Surgical resection versus watchful waiting in low-grade gliomas.

BACKGROUND: Infiltrating low-grade gliomas (LGG; WHO grade 2) typically present with seizures in young adults. LGGs grow continuously and usually transform to higher grade of malignancy, eventually causing progressive disability and premature death. The effect of up-front surgery has been controversial and the impact of molecular biology on the effect of surgery is unknown. We now present long-term results of upfront surgical resection compared with watchful waiting in light of recently established molecular markers. MATERIALS AND METHODS: Population-based parallel cohorts were followed from two Norwegian university hospitals with different surgical treatment strategies and defined geographical catchment regions. In region A watchful waiting was favored while early resection was favored in region B. Thus, the treatment strategy in individual patients depended on their residential address. The inclusion criteria were histopathological diagnosis of supratentorial LGG from 1998 through 2009 in patients 18 years or older. Follow-up ended 1 January 2016. Making regional comparisons, the primary end-point was overall survival. RESULTS: A total of 153 patients (66 from region A, 87 from region B) were included. Early resection was carried out in 19 (29%) patients in region A compared with 75 (86%) patients in region B. Overall survival was 5.8 years (95% CI 4.5-7.2) in region A compared with 14.4 years (95% CI 10.4-18.5) in region B (P < 0.01). The effect of surgical strategy remained after adjustment for molecular markers (P = 0.001). CONCLUSION: In parallel population-based cohorts of LGGs, early surgical resection resulted in a clinical relevant survival benefit. The effect on survival persisted after adjustment for molecular markers.

Did survival improve after the implementation of intraoperative neuronavigation and 3D ultrasound in glioblastoma surgery? A retrospective analysis of 192 primary operations.

BACKGROUND: Numerous observational studies indicate that more aggressive resection may prolong survival in glioblastoma patients. In Trondheim, Norway, intraoperative 3D ultrasound has been in increasing use since November 1997. The aim of the present study was to examine if the introduction of 3D ultrasound and neuronavigation (i. e., the SonoWand® system) may have had an impact on overall survival. PATIENTS/MATERIAL AND METHODS: Patient data were obtained retrospectively for the 192 glio-blastoma patients who received surgery and postoperative radiotherapy between 1990 and 2005. Overall survival, before and after 1997, was compared using the log rank test. Possible confounders were adjusted for in a multivariate Cox regression analysis. RESULTS: We observed an increase in survival for patients in the last study period (9.6 vs. 11.9 months; HR = 0.7; p = 0.034). The significant improvement in the latest time period was sustained after adjusting for age, WHO performance status (≥2) and type of radiotherapy (normofractioned or hypofractioned), and chemotherapy (yes/no), p = 0.034. 10 out of 14 patients who survived more than 3 years received treatment after the implementation of 3D ultrasound. CONCLUSION: Our study demonstrates that survival has improved within the same period that intraoperative ultrasound and neuronavigation was introduced and established in our department. The demonstrated association is a necessity for causation, but given the nature of this study, one must be cautious to claim causality. The improvement was, however, significant after adjustment for known major prognostic factors.

A new system for 3D ultrasound-guided placement of cerebral ventricle catheters.

PURPOSE: We present a new system for 3D ultrasound-guided placement of cerebral ventricle catheters. The system has been developed with the aim to provide accurate ultrasound-based guidance with only minimal changes to the current surgical technique and workflow. METHODS: The system consists of a pre-calibrated navigation adapter for the catheter and a reference frame attached to a standard surgical retractor in addition to an ultrasound-based navigation system with a probe that fits on top of a standard burr hole. RESULTS: The accuracy of the pre-calibrated system has been evaluated, and our measurements indicate that the accuracy of the pre-calibrated system is better than 3 mm. We also present a clinical case. CONCLUSIONS: The navigation accuracy is considered sufficient for clinical use, and initial clinical tests are promising. Further testing will be necessary to fully evaluate the performance of the system in a clinical setting.

SonoWand, an ultrasound-based neuronavigation system.

OBJECTIVE: We have integrated a neuronavigation system into an ultrasound scanner and developed a single-rack system that enables the surgeon to perform frameless and armless stereotactic neuronavigation using intraoperative three-dimensional ultrasound data as well as preoperative magnetic resonance or computed tomographic images. The purpose of this article is to describe our two-rack prototype and present the results of our work on image quality enhancement. DESCRIPTION OF INSTRUMENTATION: The system consists of a high-end ultrasound scanner, a modest-cost computer, and an optical positioning/digitizer system. Special technical and clinical efforts have been made to achieve high image quality. A special interface between the ultrasound instrument and the navigation computer ensures rapid transfer of digital three-dimensional data with no loss of image quality. OPERATIVE TECHNIQUE: The positioning system tracks the position and orientation of the patient, the ultrasound probe, the pointer, and various surgical instruments. This makes it possible to update the three-dimensional map during surgery and navigate by ultrasound data in a similar manner as with magnetic resonance data. METHODS: The two-rack prototype has been used for clinical testing since November 1997 at the University Hospital in Trondheim. EXPERIENCE AND RESULTS: The image quality improvements have enabled us, in most cases, to extract information from ultrasound with clinical value similar to that of preoperative magnetic resonance imaging. The overall clinical accuracy of the ultrasound-based navigation system is expected to be comparable to or better than that of a magnetic resonance imaging-based system. CONCLUSION: The SonoWand system enables neuronavigation through direct use of intraoperative three-dimensional ultrasound. Further research will be necessary to explore the potential clinical value and the limitations of this technology.

In vivo effects of adenosine A1 receptor agonist and antagonist on neuronal and astrocytic intermediary metabolism studied with ex vivo 13C NMR spectroscopy.

Adenosine is a neuromodulator, and it has been suggested that cerebral acetate metabolism induces adenosine formation. In the present study the effects that acetate has on cerebral intermediary metabolism, compared with those of glucose, were studied using the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Fasted rats received an intravenous injection of CCPA, DPCPX, or vehicle. Fifteen minutes later either [1,2-13C]acetate or [1-13C]glucose was given intraperitoneally; after another 30 min the rats were decapitated. Cortical extracts were analyzed with 13C NMR spectroscopy and HPLC analysis. DPCPX affected neuronal and astrocytic metabolism. De novo synthesis of GABA from neuronal and astrocytic precursors was significantly reduced. De novo syntheses of glutamate and aspartate were at control levels, but their degradation was significantly elevated. In glutamine the anaplerotic activity and the amount of label in the position representing the second turn in the tricarboxylic acid cycle were significantly increased, suggesting elevated metabolic activity in astrocytes. CCPA did not influence GABA, aspartate, or glutamine synthesis. In glutamate the contribution from the astrocytic anaplerotic pathway was significantly decreased. In the present study the findings in the [1,2-13C]acetate and [1-13C]glucose control, CCPA, and DPCPX groups were complementary, and no adenosine A1 agonist effects arising from cerebral acetate metabolism were detected.

Initial experience with stereoscopic visualization of three-dimensional ultrasound data in surgery.

Initial in vivo and in vitro experiments were performed to evaluate the feasibility of stereoscopically displaying three-dimensional (3D) ultrasound data from neurosurgery, laparoscopic surgery, and vascular surgery. Stereoscopic visualization was illustrated by four video sequences, which can be downloaded from http://www.us.unimed. sintef.no/. These sequences show a brain tumor, hepatic arteries in relation to the gallbladder, a model that mimics a neuroendoscope in a cyst, and a "flight" into model of an artery with an intima flap. The experiments indicate that stereoscopic display of ultrasound data is feasible when there is sufficient contrast between the objects of interest and the surrounding tissue. True 3D vision improves perception, thus enhancing the ability to understand complex anatomic structures such as irregular lesions and tortuous vessels.

Ultrasound-guided neurosurgery: a feasibility study in the 3-30 MHz frequency range.

This study, which includes seven patients, illustrates some potential values of the interactive use of ultrasound technology prior to, during and after brain tumour resection. Ultrasound B-scan and colour flow imaging were applied during open surgery using a cardiac scanner in the 3.25-7.5 MHz frequency range and an intravascular scanner with catheters at 10, 20 and 30 MHz. The tumour and vital blood vessels were localized prior to resection using low frequency imaging from the brain surface. High frequency, high resolution close-up imaging was applied during and after resection in order to identify remaining tumour tissue, as well as to detect blood vessels in the vicinity of the resection wall. The study also demonstrates that the tumour and surgical tools such as, for example, bipolar diathermy, acoustic aspirator or biopsy forceps,can be visualized simultaneously. This simplifies the localization of remaining tumour tissue.

UDP-N-acetylhexosamines and hypotaurine in human glioblastoma, normal brain tissue and cell cultures: 1H/NMR spectroscopy study.

NMR spectroscopy was used to analyse perchloric acid extracts of normal human brain, murine brain cell cultures, glioblastoma tissue and the glioblastoma cell line U-87. 1H NMR spectra revealed the presence of elevated levels of UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine in glioblastoma extracts and the glioblastoma cell line U-87, in comparison with normal brain tissue and primary cell cultures of neurons and astrocytes. UDP-N-acetylhexosamines appear to accumulate in cells that are unable to differentiate. Furthermore, it was found that the culture medium had an effect on the concentration of UDP-N-acetygalactosamine in the glioblastoma cell line. Hypotaurine, previously only associated with oligodendrocytes, has been identified in astrocyte cultures and in cerebellar granule cells. In normal brain it was not observed by NMR spectroscopy, but was easily detectable in glioblastoma tissue extracts. UDP-N-acetylhexoseamines and hypotaurine might be useful markers for brain pathology and play a role in cell differentiation and cell division.

NMR spectroscopic study of cell cultures of astrocytes and neurons exposed to hypoxia: compartmentation of astrocyte metabolism.

Primary cultures of murine cerebral cortical astrocytes or cerebellar granule neurons were exposed to 7 h of hypoxia (3 h in some cases). The culture medium was analyzed at the end of the hypoxic or normoxic period by 1H NMR spectroscopy and intracellular components were analyzed as perchloric acid extracts by 31P and 1H NMR spectroscopy. Lactate production in astrocytes increased only marginally, whereas high energy phosphate concentrations were reduced, during 7 h of hypoxia and after 17 h of reoxygenation. After 3 h of hypoxia full recovery was possible during reoxygenation. Citrate and glutamine secretion was reduced or unchanged, respectively, during 7 h of hypoxia. Succinate secretion was only observed during normoxia, whereas pyruvate was secreted during hypoxia. Cerebellar granule neurons were more efficient in increasing glycolysis and were, therefore, more resistant to the effects of hypoxia than astrocytes. In the neurons lactate production was doubled and no effects on levels of high energy phosphates were seen after 7 h of hypoxia. Astrocytes were reoxygenated for 17 h after hypoxia or normoxia in a medium containing [2-13C]acetate in order to access if astrocytes were still capable of supplying neurons with essential precursors. The media were subsequently analyzed by 13C NMR spectroscopy. After shorter periods of hypoxia (3 h) full recovery was possible. Citrate and glutamine production remained however decreased during reoxygenation after 7 h of hypoxia. 13C incorporation into glutamine was greatly reduced but that into citrate was unchanged. These results suggest that under the present conditions, neurons are more efficient than astrocytes in switching the energy metabolism from aerobic to anaerobic glycolysis and that astrocytes may suffer long term damage to mitochondria from longer periods of hypoxia. Furthermore, evidence is presented for the existence of several TCA cycles within astrocytes based on labeling ratios. During normoxia the labeling ratios in the C-2/C-4 positions in glutamine and in the equivalent positions in citrate were 0.27 and 0.11, respectively.

Cerebrospinal fluid production during proximal aortic cross-clamping.

During cross-clamping (XC) of the thoracic aorta, the cerebrospinal fluid pressure (CSFP) increases. The mechanism of the increased CSFP is unknown but increased cerebrospinal fluid (CSF) production has been suggested as one explanation. The aim of this study was to investigate whether the CSF production rate was influenced by proximal XC of the thoracic aorta in an experimental model. Using the ventriculocisternal perfusion method including [14C] inulin, the rate of CSF production was measured before, during and after XC of the thoracic aorta in seven pigs. The CSFP was measured via a catheter in the lateral ventricle and the thoracic aorta was cross-clamped just distal to the left subclavian artery for 30 minutes. Following cross-clamping the CSFP increased from 5 mmHg to 11 mmHg (p < 0.001) and remained elevated during XC. In contrast the CSF production rate was 0.09 ml/min prior to XC and was not significantly altered following XC. In conclusion this experimental study indicates that increased CSF production is not responsible for the increase in CSFP during XC.

NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) did not affect recovery of high energy phosphates and pH in early reperfusion in a rat model of transient forebrain ischemia. Or: an in vivo 31P NMR spectroscopy study.

The new non-NMDA (N-methyl-D-aspartate) receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) has previously been shown to exert a neuroprotective effect in animal models of cerebral ischemia when administered in the post-ischemic phase. In this investigation the effect of NBQX on acidosis and energy recovery in early reperfusion after 10 min of transient forebrain ischemia with the 2-vessel occlusion model in the rat was studied with 31P NMR spectroscopy. In the intervention group the animals received a bolus dose of NBQX 30 mg.kg-1 i.v. at the start of reperfusion. 31P NMR spectroscopy was used to measure intracellular pH, ATP and phosphocreatine continuously in-vivo during, and after, the ischemic event. The recovery of high energy phosphates and pH was followed during 30 min of reperfusion. Pre-ischemic levels of phosphocreatine were reached after approximately 9-10 min in both groups. Although a slight improvement could be seen in the intervention group there was no significant difference in the rate of recovery between the two groups. ATP reached 90% of preischemic levels after about 8 min without significant difference between the two groups. With respect to the recovery of intracellular pH, no difference could be shown. Our results do not contradict previously published results, but suggest that the potential protective effect of NBQX is not mediated through improved recovery of energy metabolism in early reperfusion.

Nuclear magnetic resonance spectroscopy: biochemical evaluation of brain function in vivo and in vitro.

Nuclear magnetic resonance spectroscopy (MRS) offers a unique opportunity to monitor mmolar concentrations of high energy phosphates, glucose, lactate and amino acids. The possibility of obtaining information about chemical constituents noninvasively is of great importance. MRS and chemical shift imaging (CSI) are emerging as tools for tumor grading, monitoring of treatment, ischemia research, in pediatric research for follow-up of children with borderline mental retardation, for defining brain death and to define epileptic foci. It is important to know which cell type (neuronal or glial) shows changes as a result of external manipulations (e.g. excitotoxins) or internal changes (brain pathology). Metabolic studies have been carried out on brain cell cultures. By using 13C labeled glucose and acetate in combination with 13C MRS it was shown that astrocytes release lactate, glutamine, citrate and alanine and that cerebral cortical neurons use glutamine released from astrocytes as a precursor for GABA synthesis. An important feature in MRS is the localization of N-acetyl aspartate in neurons, since this enables monitoring of neuronal reactions, such as survival after neurotoxic insults. Recent advances have yielded high speed functional echo planar imaging (EPI) techniques that are sensitive to changes in cerebral blood volume, blood flow and blood oxygenation (Functional MRI). During cognitive task performance, local alterations in neuronal activity induce local changes in cerebral metabolism and cerebral perfusion, which can now be detected with MRI.

ACTH and TSH producing ectopic suprasellar pituitary adenoma of the hypothalamic region: case report.

A 34-year-old woman with a long-term history of amenorrhoea, headache and visual disturbances was operated for a hypothalamic tumor which could be completely removed. Postoperatively the patient developed a transient SIADH-syndrome and deep vein thrombosis; otherwise the clinical course was uneventful. There has been no sign of tumor recurrence at a follow-up period of fifteen months. Histological examination of the tumor revealed an ectopic pituitary adenoma with production of ACTH and TSH shown by immunohistochemistry.

[Intracranial tumors in children (under 15 years)]. / Intrakraniale svulster hos barn (< 15 år).

Primary intracranial tumours develop in 30-35 Norwegian children each year. Of these tumours, astrocytomas are the most frequent, followed by medulloblastomas, oligoastrocytomas and ependymomas. In this article we give an overview of tumour classification, epidemiology, diagnosis, treatment and prognosis of intracranial tumours in children.

[Intracranial tumors in adults (over 15 years)]. / Intrakraniale svulster hos voksne (> 15 år).

Primary intracranial tumours develop in 420 adult Norwegians each year. Of these tumours, gliomas are the most frequent, followed by meningiomas, pituitary adenomas and acoustic neurinomas. Glioblastomas represent more than 50% of the gliomas. Less than 10% of the patients with glioblastoma survive for two years, despite aggressive therapy (surgery, radiotherapy and chemotherapy). The prognosis for low grade gliomas is much better. In the case of meningiomas, 95% of the tumours are benign. The primary treatment for meningiomas is surgery. If surgery is impossible, radiosurgery should be considered. Pituitary adenomas are often hormone-secreting (e.g. prolactin, growth hormone, adrenocorticotrophic hormone). Many prolactinomas are treated with bromocriptine alone. The rest of the pituitary adenomas are treated by microsurgery and radiotherapy. The prognosis for patients with pituitary adenomas is good. Acoustic neurinomas, which in most cases are benign, are treated by microsurgery or radiosurgery. Postoperative morbidity due to cochlear nerve and facial nerve dysfunction is a problem. Brain metastases are far more frequent than primary intracranial tumours. Solitary metastases in patients with stable systemic disease should be treated by surgery or radiosurgery.

Mrs evaluation of brain-metabolites in extracts from cell-cultures, human tumors and normal tissue from brain - cholesteryl ester, choline containing compounds and creatine as markers for development, differentiation and pathology.

A multi stage extraction procedure which gives the possibility to analyze both water soluble and lipid components stemming from the same specimen has been developed in our laboratory. Metabolites from brain cancer biopsies have been compared to metabolites in normal human brain, developing mouse brain and primary mouse cell cultures of neurons and astrocytes from cerebral cortex and cerebellum. Extraction with perchloric acid (PCA) dissolves water.soluble components such as choline containing compounds, creatine, amino acids, carbohydrates and high energy phosphates. The water insoluble fraction left after the PCA treatment was extracted with chloroform/methanol, 2/1 (vol/vol). C-13 and H-1 NMR spectra showed characteristic lipid resonances identified as those from long chain saturated and unsaturated fatty acids and cholesterol. Only glioblastomas contained detectable amounts of cholesteryl ester suggesting this compound as marker for brain pathology. It was shown that cholesterol but not cholesteryl ester is present in cultures of neurons either alone or together with astrocytes. H-1 NMR spectra of PCA extracts from biopsies showed that the creatine/choline containing compounds (Cr/Cho) ratios decreased and the N-acetylaspartate/Cho ratios decreased in glioblastomas as compared to normal brain. Cell cultures retain the Cr/Cho ratio characteristic of the developmental stage of the tissue they were prepared from.

The effects of brain temperature on temporary global ischaemia in rat brain. A 31-phosphorous NMR spectroscopy study.

31-Phosphorus magnetic resonance spectroscopy was used in a rat model of 10 min severe incomplete forebrain ischaemia (2-vessel occlusion with hypotension) to assess the effect of mild brain hypo- and hyperthermia (+/- 2 degrees C) on intracellular pH and high energy phosphates. In three experimental groups intracerebral temperature was maintained at levels of 34, 36 and 38 degrees C during ischaemia and early reperfusion. The steady level of intracellular pH during ischaemia was 6.63, 6.58 and 6.53 in the 34, 36, and 38 degrees C groups, respectively. The rate of initial recovery of intracellular pH in reperfusion was 0.046 +/- 0.012 pH units per min (+/- s.d.) in the 36 degrees C group compared to 0.056 +/- 0.010 (+/- s.d., P less than 0.05) in the 34 degrees C group and 0.032 +/- 0.009 (+/- s.d., P less than 0.01) in the 38 degrees C group. The recovery in early reperfusion of phosphocreatine and ATP was slower in the 38 degrees C group compared to the other groups. The findings were consistent with recent studies, suggesting that even mild hypothermia may afford protection to the ischaemic brain, and furthermore indicate that mild hyperthermia as fever or even subfebricity may be deleterious for the outcome in stroke patients.

Hyperglycemia in global cerebral ischemia and reperfusion: a 31-phosphorous NMR spectroscopy study in rats.

31-phosphorous magnetic resonance spectroscopy was used in a rat model of 10 min severe incomplete forebrain ischemia (two-vessel occlusion with hypotension) to assess the effect of hyperglycemia on intracellular pH and high energy phosphates during ischemia and early reperfusion. One group (n = 8) with preischemic hyperglycemia (serum glucose 20 mmol.l-1) showed an increased intracellular acidosis (pH 6.35) during ischemia compared to 6.55 in the normoglycemic control group (n = 7, P less than 0.001), but the recovery of phosphocreatine and ATP in early reperfusion was the same in the two groups. Another group (n = 7) was normoglycemic during ischemia, but received an i.v. bolus of glucose during the first minute of reperfusion. In this group the recovery of intracellular pH in early reperfusion was slower than in the control group (0.034 +/- 0.006 pH units per minute compared to 0.052 +/- 0.11 in the controls, +/- s.d. and P less than 0.01).

Quicker metabolic recovery after forebrain ischemia in rats treated with the antioxidant U74006F.

We used phosphorus-31 nuclear magnetic resonance spectroscopy in a rat model of 10 minutes' severe incomplete forebrain ischemia (two-vessel occlusion with hypotension) to study the effects of preischemic and postischemic treatment with 3 mg/kg i.v. U74006F on the recovery of high-energy phosphates and intracellular pH during early reperfusion. The mean +/- SD time to 85% recovery of phosphocreatine was 14.1 +/- 8.4 minutes in the control group (n = 10) compared with 6.6 +/- 3.5 minutes (p less than 0.05) in the preischemic (n = 8) and 4.2 +/- 1.0 minutes (p less than 0.001) in the postischemic (n = 11) treatment groups. The mean +/- SD time to 80% recovery of adenosine triphosphate was 15.4 +/- 8.5 minutes in the control group compared with 6.3 +/- 1.8 (p less than 0.005) and 5.4 +/- 2.8 (p less than 0.001) minutes in the preischemic and postischemic treatment groups, respectively. There were no differences in intracellular pH between the control and either of the treatment groups. We conclude that U74006F led to quicker recovery of high-energy phosphates during early reperfusion, and this beneficial effect was also seen with postischemic treatment.

31 phosphorous nuclear magnetic resonance spectroscopy of rat brain with temporary global cerebral ischemia--methodology.

31 P Magnetic Resonance Spectroscopy offers a technique for measuring intracellular pH and the high energy phosphates Phosphocreatine (PCr) and ATP in vivo. The 2-vessel occlusion model of temporary global cerebral ischaemia in the rat was adopted in this technique. This approach gave reliable results for intracellular pH and valuable information about PCr and ATP with an accurate time resolution for the changes during ischaemia and early reperfusion. The method may be a useful tool to evaluate possible benefits from different kinds of pre- and post ischaemic drug intervention.