Rémy Guillevin

Simulation of anisotropic growth of low-grade gliomas using diffusion tensor imaging

A recent computational model of brain tumor growth, developed to better describe how gliomas invade through the adjacent brain parenchyma, is based on two major elements: cell proliferation and isotropic cell diffusion. On the basis of this model, glioma growth has been simulated in a virtual brain, provided by a 3D segmented MRI atlas. However, it is commonly accepted that glial cells preferentially migrate along the direction of fiber tracts. Therefore, in this paper, the model has been improved by including anisotropic extension of gliomas. The method is based on a cell diffusion tensor derived from water diffusion tensor (as given by MRI diffusion tensor imaging). Results of simulations have been compared with two clinical examples demonstrating typical growth patterns of low‐grade gliomas centered around the insula. The shape and the kinetic evolution are better simulated with anisotropic rather than isotropic diffusion. The best fit is obtained when the anisotropy of the cell diffusion tensor is increased to greater anisotropy than the observed water diffusion tensor. The shape of the tumor is also influenced by the initial location of the tumor. Anisotropic brain tumor growth simulations provide a means to determine the initial location of a low‐grade glioma as well as its cell diffusion tensor, both of which might reflect the biological characteristics of invasion. Magn Reson Med, 2005.

Dynamic history of low‐grade gliomas before and after temozolomide treatment

To evaluate the natural progression and the impact of temozolomide in low‐grade gliomas and to correlate these changes with the profile of genetic alterations.

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.

Response assessment in recurrent glioblastoma treated with irinotecan-bevacizumab: comparative analysis of the Macdonald, RECIST, RANO, and RECIST + F criteria.

Traditionally, the most widely used criteria for response assessment in glioblastoma have been Macdonald and the Response Evaluation Criteria In Solid Tumors (RECIST). Recently, new criteria addressing contrast enhancement and fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity have been defined (the Response Assessment in Neuro-Oncology criteria) to better evaluate the effect of antiangiogenic therapy. Whether FLAIR/T2 imaging could also be helpful to refine RECIST criteria remains unresolved. This study proposed the RECIST + F criteria and compared the 4 methods (Macdonald, RECIST, RANO, and RECIST + F) to determine their agreement in identifying response and progression of recurrent glioblastomas to irinotecan-bevacizumab. Patients with recurrent glioblastoma treated with second-line irinotecan-bevacizumab were eligible. Clinical status, corticosteroid dose, and 1-dimensional and 2-dimensional measurements of tumor contrast enhancement and FLAIR hyperintensity were retrospectively assessed. Response and progression were determined according to each set of criteria. Seventy-eight patients were included. Response rates ranged from 34.2% with RECIST + F to 44.7% with Macdonald criteria. Agreement among the 4 methods in determining response and type of progression was high (kappa statistic > 0.75). One-third of patients exhibited nonenhancing progression with stable or improved contrast enhancement. Median progression-free survival was predicted by RECIST, at 13.6 weeks; RECIST + F, 12.3; Macdonald, 12.7; and RANO, 11.7 (P = .840). Intra- and interobserver correlations were high for both contrast enhancement and FLAIR hyperintensity measurements. There was a strong concordance among the different methods in determining response and progression to irinotecan-bevacizumab. Criteria integrating FLAIR hyperintensity tended, however, to reduce response rates and progression-free survival compared with criteria considering only contrast enhancement. The 1-dimensional approach appeared to be as valid as the 2-dimensional approach.

Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low-grade gliomas

BACKGROUND Supratentorial diffuse low-grade gliomas present a slow macroscopic tumor growth that can be quantified through the measurement of their velocity of diametric expansion. We assessed whether spontaneous velocity of diametric expansion can predict long-term outcomes as a categorical variable and as a continuous predictor. METHODS A total of 407 adult patients with newly diagnosed supratentorial diffuse low-grade gliomas in adults were studied. RESULTS The mean spontaneous velocity of diametric expansion before first-line treatment was 5.8 ± 6.3 mm/year. During the follow-up (mean, 86.5 ± 59.4 months), 209 patients presented a malignant transformation, and 87 died. The malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (median, 103 and 249 months, respectively) than in cases of fast velocity of diametric expansion (median, 35 and 91 months, respectively; P < .001). In multivariate analyses, spontaneous velocity of diametric expansion as a categorical variable (<4, ≥4 and <8, ≥8 and <12, ≥12 mm/year) was an independent prognostic factor for malignant progression-free survival (P < .001; hazard ratio, 3.87; 95% confidence interval [CI], 2.67-5.52) and for overall survival (P < .001; hazard ratio, 4.62; 95% CI, 2.58-7.97). Velocity of diametric expansion was also an independent prognostic factor for overall survival as a continuous predictor, showing a linear relationship between overall survival and spontaneous velocity of diametric expansion (hazard ratio, 1.09 per one unit increase; 95% CI, 1.06-1.12; P < .001). CONCLUSIONS Independent of the molecular status, the spontaneous velocity of diametric expansion allows the identification of rapidly growing diffuse low-grade gliomas (at higher risk of worsened evolution) during the pretherapeutic period and without delaying treatment.

Brain lymphoma: usefulness of the magnetic resonance spectroscopy

The diagnosis of primary central nervous system lymphoma (PCNSL) should always be considered as an emergency because of the therapeutic consequences it implies. In immunocompetent patients, it relies on stereotactic biopsy. Unfortunately, clinical and radiological features may be misleading and delay the diagnostic procedure. The case we report here illustrates the contribution of magnetic resonance spectroscopy in the diagnostic approach of a very atypical PCNSL.

In Vivo Structural and Functional Imaging of the Human Rubral and Inferior Olivary Nuclei: A Mini-review

Few imaging studies have been devoted to the structural and functional connectivity of the red and inferior olivary nuclei although these two nuclei represent two main targets of the cerebellum within the brainstem. However, the RN is anatomically and functionally related to a widespread sensorimotor, limbic, and executive brain network. It projects massively onto the principal olive with which it contributes to a cerebello-rubro-olivo-cerebellar loop modulated by cortical and subcortical afferents. Despite a minor role in planning and execution of rhythmic movements, the red nucleus in conjunction with the inferior olive, more specifically involved in the detection of “unexpected” events, contributes to sensorimotor, sensory and, likely, cognitive higher functions.

In vitro study of the compatibility of tris-acryl gelatin microspheres with various chemotherapeutic agents.

PURPOSE To evaluate the in-vitro effects of chemotherapeutic agents on the physical structure of tris-acryl gelatin microspheres. MATERIALS AND METHODS Microspheres (Embospheres) were mixed in vitro with carboplatin, mitomycin C, 5-fluorouracil, or pirarubicin as experimental samples and with distilled water as control samples and kept for 24 hours at 37 degrees C. The microspheres used measured 100-300 micro m and 700-900 micro m in diameter. Microsphere morphology, including appearance, overall shape, smoothness of surface, and thickness of gelatin coating, was examined with use of a microscope equipped with a cold light. Microsphere dimensions including larger diameter, smaller diameter, and surface area were measured by granulometry. Microsphere geometry was evaluated by calculating a sphericity index and surface regularity index. Qualitative and quantitative variables, respectively, were analyzed with the two-sided Fisher exact test and Wilcoxon signed-rank test for paired values, with a significance level of 0.05. RESULTS No broken microspheres or microscopic degradations in the appearance, overall shape, smoothness of surface, or thickness of gelatin coating of any microspheres were observed. The respective distributions of large and small diameters, surface area, sphericity index, or surface regularity index of the microspheres were not significantly different between the experimental samples containing carboplatin, mitomycin C, 5-fluorouracil, or pirarubicin and the control sample of microspheres with similar diameters. CONCLUSION Embosphere microspheres can be mixed with carboplatin, mitomycin C, 5-fluorouracil, or pirarubicin for chemoembolization therapy without any risk of damaging their morphology, dimensions, or geometric characteristics.

Cerebral fat embolism: usefulness of magnetic resonance spectroscopy.

We report a case of cerebral fat embolism which occurred in a 33‐year‐old man after a diaphyseal femoral fracture without cranial traumatism. The initial examination showed an incomplete picture of coma with tetrapyramidal syndrome and cutaneomucous purpura. There was no respiratory damage. We present a magnetic resonance spectroscopy analysis of the cerebral lesions observed in the initial phase of the embolism, as well as follow‐up, which has strengthened the clinical and imaging features for the diagnosis. Ann Neurol 2005;57:434–439

Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis

Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease radiation-induced fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote radiation-induced fibrosis whereas PPAR γ agonists can prevent radiation-induced fibrosis.