Surgical management of choroid plexus papilloma of the cerebellopontine and cerebellomedullary angle: classification and strategy.

Choroid plexus papillomas (CPPs) are primary neuroectodermal neoplasms that usually arise in the fourth ventricle in adults. In this study, we present 12 patients with CPP arising from the cerebellopontine angle (CPP-CPA) and/or of the cerebellomedullary angle (CPP-CMA) that were treated in our department. Patients who underwent surgery for the treatment for CPP-CPA/CMA from January 2004 to March 2020 were identified by a computer search of their files from the Department of Neurosurgery, Tübingen. CPPs were classified according to their location into type 1 (tumor portion only in the CPA,), type 2 (tumor portions only in the CMA), and type 3 (tumor portions both in the CPA and CMA). Patients were evaluated for initial symptoms, previous therapies in other hospitals, extent of tumor resection, recurrence rate, and complications by reviewing patient documents. Of approximately 1500 CPA lesions, which were surgically treated in our department in the last 16 years, 12 patients (mean age 42 ± 19 years) were found to have CPP-CPA/CMA. Five were male, and seven were female patients. Gross total resection was achieved in nine cases, and a subtotal resection was attained in three cases. Tumor recurrence in the same location after the first surgery in our hospital was observed in 2 patients after 15 and 40 months of follow-up, and in another patient, distant metastases (C3/4 and L3 levels) were observed. Surgical removal of CPP is the treatment of choice, but additional therapeutic options may be necessary in case of remnant tumor portions, recurrence, or malignant transformation.

Surgical management of anterior clinoidal meningiomas: consensus statement on behalf of the EANS skull base section.

BACKGROUND: The optimal management of clinoidal meningiomas (CMs) continues to be debated. METHODS: We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of these tumors. The data from the literature along with contemporary practice patterns were discussed within the task force to generate consensual recommendations. RESULTS AND CONCLUSION: This article represents the consensus opinion of the task force regarding pre-operative evaluations, patient's counselling, surgical classification, and optimal surgical strategy. Although this analysis yielded only Class B evidence and expert opinions, it should guide practitioners in the management of patients with clinoidal meningiomas and might form the basis for future clinical trials.

Petroclival meningiomas: update of current treatment and consensus by the EANS skull base section.

BACKGROUND: The optimal management of petroclival meningiomas (PCMs) continues to be debated along with several controversies that persist. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the management of these tumors. To achieve this, the task force reviewed in detail the literature in this field and had formal discussions within the group. RESULTS: The constituted task force dealt with the existing definitions and classifications, pre-operative radiological investigations, management of small and asymptomatic PCMs, radiosurgery, optimal surgical strategies, multimodal treatment, decision-making, and patient's counselling. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the management of PCMs.

Surgical management of collision-tumors between vestibular schwannoma and meningioma in the cerebellopontine angle in patients with neurofibromatosis type 2.

INTRODUCTION: When vestibular schwannoma (VS) collides with meningioma at the cerebellopontine angle (CPA), a particular threat occurs. Sudden acceleration of tumor growth and unpredictable involvement of cranial nerves results in a special environment that aggravates management. The goal of this study was to analyze the extent of resection, postoperative facial and cochlear function, surgical strategy, and survival rates in patients with neurofibromatosis type 2 (NF2) with meningioma-vestibular schwannoma (M-VS) collision tumors. METHODS: A total of 1284 VS, including 165 NF2 VS were operated at our department between January 2004 and May 2018. Out of these cases, a group of six NF2 patients with seven M-VS collision tumors was found following careful analysis of neuroradiological data and pathological and surgical reports. Patients were evaluated for extent of tumor resection and, furthermore, postoperative facial and hearing function. RESULTS: Six patients with NF2 with seven M-VS collision tumors were included in this study. Mean age was 32 ± 8.2 years. A gross total resection (GTR) of both colliding tumors was achieved in only one case, a GTR of the meningioma and a subtotal resection (STR) of the VS in four cases and in two cases only, the meningioma was removed. In five of the cases, facial function was intact or good (House and Brackmann grades I-II) at long-term follow-up (mean follow-up 22 months). No mortality occurred during follow-up. CONCLUSIONS: Collision between M and VS at the CPA is a particular phenomenon in NF2 patients that may aggravate the situation with less favorable surgical outcome than NF-2 VS without meningioma.

[Update on diagnostics and microsurgical treatment of vestibular schwannoma]. / Vestibularisschwannome ­ ein Update zu Krankheitsbild und mikrochirurgischer Behandlung.

Vestibular schwannomas are primary benign tumors of the cerebellopontine angle originating either from the superior or the inferior vestibular nerve. Hearing deterioration is the leading symptom, which is why the widespread name for this tumor is acoustic neuroma. Due to the widespread availability of magnetic resonance imaging (MRI), the diagnosis of vestibular schwannoma is frequently made in an early stage of the disease. In these cases a wait and scan policy is recommended. If the tumor grows, the therapeutic options are stereotactic radiotherapy or microsurgical tumor operation. Young patient age, functional hearing ability, persistent dizziness, cystic tumor consistence and large space-occupying tumor size are in favor of surgery via the retrosigmoid, transmeatal approach. In experienced hands excellent results in terms of functional preservation of the facial nerve and the cochlear nerve and radical tumor resection can be obtained.

Posterior fossa meningioma with invasion of the internal acoustic canal.

BACKGROUND: To evaluate the significance for outcome of meningioma invasion into the internal auditory canal (IAC) in posterior fossa meningiomas. METHODS: From April 2005 to September 2015, 174 posterior fossa meningiomas have been surgically treated in our Institution. Careful analysis of preoperative MRI depicted in 63 cases (36%) meningioma invasion into the IAC. A retrospective analysis was done of clinical and radiological presentation, surgical findings, outcome, and relevant prognostic factors in order to stratify the risk of complication and evaluate the surgical outcome. RESULTS: Gross total resection was achieved in 67% of patients. There was no mortality. CSF leak occurred in 5%. Postoperative moderately severe (HB 4) and severe dysfunction (HB 5) of the facial nerve was observed in 5% of patients. In 17 patients (27%), IAC was opened. Deterioration of facial function occurred in 24% of patients, hearing loss in 12%, and CSF leak in 6%. In 46 patients (73%), IAC was not opened. Deterioration of facial function occurred in 43% of patients, hearing loss in 13%, and CSF leak in 4%. Opening the IAC, a GTR was achieved in 82% while, without opening, in 61% of patients. CONCLUSIONS: Meningiomas of the posterior fossa may in one-third of the cases invade the IAC. Opening of the IAC in these cases was a crucial step for increasing the GTR. Despite the minimal increased risk of transient CSF leak, IAC opening was not associated with an increased risk of facial palsy or hearing loss in comparison to non-opening the IAC.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Case report: A vertebral bone spur as an etiology for spinal cord herniation: case presentation, surgical technique, and review of the literature.

Objective: The pathophysiology of idiopathic spinal cord herniation remains unknown. However, several different factors have been postulated, such as congenital causes (ventral dura mater duplication, preexisting pseudomeningocele, or other congenital dural defects), inflammation, remote spinal trauma, or thoracic disc herniation. Herein, the diagnosis and surgical treatment of a patient with spinal cord herniation caused by an intraspinal bone spur is presented along with a relevant literature review. Case presentation: A 56-year-old male patient presented with a non-traumatic Brown-Sequard syndrome persisting for over 1 year. A magnetic resonance imaging of the spinal axis revealed a ventral spinal cord displacement in the level of T 6/7. A supplementary thin-sliced computed tomography of the spine revealed a bone spur at the same level. For neurosurgical intervention, T 6 and T 7 laminectomy was performed. The cranial and caudal end of the right paramedian ventral dural defect was visualized and enlarged. Following extradural spinal cord mobilization by denticulate ligament transection, the spinal cord was finally released. The spinal cord was rotated and the ventral closure of the dural defect was performed by continuous suture. The patient recovered from surgery without additional deficits. The patient's postoperative gait, sensory, and motor function deficits improved, and further neurological deterioration was prevented. Conclusion: Since the first description of spinal cord herniation by Wortzman et al. in 1974, approximately 260 cases have been reported in the literature. In addition to other causes, intraspinal bone spur is a possible cause of spinal cord herniation.

Case report: Interdisciplinary treatment of complex C1/C2 fractures in a patient with concomitant three-vessel coronary artery disease requiring bypass surgery.

Background: Acute myocardial infarction (MI) frequently leads to consciousness disturbance following hemodynamic collapse. Therefore, MI can occur together with upper cervical spine trauma. Herein, we report the successful treatment of complex C1/C2 fractures in a patient with concomitant three-vessel coronary artery disease (CAD). Case presentation: A 70-year-old patient presented in our emergency outpatient clinic after a hemodynamic collapse without neurological deficits or heart-related complaints. Computed tomography (CT) scan of the cervical spine revealed a dislocated odontoid fracture Anderson and D'Alonzo type II and an unstable Gehweiler type III injury (Jefferson's fracture). An intradiploic arachnoid cyst in the posterior wall of the posterior fossa was a coincident radiological finding. Furthermore, coronary angiography confirmed three-vessel CAD with high-grade coronary artery stenosis. Indication for upper cervical spine surgery and bypass surgery was given. An interdisciplinary team of neurosurgeons, cardiothoracic surgeons and anesthesiologists evaluated the patient's case to develop the most suitable therapy concept and alternative strategies. Finally, in first step, C1-C2 fusion was performed by Harms technique under general anesthesia with x-ray guidance, spinal neuronavigation, Doppler ultrasound and cardiopulmonary monitoring. Cardiothoracic surgeons were on standby. One month later bypass surgery was performed uneventfully. Follow-up CT scan of cervical spine revealed intraosseous screw positioning and beginning fusion of the fractures. The patient did not develop neurological deficits and recovered completely from both surgeries. Conclusions: Treating complex C1/C2 fractures with concomitant severe CAD requiring treatment is challenging and carries a high risk of complications. To our knowledge, the literature does not provide any guidelines regarding therapy of this constellation. To receive upper cervical spine stability and to prevent both, spinal cord injury and cardiovascular complications, an individual approach is required. Interdisciplinary cooperation to determine optimal therapeutic algorithms is needed.

Through the orbit and beyond: Current state and future perspectives in endoscopic orbital surgery on behalf of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Introduction: Orbital surgery has always been disputed among specialists, mainly neurosurgeons, otorhinolaryngologists, maxillofacial surgeons and ophthalmologists. The orbit is a borderland between intra- and extracranial compartments; Krönlein's lateral orbitotomy and the orbitozygomatic infratemporal approach are the historical milestones of modern orbital-cranial surgery. Research question: Since its first implementation, endoscopy has significantly impacted neurosurgery, changing perspectives and approaches to the skull base. Since its first application in 2009, transorbital endoscopic surgery opened the way for new surgical scenario, previously feasible only with extensive tissue dissection. Material and methods: A PRISMA based literature search was performed to select the most relevant papers on the topic. Results: Here, we provide a narrative review on the current state and future trends in endoscopic orbital surgery. Discussion and conclusion: This manuscript is a joint effort of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Vascular endothelial growth factor signals through platelet-derived growth factor receptor ß in meningiomas in vitro.

BACKGROUND: Vascular endothelial growth factor (VEGF)-mediated angiogenesis mediates tumour growth and metastasis. Meningiomas are primarily benign, slow-growing, highly vascularised tumours. Aside from VEGF, there is little data on the function of major angiogenic proteins in meningiomas. METHODS: The VEGFA, platelet-derived growth factor B (PDGFB), and their respective receptors - VEGF receptor 2 (KDR) and PDGF receptor ß (PDGFRß) - were quantified using real-time PCR and a TaqMan Protein Assay in meningiomas in vivo and in vitro. The effect of VEGFA and PDGFB on cell proliferation and the tyrosine phosphorylation of PDGFRß were examined. RESULTS: Most meningiomas displayed no KDR protein expression but elevated PDGFRß levels. Exogenous VEGFA stimulation significantly increased cell proliferation. The PDGFRß inhibition before stimulation with VEGFA abolished the proliferative stimuli. The VEGFA induced concentration-dependent PDGFRß tyrosine phosphorylation comparable to PDGFB-induced PDGFRß tyrosine phosphorylation. The PDGFRß inhibitors gambogic acid, sunitinib, and tandutinib equally impaired the migration of meningioma cells. In addition, gambogic acid suppressed the VEGFA-induced PDGFRß tyrosine phosphorylation. CONCLUSION: Collectively, our data suggest that VEGFA primarily regulates VEGF-mediated migration through PDGFRß in meningiomas. The inhibitory effect of gambogic acid and tandutinib against meningioma growth in vitro suggests that selective PDGFRß inhibitors, in combination with VEGF inhibitors, should be evaluated further as potential therapies for recurrent and malignant meningiomas.

Predictive factors for neurocognitive function and Quality of Life after surgical treatment for Cushing's disease and acromegaly.

BACKGROUND: Cushing's disease (CD) and acromegaly (AC) are associated with impairment in quality of life (QoL) and neurocognition that can persist after successful treatment. AIM: To investigate the influence of current disease status (remission vs no remission) on neurocognitive function and QoL in treated CD and AC patients and to determine predictive factors (e.g. demographic, clinical, neurosurgical, endocrinological) for post-operative neurocognition and QoL. SUBJECTS AND METHODS: Twenty-four CD and 37 AC patients underwent neuropsychological testing 1 to 10 yr following surgical therapy. Additionally, QoL was assessed. An overnight 2-mg dexamethasone suppression test in CD and IGF-I and GH levels in AC patients were assessed to determine current disease status. The results were compared with 28 sex-, education- and age-matched healthy controls (HC). RESULTS: Impaired QoL was more pronounced than neurocognitive decrease in both pathologies compared to HC. This finding was independent of the current status of disease. In AC, persistent comorbidities were associated with impaired QoL (p<0.05). Older age at operation in AC patients was a significant predictor for adverse effects on psychomotor speed and attentional functions (p<0.05). In CD persistent hypocortisolism, not hypercortisolism, had adverse effects on neurocognition (p<0.01). CONCLUSIONS: The current status of disease plays a subordinate role in postoperative outcome concerning QoL and neurocognition in either pathology. A possible explanation might be the considerably improved endocrinopathy after treatment compared to untreated patients, even if no cure is achieved. The lasting impairments might be explained by irreversible changes that have occurred during the active phase of the disease.

Determinants of survival in patients with brain metastases from cutaneous melanoma.

BACKGROUND: This retrospective study aimed to identify prognostic factors in patients with brain metastases from cutaneous melanoma. METHODS: In all, 265 patients under regular screening according to valid national surveillance guidelines were included in the study. Kaplan-Meier analyses were performed to estimate and to compare overall survival. Cox modeling was used to identify independent determinants of the overall survival, which were used in explorative classification and regression tree analysis to define meaningful prognostic groups. RESULTS: In total, 55.5% of our patients presented with two or less brain metastases, 82.6% had concurrent extracranial metastasis and 64% were asymptomatic and diagnosed during surveillance scans. In all, 36.7% were candidates for local treatment (neurosurgery or stereotactic radiosurgery (SRS)). The median overall survival of the entire collective was 5.0 months (95% confidence interval: 4.3-5.7). Favourable independent prognostic factors were: normal pre-treatment level of serum lactate dehydrogenase (P<0.001), administered therapy (neurosurgery or SRS vs other, P=0.002), number of brain metastases (single vs multiple, P=0.032) and presence of bone metastasis (false vs true, P=0.044). Three prognostic groups with significantly different overall survival were identified. Candidates for local treatment (group I) had the longer median survival (9 months). Remaining patients could be further classified in two groups on the basis of serum lactate dehydrogenase. CONCLUSION: Applied treatment and serum lactate dehydrogenase levels were independent predictors of survival of patients with brain metastases from cutaneous melanoma. Patients receiving local therapy have overall survival comparable with general stage IV melanoma patients.

Balancing the shortcomings of microscope and endoscope: endoscope-assisted technique in microsurgical removal of recurrent epidermoid cysts in the posterior fossa.

BACKGROUND: We report about endoscope-assisted surgery of epidermoid cysts in the posterior fossa focusing on the application of neuro-endoscopy and the clinical outcome in cases of recurrent epidermoid cysts. MATERIAL AND METHODS: 25 consecutively operated patients with an epidermoid cyst in the posterior fossa were retrospectively analysed. Surgeries were performed both with an operating microscope (OPMI Pentero or NC 4, Zeiss Company, Oberkochen, Germany) and endoscopic equipment (4 mm rigid endoscopes with 30° and 70° optics; Karl Storz Company, Tuttlingen, Germany) under continuous intraoperative monitoring. Surgical reports and DVD-recordings were evaluated for identification of adhesion areas and surgical details. RESULTS: 7 (28%) of the 25 patients were recurrences of previously operated epidermoid cysts. Mean time to recurrence was 17 years (8-22 years). In 5 cases the endoscope was used as an adjunctive tool for inspection/endoscope-assisted removal of remnants. The effective time of use of the endoscope was limited to the end stage of the procedure, but was very effective. CONCLUSION: In a modern operative setting and with the necessary surgical experience recurrent epidermoid cysts may be removed with excellent clinical results. The combined use of microscope and endoscope offers relevant advantages in demanding anatomic situations.

Rapid motor cortical reorganization following subacute spinal cord dysfunction.

OBJECTIVE: Damage to the spinal cord is known to be associated with a posterior shift of the motor cortical upper limb representation, i.e. towards the somatosensory cortex. Due to missing pre-traumatic data, knowledge resulted from comparing findings between patients and healthy subjects. Here, we present a case of transient spinal cord injury resulting in a left-sided hemiparesis for 4 weeks. By chance, this patient had a pre-lesional navigated transcranial magnetic stimulation (nTMS) motor mapping 2 years before. Hence, nTMS mapping was repeated during the acute (after 1 day), sub-acute (after 10 days) and chronic (after 2 years) phase to trace the cortical reorganization following this incident. METHODS: Acute clinical work-up included magnetic resonance imaging and navigated transcranial magnetic stimulation (nTMS). Motor mapping was performed with 110% of the abductor pollicis brevis muscle (APB) resting motor threshold (rMT). Amplitudes and latencies of the motor-evoked potential (MEPs) were recorded and analyzed. In addition, motor function was evaluated by the Medical Research Council (MRC) scale, a standard Purdue Pegboard test and by a reaction time (RT) task. RESULTS: MRI revealed no aberrant findings. nTMS mapping, however, showed a posterior shift of the APB representation from the anatomical hand knob towards the somatosensory cortex in the acute in comparison to the pre-lesional phase. Concomitantly, there was an increase of rMT (6%). Within 10 days, there was an incomplete reversal of the posterior shift in parallel with improvement of the clinical motor function. Long-term follow-up revealed a complete restitution of nTMS cortical mapping and motor function. CONCLUSION: The present case report thoroughly documents a rapid cortical reorganization within a few days after a transient spinal shock. Our data adds further evidence to the literature suggesting a posterior shift of motor cortical representation following spinal cord injury. For the first time, 52 cortical reorganization was shown idiosyncratically in a single patient arising from the fortuitous fact of having a pre - lesional nTMS map.

The microglial/macrophagic response at the tumour-brain border of invasive meningiomas.

AIMS: Little is known about the immune response of the brain to invasive meningiomas. The present study was based upon the hypothesis that the microglial/macrophagic response towards brain-invasive meningiomas is dependent on the intactness of the pial-glial basement membrane. METHODS: We immunostained sections from 40 brain-invasive meningiomas that were graded according to World Health Organization (WHO) 2007 criteria. Thirty-three tumours were histologically WHO grade II (18, 'otherwise benign', and 15, 'otherwise atypical'), and seven, grade III. Microglial/macrophagic cells were labelled with antibodies directed against major histocompatibility complex class II, CD68, CD14 and CD163. Anti-collagen IV was used to visualize basement membranes. RESULTS: Twenty-five per cent (10/40) meningiomas (1/18 WHO grade II 'otherwise benign', 3/15 grade II 'otherwise atypical' and 6/7 WHO grade III) contained microglial/macrophagic cells at the tumour-brain border. The presence of these cells correlated with the absence of the pial-glial basement membrane (BM) and with WHO grade III. The monocytic response was of two kinds: one consisted of a dense layer of mononuclear cells at the tumour-brain border in nine cases, the other of an elevated number of microglial cells expressing CD14 or CD163 (two cases). CONCLUSIONS: The immune response at the tumour-brain interface correlates with the absence of the pial-glial BM and with malignancy grade. It remains to be established whether the mononuclear cells at the tumour-brain border are native microglia or blood-derived macrophages.

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

The influence of genetics on intracranial aneurysm formation and rupture: current knowledge and its possible impact on future treatment.

The etiology of intracranial aneurysm formation and rupture remains mostly unknown, but lately several studies have increasingly supported the role of genetic factors. In reports so far, genome-wide linkage studies suggest several susceptibility loci that may contain one or more predisposing genes. Depending on the examined ethnic population, several different non-matching chromosomal regions have been found. Studies of several candidate genes report association with intracranial aneurysms. To date, no single gene has been identified as responsible for intracranial aneurysm formation or rupture. In addition to the well-published environmental factors, such as alcohol intake, hypertension and smoking, only the recent progress in molecular genetics enables us to investigate the possible genetic determinants of this disease. Although a familial predisposition is the strongest risk factor for the development of intracranial aneurysms, the mode of Mendelian inheritance is uncertain in most families. Therefore, multiple genetic susceptibilities in conjunction with the environmental factors are considered to act together in the disease's etiology. Accordingly, researchers performed linkage studies and case-control association studies for the genetic analysis and have identified several genes to be susceptible to intracranial aneurysms. The identification of susceptible genes may lead to the understanding of the mechanism of formation and rupture and possibly lead to the development of a pharmacological therapy. Furthermore, should it be possible to identify a genetic marker associated with an increased risk of formation and rupture of an intracranial aneurysm, the necessity for screening and urgency of treatment could be determined more easily. In this review we summarize the current knowledge of intracranial aneurysm genetics and also discuss the method to detect the causalities. In view of the recent advances made in this field, we also give an outlook on possible future genetically engineered therapies, whose development are well underway.

Hypericin uptake: a prognostic marker for survival in high-grade glioma.

Currently adjuvant chemotherapy for glioblastoma patients can prolong survival time relative to patients who receive only surgery and radiotherapy. Despite these improvements and experimental and clinical efforts the prognosis for glioblastoma patients remains poor. At present, interest is focused on individual prognostic factors influencing patient responses to therapy. Photodynamic therapy may be a promising therapeutic option in the treatment of glioblastoma. In this investigation we examined whether uptake of hypericin (HY), a fluorescent photosensitization agent, by ex vivo glioblastoma cell lines correlates with prognosis of the individual from which the cell lines were derived. Twelve primary human glioma cell cultures were incubated with 20 micromol HY. Fluorescence intensity was measured using fluorescence microscopy. Three patients suffered from an anaplastic astrocytoma, WHO grade III, nine had a glioblastoma, WHO grade IV. In 6/12 patients complete tumour resection was possible. The mean survival time of the six patients in whom complete tumour resection was performed was 26 months, compared with 5 months for those who underwent incomplete resection. Eleven patients received radiation therapy. The five patients who received chemotherapy survived for a mean duration of 26 months, compared with the seven patients who survived for a mean duration of 5 months without chemotherapy. Statistical analysis using a parametric survival model based on the Weibull distribution showed that fluorescence intensity was the variable with the lowest p-value associated with survival (p=0.0225). An increase of 553 arbitrary units of fluorescence intensity is predicted to double survival time. Uptake of HY, a lipophilic molecule, is assumed to be related to low-density lipoprotein (LDL) uptake and metabolism. Cell proliferation is associated with a high turnover of cholesterol and membrane growth, which is related to cholesterol uptake by LDL. In summary, HY uptake by ex vivo glioblastoma cell cultures seems to be positively associated with survival of patients with malignant glioma.