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Objective Eloquent diffuse low-grade gliomas (LGGs) threaten patients' neurologic function and are also associated with inferior survival. Many neurosurgeons still refrain from early resection due to the fear of iatrogenic neurologic injury. However, the perceived safety of expectant management strategies may soon be overshadowed by the progressive deficits of tumor growth in eloquent regions. It is also known that radical and successful surgery prolongs progression-free survival, overall survival, and may reduce seizure burden and also potentially neurocognitive functions. Thus early successful surgery with preservation of function has a significant impact on patients' health. In modern neurosurgery, safe resection is often possible with detailed knowledge of anatomy and function together with the active use of various intraoperative surgical tools. We present illustrative cases of eloquent LGGs treated with different intraoperative tools. Methods An introduction to important intraoperative tools in LGG surgery is provided by experts in the field and described in five cases viewed in the context of the recent LGG literature. Results We present five cases with presumed eloquently located LGGs where extensive resection was offered using different intraoperative techniques. The clinical and radiologic outcomes are described. Conclusions Correct use of intraoperative tools together with the surgeon's knowledge of anatomy and function will provide good functional and oncologic results in eloquently located LGGs. Watchful waiting or deferral of surgery due to tumor location (i.e., claiming inoperability) is very rarely good practice.

In neurosurgery, information of blood flow is important to identify and avoid damage to important vessels. Three-dimensional intraoperative ultrasound color-Doppler imaging has proven useful in this respect. However, due to Doppler angle-dependencies and the complexity of the vascular architecture, clinical valuable 3-D information of flow direction and velocity is currently not available. In this work, we aim to correct for angle-dependencies in 3-D flow images based on a geometric model of the neurovascular tree generated on-the-fly from free-hand 2-D imaging and an accurate position sensor system. The 3-D vessel model acts as a priori information of vessel orientation used to angle-correct the Doppler measurements, as well as provide an estimate of the average flow direction. Based on the flow direction we were also able to do aliasing correction to approximately double the measurable velocity range. In vitro experiments revealed a high accuracy and robustness for estimating the mean direction of flow. Accurate angle-correction of axial velocities were possible given a sufficient beam-to-flow angle for at least parts of a vessel segment . In vitro experiments showed an absolute relative bias of 9.5% for a challenging low-flow scenario. The method also showed promising results in vivo, improving the depiction of flow in the distal branches of intracranial aneurysms and the feeding arteries of an arteriovenous malformation. Careful inspection by an experienced surgeon confirmed the correct flow direction for all in vivo examples.

OBjECTIVE: The objective of this study was to investigate the clinical applicability ; of navigated blood flow imaging (BFI) in neurovascular applications. BFI is a new 2-dimensional ultrasound modality that offers angle-independent visualization of flow. When integrated with 3-dimensional (3D) navigation technology, BFI can be considered as a first step toward the ideal tool for surgical needs: a real-time, high-resolution, 3D visualization that properly portrays both vessel geometry and flow direction. METHODS: A 3D model of the vascular tree was extracted from preoperative magnetic resonance angiographic data and used as a reference for intraoperative any-plane guided ultrasound acquisitions. A high-end ultrasound scanner was interconnected, and synehronized recordings of BFI and 3D navigation scenes were acquired. The potential of BFI as an intraoperative tool for flow visualization was evaluated in 3 cerebral aneurysms and 3 arteriovenous malformations. RESULTS: The neurovascular flow direction was properly visualized in all cases using BFI. Navigation technology allowed for identification of the vessels of interest, despite the presence of brain shift. The surgeon found BFI to be very intuitive compared with conventional color Doppler methods. BFI allowed for quality control of sufficient flow in all distal arteries during aneurysm surgery and made it easier to discern between feeding arteries and draining veins during surgery for arteriovenous malformations. CONCLUSION: BFI seems to be a promising modality for neurovascular flow visualization that may provide the neurosurgeon with a valuable tool for safer surgical interventions. However, further work is needed to establish the clinical usefulness of the proposed imaging setup.

Activation of monocytes with lymphokines from BCG-stimulated lymphocytes increased the capacity to inhibit DNA-synthesis in a tumour cell line (NHIK 3025) at all stages of monocyte maturation in vitro. However, the capacity of monocytes to suppress DNA-synthesis in mixed lymphocyte cultures (MIX) was reduced, indicating a dissociation of the immuno-suppressive and tumour cell cytostatic functions of lymphokine-activated monocytes. Supernatants of lymphokine-activated monocytes inhibited DNA synthesis in the tumour cell line, but not in MLC. Monocytes from donors with a strong tuberculin reaction produced supernatants with a stronger cytostatic activity than monocytes from donors with a weak tuberculin reaction. By in vitro maturation, even the latter monocytes acquired ability to produce supernatants that were strongly inhibitory to tumour cells.

High-grade gliomas are the most common primary brain tumour. Glioblastomas (World Health Organization Grade IV) and anaplastic astrocytomas (World Health Organization Grade III) account for 70-85% of high-grade gliomas. High-grade gliomas are associated with high morbidity and mortality. Virtually all patients with high-grade glioma will experience recurrence and will eventually die from progressing disease. Despite surgery, radiotherapy, and chemotherapy, median survival in patients with glioblastoma still does not exceed 12 months. The median survival for patients with anaplastic astrocytoma (AA) has been reported to be between 2 and 3 years. According to current guidelines, surgery is warranted to establish a histopathologic diagnosis and to achieve safe, maximal, and feasible resection. However, these aggressive tumours cannot be cured and overly aggressive resection is not recommended due to the risk of new neurological deficits. High-grade glioma surgery is a delicate balance between achieving maximal tumour resection and inducing new deficits.In our department a neuronavigation system based on preoperative 3D magnetic resonance imaging (MRI) and intraoperative 3D ultrasound is utilised when resecting high-grade gliomas. Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) and diffusion tensor tractography (DTT) are specialized MRI techniques for imaging eloquent cortices and neural tracts in grey and white matter, respectively. The neuronavigation system allows the integration of BOLD fMRI and DTT data if the tumours are located in eloquent regions.In the two first studies of this thesis we sought to investigate the use of BOLD fMRI and DTT for preoperative assessments and determine whether using these data together with 3D intraoperative ultrasound enabled safe resection of high-grade gliomas situated in eloquent regions. In the third study we wanted to explore the impact of surgical morbidity on functional outcome and survival in GBM patients. Further, we sought to determine extent of tumour resection achieved in a consecutive sample of primary GBM from our own department. In the fourth study we wanted to determine if changes in health related quality of life early after surgery could be a predictor for survival in patients with glioblastoma. The aims of the fifth study were to explore survival and the treatment provided to elderly patients (≥66 years) diagnosed with glioblastoma during a 20-year time period in a population-based cohort using the Norwegian Cancer Registry.This thesis investigated the role of surgical resection in the treatment of high-grade gliomas and the following conclusions can be drawn:- The combination of BOLD fMRI, DTT, and 3D intraoperative ultrasound may facilitate resection of high-grade gliomas harboured in eloquent areas while preserving motor and language function.- Functional neuronavigation combined with intraoperative 3D ultrasound can, in most patients, enable resection of brain lesions with general anaesthesia without jeopardizing neurological function.- Patients with perioperative complications and surgically acquired deficits were less likely to receive adjuvant therapy.- Early deterioration in HRQL after surgery was independently and markedly associated with impaired survival in patients with glioblastoma.- Advancing age remains a very strong and independent negative prognostic factor in glioblastoma. Although there has been an increase in the aggressiveness of treatment provided to elderly with glioblastoma, the gain for the oldest age group seems at best very modest. The prognosis of the oldest age group remains very poor, despite multimodal treatment.

Objective. The aims of this study were: 1) To develop protocols for, integration and assessment of the usefulness of high quality fMRI (functional magnetic resonance imaging) and DTI (diffusion tensor imaging) data in an ultrasound-based neuronavigation system. 2) To develop and demonstrate a co-registration method for automatic brain-shift correction of pre-operative MR data using intra-operative 3D ultrasound. Methods. Twelve patients undergoing brain surgery were scanned to obtain structural and fMRI data before the operation. In six of these patients, DTI data was also obtained. The preoperative data was imported into a commercial ultrasound-based navigation system and used for surgical planning and guidance. Intra-operative ultrasound volumes were acquired when needed during surgery and the multimodal data was used for guidance and resection control. The use of the available image information during planning and surgery was recorded. An automatic voxel-based registration method between preoperative MRA and intra-operative 3D ultrasound angiography (Power Doppler) was developed and tested postoperatively. Results. The study showed that it is possible to implement robust, high-quality protocols for fMRI and DTI and that the acquired data could be seamlessly integrated in an ultrasound-based neuronavigation system. Navigation based on fMRI data was found to be important for pre-operative planning in all twelve procedures. In five out of eleven cases the data was also found useful during the resection. DTI data was found to be useful for planning in all five cases where these data were imported into the navigation system. In two out of four cases DTI data was also considered important during the resection (in one case DTI data were acquired but not imported and in another case fMRI and DTI data could only be used for planning). Information regarding the location of important functional areas (fMRI) was more beneficial during the planning phase while DTI data was more helpful during the resection. Furthermore, the surgeon found it more user-friendly and efficient to interpret fMRI and DTI information when shown in a navigation system as compared to the traditional display on a light board or monitor. Updating MRI data for brain-shift using automatic co-registration of preoperative MRI with intra-operative ultrasound was feasible. Conclusion. In the present study we have demonstrated how both fMRI and DTI data can be acquired and integrated into a neuronavigation system for improved surgical planning and guidance. The surgeons reported that the integration of fMRI and DTI data in the navigation system represented valuable additional information presented in a user-friendly way and functional neuronavigation is now in routine use at our hospital. Furthermore, the present study showed that automatic ultrasound-based updates of important pre-operative MRI data are feasible and hence can be used to compensate for brain shift.

3-D imaging of blood flow based on 2-D ultrasound scanning and position sensor information can be used to portray clinical information not currently available in vascular and peripheral imaging. During surgery, information of blood flow is important to identify and avoid damage to important vessels. 3-D intraoperative ultrasound flow imaging has proven useful in this respect. However, due to Doppler angle-dependencies and the complexity of the vascular architecture, the generated 3-D image of blood vessels often have drop-outs in the vessel structure. In this work we aim to reduce the number of drop-outs in the 3-D blood flow images by combining 2-D flow images with different transmit angles. The compounded 2-D images are further reconstructed to a 3-D flow image based on information from an accurate position sensor system. The method was implemented on a research ultrasound scanner for real-time processing of the data, and in vitro trials showed promising results. The method also showed promising results in vivo using a clinical approved high-end scanner, improving the 3-D image quality of the feeding arteries of an arteriovenous malformation.

Objective: We have investigated the feasibility of using 3D ultrasound-based neuronavigation for guiding neuroendoscopy. Methods: A neuronavigation system with an integrated ultrasound scanner was used for acquiring the 3D ultrasound image data. The endoscope with a tracking frame attached was calibrated to the navigation system. The endoscope was guided based on intraoperative 3D ultrasound data in 9 operations. In 5 of the operations, ultrasound angiography data were also obtained. Updated image data (e.g., more than one 3D ultrasound dataset) were obtained in 6 of the operations. Results: We found that the image quality of 3D ultrasound was sufficient for image guidance of the endoscope. Planning of the entry point and trajectory as well as finding optimal sites for fenestration were successfully performed. Blood vessels were visualized by 3D ultrasound angiography. In one procedure of third ventriculostomy, the basilar artery was visualized. Updated image data were quickly obtained, and in two of the cases, a reduction of the size of cysts was demonstrated. Conclusions: 3D ultrasound gives accurate images of sufficiently high quality for image guidance of neuroendoscopy. Updated 3D ultrasound datasets can easily be acquired and may adjust for brain shift. Ultrasound angiography image data are also available with this technology and can visualize vessels of importance.

The purpose of the study was to investigate a method for strain calculation and its ability to discriminate between brain tumour and normal brain. During surgery of a low-grade astrocytoma and a metastasis, we acquired ultrasound (US) radiofrequency (RF) data with a hand-held probe at the dura mater. Using cross-correlation and phase-sensitive processing, we quantified the tissue displacements between consecutive US images and, subsequently, the local strain. In the elastograms, the tumour lesions were associated with lower strain levels than those found in the surrounding normal tissue. For both investigated cases, the strain images showed good agreement with the B-mode images. However, the results also indicated that the tumour interpretation might be different in the two modalities. An important finding was that the tissue motion caused by arterial pulsation is sufficient for generating elastograms. Requiring no specialised equipment or changes to acquisition procedures, strain data can be obtained as easily as conventional US imaging.

Objective This paper demonstrates a method that brings together three essential technologies for surgery planning and guidance: neuronavigation systems, 3D visualization techniques and intraoperative 3D imaging technologies. We demonstrate the practical use of an in-house interactive stereoscopic visualization module that is integrated with a 3D ultrasound based neuronavigation system. Materials and methods A stereoscopy volume visualization module has been integrated with a 3D ultrasound based neuronavigation system, which also can read preoperative MR and CT data. The various stereoscopic display modalities, such as "cut plane visualization" and "interactive stereoscopic tool guidance" are controlled by a pointer, a surgical tool or an ultrasound probe. Interactive stereoscopy was tested in clinical feasibility case studies for planning and guidance of surgery procedures. Results By orientating the stereoscopic projections in accordance to the position of the patient on the operating table, it is easier to interpret complex 3D anatomy and to directly take advantage of this 3D information for planning and surgical guidance. In the clinical case studies, we experienced that the probe-controlled cut plane visualization was promising during tumor resection. By combining 2D and 3D display, interpretation of both detailed and geometric information may be achieved simultaneously. The possibilities of interactively guiding tools in a stereoscopic scene seemed to be a promising functionality for use during vascular surgery, due to specific location of certain vessels. Conclusion Interactive stereoscopic visualization improves perception and enhances the ability to understand complex 3D anatomy. The practical benefit of 3D display is increased considerably when integrated with surgical navigation systems, since the orientation of the stereoscopic projection corresponds to the orientation of the patient on the operating table. Stereoscopic visualizations work well on MR and CT images, although volume rendering techniques are especially suitable for intraoperative 3D ultrasound image data.

We have investigated alternative ways to integrate intraoperative 3D ultrasound images and preoperative MR images in the same 3D scene for visualizing brain shift and improving overview and interpretation in ultrasound-based neuronavigation.A Multi-Modal Volume Visualizer (MMVV) was developed that can read data exported from the SonoWand neuronavigation system and reconstruct the spatial relationship between the volumes available at any given time during an operation, thus enabling the exploration of new ways to fuse pre- and intraoperative data for planning, guidance and therapy control. In addition, the mismatch between MRI volumes registered to the patient and intraoperative ultrasound acquired from the dura was qualified.The results show that image fusion of intraoperative ultrasound images in combination with preoperative MRI will make perception of available information easier by providing updated (real-time) image information and an extended overview of the operating field during surgery. This approach will assess the degree of anatomical changes during surgery and give the surgeon an understanding of how identical structures are imaged using the different imaging modalities. The present study showed that in 50% of the cases there were indications of brain shift even before the surgical procedure had started.We believe that image fusion between intraoperative 3D ultrasound and preoperative MRI might improve the quality of the surgical procedure and hence also improve the patient outcome.

Purpose: Freehand placement of external ventricular drainage is not sufficiently accurate and precise. In the absence of high quality pre-operative 3D images, we propose the use of an average model for guidance of ventricular catheters. Methods: The model was segmented to extract the ventricles and registered to five normal volunteers. The proposed method was validated by comparing the trajectory resulting from the use of the average model to the use of volunteer-specific images. Results: The distances between the target points in the model and the volunteer-specific images at the left and right foramen of Monroe were computed (Mean\(\pm \)std: 5.74\(\pm \)1.39 mm and 6.00\(\pm \)1.17 mm for the left and right side respectively). We also compared the angles between the trajectories resulting from the use of volunteer specific data and the average model and the engagement of the trajectories with the frontal horn of the ipsilateral ventricle. Conclusions: Although an average model for guidance of a surgical procedure has a number of limitations, our initial experiments show that the use of a model might provide sufficient guidance for determination of the angle of insertion. Future work will include further clinical testing and possible refinement of the model.

The aim of this study was to examine meningeal tissue under normal, reactive, and neoplastic conditions for expression of epidermal growth factor receptor (EGFR) using an improved histochemical method, namely biotinylated epidermal growth factor. EGFR was found in all the examined meningiomas (12 benign and three anaplastic) and in neonatal rat meninges, whereas normal and injured adult human and rat meninges did not exhibit detectable EGFR. These observations indicate that EGFR is involved in the development of meningeal tissue. Further, EGFR is abnormally expressed in meningeal tumours, indicating a role of EGFR in the neoplastic process of these tumours. The regular expression of EGFR in human meningiomas suggests EGFR as a tumour marker for this tumour type.

Biopsy specimens of human brain metastases were examined for amplification and expression of the proto-oncogene c-erbB1 (located on chromosome 7) encoding the epidermal growth factor receptor (EGFR). Moreover, the tumour DNA was also examined for amplification of other cancer-related genes on this chromosome: the proto-oncogene c-met, the gene for platelet-derived growth factor A-chain, and the gene for plasminogen activator inhibitory type 1. All 18 brain metastases demonstrated positive binding of biotinylated EGF on cryosections. Three out of 18 metastases had amplification of the EGFR gene; the other chromosome-7 genes tested were not amplified. Thus, an increased EGFR gene expression seems to be a general finding in a wide range of carcinomas metastatic to the brain, whereas we found only occasional selective EGFR gene amplifications in single cases.

INTRODUCTION: The use of integrated pre- and intraoperative imaging may be useful when resecting brain lesions in close proximity to eloquent areas, such as the primary motor cortex and language cortices. CASE REPORT: A 32-year-old woman with an arteriovenous malformation (AVM) located in the primary motor cortex underwent surgery using functional neuronavigation. Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) and diffusion tensor tractography (DTT) were used for preoperative mapping of primary motor areas and the corticospinal tracts, respectively. The BOLD fMRI activations and DTT tractograms were integrated into the neuronavigation system and visualized intraoperatively throughout the operation. Furthermore, stereoscopic visualizations of the angioarchitecture based on 3D MRI angiograms were used to rehearse the surgical approach to the feeder vessels. Finally, intraoperative ultrasound was used to locate and clip the feeding vessels. CONCLUSION: The AVM was carefully resected with the aid of the above-mentioned imaging techniques, and the intuitive usefulness of the techniques was further substantiated by the rewarding postoperative outcome.

The objective of the study was to investigate tissue motion and strain imposed by cardiovascular pulsation in pathologic and normal brain parenchyma, as quantified from in vivo ultrasound data. Ultrasound acquired during surgery of 16 patients with glial tumors was retrospectively processed and analyzed. The tissue velocity was quantified at depths of 1cm, 2cm and 3cm from brain cortex to investigate spatial dependency with depth. Comparison of strain and velocity in tumor and adjacent normal parenchyma was performed by selecting two regions-of-interest in the hyperechoic tumor and two regions in the low-echogenic areas interpreted as mainly normal tissue with some degree of tumor cell infiltration. The absolute maximum tissue velocity is seen to increase with increasing depths in 14 of 16 cases (87.5%). The maximum tissue velocities in the four regions close to the ultrasound visible tumor border are not statistically different (p=0.163 to p=0.975). The strain magnitudes are significantly higher in the regions with expected normal brain parenchyma than in regions with expected glial tumor tissue, both for the two regions being closest to the tumor border (p=0.0004) and for the two regions further away from the tumor border (p=0.0009). We conclude that the velocity of the brain parenchyma imposed by arterial pulsation during a cardiac cycle is generally increasing with increasing depth from cortex. The maximum velocity appears to be similar in regions with expected normal brain and tumor tissue, thus, does not seem to be affected by pathology. Strain magnitude is, however, a suitable parameter for discrimination of glial tumor and normal brain parenchyma. (E-mail: Tormod.Selbekk@sintef.no).

The purpose of the study was to compare the ability of navigated 3D ultrasound to distinguish tumour and normal brain tissue at the tumour border zone in subsequent phases of resection. Biopsies were sampled in the tumour border zone as seen in the US images before and during surgery. After resection, biopsies were sampled in the resection cavity wall. Histopathology was compared with the surgeon’s image findings. Before resection, the tumour border was delineated by ultrasound with high specificity and sensitivity (both 95%). During resection, ultrasound had acceptable sensitivity (87%), but poor specificity (42%), due to biopsies falsely classified as tumour by the surgeon. After resection, sensitivity was poor (26%), due to tumour or infiltrated tissue in several biopsies deemed normal by ultrasound, but the specificity was acceptable (88%). Our study shows that although glioblastomas are well delineated prior to resection, there seem to be overestimation of tumour tissue during resection. After resection tumour remnants and infiltrated brain tissue in the resection cavity wall may be undetected. We believe that the benefits of intraoperative ultrasound outweigh the shortcomings, but users of intraoperative ultrasound should keep the limitations shown in our study in mind.

Background Navigation systems are now frequently being used for guiding surgical procedures. Existing neuronavigation systems suffer from the lack of updated images when tissue changes during surgery as well as from userfriendly displays of all essential images for accurate and safe surgery guidance. Methods We have developed various new technologies for improved neuronavigation. Using intraoperative 3D ultrasound (US) imaging, we have developed various registration algorithms for using and updating a complete multimodal and multivolume 3D map for navigation. Results We experienced that advanced multimodal visualization makes it easy to interpret information from several image volumes and modalities simultaneously. Using high quality intraoperative 3D ultrasound, essential preoperative information could be corrected due to brain shift. fMRI and other important preoperative data could then be used together with intraoperative ultrasound imaging for more accurate, safer and improved guidance of therapy. Conclusions We claim that new features, as demonstrated in the present paper, using intraoperative 3D ultrasound in combination with advanced registration and display algorithms will represent important contributions towards more accurate, safer and more optimized future patient treatment. Copyright © 2006 John Wiley & Sons, Ltd.

In this paper, we have tested and validated a vessel-based registration technique for correction of brain-shift using retrospective clinical data from five patients: three patients with brain tumors, one patient with an aneurysm and one patient with an arteriovenous malformation. The algorithm uses vessel centerlines extracted from segmented pre-operative MRA data and intra-operative power Doppler ultrasound images to compute first a linear fit and then a thin-plate spline transform in order to achieve non-linear registration. The method was validated using (i) homologous landmarks identified in the original data, (ii) selected vessels, excluded from the fitting procedure and (iii) manually segmented, non-vascular structures. The tracking of homologous landmarks show that we are able to correct the deformation to within 1.25 mm, and the validation using excluded vessels and anatomical structures show an accuracy of 1mm. Pre-processing of the data can be completed in 30 s per dataset, and registrations can be performed in less than 30s. This makes the technique well suited for intra-operative use.

The authors describe the technical application of three-dimensional (3D) ultrasonography navigation in spinal cord tumor surgery. The spinal cord is a complex neurological structure in which there is the potential for causing neurological morbidity during tumor resection. Standard neuronavigation systems based on computed tomography or C-arm images are not adapted to tumor surgery in the spinal cord. Since 2004 the authors have been using a 3D ultrasonography-based neuronavigation system. During surgery, two-dimensional ultrasound images were acquired and reconstructed into 3D image data to assist in tumor resection. The navigation cameras read the position of a patient reference frame attached to a spinous process, the ultrasonography probe, and surgical instruments. Five- and 10-MHz phased-array ultrasonography probes equipped with optical tracking frames were used for image data acquisition. Spinal cord tumors were visualized using ultrasonography, and 3D ultrasonography-guided tumor biopsy sampling and resection were performed. The practice of attaching the reference frame to a spinous process adjacent to the spinal cord tumor, as well as performing image acquisition just before starting the resection, reduced the possible sources of inaccuracy. The technical application of a navigation system based on intraoperative 3D ultrasound image reconstruction seems feasible and may have the potential of improving functional outcome in association with spinal cord tumor surgery.

Background: Avoiding damage to blood vessels is often the concern of the neurosurgeon during tumor surgery. Using angiographic image data in neuronavigation may be useful in cases where vascular anatomy is of special interest. Since 2003, we have routinely used 3D ultrasound angiography in tumor surgery, and between January 2003 and May 2005, 62 patients with different tumors have been operated using intraoperative 3D ultrasound angiography in neuronavigation. Methods: An ultrasound-based neuronavigation system was used. In addition to 3D ultrasound tissue image data, 3D ultrasound angiography (power Doppler) image data were acquired at different stages of the operation. The value and role of navigated 3D ultrasound angiography as judged by the surgeon were recorded. Results: We found that intraoperative ultrasound angiography was easy to acquire and interpret, and that image quality was sufficient for neuronavigation. In 26 of 62 cases, ultrasound angiography was found to be helpful by visualizing hidden vessels adjacent to and inside the tumor, facilitating tailored approaches and safe biopsy sampling. Conclusions: Intraoperative 3D ultrasound angiography is straightforward to use, image quality is sufficient for image guidance, and it adds valuable information about hidden vessels, increasing safety and facilitating tailored approaches. Furthermore, with updated 3D ultrasound angiography imaging, accuracy of neuronavigation may be maintained in cases of brain shift.

In recent years there has been a considerable improvement in the quality of ultrasound (US) imaging. The integration of 3D US with neuronavigation technology has created an efficient and inexpensive tool for intra-operative imaging in neurosurgery. In this review we present the technological background and an overview of the wide range of different applications. The technology has so far mostly been applied to improve surgery of tumours in brain tissue, but it has also been found to be useful in other procedures such as operations for cavernous haemangiomas, skull base tumours, syringomyelia, medulla tumours, aneurysms, AVMs and endoscopy guidance.

OBJECTIVE: To study the application of navigated stereoscopic display of preoperative three-dimensional (3-D) magnetic resonance angiography and intraoperative 3-D ultrasound angiography in a clinical setting. METHODS: Preoperative magnetic resonance angiography and intraoperative ultrasound angiography are presented as stereoscopic images on the monitor during the operation by a simple red/blue technique. Two projections are generated, one for each eye, according to a simple ray casting method. Because of integration with a navigation system, it is possible to identify vessels with a pointer. The system has been applied during operations on nine patients with arteriovenous malformations (AVMs). Seven of the patients had AVMs in an eloquent area. RESULTS: The technology makes it easier to understand the vascular architecture during the operation, and it offers a possibility to identify and clip AVM feeders both on the surface and deep in the tissue at the beginning of the operation. All 28 feeders identified on the preoperative angiograms were identified by intraoperative navigated stereoscopy. Twenty-five were clipped at the beginning of the operation. The other three were clipped at a later phase of the operation. 3-D ultrasound angiography was useful to map the size of the nidus, to detect the degree of brain shift, and to identify residual AVM. CONCLUSION: Stereoscopic visualization enhances the surgeon's perception of the vascular architecture, and integrated with navigation technology, this offers a reliable system for identification and clipping of AVM feeders in the initial phase of the operation.

Background. The objective of the study was to test the ability of a 3D ultrasound (US) based intraoperative imaging and navigation system to delineate gliomas and metastases in a clinical setting. The 3D US data is displayed as reformatted 2D image slices. The quality of the displayed 3D data is affected both by the resolution of the acquired data and the reformatting process. In order to investigate whether or not 3D US could be used for reliable guidance in tumour surgery, a study was initiated to compare interpretations of imaged biopsy sites with histopathology. The system also enabled concomitant comparison of navigated preoperative MR with histopathology. Method. Eighty-five biopsies were sampled between 2–7 mm from the tumour border visible in the ultrasound images. Biopsies were collected from 28 operations (7 low-grade astrocytomas, 8 anaplastic astrocytomas, 7 glioblastomas and 6 metastases). Corresponding cross-sections of preoperative MR T1, MR T2 and intraoperative US were concomitantly displayed, steered by the biopsy forceps equipped with a positioning sensor. The surgeons’ interpretation of the images at the electronically indicated biopsy sites were compared with the histopathology of the samples. Findings. The ultrasound findings were in agreement with histopathology in 74% (n = 31) for low-grade astrocytomas, 83% (n = 18) for anaplastic astrocytomas, 77% (n = 26) for glioblastomas and 100% (n = 10) for metastases. Excluding irradiated patients, the results for glioblastomas improved to 80% concurrence (n = 20). As expected tumour cells were found in biopsies outside the US visible tumour border, especially in low-grade gliomas. Navigated 3D US have a significantly better agreement with histopathology than navigated MR T1 for low-grade astrocytomas. Conclusion. Reformatted images from 3D US volumes give a good delineation of metastases and the solid part of gliomas before starting the resection. Navigated 3D US is at least as reliable as navigated 3D MR to delineate gliomas and metastases.

OBJECTIVE: Three-dimensional (3-D) ultrasound is an intraoperative imaging modality used in neuronavigation as an alternative to magnetic resonance imaging (MRI). This article summarizes 4 years of clinical experience in the use of intraoperative 3-D ultrasound integrated into neuronavigation for guidance in brain tumor resection. METHODS: Patients were selected for inclusion in the study on the basis of the size and location of their lesion. Preoperative 3-D MRI data were registered and used for planning as in other conventional neuronavigation systems. Intraoperative 3-D ultrasound images were acquired three to six times, and tumor resection was guided on the basis of these updated 3-D images. RESULTS: Intraoperative 3-D ultrasound represents a good solution to the problem of brain shift in neuronavigation because it easily provides an updated, and hence more accurate, map of the patient's true anatomy in all phases of the operation. Ultrasound makes it possible to follow the progression of the operation, and it improves the radicality of tumor resection by detecting tumor tissue that would remain if the imaging technology had not been used (in 53% of the cases). Integration of 3-D ultrasound with navigation technology solves the orientation problem experienced previously with two-dimensional ultrasound in neurosurgery. The technology makes it possible to directly compare intraoperative ultrasound and MRI data regarding visualization of the lesion. Ultrasound image quality is useful for guiding surgical procedures. CONCLUSION: Intraoperative 3-D ultrasound seems to provide a time- and cost-effective way to update high-quality 3-D maps used in neuronavigation.

In 1995, a project was initiated in Trondheim, Norway, to investigate various possibilities for more frequent use of ultrasound in brain surgery. Since that time, the quality of ultrasonic images has improved considerably through technological adjustment of parameters. The objective of the present study was to explore essential clinical parameters required for the successful use of ultrasonic guidance in brain surgery.During the study period, several surgical setups designed to optimize the use of intraoperative real-time two-dimensional ultrasonic imaging were explored. These included various positions of the ultrasound probe in relation to both the operation cavity and the lesion, as well as the position of the operation channel in relation to the gravity line.All lesions from the latest period (1997-2001; n = 114) were depicted well by ultrasound imaging, with the exception of two cases. High image quality and direct image guidance of the tool were maintained best throughout the operation by imaging through an intact dura and at an angle relative to a vertical operation channel. All tumor operations were performed without complications, and ultrasound imaging was found to be an important factor in the detection of remaining tumor tissue at the conclusion of surgery. For 14 low vascular tumors, the operation was guided only by ultrasound imaging. No bleeding complications occurred. A method of minimally invasive ultrasound-guided evacuation of hematomas was developed. In 19 patients, the method was found to be efficient (i.e.,90% of the hematoma was evacuated) and without complications, except for one patient who experienced rebleeding.With proper planning and surgical setup, ultrasound imaging may provide acceptable image quality for use in image-guided brain operations.

Recently we have shown that human meningiomas overexpress epidermal growth factor receptor (EGFR) (Torp SH et al APMIS 100: 797-802, 1992). We therefore wanted to examine these tumours for the expression of the EGFR ligands epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha). Normal human meningeal tissues were used as controls. Immunohistochemistry (IH) and radioimmunoassay (RIA) demonstrated the presence of EGF and/or TGF-alpha. immunoreactivity in sixteen of nineteen meningiomas. By means of RIA detectable amount of TGF-alpha was also recorded in normal leptomeninges. Discrepancies between IH and RIA were noted and are discussed. Our findings suggest that EGFR/EGF/TGF-alpha play a role in growth regulatory mechanisms in human meningiomas.

Normal and neoplastic human intracranial tissues were examined by immunohistochemistry for c- erb B-2/HER-2 protein expression. Positive staining was observed in 141 gliomas, 12 medulloblastomas, 11 germinoma, 1116 meningiomas, 13 anaplastic meningiomas and 1119 metastatic brain carcinomas. No positive staining was observed in normal intracranial tissues. Thus, the expression of the c- erb B-2/HER-2 protein is limited to intracranial tumour tissues, principally meningiomas and metastatic carcinomas to the brain.

The aim of this study was to determine possible relationships between Ki-67 labelling index (Ki-67 LI), amplification of the epidermal growth factor receptor (EGFR) gene, and prognosis in human glioblastomas. Ki-67 LI was determined on cryosections of biopsy specimens of 20 human glioblastomas with a mouse anti-human Ki-67 monoclonal antibody. Amplification of the EGFR gene was determined by slot blot and Southern blot analyses of DNA extracted from the tumour biopsies. The Ki-67 LI was higher in the glioblastoma group with EGFR gene amplification (8 tumours, median value of Ki-67 LI 4.2, range 0.4-24.6) than in those without EGFR gene amplification (12 tumours, median value of Ki-67 LI 0.8, range 0.2-11.8) (0.05 p less than 0.1). The glioblastoma patients with Ki-67 LI greater than 1.5 (10 tumours) had a statistically significant shorter survival than those with Ki-67 LI less than 1.5 (10 tumours) (p less than 0.05). The glioblastoma patients with EGFR gene amplification lived shorter time than those without EGFR gene amplification (p greater than 0.05).

The expression of epidermal growth factor receptor (EGFR) was determined in cryosections of 42 human gliomas using biotinylated epidermal growth factor (B-EGF) and two monoclonal antibodies (mAb) against EGFR. All gliomas were found to express EGFR when examined with B-EGF, whereas 33 expressed EGFR when examined with the two mAbs. The highly malignant gliomas (glioblastomas and anaplastic astrocytomas) had a more heterogeneous staining pattern and a larger proportion of tumour cells staining strongly with B-EGF than did the low-grade gliomas (astrocytomas, oligodendrogliomas, mixed gliomas, and ependymomas). This indicates that high-grade gliomas contain more tumour cells rich in EGFR than do the low-grade gliomas. Reactive astrocytes, ependymal cells, and many types of nerve cells (cerebral cortical pyramidal cells, pyramidal and granular hippocampal cells, Purkinje cells, cerebellar granular cells and neurons in the molecular layer of the cerebellum) expressed EGFR, whereas small neurons and normal glial cells were not found to express EGFR.

Overexpression of the EGF-receptor gene is associated with the malignant nature of some tumors. We have recently reported the establishment of a human carcinoma cell line (T-CAR1), derived from a brain metastasis, that had 7 million EGF receptors per cell and was growth inhibited by EGF. The present study was carried out in order to furhter characterize the EGF-receptor protein in T-CAR1 cells, and to see if the overexpression of the EGF-receptor gene in these cells was associated with abnormalities at the genomic level. We have compared the T-CAR1 cells with the human glioblastoma cell line T-MG1, which has 135,000 EGF-receptors and is growth stimulated by EGF. The MW of the EGF receptors in T-CAR1 cells and T-MG1 cells was estimated to be 170 kDa, equal to the normal EGF-receptor. However, in T-CAR1 cells an additional protein reacted with the monoclonal antibody directed against the internal domain of the EGF receptor. The levels of EGF receptor-related RNAs in T-CAR1 cells and T-MG1 cells reflected the number of EGF receptors in these cell lines. The EGF-receptor gene was amplified ten-fold in T-CAR1 cells, while it was not amplified in T-MG1 cells. No restriction fragment length polymorphism of DNA digested with various restriction enzymes was seen in either of the cell lines. Chromosomal analysis of T-CAR1 cells showed polysomy of chromosome 7 and marker chromosomes derived partly from chromosome 7. Thus, in the T-CAR1 cell line it was an association between polysomy of chromosome 7 and EGF-receptor gene amplification.

We describe two cases of Dandy-Walker syndrome with onset in adult life. One of our cases is the oldest reported patient that has been operated on for Dandy-Walker syndrome (69 years). A review of the literature on Dandy-Walker with adult manifestation (Table) disclosed 13 additional cases of adult Dandy-Walker, and three cases that in our opinion could have been midline arachnoid cysts.

Type beta transforming growth factor (B-TGF) is a potent growth inhibitor to many human tumor cell lines. Very little is known about the mechanism for this growth inhibitory action of B-TGF. We here report the effect of B-TGF on proliferation and epidermal growth factor receptor (R-EGF) expression in a human glioblastoma cell line named T-MG1. B-TGF inhibit the soft agar growth of T-MG1 cells. Maximum inhibition was 70%, achieved with 0.5 units B-TGF. B-TGF had no effect on monolayer growth of T-MG1 cells. T-MG1 cells contained abundant R-EGF, which could be divided into two subpopulations, one high affinity and one low affinity population of R-EGF. Treatment with B-TGF caused an initial decrease (0-6 h) in EGF-binding, followed by an increase in EGF-binding which reached maximum after 24 h exposure to B-TGF. Since addition of EGF to agar cultures gave no additional increase in inhibition by B-TGF and EGF alone had no inhibitory effect, we believe that binding of EGF to its receptor is not part of the pathway mediating the inhibitory effect of B-TGF. All neoplastic cells have lost some measure of growth control and the cellular elements involved are growth factors, growth factor receptors and oncogenes. T-MG1 cells contain abundant R-EGF and this may partly explain their malignant nature (malignant nature is here defined as ability to proliferate in agarose). Type alpha transforming growth factors, which in some cancer cells act as uncontrolled autocrine growth factors, were not found in protein extracts from T-MG1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study we tested the effect of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and a combination of these immunotherapeutics on clonogenic growth of cell lines and primary cultures of malignant human brain tumors. Out of 29 primary cultures studied, 5 were inhibited 50% or more by IFN-gamma (10 ng/ml), 6 were inhibited 50% or more by TNF-alpha (10 ng/ml) and 14 were inhibited 50% or more by a combination of IFN-gamma (10 ng/ml) and TNF-alpha (10 ng/ml). The doses of the immunotherapeutics used in this in vitro study are achievable in serum after intravenous administration of IFN-gamma and TNF-alpha without causing unacceptable side effects. We believe that some glioma patients and some patients with brain metastases will benefit from receiving treatment with IFN-gamma, TNF-alpha or a combination of these immunotherapeutics. The patients should be selected for treatment with these immunotherapeutics according to in vitro sensitivity results.

Transforming growth factor-beta 1 has been shown to suppress the urokinase activity in the glioblastoma cell line T-MG1 and the carcinoma cell line T-CAR1. The molecular mechanisms behind the decrease in the proteolyic activity is shown to be at least partly due to increased synthesis of plasminogen activator inhibitor type-1 and not by decreased synthesis of urokinase.

A 17-year-old boy is reported with chronic subdural hematoma and a unilateral grade III arachnoid cyst in the middle cranial fossa. After operation he recovered completely. Attention is drawn to the liability of these arachnoidal cysts to hemorrhagic complications. Subdural hematoma, subarachnoidal hemorrhage and intracystic bleeding have all been reported. These may follow otherwise insignificant trauma to the head, and may have major legal implications in cases of assaults.

There was no difference in monocyte-mediated cytotoxicity between monocytes from patients with multiple myeloma or malignant lymphomas and monocytes from control persons after in vitro culture for 5 d. Cytostatic and cytolytic ability of lymphokine-activated monocytes cultured in medium with patient serum was significantly depressed compared to the ability of monocytes cultured with normal serum. A similar depression of cytostasis was found with non-activated monocytes of both patient and control origin. Sera from myeloma and lymphoma patients impaired the monocyte-mediated cytotoxicity equally.

Type beta transforming growth factor (beta-TGF) is a potent regulator of cell growth and differentiation. The human glioblastoma cell line, T-MGI, was growth inhibited by beta-TGF under anchorage independent conditions. The antiproliferative effect of beta-TGF was potentiated to nearly total arrest by low doses of retinoic acid (RA) or tumor necrosis factor (TNF), while epidermal growth factor, platelet-derived growth factor, interleukin-2, and gamma interferon did not have this potentiating effect. The potentiation of the beta-TGF effect by RA and TNF could not be explained by modulation of the epidermal growth factor receptor, the beta-TGF receptor, or the TNF receptor. beta-TGF alone and in combination with RA or TNF were further tested on primary cultures from freshly resected human glioma biopsies (n = 13). There was great individual variation in sensitivity to beta-TGF, RA, or TNF. The astrocytoma and oligodendroglioma cells were inhibited to various degrees by beta-TGF or TNF, while most of the glioblastomas were not sensitive to these agents. Most of the biopsies were stimulated by RA. RA or TNF did not potentiate the growth inhibitory effect of beta-TGF on biopsy cells. We therefore think it unlikely that beta-TGF in combination with RA or TNF will be effective agents in the treatment of gliomas.

Amplification and overexpression of proto-oncogenes are associated with the malignant nature of some human tumours. In this study we have determined the prevalence of amplification of the proto-oncogenes c-erb B1 (= epidermal growth factor receptor gene), c-erb B2 and c-myc in 44 human intracranial tumours (27 gliomas, six metastases to the brain and 11 meningiomas). None of the tumours had an amplified c-erb B2 gene and only two tumours had an amplified c-myc gene. Nineteen per cent (five out of 27) of the gliomas, 50% (three out of six) of the brain metastases and 0% (0 out of 11) meningiomas had an amplified EGF-receptor gene. Amplification of the EGF-receptor gene appeared to give a growth advantage when single-cell suspensions of the tumours were grown in agarose.

The cytotoxic ability of freshly isolated monocytes against the tumor cell line K-562 was severely depressed in patients with renal cell carcinoma. The impaired cytotoxicity was partly restored 2 weeks after nephrectomy. Production of monocyte-activating lymphokine, measured as ability to activate tumor cytotoxicity in control monocytes, was depressed in lymphocytes from patients with tumor burden. The impaired lymphokine production seemed to be due to factors in patient serum. Patient monocytes showed an impaired ability to be activated by lymphokines. Products from patient lymphocytes were not able to activate the tumor cytotoxicity of patient monocytes.

Type beta transforming growth factor (B-TGF) is a potent regulator of cell growth and differentiation. Growth of many human tumour cell lines are inhibited by B-TGF.

The soft agar technique for culturing human clonogenic tumor cells has been usefully applied for predicting individual clinical responses to chemotherapy, for screening of new antineoplastic drugs, and in basic biological research. The counting of colonies formed by clonogenic cells is, however, a rather time consuming and inaccurate procedure. We here report a method to combine the easy and precise registration of DNA-synthesis by 3H-thymidine incorporation with the ability of soft agar to permit proliferation of clonogenic cells and inhibit proliferation of non-neoplastic cells. The glioma cell lines U 251 MG and T-MG 1, the benignant glia cells T-BG 1, T-BG 2, T-BG 3 and fibroblasts were cultured in Furcellaran gel. Twenty hours before harvesting 3H-thymidine was added. The Furcellaran gel was resolved by 50 mM LiI. The cells were trapped on glass fiber filters and incorporated radioactivity was measured. 3H-thymidine incorporation in malignant cells increased exponentially with time, while 3H-thymidine incorporation in the benignant glia cells and fibroblasts was inhibited. The correlation between number of colonies counted after 16 days and 3H-thymidine incorporation registered after different culture times was very good. The correlation was best when the cultures were harvested after 8 days (r = 0.95), indicating that it is possible to reduce the assay time. The five glioma biopsies tested grew well with a mean plating efficiency of 0.4% (range 0.02-1.8%). The most intense proliferation seemed to take place during the first week in culture. The good correlation between 3H-thymidine incorporation on day 7 and colony number on day 14 (r = 0.93), indicate that reduction of assay time is possible also for the glioma biopsies.

A method based on growth of cells from glioma biopsies in a triple layer agarose system has been used to test the sensitivity of the tumour cells to different chemotherapeutic and immunotherapeutic agents. A special agarose that could be melted at 65 degrees C, enabled registration of proliferation by an easy and precise thymidine incorporation technique. The well known concept that agarose permits proliferation of malignant cells and inhibits growth of benign cells was confirmed in this assay by using the malignant glioma cell lines T-MG 1 and U 251 MG, and the benign glia cells T-BG 2 and T-BG 3. All of the 15 glioma biopsies grew exponentially during the first 7 days. The correlation between thymidine incorporation on day 7 and colony number on day 14 was very good for the glioma cell line (r = 0.96) and also for the glioma biopsies (r = 0.89), indicating that the sensitivity evaluation can be done as early as 7 days after the operation. Lymphokines, made by BCG-stimulated lymphocytes, had a strong inhibitory effect on the growth of some glioma biopsies, while others were only slightly inhibited or even stimulated. There was also a huge variation in the sensitivity of the biopsies to BCNU, but the sensitivity pattern was completely different for BCNU and lymphokines. rIF-A had a moderate inhibitory effect on growth of the biopsies, while rTNF had a weak inhibitory effect. The response to rIF-G varied from stimulation of some biopsies to strong inhibition of others. There was no similarity in the sensitivity pattern of the biopsies to rIF-A and rIF-G.(ABSTRACT TRUNCATED AT 250 WORDS)

In the human glioblastoma cell line, T-MG1, plasminogen activator activity (PA activity) was demonstrated by using the chromogenic substrate S-2251. Using monoclonal antibodies against human urokinase type PA (u-PA) and human tissue type PA (t-PA), only u-PA activity was found in T MG1, cell extracts. The u-PA activity in T-MG1, cells was suppressed in a dose-dependent manner by B TGF and EGF after 24 hours of exposure to these growth factors. Twenty units of B TGF caused a decrease in PA-activity of 80%, while 10 ng/ml EGF gave a decrease in PA-activity of 60%. The suppressive effects of B TGF and EGF were observed after 2 hours and 4 hours of incubation, respectively and sustained for at least 24 hours. The effects of B-TGF and EGF were not antienzymatic, but rather mediated through regulatory mechanisms. In view of the capacity of invasive growth of gliomas and the potential role of PA in invasive growth, the suppression of PA-activity in gliomas by B-TGF and EGF may be of importance.

Mononuclear blood cells were isolated from patients with different types of leukaemia and studied in vitro with regard to cell functions – adhesiveness, phagocytosis, DNA synthesis and inhibitory effects of adherent cells on non-adherent leukaemic cells and PHA stimulated lymphocytes. Cells from patients with chronic myeloid leukaemia (CML) adhered to the plastic surface of the culture dishes and showed esterase staining reactions as monocytes/macrophages. They showed a normal capacity to ingest Candida albicans, while the digestion capacity appeared reduced. Non-adherent cells from CML showed a high ability to incorporate thymidine, indicating DNA synthesis. Adhesive cells from patients with CML inhibited DNA synthesis in non-adherent CML cells and in PHA-stimulated lymphocytes to about the same extent as adhesive cells from normal donors. Blood cells from acute myeloid leukaemia and chronic lymphocytic leukaemia showed no adhesiveness and a very low spontaneous thymidine incorporation.