BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas

BRAF V600E mutations are progression factors in paediatric low-grade gliomas. Furthermore, a high percentage of paediatric brainstem gangliogliomas have BRAF V600E mutations. However, their clinical significance, including possible connections between the biomarkers and ganglioglioma’s clinical features, especially a brainstem counterpart, is unclear. To identify potential molecular features predictive of brainstem ganglioglioma’s clinical outcomes, a retrospective cohort of 28 World Health Organization (WHO) grade I brainstem gangliogliomas was analysed for BRAF V600E, IDH1 R132H, and IDH2 R172K mutations, TERT C228T/C250T promoter mutation, H3F3A K27M mutation and MGMT methylation. The volume of tumours was calculated accurately by using 3D Slicer software. The clinical data of these patients were retrospectively analysed. In tumours with BRAF V600E mutations, the tumour regrowth rate was significantly faster than that of the wild type group (p = 0.001). Moreover, the BRAF V600E mutant group had shorter progression-free survival (PFS) compared with wild type (p = 0.012). On multivariate analysis, no factor was found to be an independent prognostic factor; however, tumours with faster regrowth rates had a strong trend towards an increased risk for shorter PFS (HR = 1.027, p = 0.056). No statistical analysis could be performed to evaluate factors affecting overall survival (OS). These data suggest that BRAF V600E can predict the regrowth rate of brainstem gangliogliomas after microsurgery, and a BRAF V600E-targeted therapeutic may be a promising early intervention measure for patients who harbour BRAF V600E mutation after microsurgery.     

Co-expression of midkine and pleiotrophin predicts poor survival in human glioma

The aim of this study was to investigate whether co-expression of midkine (MK) and pleiotrophin (PTN) has prognostic relevance in human gliomas. Immunohistochemistry was used to investigate the expression of MK and PTN proteins in 168 patients with gliomas. The levels of MK and PTN mRNA in glioma tissues and paratumor tissues were evaluated in 45 paired cases by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan–Meier survival analysis was performed to assess prognostic significance. The expression levels of MK and PTN proteins in glioma tissue were both significantly higher (both p < 0.001) than those in paratumor tissues on immunohistochemistry analysis, which was confirmed by qRT-PCR analysis. Additionally, the overexpression of either MK or PTN was significantly associated with the World Health Organization Grade (p = 0.001 and 0.034, respectively), low Karnofsky Performance Status (KPS) score (p = 0.022 and 0.001, respectively), time to recurrence (p = 0.043 and 0.011, respectively) and poor overall survival (p = 0.018 and 0.001, respectively). Multivariate Cox proportional-hazards regression analysis revealed that increased expressions of MK and PTN were both independent prognostic factors for poor overall survival (p = 0.030 and 0.022, respectively). Furthermore, the co-expression of MK and PTN was more significantly (p = 0.003) associated with adverse prognosis in patients with gliomas than the respective expression of MK or PTN alone. To our knowledge, these findings are the first to indicate that the co-expression of MK and PTN is significantly correlated with prognosis in glioma patients, suggesting that the co-expression of these proteins may be used as both an early diagnostic and independent prognostic marker.     

Outcome and prognostic factors in adult cerebellar glioblastoma

Cerebellar glioblastoma multiforme (GBM) occurs rarely in adults, accounting for 0.4–3.4% of all GBM. Current studies have all involved small patient numbers, limiting the clear identification of prognostic factors. Additionally, while few studies have compared cerebellar GBM to their supratentorial counterparts, there is conflicting data regarding their relative prognosis. To better characterize outcome and identify patient and treatment factors which affect survival, the authors analyzed cases of adult cerebellar GBM from the Surveillance, Epidemiology, and End Results database. A total of 247 adult patients with cerebellar GBM were identified, accounting for 0.67% of all adult GBM. Patients with cerebellar GBM were significantly younger than those with supratentorial tumors (56.6 versus 61.8 years, p < 0.0001), but a larger percentage of patients with supratentorial GBM were Caucasian (91.7% versus 85.0%, p < 0.0001). Overall median survival did not differ between those with cerebellar and supratentorial GBM (7 versus 8 months, p = 0.24), with similar rates of long-term (greater than 2 years) survival (13.4% versus 10.6%, p = 0.21). Multivariate analysis revealed age greater than 40 years (hazard ratio [HR]: 2.20; 95% confidence interval [CI]: 1.47–3.28; p = 0.0001) to be associated with worse patient survival, while the use of radiotherapy (HR: 0.33; 95% CI: 0.24–0.47; p < 0.0001) and surgical resection (HR: 0.66; 95% CI: 0.45–0.96; p = 0.028) were seen to be independent favorable prognostic factors. In conclusion, patients with cerebellar GBM have an overall poor prognosis, with radiotherapy and surgical resection significantly improving survival. As with supratentorial GBM, older age is a poor prognostic factor. The lack of differences between supratentorial and cerebellar GBM with respect to overall survival and prognostic factors suggests these tumors to be biologically similar.     

KPNA2 predicts long term survival in patients with anaplastic oligoastrocytomas

The family of karyopherins comprises importins and exportins which are both involved in nucleocytoplasmic shuttling. Increased levels of karyopherin a2/importin 1 (KPNA2) and chromosome region maintenance protein 1/exportin 1 (CRM1) have been associated with poorer prognosis in patients with infiltrative astrocytomas. Isocitrate dehydrogenase 1 gene (IDH1) R132H mutation status was also recently identified as a prognostic factor for malignant gliomas. We evaluated KPNA2 and CRM1, as well as the IDH1 mutation status, as possible novel biomarkers for World Health Organization grade III anaplastic oligoastrocytomas (AOA). We analyzed nuclear expression of KPNA2 by immunohistochemistry in 72 primary anaplastic gliomas (29 AOA, 24 anaplastic astrocytomas, 19 anaplastic oligodendrogliomas). The IDH1 mutation status was also determined in patients with anaplastic astrocytomas and AOA, and AOA patients were additionally evaluated for CRM1 nuclear expression. Long term survivors (LTS; >8 years) with AOA showed lower KPNA2 expression levels compared to non-LTS (p = 0.005). KPNA2 expression (⩾5% versus <5%, 1–<5%, median) was found to correlate inversely with overall survival (OS) and progression-free survival (PFS) in our overall series as well as in the AOA group (anaplastic gliomas: OS p = 0.017; PFS p = 0.033; AOA: OS p = 0.017, PFS p = 0.040). Mutant IDH1-R132H was detected in 69% of the AOA cohort; a combination of KPNA2 low expression and mutant IDH1-R132H was only seen in LTS (p = 0.050). No differences between the histological subtypes were observed in terms of KPNA2 expression and IDH1-R132H mutation status. To our knowledge this is the first time it has been shown that KPNA2 expression may have potential as a prognostic biomarker for AOA as well.     

Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. Average survival is approximately 1 year, but individual survival is heterogeneous. Using a single institutional experience, we have previously identified preoperative factors associated with survival and devised a prognostic scoring system based on these factors. The aims of the present study are to validate these preoperative factors and verify the efficacy of this scoring system using a multi-institutional cohort. Of the 334 patients in this study from three different institutions, the preoperative factors found to be negatively associated with survival in a Cox analysis were age >60 years (p < 0.0001), Karnofsky Performance Scale score ?80 (p = 0.03), motor deficit (p = 0.02), language deficit (p = 0.04), and periventricular tumor location (p = 0.04). Patients possessing 0–1, 2, 3, and 4–5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 17.9, 12.3, 10, and 7.5 months, respectively. Survival of each of these grades was statistically significant (p < 0.05) in log-rank analysis. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued.     

Outcome of resection of WHO Grade II meningioma and correlation of pathological and radiological predictive factors for recurrence

This study investigated whether extent of surgical resection (Simpson and Shinshu grade) along with pathological and radiological factors influence the tumor control and recurrence-free survival (RFS) of patients with World Health Organization (WHO) grade II meningiomas. The clinical, radiological and surgical notes on the 59 patients with WHO grade II meningioma managed at our institution over 20 years were retrospectively reviewed. In this study, median survival time was 41 months. The overall recurrence rate in Simpson grades I and II resection was 31%. In grades III and IV, the overall recurrence rate was 73%, and this high recurrence rate in these groups was confined within 5 years. In Cox regression analysis, combined data of grades (I and II)/complete resection showed a significant difference in RFS compared to grades (III and IV)/subtotal resection (p = 0.0001). A similar trend of RFS (p = 0.0001) was observed with the Shinshu grading system of resection. In addition, a Ki-67% marker for proliferation less than 15% (p = 0.029), absence of certain radiological features including heterogeneous enhancement, cyst formation and peritumoral edema (p = 0.006), and repeat surgery for recurrent meningioma was associated with better survival (p = 0.014). However, radiosurgery did not have a beneficial role in the treatment of recurrence of atypical meningioma. The Simpson grading system is the primary predictor of recurrence of WHO grade II meningioma after resection. In addition, certain pathological and radiological features need to be considered as possible factors of recurrence after resection. Lastly, depending on the likely risks and surgical morbidity, repeat surgical resection should be performed for recurrent atypical meningioma.     

Downregulation of chromatin remodeling factor CHD5 is associated with a poor prognosis in human glioma

Chromodomain helicase DNA-binding protein 5 (CHD5), a member of the CHD family, is involved in key cellular processes including chromatin remodeling, cell cycle regulation, and cellular adhesion. Recent studies have demonstrated that CHD5 is the product of a novel tumor suppressor gene and is implicated in certain tumor types. However, the clinicopathological significance of CHD5 expression in human malignant gliomas remains unclear. To address this problem, CHD5 expression in human gliomas and non-neoplastic brain tissues was measured using real-time quantitative polymerase chain reaction (RT–PCR) assay, Western blot, and immunohistochemistry. The association of CHD5 immunostaining with clinicopathological factors or prognosis of glioma patients was statistically analyzed. Genetic and protein expression of CHD5 were downregulated in glioma tissues compared to corresponding non-neoplastic brain tissues (both p < 0.001). Additionally, decreased expression of CHD5 in glioma was significantly associated with pathological grade (p = 0.007); high pathological grade was associated with low CHD5 expression. Loss of CHD5 protein expression was also significantly correlated with a low Karnofsky performance scale score (p = 0.01). Moreover, overall survival of patients with low CHD5 protein expression was dramatically shorter than those of patients with high CHD5 protein expression (p = 0.003). Multivariate Cox regression analysis indicated that CHD5 expression was an independent prognostic factor for patients with gliomas (p = 0.01). In conclusion, these data offer convincing evidence for the first time that CHD5 might act as a tumor suppressor in glioma, may act as a regulator of aggressive development, and is a candidate prognostic marker for this malignancy.     

Effects of ebselen versus nimodipine on cerebral vasospasm subsequent to experimental subarachnoid hemorrhage in rats

We investigated the effect of ebselen relative to nimodipine in an animal model of subarachnoid hemorrhage. Thirty Wistar albino rats were divided into 5 groups: G1, no intervention; G2, sham surgery without subarachnoid hemorrhage (SAH); G3, SAH only; G4, SAH plus nimodipine treatment; G5, SAH plus ebselen treatment. For G2 animals, physiological saline (0.9% NaCl) was injected into the cisterna magna. For G3, G4 and G5 animals, SAH was induced by injecting autologous non-heparinized blood into the cisterna magna. One hour after injection, G4 animals received nimodipine at 6-hour intervals and G5 animals received ebselen twice a day for 48 hours. After treatment, brain tissue and blood samples were taken for biochemical and histopathological examination. Mean malonyldialdehyde concentration was significantly higher in G3 than in G1 (p < 0.0001), G2 (p = 0.01), G4 (p = 0.002) and G5 (p = 0.014), and significantly higher in G5 than in G1 (p = 0.013). Mean superoxide dismutase activity was significantly lower in G4 than in both G1 (p = 0.025) and G2 (p = 0.02). Mean wall thickness was significantly greater in G3 than in G1 (p < 0.0001), G2 (p = 0.01), G4 (p < 0.0001) and G5 (p < 0.0001). Mean wall thickness was also significantly greater in both G1 and G2 than in G4 (p < 0.0014 and p < 0.0001) and G5 (p < 0.0001 and p < 0.0001). Mean luminal diameter of the basilar artery was significantly smaller in G3 than in G2 (p = 0.02), G4 (p < 0.018) and G5 (p < 0.001). Our results confirm that ebselen may have neuroprotective effects by acting to prevent vasospasm.     

Multiplexed protein profiling after aneurysmal subarachnoid hemorrhage: Characterization of differential expression patterns in cerebral vasospasm

Cerebral vasospasm is a major contributor to delayed morbidity following aneurysmal subarachnoid hemorrhage. We sought to evaluate differential plasma protein levels across time in patients with aneurysmal subarachnoid hemorrhage to identify potential biomarkers and to better understand the pathogenesis of cerebral vasospasm. Nine female patients with aneurysmal subarachnoid hemorrhage underwent serial analysis of 239 different serum protein levels using quantitative, multiplexed immunoassays (DiscoveryMAP 250+ v2.0, Myriad RBM, Austin, TX, USA) on post-hemorrhage days 0 and 5. A repeated measures analysis of variance determined that mean protein concentration decreased significantly in patients who developed vasospasm versus those who did not for alpha-2-macroglobulin (F [1.00,7.00] = 16.33, p = 0.005), angiogenin (F [1.00,7.00] = 7.65, p = 0.028), apolipoprotein A-IV (F [1.00,7.00] = 6.308, p = 0.040), granulocyte colony-stimulating factor (F [1.00,7.00] = 9.08, p = 0.020), macrophage-stimulating protein (F [1.00,7.00] = 24.21, p = 0.002), tetranectin (F [1.00,7.00] = 5.46, p < 0.039), vascular endothelial growth factor receptor 3 (F [1.00,7.00] = 6.94, p = 0.034), and significantly increased for vitronectin (F [1.00,7.00] = 5.79, p = 0.047). These biomarkers may be of value in detecting cerebral vasospasm, possibly aiding in the identification of patients at high-risk prior to neurological deterioration.     

Predicting outcome in childhood diffuse midline gliomas using magnetic resonance imaging based texture analysis

BackgroundDiffuse midline gliomas (DMG) are aggressive brain tumours, previously known as diffuse intrinsic pontine gliomas (DIPG), with 10% overall survival (OS) at 18 months. Predicting OS will help refine treatment strategy in this patient group. MRI based texture analysis (MRTA) is novel image analysis technique that provides objective information about spatial arrangement of MRI signal intensity (heterogeneity) and has potential to be imaging biomarker.ObjectivesTo investigate MRTA in predicting OS in childhood DMG.MethodsRetrospective study of patients diagnosed with DMG, based on radiological features, treated at our institution 2007–2017. MRIs were acquired at diagnosis and 6 weeks after radiotherapy (54 Gy in 30 fractions). MRTA was performed using commercial available TexRAD research software on T2 W sequence and Apparent Diffusion Coefficient (ADC) maps encapsulating tumour in the largest single axial plane. MRTA comprised filtration-histogram technique using statistical and histogram metrics for quantification of texture. Kaplan-Meier survival analysis determined association of MRI texture parameters with OS.ResultsIn all, 32 children 2–14 years (median 7 years) were included. MRTA was undertaken on T2W (n = 32) and ADC (n = 22). T2W-MRTA parameters were better at prognosticating than ADC-MRTA. Children with homogenous tumour texture, at medium scale on diagnostic T2W MRI, had worse prognosis (Mean of Positive Pixels (MPP): P = 0.005, mean: P = 0.009, SD: P = 0.011, kurtosis: P = 0.037, entropy: P = 0.042). Best predictor MPP was able to stratify patients into poor and good prognostic groups with median survival of 7.5 months versus 17.5 months, respectively.ConclusionsDMG with more homogeneous texture on diagnostic MRI is associated with worse prognosis. Texture parameter MPP is the most predictive marker of OS in childhood DMG.     

IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy

ObjectiveIsocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II–IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency.MethodsThis was a retrospective study. Patients with grades II–IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A — postoperative seizure freedom; Group B — 1–11 seizures over 12 months (less than one seizure per month); and Group C — greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data.ResultsOne hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12 months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p = 0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p = 0.032) and Group B (RR 9.70, p = 0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p = 0.004).SignificanceIn patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy.     

Predicting long-term outcome in poor grade aneurysmal subarachnoid haemorrhage patients utilising the Glasgow Coma Scale

The Glasgow Coma Scale (GCS) is the most universally accepted system for grading level of consciousness. Predicting outcome is particularly difficult in poor grade aneurysmal subarachnoid haemorrhage (aSAH) patients. We hypothesised that the GCS and individual examination components would correlate with long-term outcome and have varying prognostic value depending on assessment time points. GCS scores of 160 aSAH patients presenting in stupor or coma were prospectively recorded on admission and each subsequent day until hospital day 14. Early treatment was planned for each patient unless the patient’s family refused aggressive intervention or the patient died before surgery. Outcomes were assessed by the modified Rankin scale (mRS) at 14 days, 3 months, and one year.All patients who did not receive surgical treatment died within one year. Of the 104 patients who received surgical treatment, 13.5% of them had a favourable outcome at 14 days, 38.5% at 3 months, and 51% at one year (p < 0.0001). Admission GCS scores significantly correlated with outcome (Spearman rank test, rs = 0.472, p < 0.0001). On admission, motor examination correlated best with one-year outcome (rs = 0.533, p < 0.0001). Each point increase in motor examination predicted a 1.8-fold increased odds of favourable long-term outcome (95% confidence interval [CI], 1.4–2.3). At discharge, eye examination (rs = 0.760, p < 0.0001) correlated best with one-year outcome, and a one point increase in eye examination predicted a 3.1-fold increased odds of favourable outcome (95% CI, 1.8–5.4). During hospitalisation, the best eye exam (rs = 0.738, p < 0.0001) and worst motor exam (rs = 0.612, p < 0.0001) were the most highly correlated with the one-year outcome.Long-term follow-up is necessary when evaluating recovery after aSAH, as outcomes improve significantly during the first year. The GCS and its individual components correlate well with long-term outcome. Admission motor examination and spontaneous eye opening during hospitalisation are most predictive of favourable recovery.     

Prognostic factors and treatment options for paediatric ependymomas

The aim of this study was to determine factors of prognostic relevance for paediatric ependymomas, and evaluate the efficacy of treatment modalities. This is a retrospective study of 43 patients with ependymoma (<18 years) who underwent a combination of surgical excision, chemotherapy, and/or radiotherapy treatment at The Prince of Wales Cancer Centre between 1969 and 2009. Statistical analysis was performed to assess the prognostic relevance of various parameters affecting the two-year and five-year overall survival (OS) and progression-free survival (PFS). The five-year OS and PFS were 50.3% and 44.8% respectively (median follow-up 50 months). Eighteen patients (41.9%) experienced tumour recurrence: 13 had a local recurrence (LR) and five had both LR and distant recurrence. On univariate analysis, a more favourable prognosis in terms of both OS and PFS was evident for supratentorial tumours compared to infratentorial tumours (OS p = 0.007, PFS p = 0.045), stereotactic radiosurgery/ fractionated stereotactic radiotherapy compared to craniospinal irradiation or local posterior fossa/local brain ± boost radiotherapy modalities (OS p = 0.047, PFS p = 0.031), total radiotherapy dose >50 Gy compared to ?50 Gy (OS p = 0.008, PFS p = 0.005), and in patients with no tumour recurrence compared to those with recurrence (OS p = 0.03, PFS p < 0.001). Although not statistically significant, a more favourable multivariate outcome was evident in patients who underwent complete surgical resection. Chemotherapy treatment and histopathological grade, however, were not relevant to prognosis. This study supports the need to pursue more aggressive treatment for infratentorial and/or recurrent tumours. Ideal treatment involves maximal surgical resection, followed by adjuvant radiotherapy (>50 Gy).     

The association of somatic arousal with the symptoms of upper airway resistance syndrome

ObjectivesWe tested the hypothesis that the symptoms of upper airway resistance syndrome (UARS) are manifestations of chronic stress. To accomplish this, we utilized the score on a self-report questionnaire for somatic arousal (a component of stress) to compare somatic arousal between UARS patients and healthy controls and, among all participants, to correlate the level of somatic arousal with the severity of UARS symptoms.MethodsWe administered the Mood and Anxiety Symptom Questionnaire anxious arousal subscale (MASQaas; a 17-item questionnaire with increasing levels of arousal scored 17–85) to 12 UARS patients and 12 healthy controls and compared scores between groups. For all participants, we correlated the MASQaas scores with scores for the Epworth Sleepiness Scale (ESS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, Pittsburgh Sleep Quality Index (PSQI), SF-36 Health Survey, and Perceived Deficits Questionnaire (PDQ; assessing cognitive function).ResultsCompared to healthy controls, UARS patients demonstrated increased somatic arousal (MASQaas scores of 18 ± 2 and 28 ± 7, respectively; p < 0.0001). For all participants, the MASQaas scores correlated significantly with scores of the ESS (r = 0.64; p = 0.0008), the FACIT-Fatigue scale (r = −0.89; p < 0.0001), the PSQI (r = 0.70; p = 0.0002), SF-36 Physical component (r = −0.78; p < 0.0001), SF-36 Mental component (r = −0.74; p < 0.0001), and the PDQ (r = 0.89; p < 0.0001).ConclusionsOur findings suggest that UARS patients have increased levels of the stress component, somatic arousal, proportionate to the severity of their symptoms.     

Impact of prognostic nutritional index on survival in recurrent glioblastoma

BackgroundPrimary brain tumors are relatively rare malignancy, with high-grade gliomas (glioblastoma multiforme and anaplastic gliomas) are the most common types. We aimed to evaluate the prognostic value of Prognostic Nutritional Index (PNI), which is calculated by lymphocyte count and albumin, in recurrent glioblastoma patients treated with systemic treatment.MethodsData of 64 patients with recurrent glioblastoma who received systemic treatment and followed in our clinic between 2012 and 2018 was retrospectively collected and analyzed. PNI was calculated as: [(10 × serum albumin (g/dL)) + (0.005 × total lymphocyte count)]. Patients were categorized according to the median PNI value. We investigated the prognostic role of PNI groups, and survival outcomes.ResultsMedian value of PNI was 45.7, and median follow-up duration was 9 months (1–68 months). Median overall survival (OS) was 7.9 months (95%CI: 5.5–10.4). Median OS was significantly longer in patients with PNI > 45.7 compared to patients with PNI ≤ 45.7 (13.9 months (95%CI: 10.5–17.4), and 4.6 months (95%CI: 2.5–6.8), p < 0.001, respectively). In multivariate analysis, PNI was found to be an independent prognostic factor for OS [HR:0.41 (95%CI:0.22–0.74), p = 0.03)].ConclusionIn our study, the PNI was found to be an independent prognostic biomarker in patients with recurrent glioblastoma, but further prospective trials are necessary to validate its prognostic role.     

Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder

Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p < 0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p < 0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d = −0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.     

The effectiveness of dexmedetomidine in experimental spinal cord injury compared to methylprednisolone in rats

The present study aimed to investigate the neuroprotective efficacy of dexmedetomidine in a rat experimental spinal cord injury model. The rats (n = 40) were equally divided into four groups: G1, G2, G3, and G4. Rats in the G1 group underwent a laminectomy only. For the rats in the G2, G3, and G4 groups, spinal cord injury was induced by placing an aneurysm clip extradurally for 60 s at T10. The rats in G2 did not receive any post-injury treatment. Immediately after trauma was induced, rats in G3 were given methylprednisolone (30 mg/kg) and in G4, dexmedetomidine (10 μg/kg), both intraperitoneally. The rats were sacrificed under anesthesia 24 hours later and 1.5 cm lengths of injured spinal cord were obtained. Malonyldialdehyde values were significantly increased in G2 compared to G1, G3 and G4 (p < 0.05). The neuronal cell count in G1 was significantly higher than in G2 and G3 (p = 0.0001; p = 0.007). G4 had higher cell counts compared to G2 and G3 (p = 0.0001; p = 0.05). These findings indicated that dexmedetomidine might have neuroprotective effects in spinal cord injury.     

Quality of life,mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group

ObjectiveBrain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated.Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n = 19) treated with Levetiracetam as an add-on.MethodsWe recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3 months and at 6 months.This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28–70) with uncontrolled partial-onset seizures treated with LEV as add-on.The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency.ResultsTwelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400 mg/die (mean final dose 300 mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy.In the historical control group treated with LEV (mean final dose 2000 mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs.In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures ≥ 50%, 2 stable and 1 patient with number of seizures increased.Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P = 0.005). The Responder Rate was 86.4%.Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p = 0.31).In our patients treated with LCM we didn't observe significant difference at 3 and 6 months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6 months of follow-up (KPS p = 0.003; BI p = 0.007).No clinical side effects were observed.ConclusionComparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV.In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life.     

Efficacy and safety of doxepin 6 mg in a model of transient insomnia

IntroductionThe efficacy and safety of doxepin (DXP) 6 mg tablets were evaluated in healthy adults in a model of transient insomnia.MethodsThis was a randomized, double-blind, parallel-group, placebo-controlled study in healthy adults using a model of transient insomnia. A first-night effect combined with a 3-h phase advance was implemented to induce transient insomnia in healthy adults. Subjects received a single night time dose of placebo (PBO; N = 282) or DXP 6 mg (N = 283) in a sleep laboratory. Efficacy was evaluated objectively (polysomnography; PSG) and subjectively (morning questionnaire). Consistent with the model utilized, the primary endpoint was latency to persistent sleep (LPS); secondary PSG endpoints included wake after sleep onset (WASO; key secondary endpoint), total sleep time (TST), wake time after sleep (WTAS) and sleep efficiency (SE; overall, by quarter of the night and hourly); secondary subjective endpoints included latency to sleep onset (LSO), subjective WASO (sWASO), subjective TST (sTST) and sleep quality.ResultsDXP 6 mg demonstrated statistically significant improvements in LPS (13 min decrease versus PBO; p < 0.0001), WASO (39 min less than PBO; p < 0.0001), TST (51 min more than PBO; p < 0.0001), WTAS (p < 0.0001), overall SE (p < 0.0001), SE in each quarter of the night (p < 0.0001) and SE in each of the 8 h (p ? 0.0003), all versus PBO. Additionally, DXP 6 mg significantly improved subjective variables including LSO (p < 0.0001), sWASO (p = 0.0063), sTST (p < 0.0001), and sleep quality (p = 0.0004), versus PBO. There was no consistent evidence of next-day residual sedation and also minor sleep stages alterations. The incidence of adverse events was comparable to placebo.ConclusionsIn this model of transient insomnia, DXP 6 mg demonstrated significant improvements in sleep onset, sleep maintenance, sleep duration and sleep quality, and also appeared to reduce early morning awakenings. These data suggest that DXP 6 mg may be effective and well tolerated in adults experiencing transient insomnia.     

Treatment of elderly primary insomnia patients with EVT 201 improves sleep initiation,sleep maintenance,and daytime sleepiness

ObjectiveTwo doses of EVT 201, a partial positive allosteric modulator of the GABA_A system, were evaluated in elderly primary insomnia patients with daytime sleepiness.Patients and methodsParticipants were 149 elderly patients with DSM-IV primary insomnia including evidence of daytime sleepiness (53 males, 96 females; mean age 71.3 yrs, range 65–86 yrs). A randomized, multicentre, double-blind, placebo-controlled, parallel-group design was used to assess the hypnotic efficacy of EVT 201 1.5 and 2.5 mg during seven consecutive nights. Polysomnography (PSG) was performed on nights 1, 6 and 7 of treatment. Daytime assessments on Day 8 included the multiple sleep latency test (MSLT), Rey Auditory Verbal Learning Test (RAVLT), Psychomotor Vigilance Task (PVT) and the Karolinska Sleepiness Scale (KSS). The primary endpoint was total sleep time (TST) and the key secondary endpoint was mean MSLT latency.ResultsCompared to placebo, EVT 201 1.5 and 2.5 mg increased TST (30.9, 56.4 min, respectively; p = 0.0001, p < 0.0001); reduced wake after sleep onset (WASO; ?15.2, ?36.1 min, respectively; p = 0.014, p < 0.0001); reduced latency to persistent sleep (LPS; ?15.9, ?19.9 min, respectively; p = 0.009, p = 0.001). The 2.5 mg dose also reduced WASO in hours 5–8 (?16.3 min, p = 0.001). Both doses also improved subjective sleep quality and usual subjective efficacy measures. A significantly longer mean MSLT latency was observed on Day 8 with both doses, compared to placebo (2 min increase; p = 0.03, both doses). The PVT, RAVLT, and POMS did not differ among treatment groups. No serious or unexpected treatment emergent adverse events were noted.ConclusionEVT 201 improved PSG measures of sleep onset and sleep maintenance and significantly reduced daytime physiological sleep tendency. These findings suggest that treatment of primary insomnia in older patients has the potential to improve daytime sleepiness as well as sleep.