Immunohistochemical expression of receptor tyrosine kinase PDGFR-α, c-Met, and EGFR in skull base chordoma.

Chordomas are rare, locally aggressive malignancies that often exhibit an insidious natural history and are difficult to eradicate. Surgery and radiotherapy are the treatment mainstays of chordoma, but the chance of local recurrence remains high. Reports of receptor tyrosine kinase (RTK) expression in chordoma suggest that these tumors may respond to kinase inhibitor therapy. Currently, there are no effective chemotherapeutic protocols for chordoma. A tissue microarray containing 74 tumor specimens from primary chordoma patients and 71 from their recurrent tumors for a total of 145 tumor specimens was immunohistochemically analyzed for expression of a number of proteins involved in signal transduction from RTKs. Platelet-derived growth factor receptor-α (PDGFR-α), epidermal growth factor receptor (EGFR), c-Met, and CD-34 were detected in 100, 92, 100, and 59% of cases, respectively. PDGFR-α and c-Met staining was of moderate to strong intensity in all cases. In contrast, total EGFR staining was variable; weak staining was detected in 10 cases. Our results contribute to the understanding of the expression of RTKs in skull base chordomas and support the development of targeted therapies that inhibit RTKs, which may have a synergistic effect for chemotherapy in patients. There were statistically significant correlations between the expression of PDGFR-α, c-Met, and EGFR and disease-free survival. The results nonetheless suggest that chordomas may respond to RTK inhibitors or modulators of other downstream signaling.

Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors.

Chordomas are locally invasive tumors that have a tendency to relapse despite optimal treatment. Specific biological markers might be used to describe their behavior. There is currently no agreement regarding the best way to manage intracranial chordomas. We studied the expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in 145 paraffin-embedded tumors. The purpose of our study was to determine: (a) the role of potent angiogenic factors VEGFR-2 and iNOS and their relationship to each other in skull base chordoma and (b) the role of monocytes/macrophages as a potential iNOS source in the angiogenic process. A series of 74 chordoma patients for a total of 145 lesions (including 71 recurrent lesions) and 10 specimens from embryonic notochord were investigated for the expression of iNOS, VEGFR-2, Ki-M1P, and CD-34 using immunohistochemistry. In the majority of the chordomas, correlations were found between iNOS and the immunoreactivity of Ki-M1P (r = 0.5303, P < 0.0001). Furthermore, the expressions of Ki-M1P was correlated with VEGFR-2 (r = 0.4181, P < 0.0001). Our results indicate that chordomas may respond to receptor tyrosine kinase inhibitors such as VEGFR-2 or modulators of other downstream signaling molecules. The future of VEGFR-2 and iNOS inhibitors as therapeutic agents in the treatment of chordoma will be clearer over the next years as results of the current clinical trials become available and as the factors regulating angiogenesis and the interactions between these factors are elucidated. However, appropriate functional experiments remain to be conducted to prove such a hypothesis.

Value of endoscopic third ventriculostomy instead of shunt revision.

BACKGROUND: The purpose of this study was to analyze the value of endoscopic third ventriculostomy (ETV) in patients with shunt malfunction or infection. METHODS: ETV was performed in 263 patients in Greifswald between 1993 and 2008. We reviewed the data of all patients with previous shunts who underwent ETV instead of shunt revision. The procedure was successful when subsequent shunt implantation was avoided. RESULTS: Neuroendoscopy was performed in 30/31 previously shunted patients. The average age of the patients was 26.4 years ranging from 6 months to 69 years (male/female ratio: 18/12). The primary cause of hydrocephalus was aqueductal stenosis in 11, myelomeningocele in 5, posthemorrhagic in 5, postmeningitic in 3, tumor-related obstruction in 2, supracerebellar arachnoid cyst in 2, posttraumatic in 1 and a complex congenital hydrocephalus in 1. ETV was successful in 18 patients (60%) with a mean follow-up period of 51 months. 12 patients (40%) did not benefit from ETV and required a permanent shunt. 11 of them received the shunt within 3 months after failed ETV. ETV failed in all children <2 years of age. A benefit of ETV without subsequent shunt procedures was recognized in 18/27 (66.7%) with an obstructive and 0/3 (0%) patients with a communicating cause of the hydrocephalus. Complications occurred in 2 patients (6.7%). CONCLUSIONS: ETV is a potential treatment option when shunts fail in patients with obstructive hydrocephalus. If MR imaging shows no obstruction, a shunt revision is recommended. Patients with a posthemorrhagic and postmeningitic hydrocephalus are poor candidates for ETV.

Brain abscess formation within an endodermal cyst of the frontal lobe: case report.

A 38-year-old man with a right frontal lobe cyst was treated by endoscopic cystoventriculostomy in 1998. Cyst capsule histology revealed surprisingly an endodermal cyst. The patient was reoperated for cyst expansion by endoscopic re-cystoventriculostomy in 2005. In 2007, the patient suffered from brain abscess formation within the cyst which was punctured. The history was positive for a dental infection. In 2008, a recurrent brain abscess in the cyst occurred. The cyst was completely resected. There was no history of trauma or sinusitis. In all, endodermal cysts may mimic a paraxial arachnoid cyst. It may predispose for recurrent brain abscess formation - especially due to bacteraemia. This report confirms earlier presentations that endodermal cysts should be resected, and endoscopic cyst opening is not sufficient.

On the psychopathology of unilateral temporal lobe epilepsy.

Personality adjustment of patients with unilateral temporal lobe epilepsy (TLE) was investigated in the light of special characteristics of the epilepsy process, psychosocial stressors, and the cognitive status of the patients. Thirty-seven patients with medically intractable unilateral temporal lobe epilepsy (16-55 years of age; 20 right temporal and 17 left temporal foci) were examined with standardized personality inventories (FPI, STAI, IPC, TSK) supplemented by a rating scale evaluated by the neuropsychologist (GEWLE). Patients with left temporal lobe epilepsy were characterized by increased emotional dependency, less externally judged composedness, increased depressive drive and mood, increased nervousness, increased search for information and exchange of disease experience, and greater tendency to persevere (P < 0.05). Cognitive status and psychosocial status did not significantly differ. The evaluation of personality adjustment contributes to the lateralization of the epileptogenic focus and reveals interesting patterns in the preoperative diagnostic puzzle, and in addition provides a strategy to individualize psychotherapeutic strategies.

Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy.

OBJECTIVE: Dysembryoplastic neuroepithelial tumors (DNT) are relatively benign brain lesions that often cause medically intractable epilepsy. There is mounting evidence that multidrug transporters such as P-glycoprotein (P-gp) or multidrug resistance-associated proteins (MRP) play an important role in the development of resistance to antiepileptic drugs (AED). MATERIAL AND METHODS: In the present study, we examined the expression of several multidrug transporters in 14 cases of DNT. The peritumoral brain tissue as well as 9 cases of arteriovenous malformations (AVM) served as controls. P-gp, MRP2, MRP5 and breast cancer resistance protein (BCRP) expression was evaluated qualitatively and quantitatively using immunohistochemistry. RESULTS: All transporters were overexpressed quantitatively in DNT, but each revealed a different labeling pattern. P-gp and BCRP were predominantly located in the endothelium of brain vessels. MRP5 was detected primarily in endothelial cells, but notably also in neurons. The expression of P-gp, MRP2 and MRP5 was low in AVM, whereas BCRP demonstrated strong staining. Examination of MDR1 gene polymorphisms revealed no correlation with P-gp expression whereas the MRP2 exon 10 G1249A polymorphism was associated with different MRP2 labelling. CONCLUSIONS: Our results show that multidrug transporters are overexpressed in DNT. This finding supports the view that several of these transport proteins may play an important role in the mechanisms of drug resistance in epileptic brain tissue.

Limitations of dorsal transpedicular stabilization in unstable fractures of the lower thoracic and lumbar spine: an analysis of 133 patients.

The optimal treatment of thoracic and lumbar fractures remains controversial. While many authors recommend dorsal instrumentation with an internal fixator, others favour an anterior approach. To evaluate the posterior approach and to identify conditions under which an anterior approach should be preferred, 133 patients with unstable thoracic and lumbar fractures of the spine who underwent dorsal instrumentation with an internal fixator were analyzed. Clinical data were recorded prospectively with respect to fracture type, neurological findings, operative complications, spinal deformation correction, and long-term outcome. All fractures were located between the 7th thoracic and the 5th lumbar vertebrae and were considered to be unstable with respect to the three column model. Seventy-six patients (57%) received surgery within the first seven days after the trauma. Postoperatively, 98% of patients with a radicular lesion or an incomplete transverse syndrome (47 patients, 35%) improved. Stable fracture consolidation after fixator removal was obtained in 98% (130 of 133 patients). The preoperative kyphosis angle decreased from an average of 10.1 degrees to 7.4 degrees at the three year follow up. Major operative complications consisted of two isolated nerve root lesions (1.5%), two deep wound infections with need of fixator removal (1.5%), and mallocation of two pedicle screws with need for another procedure in two patients (1.5%). Three patients (2%) suffered from insufficient bony fusion with increase of kyphotic deformation and required subsequent anterior stabilization. These three patients presented with an initial kyphosis or wedge angle of 20 degrees or higher. In conclusion, dorsal stabilization with the internal fixator is a safe and reliable treatment for unstable fractures of the lower thoracic and lumbar spine. The authors recommend this procedure because of its low-invasiveness in conjunction with satisfactory reconstruction and stabilization. However, an anterior approach should be considered in fractures with initial kyphotic deformation or wedge angle of 20 or more degrees.

Towards waterjet dissection in neurosurgery: experimental in-vivo results with two different nozzle types.

Waterjet dissection is under close investigation as a new neurosurgical tool. Experimentally, a precise tissue dissection with vessel preservation has been demonstrated in the porcine cadaver brain. The safety of the device has been shown in first clinical applications. However, a detailed in-vivo analysis of the waterjet device is still awaited. In the present study, two often applied nozzle types (100 microm diameter emitting a coherent straight jet; 120 microm diameter emitting a helically rotating jet) were experimentally studied in vivo. Forty-one rabbits received a frontal waterjet corticotomy on either side with one nozzle type after microsurgical removal of the arachnoid membranes. Animals were sacrificed at 1, 3, 7 days and 6 weeks after surgery. Dissection morphology and vessel preservation were evaluated. Tissue trauma was analyzed by the extent of intra-operative haemorrhage, postsurgical oedema formation and astrocytic as well as microglial reactions. In all animals, reliable brain dissection was observed. Macroscopically, only minor bleeding occurred. Microscopically, also very precise brain dissection with both nozzle types was found. Vessels were preserved with both pressures applied (5 and 10 bar). Dissections with the 100 microm straight nozzle were more precise with respect to dissection margins. However, no significant difference in vessel preservation and extent of haemorrhage, oedema formation, astrocytic and microglial reactivity was shown. Malfunction defined as clotting of the instrument occurred only with the 100 microm nozzle. In four 100 microm straight nozzle hemispheres, even no brain dissection was seen. The results indicate that the waterjet enables very precise and reliable brain parenchyma dissection with minimal trauma and vessel preservation in vivo. If this can be proven to be of clinical relevance, the instrument will become a valuable neurosurgical tool. Based on these results, the authors selected the 120 microm Helix nozzle for further research with this device in the CNS.

Hypothalamic neuropeptide release after experimental subarachnoid hemorrhage: in vivo microdialysis study.

OBJECTIVES: As evidence exists about independent regulation of peripheral and central release of the vasoactive and natriuretic neuropeptides arginine-vasopressin (AVP) and oxytocin (OXT), we investigated their release patterns following subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: After injection of 0.1 ml arterial blood or saline into the great cistern of 33 Wistar rats, AVP and OXT levels were measured in blood and by microdialysis in the hypothalamic supraoptic (SON) and paraventricular nucleus (PVN). For statistical analysis, the analysis of variance (ANOVA) was used with Tukey HSD post hoc ANOVA tests to determine specific group differences. RESULTS: Plasma AVP and OXT peaked 2 h after SAH (P < 0.05), and normalized at 4 h. In the SON, both AVP and OXT peaked 4 h after SAH (P < 0.05). In the PVN, AVP increased in both groups (P < 0.05), while no OXT release occurred. By the sham group, any effect of experimental procedure was excluded. CONCLUSIONS: The SAH-specific central neuropeptide release, which exceeded peripheral release and continued longer, may contribute to pathophysiological events following SAH.

Waterjet resection of brain metastases - first clinical results with 10 patients.

The waterjet technique enables precise tissue dissection without thermal damage and with preservation of vessels in general surgery. In neurosurgery, these qualities could help to avoid damage of intact brain parenchyma in tumour resections. The present study reports our first results with this technique in brain metastases. Ten patients with intracranial metastases underwent surgery with the aid of the waterjet. Resection was performed in combination with conventional neurosurgical methods. The follow-up consisted of neurological examination and MRI studies. Intraoperatively, the device was easy to handle. No complications due to the device were observed. Vessels were preserved at pressures below 20 bars. Six of the tumours consisted of soft tissue which was poorly demarcated from the surrounding brain. In these tumours, the waterjet was very helpful. It enabled tumour debulking by aspiration and - more important - precise separation of tumour and brain parenchyma. The remaining four cases were rather hard and well demarcated metastases. In these only separation of the tumour from the surrounding brain was achieved. In conclusion, the waterjet can be applied in surgery of brain metastases without complications. The device appears particularly suitable for soft, poorly demarcated metastases. Further clinical studies with this device are required.

Frameless neuronavigation in intracranial endoscopic neurosurgery.

OBJECT: Frameless computerized neuronavigation has been increasingly used in intracranial endoscopic neurosurgery. However, clear indications for the application of neuronavigation in neuroendoscopy have not yet been defined. The purpose of this study was to determine in which intracranial neuroendoscopic procedures frameless neuronavigation is necessary and really beneficial compared with a free-hand endoscopic approach. METHODS: A frameless infrared-based computerized neuronavigation system was used in 44 patients who underwent intracranial endoscopic procedures, including 13 third ventriculostomies, nine aqueductoplasties, eight intraventricular tumor biopsy procedures or resections, six cystocistemostomies in arachnoid cysts, five colloid cyst removals, four septostomies in multiloculated hydrocephalus, four cystoventriculostomies in intraparenchymal cysts, two aqueductal stent placements, and fenestration of one pineal cyst and one cavum veli interpositi. All interventions were successfully accomplished. In all procedures, the navigational system guided the surgeons precisely to the target. Navigational tracking was helpful in entering small ventricles, in approaching the posterior third ventricle when the foramen of Monro was narrow, and in selecting the best approach to colloid cysts. Neuronavigation was essential in some cystic lesions lacking clear landmarks, such as intraparenchymal cysts or multiloculated hydrocephalus. Neuronavigation was not necessary in standard third ventriculostomies, tumor biopsy procedures, and large sylvian arachnoid cysts, or for approaching the posterior third ventricle when the foramen of Monro was enlarged. CONCLUSIONS: Frameless neuronavigation has proven to be accurate, reliable, and extremely useful in selected intracranial neuroendoscopic procedures. Image-guided neuroendoscopy improved the accuracy of the endoscopic approach and minimized brain trauma.

Cranial neuronavigation in neurosurgery: assessment of usefulness in relation to type and site of pathology in 284 patients.

OBJECTIVE: Neuronavigation improves intraoperative topographical orientation in neurosurgery. We wanted to better define the practical value of this technique in relation to the pathology operated on and the types of cranial surgery that profit the most from it. METHODS: Usefulness, interactive use and probably preventive effect of neuronavigation in cranial neurosurgery were assessed in a consecutive series of 284 patients on the basis of questionnaires with two- or five-point scale ratings by different neurosurgeons. RESULTS: Neuronavigation was most helpful in tumors of the hemispheres (particularly the central area) not visible at the cortical surface or resembling normal white matter, and in endoscopic procedures within small ventricles or cysts with non-translucent walls or when vision was blurred by cloudy CSF. In the same pathologies and surgical procedures, the device was interactively used, taking advantage of the specific possibilities of interactive image-guided neurosurgery. A probably preventive effect of neuronavigation was noted in operations in eloquent areas; highest scores were given for intraaxial tumors of the central region. The subjective assessments of usefulness, interactive use or preventive effect were not dependent on the involvement of the neurosurgeons in this study. CONCLUSION: We recommend this technique in resecting tumors in eloquent areas of the cortex or white matter, in approaching deep-seated processes not visible at the cortical surface, in defining borders of tumors resembling normal brain tissue, and in guiding endoscopes where ventricles are small or vision is blurred. This recommendation applies to any neurosurgeon familiar with the technique and managing neurosurgical cases requiring precise topographical orientation where normal anatomic landmarks are missing.

Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia.

The present study was conducted to evaluate the effects of nimodipine and mannitol on infarct size and on the amount of apoptosis after transient focal cerebral ischemia. Focal cerebral ischemia was induced in male Sprague-Dawley rats (weight 300-380 g) by transient occlusion of the right middle cerebral artery (MCAO) using an intraluminal thread model. All animals underwent ischemia for 2 h, followed by 24 h of reperfusion. Group I (n=16) was untreated. Group II (n=16) received 15% mannitol (1 g/kg as bolus) and group III (n=9) received 15 microg/kg/h nimodipine intravenously beginning 15 min prior to MCAO. Twenty-four hours after reperfusion, the brain was taken and sectioned in coronal slices. The slices were stained with H&E and with the transferase dUTP nick-end labeling (TUNEL) technique. Histopathological analysis revealed a significant (P<0.05) decrease in infarct size in the striatum with both drugs: mannitol (group II) 25.4+/-5.9% and nimodipine (group III) 21.5+/-11.0% versus control (group I) 34.9+/-7.0% and in the cortex 2.7+/-2.0% (group II) and 6.3+/-2.4% (group III) versus control 14.4+/-9.0% (group I). The number of apoptotic cells was statistically lower in the therapy groups (group III 9.6, group II 25.8) versus control (group I 57.9) (Mann-Whitney-Wilcoxon U-test Z>1.96, P<0.05). This study indicates that mannitol and nimodipine provide neuroprotection by preventing both the necrotic and apoptotic components of cell death after transient focal cerebral ischemia and may be effective as neuroprotective drugs for cerebrovascular surgery.

Analysis of aqueductal cerebrospinal fluid flow after endoscopic aqueductoplasty by using cine phase-contrast magnetic resonance imaging.

OBJECT: The purpose of this prospective study was to evaluate aqueductal cerebrospinal fluid (CSF) flow after endoscopic aqueductoplasty. In all patients, preoperative magnetic resonance (MR) imaging revealed hydrocephalus caused by aqueductal stenosis and lack of aqueductal CSF flow. METHODS: In 14 healthy volunteers and in eight patients with aqueductal stenosis who had undergone endoscopic aqueductoplasty, aqueductal CSF flow was investigated using cine cardiac-gated phase-contrast MR imaging. For qualitative evaluation of CSF flow, the authors used an in-plane phase-contrast sequence in the midsagittal plane. The MR images were displayed in a closed-loop cine format. Quantitative through-plane measurements were performed in the axial plane perpendicular to the aqueduct. Evaluation revealed no significant difference in aqueductal CSF flow between healthy volunteers and patients with regard to temporal parameters, CSF peak and mean velocities, mean flow, and stroke volume. All restored aqueducts have remained patent 7 to 31 months after surgery. CONCLUSIONS: Aqueductal CSF flow after endoscopic aqueductoplasty is similar to aqueductal CSF flow in healthy volunteers. The data indicate that endoscopic aqueductoplasty seems to restore physiological aqueductal CSF flow.

[Neuro-navigation in the central area: impact on different surgical steps related to the location and various pathological processes]. / Neuronavigation in der Zentralregion: Bedeutung für einzelne Operationshasen bei verschiedenen Prozesslokalisationen.

The neurosurgical treatment of space occupying processes in the central area bears a relatively high risk of either postoperative neurological deficits ("radical approach") or of residual tumor ("conservative approach"). Therefore, special techniques of intraoperative topographic orientation (image-guided surgery) play an important role here. The possible impact of neuronavigation on different neurosurgical steps (craniotomy, corticotomy, localization of the process, definition of borders of resection) was studied in relation to the site of pathology (extraaxial, intraaxial/superficial, intraaxial/deep) in 46 patients harbouring space occupying lesions of the central area. In intraaxial pathologies, additional electrophysiological monitoring was done. It could be shown, that in cases of deep seated processes, neuronavigation had the greatest impact on craniotomy, corticotomy and localization of the process, whereas the borders of resection were defined predominantly on the basis of differences in colour or consistency. In extraaxial pathologies, neuronavigation was of significance only for craniotomy; in intraaxial processes visible at the surface, it had an impact on craniotomy and--in a few cases--on definition of resection borders. In neurosurgery of intraaxial pathologies of the central area (particularly those not visible at the surface), the use of neuronavigation (or another method of intraoperative localization) in combination with neurophysiologic monitoring is strongly recommended.

Endoscopic aqueductoplasty: technique and results.

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of endoscopic aqueductoplasty in patients with hydrocephalus caused by aqueductal stenosis. The controversy of third ventriculostomy and aqueductoplasty is discussed. METHODS: A series of 17 patients who underwent endoscopic aqueductoplasty is reported. Rigid rod-lens scopes were used for inspecting the aqueductal entry and performing balloon aqueductoplasty. With the aid of a 2.5-mm flexible endoscope, the aqueduct and fourth ventricle were explored and aqueductal membranous obstructions were perforated. Third ventriculostomies were performed simultaneously in nine patients. One aqueductal stent was inserted. In six patients, frameless computerized neuronavigation was used for an accurate approach to the aqueduct. The average duration of the endoscopic procedures was 59 minutes (range, 25-100 min). RESULTS: There was no endoscopy-related mortality. Surgical complications included an asymptomatic fornix contusion and two injuries to the aqueductal roof, which resulted in permanent diplopia due to dysconjugate eye movement (one patient) and transient trochlear palsy (one patient). In addition, two patients developed transient dysconjugate eye movements, and one patient had an asymptomatic epidural hematoma. Eleven patients showed improvement in their symptoms. The conditions of five patients were unchanged. One patient died of stroke 1 month after the operation. No patient required shunting. The ventricles decreased in size in nine patients and were unchanged in the remaining eight patients. CONCLUSION: Endoscopic aqueductoplasty is an effective alternative to third ventriculostomy for the treatment of hydrocephalus caused by short aqueductal stenosis. However, longer follow-up periods are necessary to evaluate long-term aqueductal patency after aqueductoplasty.

Fatal subarachnoid hemorrhage after endoscopic third ventriculostomy. Case report.

In recent years, endoscopic third ventriculostomy has become a well-established procedure for the treatment of various forms of noncommunicating hydrocephalus. Endoscopic third ventriculostomy is considered to be an easy and safe procedure. Complications have rarely been reported in the literature. The authors present a case in which the patient suffered a fatal subarachnoid hemorrhage (SAH) after endoscopic third ventriculostomy. This 63-year-old man presented with confusion and drowsiness and was admitted in to the hospital in poor general condition. Computerized tomography scanning revealed an obstructive hydrocephalus caused by a tumor located in the cerebellopontine angle. An endoscopic third ventriculostomy was performed with the aid of a Fogarty balloon catheter. Some hours postoperatively, the patient became comatose. Computerized tomography scanning revealed a severe perimesencephalic-peripontine SAH and progressive hydrocephalus. Despite emergency external ventricular drainage, the patient died a few hours later. Although endoscopic third ventriculostomy is considered to be a simple and safe procedure, one should be aware that severe and sometimes fatal complications may occur. To avoid vascular injury, perforation of the floor of the third ventricle should be performed in the midline, halfway between the infundibular recess and the mammillary bodies, just behind the dorsum sellae.