Combined frameless stereotactical biopsy and intraoperative cerebral angiography by 3D-rotational fluoroscopy with intravenous contrast administration: a feasibility study.

BACKGROUND: Mobile 3-dimensional fluoroscopes are an integral part of modern neurosurgical operating theatres and can also be used in combination with free available image post processing to depict cerebral vessels. In preparation of stereotactic surgery, preoperative Computed Tomography (CT) may be required for image fusion. Contrast CT may be of further advantage for image fusion as it regards the vessel anatomy in trajectory planning. Time-consuming in-hospital transports are necessary for this purpose. Mobile 3D-fluoroscopes may be used to generate a CT equal preoperative data set without an in-hospital transport. This study was performed to determine the feasibility and image quality of intraoperative 3-dimensional fluoroscopy with intravenous contrast administration in combination with stereotactical procedures. METHODS: 6 patients were included in this feasibility study. After fixation in a radiolucent Mayfield clamp a rotational fluoroscopy scan was performed with 50 mL iodine contrast agent. The image data sets were merged with the existing MRI images at a planning station and visually evaluated by two observer. The operation times were compared between the frame-based and frameless systems ("skin-to-skin" and "OR entry to exit"). RESULTS: The procedure proves to be safe. The entire procedure from fluoroscope positioning to the transfer to the planning station took 5-6 min with an image acquisition time of 24 s. In 5 of 6 cases, the fused imaging was able to reproduce the vascular anatomy accurately and in good quality. Both time end-points were significantly shorter compared to frame-based interventions. CONCLUSION: The images could easily be transferred to the planning and navigation system and were successfully merged with the MRI data set. The procedure can be completely integrated into the surgical workflow. Preoperative CT imaging or transport under anaesthesia may even be replaced by this technique in the future. Furthermore, hemorrhages can be successfully visualized intraoperatively and might prevent time delays in emergencies.

Primary brain amyloidoma, both a neoplastic and a neurodegenerative disease: a case report.

BACKGROUND: Scattered extracellular deposits of amyloid within the brain parenchyma can be found in a heterogeneous group of diseases. Its condensed accumulation in the white matter without evidence for systemic amyloidosis is known as primary brain amyloidoma (PBA). Although originally considered as a tumor-like lesion by its space-occupying effect, this condition displays also common hallmarks of a neurodegenerative disorder. CASE PRESENTATION: A 50-year-old woman presented with a mild cognitive decline and seizures with a right temporal, irregular and contrast-enhancing mass on magnetic resonance imaging. Suspecting a high-grade glioma, the firm tumor was subtotally resected. Neuropathological examination showed no glioma, but distinct features of a neurodegenerative disorder. The lesion was composed of amyloid AL λ aggregating within the brain parenchyma as well as the adjacent vessels, partially obstructing the vascular lumina. Immunostaining confirmed a distinct perivascular inflammatory reaction. After removal of the PBA, mnestic impairments improved considerably, the clinical course and MRI-results are stable in the 8-year follow-up. CONCLUSION: Based on our histopathological findings, we propose to regard the clinicopathological entity of PBA as an overlap between a neoplastic and neurodegenerative disorder. Since the lesions are locally restricted, they might be amenable to surgery with the prospect of a definite cure.

High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with Treg depletion.

High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ+ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4+/CD8+ T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (Treg). In parallel to Treg-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8+VLA-4+ T-cells with CNS-homing properties, but not of CD4+ VLA-4+ T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses.

3D rotational fluoroscopy for intraoperative clip control in patients with intracranial aneurysms--assessment of feasibility and image quality.

BACKGROUND: Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. In this series, the image quality and value of intraoperative 3D fluoroscopy with intravenous contrast agent for the evaluation of aneurysm occlusion and vessel patency after clip placement was assessed in patients who underwent surgery for intracranial aneurysms. MATERIALS AND METHODS: Twelve patients were included in this retrospective analysis. Prior to surgery, a 360° rotational fluoroscopy scan was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® free software. The procedure was repeated after clip placement. Both image sets were compared for assessment of aneurysm occlusion and vessel patency. RESULTS: Image acquisition and contrast administration caused no adverse effects. Image quality was sufficient to follow the patency of the vessels distal to the clip. Metal artifacts reduce the assessability of the immediate vicinity of the clip. Precise image subtraction and post-processing can reduce metal artifacts and make the clip-site assessable and depict larger neck-remnants. CONCLUSION: This technique quickly supplies images at adequate quality to evaluate distal vessel patency after aneurysm clipping. Significant aneurysm remnants may be depicted as well. As it does not require visual control of all vessels that are supposed to be evaluated intraoperatively, this technique may be complementary to other intraoperative tools like indocyanine green videoangiography and micro-Doppler, especially for the assessment of larger aneurysms. At the momentary state of this technology, it cannot replace postoperative conventional angiography. However, 3D fluoroscopy and image post-processing are young technologies. Further technical developments are likely to result in improved image quality.

Intraoperative 3D rotational angiography: an emergency tool for the diagnosis of intracranial aneurysms.

It was the objective of this report to present a case of recurrent aneurysmal subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) in which an MCA aneurysm was detected by 3D rotational fluoroscopy in an emergency situation. A 44-year-old woman was admitted from an external department after repeated SAH and temporal ICH. Due to progressive anisocoria and cardiocirculatory instability, she was transferred to the operating room without angiography. After a 3D rotational fluoroscopy baseline scan, another scan with 50 ml of iodine contrast agent was performed. The Digital Imaging and Communications in Medicine (DICOM) data sets were subtracted and reconstructed using the OsiriX® free imaging software. No adverse effect was observed during and after the administration of the contrast agent. The entire procedure from positioning of the fluoroscope to the production of utilizable 3D images was completely integrated into the surgical workflow with an image acquisition time of 2 × 24 s. The configuration of the aneurysm, the aneurysm-carrying vessel, and the distal vessel anatomy were well assessable. This technique quickly supplies images at adequate quality to assess the configuration of an intracranial aneurysm and is a useful diagnostic tool if the patient's critical condition prohibits aneurysm diagnostics by angiography or CT angiography.

Optimization of radiation settings for angiography using 3D fluoroscopy for imaging of intracranial aneurysms.

Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. We recently reported its use for imaging cerebral vascular malformations and aneurysms. This study was conducted to evaluate various radiation settings for the imaging of cerebral aneurysms before and after surgical occlusion. Eighteen patients with cerebral aneurysms with the indication for surgical clipping were included in this prospective analysis. Before surgery the patients were randomized into one of three different scan protocols according (default settings of the 3D fluoroscope): Group 1: 110 kV, 80 mA (enhanced cranial mode), group 2: 120 kV, 64 mA (lumbar spine mode), group 3: 120 kV, 25 mA (head/neck settings). Prior to surgery, a rotational fluoroscopy scan (duration 24 s) was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® MD 10.0 software. The procedure was repeated after clip placement. The image quality regarding preoperative aneurysm configuration and postoperative assessment of aneurysm occlusion and vessel patency was analyzed by 2 independent reviewers using a 6-grade scale. This technique quickly supplies images of adequate quality to depict intracranial aneurysms and distal vessel patency after aneurysm clipping. Regarding these features, a further optimization to our previous protocol seems possible lowering the voltage and increasing tube current. For quick intraoperative assessment, image subtraction seems not necessary. Thus, a native scan without a contrast agent is not necessary. Further optimization may be possible using a different contrast injection protocol.

Malignant "Angioglioma": Clinical, Radiologic, and Histopathologic Features.

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent malignant neoplasm in the adult brain. In contrast, arteriovenous malformations (AVMs) are presumably congenital lesions, usually presenting with hemorrhage. Hypervascular low-grade gliomas associated with AVMs were previously called "angioglioma." An association of AVMs and GBM was also described. STUDY AIMS: We discuss the data of the largest series of locally coincident GBM with AVM in a single institution so far. All analyses were explorative only. PATIENTS: We report a series of four patients presenting at our department from 2006 to 2014. All patients underwent surgery. The cases were analyzed regarding initial presentation, clinical findings, tumor localization, and histopathologic results. CONCLUSIONS: A local coincidence of cerebral AVM and GBM is rare. Only a few reports can be found in the literature. The radiologic as well as the clinical presentations are individual. Proangiogenic factors are discussed as involved in the appearance of both entities in the same location. However, the presence of pathologic vessels within malignant gliomas is well known to all neurosurgeons and proangiogenic activity has been proven. Therefore, it seems possible that tumor activity itself contributes to the pathogenesis of a vascular malformation.

Complete radiological response following subtotal resection in three glioblastoma patients under treatment with Tumor Treating Fields.

Glioblastoma multiforme (GBM) treatment consists of surgery, radiotherapy and chemotherapy with Temozolomide (TMZ). After subtotal resection (STR), residual tumors rarely undergo spontaneous regression. Overall survival (OS) and progression-free survival (PFS) are reduced when compared with gross total resection. There is evidence that adding Tumor Treating Fields (TTFields) to standard management may lead to a significant increase in PFS and OS. In 2015 and 2016, STR was performed in 27 patients with GBM. Of these, four subsequently received TTFields therapy in addition to chemotherapy. The present study presents a series of three patients with GBM (44-54 years; isocitrate dehydrogenase wild-type, methylated O6-methylguanine-DNA methyltransferase promoter) that were treated with radiochemotherapy and TTFields after STR. Therapy with TTFields started concomitantly to TMZ following radiotherapy and was maintained for 14, 24 and 37 months. TTFields were used as monotherapy in one case, as TMZ treatment had to be stopped due to toxicity for 1 month. In all patients, TTFields therapy was well tolerated at high compliance levels, resulting in complete response (CR) after 4, 5 and 7 months, respectively. Two patients remain tumor-free at 16 and 40 months after STR. One patient exhibited multifocal recurrence 11 months after the beginning of TTFields treatment but remains alive, presenting a mild neurological decline 24 months after starting TTFields. All three presented patients gave written informed consent for their data to be published. In conclusion, the current report detailed three patients with GBM who underwent STR and were subsequently treated with TMZ and TTFields. TTFields treatment was tolerated well and was applied accurately and with high compliance by these patients, which may have contributed to the complete response. Four of the 27 patients treated with STR received additional TTFields treatment. Three of these 4 showed a CR, while a CR was observed only 2 of the remaining 23 patients without TTFields. The current series supports the effects in clinical practice, as demonstrated in recent clinical trials. The results also demonstrated that adjuvant TTFields therapy can structurally affect residual tumors after STR.

Prognostic Value of O-(2-[18F]Fluoroethyl)-L-Tyrosine PET/CT in Newly Diagnosed WHO 2016 Grade II and III Glioma.

PURPOSE: The use of [18F]fluoroethyl)-L-tyrosine ([18F]FET) positron emission tomography/computed tomography (PET/CT) has proven valuable in brain tumor management. This study aimed to investigate the prognostic value of radiotracer uptake in newly diagnosed grade II or III gliomas according to the current 2016 World Health Organization (WHO) classification. PROCEDURES: A total of 35 treatment-naive patients (mean age, 48 ± 17 years) with histologically proven WHO grade II or III gliomas as defined by the current 2016 WHO classification were included. Static PET/CT imaging was performed 20 min after intravenous [18F]FET injection. Images were assessed visually and semi-quantitatively using regions of interest for both tumor (SUVmax, SUVmean) and background (BKGmean) to calculate tumor-to-background (TBR) ratios. The association among histological results, molecular markers (including isocitrate dehydrogenase enzyme and methylguanine-DNA methyltransferase status), clinical features (age), and PET findings was tested and compared with outcome (progression-free [PFS] and overall survival [OS]). RESULTS: Fourteen patients presented with grade II (diffuse astrocytoma n = 10, oligodendroglioma n = 4) and 21 patients with grade III glioma (anaplastic astrocytoma n = 15, anaplastic oligodendroglioma n = 6). Twenty-seven out of the 35 patients were PET-positive (grade II n = 8/14, grade III n = 19/21), with grade III tumors exhibiting significantly higher amino acid uptake (TBRmean and TBRmax; p = 0.03 and p = 0.02, respectively). PET-negative lesions demonstrated significantly prolonged PFS (p = 0.003) as compared to PET-positive gliomas. PET-positive disease had a complementary value in prognostication in addition to patient age, glioma grade, and molecular markers. CONCLUSIONS: Amino acid uptake as assessed by [18F]FET-PET/CT imaging is useful as non-invasive read-out for tumor biology and prognosis in newly diagnosed, treatment-naive gliomas according to the 2016 WHO classification.

Tumor growth under rhGM-CSF application in an orthotopic rodent glioma model.

Regulation of the host immune response serves a pivotal role in the persistence and progression of malignant glioma. To date, cytotoxic cluster of differentiation (CD)-8+ T and natural killer cells are considered the main cellular components of host tumor control. The influence of macrophages in an orthotropic C6 tumor implantation model was investigated and the aim of the present study was to characterize the effects of systemic macrophage-activation on glioma growth by using the granulocyte macrophage colony stimulating factor (rhGM-CSF). A total of 20 male Sprague-Dawley rats were orthotopically implanted with C6 glioma spheroids and treated subcutaneously with 10 µg/kg rhGM-CSF every other day; 9 animals served as controls. Serial magnetic resonance imaging was performed on days 7, 14, 21, 28, 32 and 42 post-implantation to monitor tumor volume. Histological work-up included hematoxylin and eosin, CD68/ED-1 macrophage, CD8 T-cell and Ki-67 MIB1 proliferation staining in gliomas and spleen. Experimental C6-gliomas developed in 15/20 (75%) animals. In rhGM-CSF treated rats, tumors developed significantly later and reached a smaller size (median, 134 mm3) compared with the controls (median, 262 mm3). On day 14, solid tumors presented in 11/17 (65%) rhGM-CSF-treated animals; in control animals tumor growth was detected in 3/9 animals on day 7 and in all animals on day 14. The mean survival time was 35 days in the rhGM-CSF group and significantly longer when compared with the control group (24 days). Immunohistochemistry exhibited significantly more macrophages in tumors, particularly in the perivascular zone of the rhGM-CSF group when compared with untreated animals; intratumoral CD8+ counts were equal in both groups. A systemic stimulation of macrophages by rhGM-CSF resulted in significantly reduced and delayed tumor growth in the rodent C6 glioma model. The present data suggested a significant role of macrophages in host control of experimental gliomas on the innate immune response. Until now, the role of macrophages may have been underestimated in host glioma control.

Circulating MACC1 Transcripts in Glioblastoma Patients Predict Prognosis and Treatment Response.

Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacks reliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associated in colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinical outcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher in patients compared to controls. Low MACC1 levels clustered together with other prognostically favorable markers. It was associated with patients' prognosis in conjunction with the isocitrate dehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable (median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (median OS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months). No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levels receiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1 levels (median OS 8.1 months). Patients not receiving the standard regimen showed the worst prognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulating MACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcome prediction and help define more precise risk categories of glioblastoma patients.

Clinical Utility of Different Approaches for Detection of Late Pseudoprogression in Glioblastoma With O-(2-[18F]Fluoroethyl)-L-Tyrosine PET.

PURPOSE: PET/CT using O-(2-[F]fluoroethyl)-L-tyrosine (F-FET) has proven valuable in differentiating tumor recurrence and progression from therapy-induced changes. This study aimed to investigate the diagnostic performance of several analytic approaches in the setting of suspected late pseudoprogression (PsP) in glioblastoma multiforme (GBM). METHODS: Retrospective analysis of tumor recurrence was performed in 36 patients with histopathologically confirmed GBM and suspicion of recurrence/disease progression more than 12 weeks from cessation of irradiation based on MRI and Response Assessment in Neuro-Oncology working group criteria. For differentiation of late PsP from true tumor recurrence, images were analyzed semiquantitatively employing tumor-to-brain ratios using 5 different approaches for tumor and normal brain reference region definition, respectively. Histopathology and/or clinical and imaging follow-up served as reference. Respective areas under the receiver operating characteristic curve were compared. RESULTS: F-FET PET was able to reliably differentiate PsP from true tumor progression with areas under the receiver operating characteristic curve ranging from 0.80 to 0.88 (all P < 0.01). Irrespective of the approach chosen, the classification differences between the applied methods were not significant (all P > 0.05), albeit approaches focusing on voxels with the highest uptake tended to perform superior. CONCLUSIONS: Irrespective of the analytical approach, F-FET PET is a robust tool for detection of late PsP with only minor differences between different analytical approaches. However, methodological standardization and harmonization are needed to ensure comparability between different centers.

Early Transient Mild Hypothermia Attenuates Neurologic Deficits and Brain Damage After Experimental Subarachnoid Hemorrhage in Rats.

OBJECTIVE: Metabolic exhaustion in ischemic tissue is the basis for a detrimental cascade of cell damage. In the acute stage of subarachnoid hemorrhage (SAH), a sequence of global and focal ischemia occurs, threatening brain tissue to undergo ischemic damage. This study was conducted to investigate whether early therapy with moderate hypothermia can offer neuroprotection after experimental SAH. METHODS: Twenty male Sprague-Dawley rats were subjected to SAH and treated by active cooling (34°C) or served as controls by continuous maintenance of normothermia (37.0°C). Mean arterial blood pressure, intracranial pressure, and local cerebral blood flow over both hemispheres were continuously measured. Neurologic assessment was performed 24 hours later. Hippocampal damage was assessed by hematoxylin-eosin and caspase-3 staining. RESULTS: By a slight increase of mean arterial blood pressure in the cooling phase and a significant reduction of intracranial pressure, hypothermia improved cerebral perfusion pressure in the first 60 minutes after SAH. Accordingly, a trend to increased cerebral blood flow was observed during this period. The rate of injured neurons was significantly reduced in hypothermia-treated animals compared with normothermic controls. CONCLUSIONS: The results of this series cannot finally answer whether this form of treatment permanently attenuates or only delays ischemic damage. In the latter case, slowing down metabolic exhaustion by hypothermia may still be a valuable treatment during this state of ischemic brain damage and prolong the therapeutic window for possible causal treatments of the acute perfusion deficit. Therefore, it may be useful as a first-tier therapy in suspected SAH.

Early Administration of Hypertonic-Hyperoncotic Hydroxyethyl Starch (HyperHES) Improves Cerebral Blood Flow and Outcome After Experimental Subarachnoid Hemorrhage in Rats.

OBJECTIVE: Early cytotoxic brain edema may be a decisive factor that maintains cerebral malperfusion after subarachnoid hemorrhage (SAH). In addition, endothelial cell swelling may be an independent factor restricting cerebral blood flow (CBF) in a very early stage after SAH. Immediate and aggressive treatment may be able to restore CBF in this critical period. METHODS: Male Sprague-Dawley rats were subjected to SAH by the endovascular filament model and treated by a bolus of hyperoncotic-hypertonic hydroxyethyl starch (4 mL/kg body weight) immediately after vessel perforation and 150 minutes later (n = 12) or by the same amount of normal saline (n = 9). Mean arterial blood pressure, intracranial pressure, and local CBF over both hemispheres were continuously measured by laser-Doppler flowmetry. Neurologic assessment was performed 24 hours later. Hippocampal damage was assessed by hematoxylin-eosin and Caspase-3 staining. RESULTS: Arterial blood gases and mean arterial blood pressure were not significantly different between the 2 groups. Intracranial pressure was significantly reduced in the treatment group (P < 0.05). Local CBF was significantly improved in the treatment group over both hemispheres (P < 0.05; 180 minutes after treatment, P < 0.01). There was a trend to better neurologic performance in the treatment group. The rate of injured neurons was significantly reduced in animals of the treatment group compared with controls (P < 0.01). The number of Caspase-3-positive neurons in the hippocampal CA1 field was not reduced. CONCLUSIONS: In this study, the effects of very early and repeated treatment with a high-dose hyperoncotic-hypertonic hydroxyethyl starch were investigated. The results of this series show that this therapy can be highly effective to improve CBF and attenuate hippocampal cell damage in the early stage of SAH. Whether delayed cell death could be treated by longer therapy cannot be answered by this study. Because no differential diagnosis of the clinical suspicion of SAH prohibits the administration of hypertonic-hyperoncotic solutions, it may be useful as a first-tier preclinical therapy in suspected SAH and could even be used by emergency rescue services before the patient is admitted to a hospital.

Imaging of Cerebral Arteriovenous Malformations and Arteriovenous Fistulas and Occlusion Control Using Intraoperative 3-Dimensional Rotational Fluoroscopy.

BACKGROUND: Intraoperative resection or occlusion control is indispensable in the surgery of vascular anomalies. This can be conducted using local vascular imaging modalities or angiographic techniques. This series was performed to assess whether cerebral arteriovenous malformations (AVMs) and dural arteriovenous fistulae (dAVFs) can be detected in a sufficient quality by intraoperative 3-dimensional (3D) fluoroscopy with intravenous contrast application. MATERIALS AND METHODS: Five patients were included in the analysis (2 AVMs, 3 dAVFs). All patients had preoperative digital subtraction angiography. The head was fixed in a carbon MAYFIELD clamp. After a 3D rotational fluoroscopy scan without contrast agent, a second scan with 50 mL of iodine contrast agent was performed. The Digital Imaging and Communications in Medicine data of both scans were subtracted and reconstructed using the OsiriX imaging software. In 2 patients with dAVF, occlusion control was performed after obliteration of the fistula. RESULTS: In the 2 patients with cerebral AVM, 3D fluoroscopy with intravenous contrast administration resulted in good image quality. Preoperative embolization with Onyx produces significant artifacts that can be largely removed by simple digital subtraction techniques. In dural AVF, occlusion control was well feasible after obliteration of the draining vein at its dural origin. CONCLUSIONS: This technique quickly supplies intraoperative images of adequate quality to locate cerebral AVM and dAVF. However, it does not produce dynamic images. Thus, early draining veins cannot be located unless anatomically identified based on the preoperative DSA. In this case, it can be used for intraoperative obliteration control.

Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients.

BACKGROUND: ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM. PATIENTS AND METHODS: ATF5 mRNA was extracted from frozen samples of patients' GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry. RESULTS: ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients' age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan-Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t,12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084). CONCLUSION: ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.

Influence of Myelography and Postmyelographic CT on Therapeutic Decisions in Degenerative Diseases of the Cervical Spine.

STUDY DESIGN: A retrospective analysis of clinical records and radiologic imaging by 3 independent reviewers to assess the indication for surgical treatment with and without myelography and postmyelographic computed tomography (MCT). OBJECTIVE: To evaluate whether myelography and MCT obtained in addition to magnetic resonance imaging (MRI) influence therapeutic decisions in degenerative diseases of the cervical spine. SUMMARY OF BACKGROUND DATA: MRI has become the standard examination in spinal diseases. The role of myelography and MCT is not clearly defined in the modern diagnostic setup. In many departments, they are used if MRI leaves some diagnostic uncertainty. It has not been examined yet whether additional myelography and MCT change therapeutic strategies. MATERIALS AND METHODS: Three investigators independently reviewed the anonymized clinical data and image files of 105 patients who had all undergone MRI, myelography, and MCT. They determined their treatment decisions after each of 2 assessment rounds based on the following: (1) MRI and, if available, native CT, and plain radiographs. (2) Additional myelography and MCT. The intraobserver variability was the primary endpoint. RESULTS: Myelography and MCT had been performed in multilevel disease, recurrent complaints after surgery, or if MRI had not revealed a clear finding. The intraobserver variability was 26.3% and varied markedly between the 3 investigators (17%-41 %). It was the highest in cases of multilevel disease. If noninvasive imaging included native CT and plain radiographs, the intraobserver variability was significantly reduced to 10.3%. CONCLUSIONS: In unclear cases of degenerative disorders of the cervical spine, particularly multilevel stenosis, myelography and MCT add relevant information for therapeutic decisions in more than a quarter of the patients in comparison with MRI as the sole diagnostic modality, and changes therapeutic strategies. However, a significant part of the information drawn out of myelography and MCT can be obtained by a completion of noninvasive examinations (native CT and radiographs).

Fourth Ventricular AVM with Transdural Drainage.

Arteriovenous malformations (AVMs) of the fourth ventricle are exceptionally rare subtypes of brainstem AVMs. This report illustrates the case of a young man who suffered intraventricular and subarachnoid hemorrhage. Angiography depicted a fourth ventricular AVM that was supplied by branches of the right posterior inferior cerebellar artery and drained via a posterior medullary midline vein into the marginal sinus and cervical radicular and nuchal veins. The drainage pattern is highly uncommon and constitutes a particular challenge for the operative approach.

High-Efficiency Transfection of Glioblastoma Cells and a Simple Spheroid Migration Assay.

Despite international research efforts, patients with glioblastoma multiforme (GBM)-the most common malignant brain tumors in adults-exhibit a very unfavorable prognosis. Their aggressive local growth pattern and increased invasiveness, due to a high motility of the tumor cells, hamper treatment. However, the molecular mechanisms regulating glioblastoma cell migration are still elusive. Here, we describe the combination of a highly efficient cell transfection by Nucleofection® technology and the generation of spheroids from these transfected glioblastoma cell lines. Nucleofection allows the manipulation of protein expression by overexpression and siRNA mediated protein knockdown. Transfection efficiencies >70% can be achieved with some GBM cell lines. Transfected neurospheres then can be used for migration assays (as described here in detail) and a multitude of other functional assays. In comparison to monolayer cultures, the advantage of spheroids is their resemblance with organized tissue in combination with the accuracy of in vitro methodology and marked experimental flexibility.