Grade II meningiomas and Gamma Knife radiosurgery: analysis of success and failure to improve treatment paradigm.

OBJECTIVE Grade II meningiomas, which currently account for 25% of all meningiomas, are subject to multiple recurrences throughout the course of the disease and represent a challenge for the neurosurgeon. Radiosurgery is increasingly performed for the treatment of Grade II meningiomas and is quite efficient in controlling relapses locally at the site of the lesion, but it cannot prevent margin relapses. The aim of this retrospective study was to analyze the technical parameters involved in producing marginal relapses and to optimize loco-marginal control to improve therapeutic strategy. METHODS Eighteen patients presenting 58 lesions were treated by Gamma Knife radiosurgery (GKRS) between 2010 and 2015 in Hopital de la Pitié-Salpêtrière. The median patient age was 68 years (25%-75% interval: 61-72 years), and the sex ratio (M/F) was 13:5. The median delay between surgery and first GKRS was 3 years. Patients were classified as having Grade II meningioma using World Health Organization (WHO) 2007 criteria. The tumor growth rate was computed by comparing 2 volumetric measurements before treatment. After GKRS, iterative MRI, performed every 6 months, detected a relapse if tumor volume increased by more than 20%. Patterns of relapse were defined as being local, marginal, or distal. Survival curves were estimated using the Kaplan-Meier method, and the relationship between criterion and potential risk factors was tested by the log-rank test and univariable Cox model. RESULTS The median follow-up was 36 months (range 8-57 months). During this period, 3 patients presented with a local relapse, 5 patients with a marginal relapse, and 7 patients with a distal relapse. Crude local control was 84.5%. The local control actuarial rate was 89% at 1 year and 71% at 3 years. The marginal control actuarial rate was 81% at 1 year and 74% at 2 years. The distal control actuarial rate was 100% at 1 year, 81% at 2 years, and 53% at 3 years. Median distal control was 38 months. Progression-free survival (PFS) was 71% at 1 year, 36% at 2 years, and 23% at 3 years. Median PFS was 18 months. Lesions treated with a minimum radiation dose of ≤ 12 Gy had significantly more local relapses than those treated with a dose > 12 Gy (p = 0.04) in univariate analysis. Marginal control was significantly influenced by tumor growth rate, with a lower growth rate being highly associated with improved marginal control (p = 0.002). There was a trend toward a relationship between dose and marginal control, but it was not significant (p = 0.09). PFS was significantly associated with delay between first surgery and GKRS (p = 0.03). The authors noticed few complications with no sequelae. CONCLUSIONS In order to optimize loco-marginal control, radiosurgical treatment should require a minimum dose of > 12 Gy and an extended target volume along the dural insertion. Ideally, these parameters should correspond to the aggressiveness of the lesion, based on genetic features of the tumor.

Predictors of Trigeminal Neuropathy After Radiosurgery for Vestibular Schwannomas.

PURPOSE: To analyze the relationship between dosimetric characteristics and symptoms related to trigeminal neuropathy (TN) observed after radiosurgery (RS) for vestibular schwannomas (VS); to propose guidelines to optimize planification in VS RS regarding TN preservation; and to detail the mechanism of TN impairment after VS RS. METHODS AND MATERIALS: One hundred seventy-nine patients treated between 2011 and 2013 for VS RS and without trigeminal impairment before RS were included in a retrospective study. Univariate and multivariate analyses were performed to determine predictors of TN among characteristics of the patients, the dosimetry, and the VS. RESULTS: There were 20 Koos grade 1, 99 grade 2, 57 grade 3, and 3 grade 4. Fourteen patients (7.8%) presented a transitory or permanent TN. Between the patients with and without TN after VS RS, there was no significant difference regarding dosimetry or VS volume itself. Significant differences (univariate analysis P<.05, Mann-Whitney test) were found for parameters related to the cisternal portion of the trigeminal nerve: total integrated dose, maximum dose, mean dose, volume of the Vth nerve (Volv), and volume of the Vth nerve receiving at least 11 Gy (VolVcist>11Gy), but also for maximal dose to the Vth nerve nucleus and intra-axial portion (Dose maxVax). After multivariate analysis, the best model predicting TN included VolVcist>11Gy (P=.0045), Dose maxVax (P=.0006), and Volv (P=.0058). The negative predictive value of this model was 97%. CONCLUSIONS: The parameters VolVcist>11Gy, Dose maxVax, and Volv should be checked when designing dosimetry for VS RS.

Whole brain radiotherapy: prognostic factors and results of a radiation boost delivered through a conventional linear accelerator.

PURPOSE: Assess prognostic factors for overall survival and the potential benefit of a boost in patients treated with whole brain radiation therapy (WBRT). METHODS AND MATERIALS: From 2002 to 2006, a retrospective analysis was made from 250 unselected consecutive patients with secondary brain metastases from lung cancer, breast cancer and melanoma. Eighteen patients received surgery and were excluded from analysis. Four potential prognostic factors have been studied: primary tumor type, gender, number of metastases and improvement of neurological symptoms after radiation therapy. A subgroup analysis was performed to determine whether an additional boost could potentially improve outcome in patients who presented with less than three metastases, performance status <2, and no surgical resection of their metastasis. RESULTS: Average follow-up was 10.3 months. Median overall survival was 5.6 months and survival rates at 1 and 2 years were 22.7% and 10%, respectively. Age less than 65 (p<0.01), neurological improvement after WBRT (p<0.01), and presence of less than three metastases were significant factors for overall survival in multivariate analysis. When focusing on the selected subgroup (120 assessable patients), median overall survival was 4.0 months in patients with no radiation boost, versus 8.9 months in patients with radiation boost (p=0.0024). CONCLUSIONS: Survival and prognostic factors were similar to those found in the literature. Boost delivered after WBRT by a conventional particle accelerator could provide a benefit in selected patients, especially for centers that do not have radiotherapy techniques in stereotactic conditions. This warrants further prospective assessment.

Minimized doses for linear accelerator radiosurgery of brainstem metastasis.

PURPOSE: Treatment of cerebral metastases located inside the brainstem remains a challenge, as the brainstem is considered to be a neurological organ at risk, whatever the treatment strategy. We report a retrospective study of 30 consecutive patients treated in our institution between 2005 and 2007 with micromultileaf linear accelerator (LINAC)-radiosurgery for brainstem metastases, with reduced doses compared to those usually reported in the literature. METHODS AND MATERIALS: Mean follow-up was 311 days (range, 41-1351). Median age was 57 years (range, 37-82), Mean Karnofsky Index (KI) was 80. Primary tumor site was lung (n = 13), breast (n = 4), kidney (n = 4), skin (melanoma; n = 3), and others (n = 6). Primary tumor was controlled in 17 cases; extracranial metastases were controlled in 12 cases. Mean number of metastases was 1.46 (one to three); median volume was 2.82 cc (0.06-18). Dose was delivered by a micromultileaf collimator 6-MV LINAC . RESULTS: Dose administered at the 70% isodose was 13.4 Gy (range, 8.2-15). Median survival was 10 months. Local control rates at 3, 6, and 12 months were 100%, 100%, and 79% respectively. Median neurological control duration was 5 months. Neurological control rates at 3, 6, and 12 months were 73%, 42%, and 25%, respectively. No parameter was found to significantly correlate with survival, local, or cerebral control. No patients had severe side effects (Grade III-IV), according to the Radiation Therapy Oncology Group (RTOG) scale. CONCLUSION: Lower doses than previously reported can achieve the same local control and survival rates in brain metastases, with minimal side effects.

Gulf War illness: Effects of repeated stress and pyridostigmine treatment on blood-brain barrier permeability and cholinesterase activity in rat brain.

After the first Persian Gulf War, many soldiers have complained of a variety of symptoms designated as "Gulf War Illness". Among several factors, implication of pyridostigmine (PB) in late cognitive dysfunction is highly likely. As a hypothesis to explain these behavioural disorders is a potentiation of the operational stress effects by pyridostigmine. We have previously described that repeated stress combined to pyridostigmine treatment induces learning dysfunction linked to genomic cerebral modifications [Barbier L, Diserbo M, Lamproglou I, Amourette C, Peinnequin A, Fauquette W. Repeated stress in combination with pyridostigmine: part II-changes in selected cerebral genes expression. Behav Brain Res 2009;197:292-300; Lamproglou I, Barbier L, Diserbo M, Fauvelle F, Fauquette W, Amourette C. Repeated stress in combination with pyridostigmine: part I-long-term behavioural consequences. Behav Brain Res 2009;197:301-10]. In the present study, using the same experimental model, we attempted to determine if such modifications are linked to a central passage of pyridostigmine under stress. Indeed it is known that exposure to stress can disrupt blood-brain barrier (BBB) and thereby increase the neurotoxicity induced by chemicals in many cerebral areas. Adult rats were subjected to repeated stress based on a modification of the pole climbing avoidance technique and treated daily by PB (1.5mg/kg/day, oral in water), for two 5-day periods separated by 2-day rest. Just after the last stress session, (3)H-pyridostigmine was administered as a tracer to evaluate BBB breakdown. In brain micro-punches and brain coronal cryosections, we failed to detect any radioactivity in animals chronically stressed and treated by pyridostigmine. Accordingly, no change of ChE activity was noted in any brain area studied. It thus appears that, in our experimental model, pyridostigmine induces effects on central nervous system, but these effects do not seem to be mediated by a central passage of pyridostigmine linked to a BBB opening under stress. These results suggest that pyridostigmine may have central effects, under stress, via indirect mechanisms emerging from a peripheral pathway.

Repeated stress in combination with pyridostigmine Part I: long-term behavioural consequences.

Since their return from the first Persian Gulf War, some veterans have complained of a variety of symptoms that were designated as "Gulf War Illness" (GWI). Among other factors, pyridostigmine, used as a prophylaxis treatment against intoxication by nerve agents, has been proposed by many authors as a cause of late social and/or cognitive dysfunction related to GWI. One of the hypotheses placed to explain these behavioural disorders is that operational stress has modified the side effects of pyridostigmine given to soldiers. In an attempt to establish an experimental model of GWI to evaluate the long-term behavioural effects of pyridostigmine administered in stressful conditions, we have developed a new model of repeated stress based on the pole-climbing avoidance technique. We used it to evaluate the effects of pyridostigmine treatment combined to repeated stress over the months following the end of the treatment. We observed that this stress induces impulsiveness and aggressiveness in adult male rat. Moreover, pyridostigmine treatment administered daily 30 min before each stressful session amplifies these behavioural disorders and induces long-term learning dysfunction and slight but significant decrease in phosphocholine level in hippocampus. This suggests that repeated administration of pyridostigmine combined to pole-climbing avoidance (PCA) stress conditions can induce adverse effects in rat central nervous system.

Repeated stress in combination with pyridostigmine Part II: changes in cerebral gene expression.

Organophosphates (OP) represent a potential threat in terrorism or during military conflicts. Due to its faculty to protect cholinesterase (ChE) activity against irreversible inactivation by OP, pyridostigmine bromide (PB) was used as a prophylaxis treatment during the first Persian Gulf War. To explain dysfunctions reported by Gulf War Veterans (GWV), it was suggested a potentiation of the operational stress effects by PB given to soldiers. Our companion paper (see part 1 in the same journal issue) describes that PB treatment administered in repeated stress conditions results in long-term perturbations of learning and social behaviour. The present paper examines, in adult male Wistar rats, consequences of the association of repeated stress and PB treatment on gene expression in hypothalamus and hippocampus. PB treatment (1.5 mg/kg/day) was orally administered 30 min before each stress session to inhibit 40% of blood ChE as recommended by NATO. 10 days of stress alone induce a decrease in hypothalamic Il-1alpha expression. Treatment with PB alone increases mineralocorticoid receptor expression in hypothalamus which means that PB may thus modify stress perception by animals. Stressed-PB animals showed increase in hippocampal expression of BDNF, TrkB and CamKIIalpha, three genes implicated in memory development. As a supplement to previous studies showing behavioural and biochemical effects of the association of stress with PB, our data reveal that behavioural effects of this association may be linked with genomic changes in hippocampus. Mechanisms underlying these modifications and their link with memory disturbances reported by GWV remain to be further determined.

Post-seizures amygdaloallocortical microvascular lesion leading to atrophy and memory impairment.

Although the incidence of seizures after a cerebrovascular event including intracerebral hemorrhage has been widely recognized, the present studies have demonstrated that generalized convulsive seizures can cause multifocal amygdaloallocortical hemorrhage and tissue necrosis, the origin of which remains to be established. The seizure-elicited amygdaloallocortical injured area, which we refer to as a focal injury-prone area (FIPA), was caused by cholinergic stimulation of the ventroposterolateral and thalamic reticular nuclei. The amygdaloallocortical injury was preceded by focal absence of neuronal COX-2 and presence of microvascular immunoreactivity to the pro-inflammatory cytokines, IL-1beta and TNF-alpha. The microvascular inflammation was followed by edema and multifocal amygdaloallocortical microhemorrhages, leading to atrophy and cognitive impairment. On the basis of the present results, we conclude that generalized convulsive seizures may be at the origin of amygdaloallocortical microvascular injury suggesting that, in addition to anticonvulsant treatment, an appropriate clinical evaluation and therapy for seizures-associated cerebrovascular accidents should be considered.

Radiation-induced cognitive dysfunction: the protective effect of ethyol in young rats.

PURPOSE: To evaluate the protective learning and memory effect of Ethyol in irradiated young rats. METHODS AND MATERIALS: One hundred twenty-eight 45-day-old Wistar rats received whole brain fractionated radiation (30 Gy), whereas 48 rats received sham irradiation. Four irradiated subgroups were defined: saline, 37.5 mg/kg, 75 mg/kg, and 150 mg/kg Ethyol. Sequential behavioral studies including one-way and two-way avoidance tasks were undertaken before and after radiation. RESULTS: Before radiation, the performances of all groups were similar. For the one-way avoidance task, at 1, 3, and 6 months postradiation, saline-irradiated rats had a lower percentage of avoidance than sham- or Ethyol- (75 or 150 mg/kg) irradiated rats (p

Blood-brain barrier permeability after gamma whole-body irradiation: an in vivo microdialysis study.

The effects of total-body irradiation on the permeability of rat striatal blood-brain barrier (BBB) to [3H]alpha-aminoisobutyric acid (AIBA) and [14C]sucrose were investigated using the microdialysis technique. Seven days, 3 and 6 weeks, and 3, 5, and 8 months after gamma exposure at a dose of 4.5 Gy, no modification of the permeability to both [3H]AIBA and [14C]sucrose was observed. But, in the course of the initial syndrome, we observed a significant but transient increase in the BBB permeability to the two markers between 3 and 17 h after exposure. A secondary transient "opening" of the BBB to [14C]sucrose was noticed about 28 h following irradiation without the corresponding increase in BBB permeability to [3H]AIBA. On the contrary, the transport of [3H]AIBA through the BBB was decreased between 33 and 47 h postradiation. In conclusion, our experiments showed early modifications of BBB permeability after a moderate-dose whole-body exposure. Confirmation of these results with other tracers, in another experimental model or in humans, would have clinical applications for designing appropriate pharmacotherapy in radiotherapy and treatment of accidental overexposure.