Neuropsychological Function and Quality of Life after Resection of Suspected Lower-Grade Glioma in the Face Primary Motor Area.

The negative side effects of neurosurgical resection of the lower third of the primary motor cortex (M1) are often described as relatively mild. However, detailed descriptions of how these resections affect neurocognitive function, speech, mental health and quality of life (QoL) are sparse. In the present study, seven patients with suspected lower-grade glioma (WHO II-III) in the inferior M1 were assessed for facial motor function, cognitive function, anxiety and QoL before and after awake surgical resections. The main finding was that after surgery, six of the seven patients experienced a mild facial motor dysfunction, mainly affecting the mouth, tongue and throat. At the group level, we were also able to observe a significant postoperative decline in maximum verbal speed, whereas no negative effects on measures of word production (i.e., verbal fluency) were seen. Self-reported QoL data suggest that some patients experienced increased social isolation postoperatively but do not lend support to the interpretation that this was caused by direct neurological side effects of the surgery. The results appear to support the general notion that awake surgery in the lower M1 can be performed safely and with postoperative deficits that are most often perceived by the patient as tolerable.

Phenomenology of glioma resection in the dorsal medial frontal cortex.

BACKGROUND: During the latest decades, the hypothesis that the subjective experience of free will is determined by preconscious activity in the dominant dorsal medial frontal cortex (dMFC) has repeatedly challenged our commonly held concepts of moral responsibility. AIMS OF THE STUDY: To investigate whether dMFC activity determines the sense of free will and to investigate the effects of resections in this area on quality of life (QoL). METHODS: A cohort of nine patients affected by transient declines in speech and movement skills after surgery involving the left dMFC answered questions about their post-operative, subjective experiences of volition in relation to symptoms. In eight cases, resections were performed as part of glioma surgery, and in the ninth case, a meningioma adjacent to the dMFC was resected. In addition, a QoL questionnaire was administrated before and after surgery. RESULTS: None of the patients perceived the transient disabilities related to surgery as associated with a loss or absence of volition. No declines in QoL were detected after surgery. Two QoL domains showed improved function (motor dysfunction and future uncertainty). CONCLUSIONS: The subjective sense of volition is not contingent on dMFC activity. Surgical resections of this area are not typically associated with declines in QoL.

Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma.

Recently, a genome-wide association study showed that a single nucleotide polymorphism (SNP) -rs11706832-in intron 2 of the human LRIG1 (Leucine-rich repeats and immunoglobulin-like domains 1) gene is associated with susceptibility to glioma. However, the mechanism by which rs11706832 affects glioma risk remains unknown; additionally, it is unknown whether the expression levels of LRIG1 are a relevant determinant of gliomagenesis. Here, we investigated the role of Lrig1 in platelet-derived growth factor (PDGF)-induced experimental glioma in mice by introducing mono-allelic and bi-allelic deletions of Lrig1 followed by inducing gliomagenesis via intracranial retroviral transduction of PDGFB in neural progenitor cells. Lrig1 was expressed in PDGFB-induced gliomas in wild-type mice as assessed using in situ hybridization. Intriguingly, Lrig1-heterozygous mice developed higher grade gliomas than did wild-type mice (grade IV vs. grade II/III, p = 0.002). Reciprocally, the ectopic expression of LRIG1 in the TB107 high-grade human glioma (glioblastoma, grade IV) cell line decreased the invasion of orthotopic tumors in immunocompromised mice in vivo and reduced cell migration in vitro. Concomitantly, the activity of the receptor tyrosine kinase MET was downregulated, which partially explained the reduction in cell migration. In summary, Lrig1 is a haploinsufficient suppressor of PDGFB-driven glioma, possibly in part via negative regulation of MET-driven cell migration and invasion. Thus, for the first time, changes in physiological Lrig1 expression have been linked to gliomagenesis, whereby the SNP rs11706832 may affect glioma risk by regulating LRIG1 expression.

Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS.

OBJECTIVE: In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum. METHODS: Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point. RESULTS: One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum. CONCLUSIONS: The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally. CLINICALTRIALSGOV IDENTIFIER: NCT01719159.

The efficacy of P6 acupressure with sea-band in reducing postoperative nausea and vomiting in patients undergoing craniotomy: a randomized, double-blinded, placebo-controlled study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a multifactorial problem after general anesthesia. Despite antiemetic prophylaxis and improved anesthetic techniques, PONV still occurs frequently after craniotomies. P6 stimulation is described as an alternative method for preventing PONV. The primary aim of this study was to determine whether P6 acupressure with Sea-Band could reduce postoperative nausea after elective craniotomy. Secondary aims were to investigate whether the frequency of vomiting and the need for antiemetics could be reduced. METHODS: In this randomized, double-blinded, placebo-controlled study, patients were randomized into either a P6 acupressure group (n=43) or a sham group (n=52). Bands were applied unilaterally at the end of surgery, and all patients were administered prophylactic ondansetron. Postoperative nausea was evaluated with a Numerical Rating Scale, 0 to10, and the frequency of vomiting was recorded for 48 hours. RESULTS: We found no significant effect from P6 acupressure with Sea-Band on postoperative nausea or vomiting in patients undergoing craniotomy. Nor was there any difference in the need for rescue antiemetics. Altogether, 67% experienced PONV, and this was especially an issue at >24 hours in patients recovering from infratentorial surgery compared with supratentorial surgery (55% vs. 26%; P=0.014). CONCLUSIONS: Unilateral P6 acupressure with Sea-Band applied at the end of surgery together with prophylactic ondansetron did not significantly reduce PONV or the need for rescue antiemetics in patients undergoing craniotomy. Our study confirmed that PONV is a common issue after craniotomy, especially after infratentorial surgery.

Loud noise exposure and acoustic neuroma.

The results from studies of loud noise exposure and acoustic neuroma are conflicting. A population-based case-control study of 451 acoustic neuroma patients and 710 age-, sex-, and region-matched controls was conducted in Sweden between 2002 and 2007. Occupational exposure was based on historical measurements of occupational noise (321 job titles summarized by a job exposure matrix) and compared with self-reported occupational noise exposure. We also evaluated self-reported noise exposure during leisure activity. Conditional logistic regression was used to estimate odds ratios. There was no statistically significant association between acoustic neuroma and persistent occupational noise exposure, either with or without hearing protection. Exposure to loud noise from leisure activity without hearing protection was more common among acoustic neuroma cases (odds ratio = 1.47, 95% confidence interval: 1.06, 2.03). Statistically significant odds ratios were found for specific leisure activities including attending concerts/clubs/sporting events (odds ratio = 1.82, 95% confidence interval: 1.09, 3.04) and participating in workouts accompanied by loud music (odds ratio = 2.84, 95% confidence interval: 1.37, 5.89). Our findings do not support an association between occupational exposure to loud noise and acoustic neuroma. Although we report statistically significant associations between leisure-time exposures to loud noise without hearing protection and acoustic neuroma, especially among women, we cannot rule out recall bias as an alternative explanation.

Long-term mobile phone use and acoustic neuroma risk.

BACKGROUND: There is concern about potential effects of radiofrequency fields generated by mobile phones on cancer risk. Most previous studies have found no association between mobile phone use and acoustic neuroma, although information about long-term use is limited. METHODS: We conducted a population-based, nation-wide, case-control study of acoustic neuroma in Sweden. Eligible cases were persons aged 20 to 69 years, who were diagnosed between 2002 and 2007. Controls were randomly selected from the population registry, matched on age, sex, and residential area. Postal questionnaires were completed by 451 cases (83%) and 710 controls (65%). RESULTS: Ever having used mobile phones regularly (defined as weekly use for at least 6 months) was associated with an odds ratio (OR) of 1.18 (95% confidence interval = 0.88 to 1.59). The association was weaker for the longest induction time (≥10 years) (1.11 [0.76 to 1.61]) and for regular use on the tumor side (0.98 [0.68 to 1.43]). The OR for the highest quartile of cumulative calling time (≥680 hours) was 1.46 (0.98 to 2.17). Restricting analyses to histologically confirmed cases reduced all ORs; the OR for ≥680 hours was 1.14 (0.63 to 2.07). A similar pattern was seen for cordless land-line phones, although with slightly higher ORs. Analyses of the complete history of laterality of mobile phone revealed considerable bias in laterality analyses. CONCLUSIONS: The findings do not support the hypothesis that long-term mobile phone use increases the risk of acoustic neuroma. The study suggests that phone use might increase the likelihood that an acoustic neuroma case is detected and that there could be bias in the laterality analyses performed in previous studies.

EGFR gene variants are associated with specific somatic aberrations in glioma.

A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

Synergistic killing of glioblastoma stem-like cells by bortezomib and HDAC inhibitors.

BACKGROUND: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge. MATERIALS AND METHODS: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy. RESULTS: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments. CONCLUSION: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.

Role of tobacco use in the etiology of acoustic neuroma.

Two previous studies suggest that cigarette smoking reduces acoustic neuroma risk; however, an association between use of snuff tobacco and acoustic neuroma has not been investigated previously. The authors conducted a case-control study in Sweden from 2002 to 2007, in which 451 cases and 710 population-based controls completed questionnaires. Cases and controls were matched on gender, region, and age within 5 years. The authors estimated odds ratios using conditional logistic regression analyses, adjusted for education and tobacco use (snuff use in the smoking analysis and smoking in the snuff analysis). The risk of acoustic neuroma was greatly reduced in male current smokers (odds ratio (OR) = 0.41, 95% confidence interval (CI): 0.23, 0.74) and moderately reduced in female current smokers (OR = 0.70, 95% CI: 0.40, 1.23). In contrast, current snuff use among males was not associated with risk of acoustic neuroma (OR = 0.94, 95% CI: 0.57, 1.55). The authors' findings are consistent with previous reports of lower acoustic neuroma risk among current cigarette smokers than among never smokers. The absence of an association between snuff use and acoustic neuroma suggests that some constituent of tobacco smoke other than nicotine may confer protection against acoustic neuroma.

Bilateral deep brain stimulation for cervical dystonia in patients with previous peripheral surgery.

BACKGROUND: There are no data available concerning whether patients with cervical dystonia who have recurrent or new symptoms after peripheral denervation surgery benefit similarly from pallidal deep brain stimulation compared with patients who receive primarily pallidal stimulation. METHODS: Data on 7 cervical dystonia patients with recurrent or progressive dystonia after peripheral denervation who underwent pallidal stimulation were prospectively collected. Deep brain stimulation was performed in Mannheim/Hannover, Germany, or in Umea, Sweden. To the subgroup from Mannheim/Hannover, a second group of patients without previous peripheral surgery was matched. Assessments included the Toronto Western Spasmodic Torticollis Rating Scale and the Burke-Fahn-Marsden dystonia rating scale, as well as the Tsui scale in the Swedish patients. RESULTS: The 4 patients from Mannheim/Hannover experienced sustained improvement from pallidal stimulation by a mean of 57.5% according to the Toronto Western Spasmodic Torticollis Rating Scale (P < .05) and by a mean of 69.5% according to the Burke-Fahn-Marsden dystonia rating scale (P < .05) at long-term follow-up of 40.5 months. The patients from Umea had a mean Tsui score of 7 prior to surgery and a mean score of 3 at the mean follow-up of 8 months (62.5%). In the matched group the Toronto Western Spasmodic Torticollis Rating Scale improved by 58.8% and the Burke-Fahn-Marsden dystonia rating scale by 67% (P < .05) at long-term follow-up (mean, 41.5 months). CONCLUSIONS: Patients who had prior peripheral surgery for cervical dystonia experience improvement from subsequent pallidal stimulation that is comparable to that of de novo patients.

Long term follow-up of deep brain stimulation of the caudal zona incerta for essential tremor.

PURPOSE: The ventral intermediate nucleus of thalamus is the standard target for deep brain stimulation (DBS) in essential tremor (ET). However, favourable data have recently highlighted the caudal zona incerta (cZi) as an alternative target. Reports concerning the long-term results are however lacking, and we have therefore evaluated the long-term effects in our patients with ET and cZi DBS. METHODS: 18 patients were evaluated using the Essential Tremor Rating Scale (ETRS) before and on-/off-stimulation at 1 and 3-5 years after surgery (mean 48.5±10.6 months). Two patients were operated on bilaterally but all electrodes were evaluated separately. The stimulation parameters were recorded and the stimulation strength calculated. RESULTS: A baseline total ETRS mean score of 46.0 decreased to 21.9 (52.4%) at the final evaluation. On the treated side, tremor of the upper extremity (item 5 or 6) improved from 6.1 to 0.5 (91.8%) and hand function (items 11-14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in stimulation strength over time. CONCLUSION: cZi DBS is a safe and effective treatment for the long term suppression of ET.

A family with a hereditary form of torsion dystonia from northern Sweden treated with bilateral pallidal deep brain stimulation.

To evaluate pallidal DBS in a non-DYT1 form of hereditary dystonia. We present the results of pallidal DBS in a family with non-DYT1 dystonia where DYT5 to 17 was excluded. The dystonia is following an autosomal dominant pattern. Ten members had definite dystonia and five had dystonia with minor symptoms. Four patients received bilateral pallidal DBS. Mean age was 47 years. The patients were evaluated before surgery, and "on" stimulation after a mean of 2.5 years (range 1-3) using the Burke-Fahn-Marsden scale (BFM). Mean BFM score decreased by 79 % on stimulation, from 42.5 +/- 24 to 9 +/- 6.5 at the last evaluation. Cervical involvement improved by 89%. The 2 patients with oromandibular dystonia and blepharospasm demonstrated a reduction of 95% regarding these symptoms. The present study confirms the effectiveness of pallidal DBS in a new family with hereditary primary segmental and generalized dystonia.

Liquid ionization chamber calibrated gel dosimetry in conformal stereotactic radiotherapy of brain lesions.

UNLABELLED: Hypofractionated conformal stereotactic radiotherapy (HCSRT) is an established method of treating brain lesions such as arteriovenous malformations (AVMs) and brain metastases. The aim of this study was to investigate the reliability of treatment plans in the terms of dose distribution and absorbed dose for HCSRT. METHODS AND MATERIALS: Treatment plans for three different clinical intracerebral targets, AVMs, were transferred to a CT study of a spherical water filled phantom simulating the human head and recalculated for the phantom geometry using a standard treatment planning system utilizing a pencil beam algorithm for dose calculation. The calculated absorbed dose, relative three dimensional (3D) dose distribution and dose conformity were investigated using gel dosimetry normalized to liquid ionization chamber (LIC) measurements. RESULTS: The measured absorbed dose to the dose reference point was found to be within 2% of the calculated dose for all three targets. The measured dose distribution was found to be within 3% and 2 mm of the calculated dose for more than 93% of all points in the target volume for all three targets. CONCLUSIONS: The results show that the investigated standard treatment planning system can correctly predict the absorbed dose and dose distribution in different types of intracerebral targets and that the treatment can be delivered according to the plan.

Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors.

We have previously characterized three human leucine-rich repeats and immunoglobulin-like domains (LRIG) genes and proteins, named LRIG1-3 and proposed that they may act as suppressors of tumor growth. The LRIG1 transmembrane protein antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases. In this study, we evaluated the mRNA expression level of LRIG1-3 in human glioma cell lines and control-matched glioma tissues, characterized the sub-cellular localization of an LRIG3-GFP fusion protein, and analyzed the relationship between sub-cellular localization of LRIG1-3 and clinical parameters in 404 astrocytic tumors by immunohistochemistry. LRIG1-3 mRNA was detected in all human glioma cell lines and matched glioma samples, with large differences in the expression levels. Ectopically expressed LRIG3-GFP localized to perinuclear and cytoplasmic compartments, and to the cell surface of transfected glioma cells. Perinuclear staining of LRIG1-3 was associated with low WHO grade and better survival of the patients. Perinuclear staining of LRIG3 was associated with a lower proliferation index and was in addition to tumor grade, an independent prognostic factor. Furthermore, within the groups of grade III and grade IV tumors, perinuclear staining of LRIG3 significantly correlated with better survival. These results indicate that expression and sub-cellular localization of LRIG1-3 might be of importance in the pathogenesis and prognosis of astrocytic tumors.

The antimicrotubule drug estramustine but not irradiation induces apoptosis in malignant glioma involving AKT and caspase pathways.

Irradiation is one of the cornerstones used in the treatment of malignant glioma. However, the effect is modest and glioma cells generally display a pronounced radio-resistance. In this study, the effect of irradiation, alone and in combination with the antimicrotubule drug estramustine (EaM), was investigated in vitro using the BT4C rat glioma cell line, and in vivo the BT4C rat intracerebral glioma model was used. Apoptosis was detected by analysing DNA laddering, in situ end labelling (ISEL) and Annexin V reactivity. In addition, phosphorylation status of MAPK, JNK, p38, and AKT, proteins involved in pro- and anti-apoptotic signalling pathways was analysed by Western blotting. Irradiation did not induce apoptosis, neither in vitro nor in vivo. EaM, however, induced apoptosis in vivo and in vitro, regardless of whether EaM was given alone, before or after irradiation. When BT4C cells were treated with the caspase-3 inhibitor Ac-DEVD-CHO prior to EaM, the number of apoptotic cells was decreased, indicating an involvement of caspase-3. The signalling pathways regulating apoptosis are complex and involve kinases such as MAPK, JNK, p38 and AKT. Irradiation did not induce any changes in the expression levels or phosphorylation status of these proteins. On the other hand, the phosphorylation level of AKT was reduced after EaM treatment, which might, in part, propose how EaM induces apoptosis in glioma cells.