Distinct metabolic hallmarks of WHO classified adult glioma subtypes.

BACKGROUND: Gliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy. METHODS: Cross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors-oligodendroglioma (n = 31), astrocytoma (n = 31) and glioblastoma (n = 162)-were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2-4, and MGMT promoter methylation. RESULTS: Distinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides, and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue. CONCLUSION: Key metabolic differences exist across adult glioma subtypes.

Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin.

PURPOSE: This study evaluates the application of a microdialysis technique for interstitial chemotherapy using cisplatin in high-grade glioma. METHOD: An in vitro study demonstrated that cisplatin can be administered through retrograde microdialysis and defined the recovery for cisplatin. In a subsequent phase I study, 1-4 microdialysis catheters were implanted in tumor tissue, brain adjacent to tumor (BAT) tissue, and subcutaneous tissue in 10 patients with recurrent high-grade glioma. Cisplatin was administered continuously in daily doses between 0.3 and 3.9 mg for 4 to12 days. Microdialysis samples were continuously collected and analyzed for glucose metabolites, glutamate, glycerol, and cisplatin concentrations. Treatment tolerability was evaluated through clinical monitoring. Quality of life was assessed using the EORTC-QLQ-C30 questionnaire for up to 3 months after treatment. RESULTS: This in vitro study showed that cisplatin could be administrated with a recovery of 41-97%, depending on flowrate, type of catheter, and cisplatin concentration. During the treatment, patients were exposed to a total dose of 1.2-36.8 mg cisplatin. The concentration of cisplatin in BAT, serum, and subcutaneous tissue was close to detection level in all but two patients. A transient neurologic deterioration due to edema was commonly observed, but no systemic side effects were recorded. After onset of treatment, concentrations of glutamate and glycerol were significantly increased in tumor tissue but not in BAT, with a peak after 3 days, and consistent for the rest of the treatment. Five of the patients survived between 153 and 492 days after treatment. CONCLUSION: This phase I study demonstrates that retrograde microdialysis can be used to administer cisplatin interstitially into high-grade glioma tissue. A high cytotoxicity was detected in tumor tissue, but not in the surrounding brain. Retrograde microdialysis appears to be a clinically useful method for intratumoral drug administration in high-grade glioma.

Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma.

BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses. METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects. RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment. CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.

Improved treatment of glioblastoma - changes in survival over two decades at a single regional Centre.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor with a short overall survival (OS) in general. The treatment of GBM has evolved over the last decades and is today multimodal including surgical resection followed by radiochemotherapy and adjuvant chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single regional center. PATIENTS AND METHODS: Survival was studied for 571 patients in our region diagnosed with GBM between 1995 and 2015. Samples from 244 patients out of those treated 2005-2015 have been included in a tissue/blood bank and a clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment. RESULTS: The median OS for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995-1996 and 2010-2015, respectively (p < .05). The 2-year survival for the same time periods improved from 7% to 18% (p < .01). After introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased OS was noted and following implementation of intraoperative 5-aminolevulinic acid the number of tumor resection ≥95% did increase from 33% to 54% (p < .001). Positive prognostic factors for survival were young age, good performance status, absence of inflammatory disease, absence of diabetes or metabolic disease, tumor resection ≥95%, and completion of postoperative radiochemotherapy. DISCUSSION: The results of this study are consistent with earlier results regarding survival and prognostic factors and confirm results from randomized controlled trials in a clinical setting. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.

One Hundred Eleven Percutaneous Balloon Compressions for Trigeminal Neuralgia in a Cohort of 66 Patients with Multiple Sclerosis.

BACKGROUND: Trigeminal neuralgia associated with multiple sclerosis (MS-TN) is comparatively rare and larger series of percutaneous balloon compression (PBC) in such cases are few in the literature. OBJECTIVE: To evaluate the results after PBC for MS-TN with regards to therapeutic effect, side effects, and complications. METHODS: One hundred eleven procedures with PBC performed in 66 cases of MS-TN were analyzed. Therapeutic effect was measured as postoperative time to pain recurrence without medication. All complications were compiled and the sensory function was evaluated in a subgroup of cases. RESULTS: The initial pain free rate was 67% and the median time to pain recurrence was 8 mo. Thirty-six patients were treated with PBC only, and among them, the results were worse if treated 3 to 4 times before, compared to first treatment (P = .009-.034). Patients who had several PBCs had worse results already after the first surgery (P < .001). A significant number of patients had impaired sensation to light touch directly after surgery, which was normalized at the late follow-up. Sensimetric testing showed raised thresholds for perception and pain directly after surgery (P = .004-.03), but these were also normalized at the late follow-up. CONCLUSION: PBC is a treatment that can be effective for many patients with MS-TN. Repeated previous surgeries is a risk factor for an unsatisfactory outcome. However, the patients with multiple surgeries had less satisfactory results already at the first procedure, indicating that a therapy resistant disease can be predicted after the first two PBCs. Postoperative sensory deficits were common but not lasting.

Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study.

The knowledge of response to radiation in the immuno-microenvironment of high grade gliomas is sparse. In vitro results have indicated an inflammatory response of myeloid cells after irradiation. Therefore, microdialysis was used to verify whether this is operative in tumor tissue and brain adjacent to tumor (BAT) after clinical radiotherapy of patients with high grade glioma. Stereotactic biopsies and implantation of microdialysis catheters in tumor tissue and BAT were performed in eleven patients with high-grade glioma. The patients were given daily radiation fractions of 2-3.4 Gy. Microdialysis samples were collected before radiotherapy and during the first five days of radiation. Cytokines, glucose metabolites, glutamate and glycerol were analyzed. Immunohistochemistry was performed to detect macrophages (CD68) and monocytes (CD163) as well as IL-6, IL-8 and MCP-1. A significant increase of IL-8, MCP-1 and MIP-1a were detected in tumor tissue already after the first dose of radiation and increased further during 5 days of radiation. IL-6 did also increase but after five fractions of radiation. In BAT, the cytokine response was modest with significant increase of IL-8 after third dose of radiation. We found a positive correlation between baseline IL-8 and IL-6 microdialysis levels in tumor tissue and survival. Glucose metabolites or glycerol and glutamate did not change during radiation. In all tumors staining for macrophages was demonstrated. IL-6 was found in viable tumor cells while MCP-1 was demonstrated in macrophages or tumor matrix. Our findings suggest that radiation induces a rapid enhancement of the prevailing inflammation in high-grade glioma tissue. The microdialysis technique is feasible for this type of study and could be used to monitor metabolic changes after different interventions.

Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas.

BACKGROUND: Glioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for supplementary biomarkers that could provide reliable and early assessment of treatment efficacy. Analysis of alterations in the metabolome may be a source for identification of new biomarker patterns harboring predictive information. Ideally, the biomarkers should be found within an easily accessible compartment such as the blood. METHOD: Using gas-chromatographic- time-of-flight-mass spectroscopy we have analyzed serum samples from 11 patients with glioblastoma during the initial phase of radiotherapy. Fasting serum samples were collected at admittance, on the same day as, but before first treatment and in the morning after the second and fifth dose of radiation. The acquired data was analyzed and evaluated by chemometrics based bioinformatics methods. Our findings were compared and discussed in relation to previous data from microdialysis in tumor tissue, i.e. the extracellular compartment, from the same patients. RESULTS: We found a significant change in metabolite pattern in serum comparing samples taken before radiotherapy to samples taken during early radiotherapy. In all, 68 metabolites were lowered in concentration following treatment while 16 metabolites were elevated in concentration. All detected and identified amino acids and fatty acids together with myo-inositol, creatinine, and urea were among the metabolites that decreased in concentration during treatment, while citric acid was among the metabolites that increased in concentration. Furthermore, when comparing results from the serum analysis with findings in tumor extracellular fluid we found a common change in metabolite patterns in both compartments on an individual patient level. On an individual metabolite level similar changes in ornithine, tyrosine and urea were detected. However, in serum, glutamine and glutamate were lowered after treatment while being elevated in the tumor extracellular fluid. CONCLUSION: Cross-validated multivariate statistical models verified that the serum metabolome was significantly changed in relation to radiation in a similar pattern to earlier findings in tumor tissue. However, all individual changes in tissue did not translate into changes in serum. Our study indicates that serum metabolomics could be of value to investigate as a potential marker for assessing early response to radiotherapy in malignant glioma.

Percutaneous Balloon Compression vs Percutaneous Retrogasserian Glycerol Rhizotomy for the Primary Treatment of Trigeminal Neuralgia.

BACKGROUND: Despite >30 years of clinical use, the literature is still sparse when it comes to comparisons between percutaneous balloon compression (PBC) and percutaneous retrogasserian glycerol rhizolysis (PRGR) as treatments for trigeminal neuralgia. OBJECTIVE: To perform a retrospective cohort comparison between PBC and PRGR with regard to therapeutic effect, side effects, and complications. METHODS: Medical records and follow-up data from 124 primary PRGRs performed from 1986 to 2000 and 82 primary PBCs performed from 2000 to 2013 were reviewed. All patients had undergone clinical sensory testing and assessment of sensory thresholds. Analyses were performed to compare duration of pain relief, frequency of sensory disturbances, and side effects. RESULTS: Median duration of pain relief was 21 months after PRGR and 20 months after PBC. Both methods carried a high risk of hypesthesia/hypalgesia (P < .001) that was partly reversed with time. Decreased corneal sensibility was common after PRGR (P < .001) but not after PBC. Dysesthesia was more common after PRGR (23%) compared after PBC (4%; P < .001). Other side effects were noted but uncommon. CONCLUSION: PBC and PRGR are both effective as primary surgical treatment of trigeminal neuralgia. Both carry a risk of postoperative hypesthesia, but in this series, the side effect profile favored PBC. Furthermore, PBC is technically less challenging, whereas PRGR requires fewer resources. Between these 2 techniques, we propose PBC as the primary surgical technique for percutaneous treatment of trigeminal neuralgia on the basis of its lower incidence of dysesthesia, corneal hypesthesia, and technical failures.

Metabolomic Screening of Tumor Tissue and Serum in Glioma Patients Reveals Diagnostic and Prognostic Information.

Glioma grading and classification, today based on histological features, is not always easy to interpret and diagnosis partly relies on the personal experience of the neuropathologists. The most important feature of the classification is the aimed correlation between tumor grade and prognosis. However, in the clinical reality, large variations exist in the survival of patients concerning both glioblastomas and low-grade gliomas. Thus, there is a need for biomarkers for a more reliable classification of glioma tumors as well as for prognosis. We analyzed relative metabolite concentrations in serum samples from 96 fasting glioma patients and 81 corresponding tumor samples with different diagnosis (glioblastoma, oligodendroglioma) and grade (World Health Organization (WHO) grade II, III and IV) using gas chromatography-time of flight mass spectrometry (GC-TOFMS). The acquired data was analyzed and evaluated by pattern recognition based on chemometric bioinformatics tools. We detected feature patterns in the metabolomics data in both tumor and serum that distinguished glioblastomas from oligodendrogliomas (p(tumor) = 2.46 × 10(-8), p(serum) = 1.3 × 10(-5)) and oligodendroglioma grade II from oligodendroglioma grade III (p(tumor) = 0.01, p(serum) = 0.0008). Interestingly, we also found patterns in both tumor and serum with individual metabolite features that were both elevated and decreased in patients that lived long after being diagnosed with glioblastoma compared to those who died shortly after diagnosis (p(tum)(o)(r) = 0.006, p(serum) = 0.004; AUROCC(tumor) = 0.846 (0.647-1.000), AUROCC(serum) = 0.958 (0.870-1.000)). Metabolic patterns could also distinguish long and short survival in patients diagnosed with oligodendroglioma (p(tumor) = 0.01, p(serum) = 0.001; AUROCC(tumor) = 1 (1.000-1.000), AUROCC(serum) = 1 (1.000-1.000)). In summary, we found different metabolic feature patterns in tumor tissue and serum for glioma diagnosis, grade and survival, which indicates that, following further verification, metabolomic profiling of glioma tissue as well as serum may be a valuable tool in the search for latent biomarkers for future characterization of malignant glioma.

Hypofractionated stereotactic radiotherapy in medium-sized to large arteriovenous malformations.

We have reviewed treatment results in terms of obliteration and complications in 24 patients with medium to large sized cerebral arteriovenous malformations (AVMs) (mean volume 18.5±8.9cm(3); range: 10-42) treated with hypofractionated stereotactic radiotherapy (HSRT). AVMs are congenital lesions associated with a high morbidity and mortality. Radiosurgery is one option for treatment. However, in larger AVMs with volumes exceeding 10cm(3) obliteration rates are less favourable and radiation induced complications more frequent. For larger AVMs, volume-staged radiosurgery is one option while another option may be the use of HSRT. Patients were treated with 6-7Gy in five fractions to a total dose of 30-35Gy (mean total dose 32.9±1.6Gy [standard error of the mean]). Sixteen patients (69.6%) showed obliteration after a mean time of 35.2±14.8 months (range: 24-60). Only one patient (4.2%) experienced symptomatic radionecrosis. Our treatment with HSRT seems safe and efficient for treatment of medium to large sized AVMs. Treatment results seem to be in line with volume-staged radiosurgery and may be an alternative for AVMs not suitable for single fraction radiosurgery.

Selective peripheral denervation for cervical dystonia: long-term follow-up.

OBJECTIVE: 61 procedures with selective peripheral denervation for cervical dystonia were retrospectively analysed concerning surgical results, pain, quality of life (QoL) and recurrences. METHODS: The patients were assessed with the Tsui torticollis scale, Visual Analogue Scale (VAS) for pain and Fugl-Meyer scale for QoL. Evaluations were performed preoperatively, early postoperatively, at 6 months, then at a mean of 42 (13-165) months. All patients underwent electromyogram at baseline, which was repeated in cases who presented with recurrence of symptoms after surgery. RESULTS: Six months of follow-up was available for 55 (90%) of the procedures and late follow-up for 34 (56%). The mean score of the Tsui scale was 10 preoperatively. It improved to 4.5 (p<0.001) at 6 months, and 5.3 (p<0.001) at late follow-up. VAS for pain improved from 6.5 preoperatively to 4.2 (p<0.001) at 6 months and 4 (p<0.01) at late follow-up. The Fugl-Meyer score for QoL improved from 43.3 to 46.6 (p<0.05) at 6 months, and to 51.1 (p<0.05) at late follow-up. Major reinnervation and/or change in the dystonic pattern occurred following 29% of the procedures, and led in 26% of patients to reoperation with either additional denervation or pallidal stimulation. CONCLUSIONS: Selective peripheral denervation remains a surgical option in the treatment of cervical dystonia when conservative measures fail. Although the majority of patients experience a significant relief of symptoms, there is a substantial risk of reinnervation and/or change in the pattern of the cervical dystonia.

Percutaneous retrogasserian balloon compression for trigeminal neuralgia: review of critical technical details and outcomes.

OBJECTIVE: To describe percutaneous balloon compression (PBC) of the trigeminal rootlets as treatment for trigeminal neuralgia (TN), including history, operative techniques, outcomes, side effects, and some recent findings increasing the likelihood of a positive outcome. METHODS: PBC is indicated in patients with TN in whom microvascular decompression is considered less suitable. The procedure is simplified by the use of biplanar fluoroscopy, although it is usually carried out with C-arm fluoroscopy to facilitate the introduction of the needle and the visualization of the inflated catheter. In the right position, a clearly defined pear shape usually appears after injection of 0.5-0.7 mL of contrast material. The balloon is kept inflated for 1.5-3 minutes. It is crucial to obtain a pear shape because this probably is the most significant factor for obtaining good, long-lasting pain relief. RESULTS: An analysis of 100 consecutive PBC procedures showed an initial success rate of 90% and a median pain-free time without medication of 28 months. Subdividing these patients into primary TN (n = 77) and TN secondary to multiple sclerosis (n = 23), the median pain-free times were 33 months and 24 months (P = 0.2), indicating that the outcome may depend on the preoperative conditions. CONCLUSIONS: Complications and side effects include cardiovascular stress during the procedure, local hemorrhages in the cheek, postoperative sensory disturbance, masseter weakness, infections, and transitory diplopia after surgery. Measures to minimize side effects are proposed. With meticulous technique, PBC is a straightforward, effective, and fast procedure that compares well with other percutaneous therapies for TN.

Trauma infant neurologic score predicts the outcome of traumatic brain injury in infants.

To investigate the clinical features of infancy traumatic brain injury (TBI) and the prognostic value of the Trauma Infant Neurologic Score (TINS), infants < 2 years of age with TBI who were admitted from 2000 to 2007 were retrospectively studied. Fifty-six patients with a mean age of 13.3 ± 6.5 months (range = 2-24) were identified. The clinical diagnoses, in terms of the severest injury, included scalp hematomas (n = 2), skull bone fractures (n = 3), epidural hematomas (n = 21), subdural hematomas (n = 14), cerebral contusion and laceration (n = 4), intracerebral hematomas (n = 7), traumatic subarachnoid hemorrhage (n = 2), diffuse axonal injury (n = 2) and diffuse brain swelling (n = 1). The most common clinical presentations were vomiting (66.1%), paleness (55.4%), irritability (37.3%), pupillary abnormalities (35.7%) and altered consciousness (32.1%). The mechanism of injury included falls (n = 41), vehicle accident (n = 9), abuse (n = 4) and unknown (n = 2). The TINS score ranged from 1 to 10 with a mean of 3.6 (SD = 2.4) in the whole patient cohort. The Children's Coma Scores (CCS) on admission were 13-15 (n = 31), 9-12 (n = 7) and 3-8 (n = 18). Thirty-nine of the infants were operated on and the other 17 infants were treated nonsurgically. Forty-eight patients (86%) were followed up for a period of 1-8 years (mean = 4.4) after discharge. In the followed-up patient cohort, the mean TINS score at admission was 3.8 ± 2.5. The total clinical outcome, according to the Glasgow Outcome Scale (GOS), was: 37 (77.1%) good recovery, 4 (8.3%) moderately disabled, 1 (2.1%) vegetative and 6 (12.5%) dead. For those who were operated on the outcome was: 25 (78.1%) good recovery, 4 (12.5%) moderately disabled and 3 (9.4%) dead, and for those who were not operated on: 12 (75.0%) good recovery, 1 (6.3%) vegetative and 3 (25.0%) dead. At two years of follow-up, the GOS included 34 (73.9%) good recovery, 3 (6.5%) moderately disabled, 2 (4.3%) severely disabled, 1 (2.2%) vegetative and 6 (13.0%) dead. Statistical tests revealed that the TINS scores were highly associated with the GOS. Higher TINS scores resulted in worse clinical outcome. The CCS scores were also to some degree associated with the GOS score. However, the CCS score on admission was not as discriminating as TINS, predicting only the best and worst outcome in our series. Our study showed that the clinical features of TBI in infants were different from those seen in adults regarding both the distribution of the pathology type and the clinical presenting symptoms. We found that the TINS scoring system is useful for predicting prognosis and outcome in infancy TBI and suggest that it could be routinely used in the infantile population.

Vandetanib alters the protein pattern in malignant glioma and normal brain in the BT4C rat glioma model.

The treatment of glioblastoma is unsatisfactory. Improved understanding of the biological effects of treatment, together with development of new tools to predict outcome of the initiated treatment are therefore of great need. Vandetanib (ZD6474) is mainly a vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptor tyrosine kinase inhibitor. This study investigated the pattern of protein expression in brain tumor and normal brain tissue, following treatment with vandetanib in a rat glioma model. BT4C-cells were stereotactically implanted into the brain of BD IX rats. The rats were divided into three different experiments. The treatment schedule for experiments one and two consisted of daily, oral doses of vandetanib from day 6 until day 12 or 20 after implantation, respectively. In the third experiment, each animal received a single dose of vandetanib on day 19 after implantation and was then sacrificed 2, 8 or 24 h thereafter. The protein expression profiles were analyzed by SELDI-TOF-MS and evaluated with multivariate statistical methods. Following treatment with vandetanib, we found significantly altered protein expression pattern in malignant glioma and normal brain. Analyzing protein spectra is an interesting option to assess biological effects induced in brain tissue by signal transduction inhibitors such as vandetanib.

Metabolomic patterns in glioblastoma and changes during radiotherapy: a clinical microdialysis study.

We employed stereotactic microdialysis to sample extracellular fluid intracranially from glioblastoma patients, before and during the first five days of conventional radiotherapy treatment. Microdialysis catheters were implanted in the contrast enhancing tumor as well as in the brain adjacent to tumor (BAT). Reference samples were collected subcutaneously from the patients' abdomen. The samples were analyzed by gas chromatography-time-of-flight mass spectrometry (GC-TOF MS), and the acquired data was processed by hierarchical multivariate curve resolution (H-MCR) and analyzed with orthogonal partial least-squares (OPLS). To enable detection of treatment-induced alterations, the data was processed by individual treatment over time (ITOT) normalization. One-hundred fifty-one metabolites were reliably detected, of which 67 were identified. We found distinct metabolic differences between the intracranially collected samples from tumor and the BAT region. There was also a marked difference between the intracranially and the subcutaneously collected samples. Furthermore, we observed systematic metabolic changes induced by radiotherapy treatment among both tumor and BAT samples. The metabolite patterns affected by treatment were different between tumor and BAT, both containing highly discriminating information, ROC values of 0.896 and 0.821, respectively. Our findings contribute to increased molecular knowledge of basic glioblastoma pathophysiology and point to the possibility of detecting metabolic marker patterns associated to early treatment response.

The predictive power of balloon shape and change of sensory functions on outcome of percutaneous balloon compression for trigeminal neuralgia.

OBJECT: Percutaneous balloon compression is a simple and effective treatment of trigeminal neuralgia. However, results between and within different series are varying. To further improve the results in terms of pain relief, the authors believe that a careful study of the surgical procedure is important. The object of this study was to analyze the impact of balloon shape, balloon position, balloon volume, and compression time on duration of the therapeutic effect following percutaneous balloon compression. Furthermore, they analyzed the sensory side effects associated with this treatment, and how these relate to surgical parameters. METHODS: Medical records and intraoperative radiographs from 87 balloon compressions were reviewed, and different surgical parameters were categorized. Univariate and multivariate analyses were performed to correlate surgical parameters to pain relief. Sensory testing with a transcutaneous electrical stimulation technique and clinical examination data were reviewed to analyze changes in sensory function. RESULTS: The balloon shape had a significant impact on time to recurrence of pain. A pear-shaped balloon resulted in a far better surgical result than a non-pear-shaped balloon (p < 0.001). The difference between a distinct and a less distinct pear shape was not significant (p = 0.14). Statistical significance was not reached for any of the other parameters in relation to duration of therapeutic effect. A pear-shaped balloon was also significantly associated with increased thresholds for percutaneous electrical stimulation in the immediate postoperative period, but the perception thresholds were normalized at the late follow-up at 3-9 months. A similar outcome was found for clinical testing with light touch and pinprick. CONCLUSIONS: The authors have demonstrated that using a pear-shaped balloon when performing percutaneous balloon compression for trigeminal neuralgia results in longer pain relief than non-pear-shaped balloons. Other surgical parameters seemed less important with respect to pain relief. Balloon compression also, in many cases, results in hypesthesia.

Radiation schedules in relation to obliteration and complications in hypofractionated conformal stereotactic radiotherapy of arteriovenous malformations.

AIMS: The purpose of this investigation was to assess the obliteration rate and complications following different radiation schedules of hypofractionated conformal stereotactic radiotherapy for cerebral arteriovenous malformations (AVMs). METHODS: Twenty-five patients were treated with 35 Gy in 5 fractions, whereas 31 patients were treated with 30-32.5 Gy (mean: 31.6 +/- 0.23 Gy) in 5 fractions. A complete angiographic follow-up is available for 40 patients. RESULTS: Thirty-seven out of 40 patients (92.5%) have so far shown obliteration of their AVMs after a mean time of 3.2 +/- 0.26 years (range: 2-8 years). The mean AVM volume in these patients was 8.2 +/- 1.0 cm(3) (range: 1.5-29 cm(3)). There was a higher rate of obliteration (88%) in patients treated with 35 Gy compared to those treated with < 35 Gy (78%), even if this was not statistically significant. There was a significantly shorter time to obliteration in patients treated with 35 Gy. All patients who experienced symptomatic radionecrosis belonged to the group treated with 35 Gy. CONCLUSION: A radiation schedule of 35 Gy in 5 fractions may be more effective than a radiation schedule of <35 (30-32.5) Gy in obliterating AVMs. This may, however, be at the price of an increased risk of symptomatic radionecrosis.

Genome-wide association study identifies five susceptibility loci for glioma.

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

Proteomic profiles differ between bone invasive and noninvasive benign meningiomas of fibrous and meningothelial subtype.

Meningiomas of WHO grade I can usually be cured by surgical resection. However, some tumors may, despite their benign appearance, display invasive growth behavior. These tumors constitute a difficult clinical problem to handle. By histology alone, bone invasive meningiomas may be indistinguishable from their noninvasive counterparts. In this study we have examined the protein spectra in a series of meningiomas in search of protein expression patterns that may distinguish between bone invasive and noninvasive meningiomas. Tumor tissue from 13 patients with fibrous (6 invasive and 7 noninvasive) and 29 with meningothelial (10 invasive and 19 noninvasive) grade I meningiomas were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI). Multivariate statistical methods were applied for data analyses. Comparing the protein spectra from invasive and noninvasive fibrous meningioma we found 22 peaks whose intensities were significantly different between the two groups (P < 0.001). Based on the expression pattern of these peaks we were able to perfectly separate the two entities (area under ROC curve = 1.0). In meningothelial meningioma the same comparison yielded six significantly differentially expressed peaks (P < 0.001), which to a large degree separated the invasive from noninvasive tissue (area under ROC curve = 0.873). By analyzing the protein spectra in benign meningiomas we could differentiate between invasive and noninvasive growth behavior in both fibrous and meningothelial meningiomas of grade I. A possibility for early identification of invasive grade I meningiomas may have a strong influence on the follow-up policy and the issue of early or late radiotherapy.

A comparison between surgical resection in combination with WBRT or hypofractionated stereotactic irradiation in the treatment of solitary brain metastases.

BACKGROUND: The standard treatment of solitary brain metastases previously has been tumour resection in combination with whole-brain radiation therapy (WBRT). Stereotactic radiotherapy has emerged as a non-invasive treatment option especially for small brain metastases. We now report our results on resection + WBRT or hypofractionated stereotactic irradiation (HCSRT) in the treatment of solitary brain metastases. METHODS: Between 1993 and 2004 patients with metastatic cancer and solitary brain metastases were selected for surgical resection + WBRT or HCSRT alone at the Umeå University Hospital. Fifty-nine patients were treated with surgical resection + WBRT (34 male, 25 female, mean age 63.3 years). Forty-seven patients were treated with HCSRT alone (15 male, 32 female, mean age 64.9 years). FINDINGS: In patients followed radiologically, 28% treated with resection + WBRT showed a local recurrence after a median time of 8.0 months, whereas there was a lack of local control in 16% in the HCSRT group after a median time of 3.0 months. There was a significantly longer survival time for patients treated with resection + WBRT (median 7.9, mean 12.9 months) compared to HCSRT (median 5.0, mean 7.6 months). Even in patients with a tumour volume <10 cc, there was a significantly longer survival in favour of resection + WBRT (median 8.4, mean 17.4 months) compared to HCSRT (median 5.0, mean 7.9 months). CONCLUSION: This retrospective and non-randomised study indicates that surgical resection in combination with WBRT may be an option even for small brain metastases suitable for treatment with HCSRT. Since survival and local control following resection + WBRT was at least as favourable as compared to HCSRT alone, tumour location and expected neurological outcome may be the strongest aspect when selecting treatment modality.