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Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.

Background We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma. Methods Forty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS). Results Median age was 59 years (range: 25–85). Median follow-up, OS and TTP were 22.7 months (range 7.5–69.7 months), 22.7 months (95% CI 14.5–26.2 months) and 6.4 months (95% CI 4.4–9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p  = 0.014) and TTP (4.6 vs 12.9 months, p  = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p  = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p  = 0.012 and HR = 2.67, p  = 0.047, respectively). Conclusion Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.

Sedentary aging is associated with oxidative stress and endothelial dysfunction. The aim of this study was to evaluate the relationship between long-term physical activity, plasma antioxidant status, and conduit artery endothelial function in young and older healthy men. In young ( n = 16) and older athletes ( n = 16) and in matched healthy sedentary subjects, endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent response to glyceryl trinitrate (GTN), 400 μg, were measured in the brachial artery from high-resolution ultrasonography. Plasma malondialdehyde (MDA) and antioxidant capacity as total oxyradical scavenging capacity (TOSC) were also evaluated. We found that FMD was lower (≤0.01) in sedentary older subjects (2.3% ± 1.0%) as compared with older athletes (5.3% ± 3.2%) and both sedentary (5.4% ± 2.0%) and athletically trained (6.1% ± 3.2%) young subjects. Sedentary older subjects showed higher ( P ≤ .05) MDA levels and lower ( P < .0001) plasma antioxidant capacity as compared with the other subgroups, whereas in older athletes MDA levels and antioxidant capacity were similar to those observed in the young subgroups. In the whole group, FMD, but not GTN, was negatively related to age ( r = −0.31, P < .05) and directly related ( P ≤ .01) to VO 2max ( r = 0.49) and TOSC against peroxyl ( r = 0.69) and hydroxyl radicals ( r = 0.53). In the multivariate analysis, TOSC against peroxyl radicals resulted as the most significant predictor of FMD ( R 2 = 0.60; P = .003). These results suggest that regular physical activity is associated with preserved antioxidant defenses and endothelial function in older individuals.

We aimed to assess the efficacy of stereotactic irradiation for patients with recurrent high-grade glioma (HGG) and identify predictive factors of progression-free survival (PFS) and overall survival (OS) following reirradiation. We identified 32 patients with recurrent brain HGG who had been treated with either single-dose (stereotactic radiosurgery) or fractionated stereotactic radiotherapy between April 2008 and October 2015. Median follow up was 21.4 months (range 12.9–23.2) and median PFS was and 3.3 months (95% CI [2.3–4.7]), respectively. OS was 90.40% (95% CI [73.09–96.80]) at 6 months and 79.55% (95% CI [59.9–90.29]) at 12 months. Univariate analysis showed that biological effective dose at isocenter ≤ 76 Gy was a poor prognostic factor for both OS (83.33 vs. 100% at 6 months, p = 0.032) and median PFS (2.7 vs. 4.7 months, p = 0.025), as was gross tumor volume (GTV) above 1 cm3 for OS (86.15 vs. 94.12% at 6 months, p = 0.043). Contact with the subventricular zone (SVZ) was also a poor prognostic factor for median PFS (2.3 vs. 4.7 months, p = 0.002). Multivariate analysis showed that SVZ contact remained a poor prognostic factor for PFS (hazard ratio = 3.44, 95% CI [1.21–9.82], p = 0.021). Results suggest that reirradiation is a safe and effective treatment option for recurrent HGG in patients with a good Karnosfsky Performance Scale score, a long progression-free interval since first radiation and limited GTV, and that contact to SVZ is a strong prognostic factor for PFS.

Although the majority of people worldwide are bilingual, the brain representation of language in bilingual persons is still a matter of debate. Since the beginning of the studies conducted on bilinguals, most authors denied that learning a new language requires a new semantic processing or the involvement of new cortical areas. In this paper, we review neurosurgical studies using direct electrocortical or subcortical stimulation techniques for brain mapping in bilingual subjects and compare this data with that obtained from other brain mapping methods. The authors focused on the most controversial issue whether multiple languages are represented in common or distinct cerebral areas. Seven direct brain mapping studies from different teams focused on bilingualism and multilingualism. All these studies showed that even if cerebral representation of language in multilingual patients could be grossly located in the same cortical region, it was possible to individualise distinct language-specific areas by direct cortical stimulation in the dominant frontal and temporo-parietal regions. Task- and language-specific sites were also described, demonstrating an important specialisation of some cortical areas. Using subcortical stimulation, some authors were able to find specific white matter tracts for different languages. Finally, all authors recommend in bilingual patients who need brain mapping for neurosurgical purpose to test all languages in which the subjects are fluent.

Background Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival. Methods/design In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status. Discussion This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging. Trial registration NCT01507506 , registration date December 20, 2011.

Superoxide dismutase (SOD) is reported to be the major enzymatic defence against free radicals and common oxidants. EC-SOD is the only extracellular form of SOD present at a high concentration in vascular intima. The aims of the present study were to elucidate the role of EC-SOD in patients with coronary artery disease (CAD) and evaluate its association with free radicals, inflammation and with the severity of the disease. The study included 36 consecutive subjects with CAD being treated in the Institute of Clinical Physiology (33 males, 3 females) and 19 controls (16 males, 2 females). Each subject, after cardiac catheterisation and coronariography, was evaluated for serum EC-SOD activity, peroxy radicals, high-sensitive interleukin-6 (hs-IL-6), high-sensitive tumour necrosis factor (hs-TNFa) and high-sensitive C-reactive protein (hs-CRP) serum levels. The analysis of EC-SOD serum activity did not show any particular difference between patients and controls, while the serum levels of peroxy radicals, hs-IL-6 and hs-CRP showed a significant difference between the two groups (respectively: P<0.01, P<0.001, P<0.01). Moreover, enhancement of hs-IL-6 serum levels was also observed in severe disease (involvement of 3, 4 coronary arteries; P<0.05), while EC-SOD activity showed a slight increment in association with the number of arteries involved. hs-IL-6 concentrations were statistically significantly associated with peroxy radicals and CRP levels (respectively: P<0.05, r2=0.1; P<0.05, r2=0.14). The present study suggests a low effectiveness of EC-SOD activity in prevention against CAD and further confirms hs-IL-6 as a useful marker in diagnostic prevention and in clinical characterisation of CAD.

To establish whether C-reactive protein (CRP) is an independent predictor of all-cause mortality and hospitalization in chronic obstructive pulmonary disease (COPD), we followed 200 patients with COPD and 201 age- and gender -matched controls for a median time of 4.2 years (range, 0.2–5.1 years). Airflow obstruction was rated moderate if forced expiratory volume in one second (FEV 1 ) was 50–69% of the predicted value, or severe if FEV 1 was <50%. The CRP level was categorized as low (≤3 mg/L) or high (>3 mg/L). The hazard of death was estimated by a proportional hazard regression model, using controls with low CRP as the reference category. Fifty subjects died: 41 (21%) among the COPD and 9 (4%) among the controls ( p  < 0.0001). The hazard of death in moderate COPD was not significantly higher than in the reference category, independently of the CRP level. In severe COPD with a low CRP, the hazard of death is 3.4 times higher than in the reference category ( p  = 0.008); in severe COPD and a high CRP it is 9.6 times higher ( p  < 0.0001). The rate of hospitalization in COPD patients with a high CRP is 1.9 times higher than in those with a low CRP [95% confidence interval (CI), 1.2–3.2]. In severe COPD, it is 6.9 times higher than in moderate COPD (95% CI, 3.8–12.7). A high CRP level is a significant amplifier of the risk of death only in severe COPD. The degree of airflow obstruction is a strong independent predictor of COPD-related outcomes.

To determine whether a new transdermal fentanyl patch (TFP) is a good choice for the postoperative pain management of patients undergoing primary total hip arthroplasty compared with patient-controlled analgesia (PCA). Randomized, prospective study. University hospital. 30 patients undergoing primary total hip arthoplasty. Patients received either a TFP (group T; Duragesic 50 μg/h, matrix fentanyl patch, Janssen-Cilag) applied approximately 10 hours before induction of general anesthesia and PCA programmed in the postanesthesia care unit (PACU), or PCA programmed in the PACU (group P). Intraoperative sufentanil and additional postoperative morphine administration were recorded, as well as visual analog scores and routine vital signs at predetermined intervals during the first 48 hours. Morphine consumption on arrival in the PACU was 3.5 ± 3 mg in group T versus 13 ± 5 mg in group P ( P < 0.0001). Visual analog scores on arrival in the PACU were 37 ± 22 mm in group T versus 73 ± 13 mm in group P ( P < 0.0001). Cumulative morphine consumption at the 24th hour was 43 ± 16 mg in group P and 4 ± 3 mg in group T ( P < 0.0001). Cumulative morphine consumption at the 48th hour was 54 ± 26 mg in group P and 5 ± 4 mg in group T ( P < 0.0001). Intraoperative sufentanil consumption was 38 ± 15 μg in group T versus 30 ± 5 μg in group P (not significant). The sedation score was 0 in both groups during the first 48 postoperative hours. Preoperative TFP application decreases pain scores and morphine consumption in the PACU and appears to have prolonged effects spanning the first 48 postoperative hours.

Hypercholesterolemia is reported to be associated with an increased oxidative inactivation of nitric oxide (NO) and a reduced endothelium dependent vasodilation. However, experimental studies suggest an increased release of NO in early stages of hypercholesterolemia possibly related to endothelial activation and enhanced activity of inducible NO synthetase. Aim of the study was to assess systemic NO generation and endothelial dependent and independent vasodilation in young subjects with early diagnosed familial hypercholesterolemia (FHC) and without cardiovascular disease. Patients and Methods: brachial artery diameter was measured by high-resolution ultrasound at rest, during reactive hyperemia following 5 min forearm ischemia (endothelium-dependent vasodilation) and after sublingual glyceryl trinitrate (GTN 400 μg; endothelium-independent dilatation) in 12 subjects (age 28±2 years, mean±DS) with familial hypercholesterolemia (271 mg/dl ± 21.9) and 12 healthy controls (26±3 years, mean ± DS). Plasma concentration of nitrates and nitrites (Nox markers of No release) were measured by a colorimetric assay based on Griess reaction. Plasma Nox were significantly higher in FHC than in controls (87.11±10.07 vs 35.28±25.8 mmol; p<0,01). At humeral artery level at baseline flow velocity was comparable between groups while cross sectional vessel area tended to be lower in FHC (9,6±3,8 vs 22,56±3,0 mm2 p=NS) resulting in a significantly lower volumetric flow (FHC 121,23±86,6 vs N 236,57±15,5 ml/min, p<0.05). As compared to controls, after reactive hyperemia in FHC volumetric flow and humoral artery area were slightly lower (1526,17±30.17 vs 561.98±21.63 ml/min, N.S. and 25,22±3,1 vs 13,31±4 mm2, N.S.), while % area increase was significantly higher (13,49±6,4 vs 25,54±13,5%, p<0,01). Dilatation in response to GTN was comparable in all groups. In young subjects with early FHC and no cardiovascular disease, baseline lumen arterial size and flow seem to be lower than in normals, while endothelial dependent and independent vasodilation appear preserved in presence of an increased of NO release.