of incidental world health organization grade II gliomas

Seizure is the presenting symptom in most of World Health Organization grade II gliomas (GIIGs). Rarely, a GIIG is discovered incidentally on imaging. Little is known about the natural course and prognosis of incidental GIIGs. The aim of the present study is to characterize their natural history and to investigate whether their clinical and radiological behaviors differ from those of symptomatic GIIGs.

NG2+/Olig2+ Cells are the Major Cycle‐Related Cell Population of the Adult Human Normal Brain

A persistent cycling cell population in the normal adult human brain is well established. Neural stem cells or neural progenitors have been identified in the subventricular zone and the dentate gyrus subgranular layer (SGL), two areas of persistent neurogenesis. Cycling cells in other human normal brain areas, however, remains to be established. Here, we determined the distribution and identity of these cells in the cortex, the white matter and the hippocampal formation of adult patients with and without chronic temporal lobe epilepsy using immunohistochemistry for the cell cycle markers Ki‐67 (Mib‐1) and minichromosome maintenance protein 2. Rare proliferative neuronal precursors expressing the neuronal antigen neuronal nuclei were restricted to the SGL. In contrast, the oligodendrocyte progenitor cell markers Olig2 and the surface antigen NG2 were expressed by the vast majority of cycling cells scattered throughout the cortex and white matter of both control and epileptic patients. Most of these cycling cells were in early G1 phase, and were significantly more numerous in epileptic than in non‐epileptic patients. These results provide evidence for a persistent gliogenesis in the human cortex and white matter that is enhanced in an epileptic environment.

Computational modeling of the WHO grade II glioma dynamics: principles and applications to management paradigm

The advent of magnetic resonance imaging (MRI) has allowed the follow-up of tumor growth by precise volumetric measurements. Such information about tumor dynamics is, however, usually not fully integrated in the therapeutic management, and the assessment of tumor evolution is still limited to qualitative description. In parallel, computational models have been developed to simulate in silico tumor growth and treatment efficacy. Nevertheless, direct clinical interest of these models remains questionable, and there is a gap between scientific advances and clinical practice. In this paper, WHO grade II glioma will serve as a paradigmatic example to illustrate that computational models allow characterizing tumor dynamics from serial MRIs. The role of these dynamics for both therapeutic management and biological research will be discussed.

Imaging of non-tumorous and tumorous human brain tissues with full-field optical coherence tomography☆

A prospective study was performed on neurosurgical samples from 18 patients to evaluate the use of full-field optical coherence tomography (FF-OCT) in brain tumor diagnosis. FF-OCT captures en face slices of tissue samples at 1 μm resolution in 3D to a penetration depth of around 200 μm. A 1 cm2 specimen is scanned at a single depth and processed in about 5 min. This rapid imaging process is non-invasive and requires neither contrast agent injection nor tissue preparation, which makes it particularly well suited to medical imaging applications. Temporal chronic epileptic parenchyma and brain tumors such as meningiomas, low-grade and high-grade gliomas, and choroid plexus papilloma were imaged. A subpopulation of neurons, myelin fibers and CNS vasculature were clearly identified. Cortex could be discriminated from white matter, but individual glial cells such as astrocytes (normal or reactive) or oligodendrocytes were not observable. This study reports for the first time on the feasibility of using FF-OCT in a real-time manner as a label-free non-invasive imaging technique in an intraoperative neurosurgical clinical setting to assess tumorous glial and epileptic margins.

Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas

Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). PCV (procarbazine, CCNU, vincristine) chemotherapy has demonstrated efficacy in treating LGGs, but this therapy cannot be used for a prolonged period because of the cumulative toxicity. The aim of the present study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth kinetics. The mean tumor diameter (MTD) of 21 LGGs was measured on serial magnetic resonance images before (n=13), during, and after PCV onset (n=21). During PCV treatment, a decrease in the MTD was observed in all patients. After PCV discontinuation, an ongoing decrease in MTD was observed in 20 of the 21 patients. Median duration of the MTD decrease was 3.4 years (range, 0.8-7.7) after PCV onset and 2.7 years (range, 0-7) after the end of PCV treatment with 60% of LGGs, demonstrating an ongoing and prolonged (>2 years) response despite chemotherapy no longer being administered. According to McDonalds criteria, the rates of partial and minor responses were 5% and 38% at the end of PCV but 38% and 42% at the time of maximal MTD decrease, which occurred after a median period of 3.4 years after PCV onset. These results challenge the idea that a prolonged duration of chemotherapy is necessary for treating LGGs and raise the issue of understanding the mechanisms involved in the persistent tumor volume decrease once chemotherapy is terminated.