Optical Neuronavigation without Rigid Head Fixation During Awake Surgery.

OBJECTIVE: Optical neuronavigation without rigid pin fixation of the head may lead to inaccurate results because of the patient's movements during awake surgery. In this study, we report our results using a skull-mounted reference array for optical tracking in patients undergoing awake craniotomy for eloquent gliomas. METHODS: Between March 2013 and December 2014, 18 consecutive patients (10 men, 8 women) with frontotemporal (n = 16) or frontoparietal (perirolandic; n = 2) lesions underwent awake craniotomy without rigid pin fixation. All patients had a skull-mounted reference array for optical tracking placed on the forehead. Accuracy of navigation was determined with pointer tip deviation measurements on superficial and bony anatomic structures. Good accuracy was defined as a tip deviation <2 mm. RESULTS: Gross total resection (>98%) was achieved in 7 patients (38%); >90% of tumor was resected in 8 patients (44%). In 3 patients, only subtotal resection or biopsy was performed secondary to stimulation results. In all patients, good accuracy of the optical neuronavigation system could be demonstrated without intraoperative peculiarities or complications. The reference array had to be repositioned because of loosening in 1 patient. Neuronavigation could be reliably applied to support stimulation-based resection. CONCLUSIONS: A skull-mounted reference array is a simple and safe method for optical neuronavigation tracking without rigid pin fixation of the patient's head.

Decompressive Hemicraniectomy in Malignant Middle Cerebral Artery Infarction: The 'Real World' Beyond Studies.

BACKGROUND: Decompressive hemicraniectomy (DHC) is life-saving in patients with malignant middle cerebral artery infarction (MMI), but outcome, perspectives and complications after DHC in daily practice are largely unknown. METHODS: From 2008 until 2014, we extracted patient's characteristics as well as complications from our database for patients with MMI who underwent DHC. Additionally, we analysed medical records from the different rehabilitation steps. RESULTS: We identified 48 consecutive patients (mean 57 years, 21 male, 41.7% >60 years) with MMI who underwent DHC. The decision for DHC was made on an individual basis, including patients without impaired consciousness or stroke onset >48 h. In-hospital patients achieved only marginal clinical improvement. Seventy-five percent attended an early-rehabilitation, 44% achieved post-stroke rehabilitation and 6% carried on late-stage rehabilitation. In all, 45.5% returned home after rehabilitation. In-hospital mortality was 14.6%, overall mortality was 16.7%. Surviving patients (78.9%) had a modified Rankin Scale of 4-5. Frequent neurologic complications were symptomatic epilepsy and delirium. Following DHC/bone-flap-reimplantation, wound-healing disorders, epidural hematoma and wound infections were major surgery-related complications. Pulmonary infections were frequent in the acute-phase and urinary tract infections were predominant in the late-phase. CONCLUSIONS: DHC is a life-saving technique in patients with MMI, but complications are frequent, were underestimated in randomized clinical trials and may worsen the functional outcome.

Retinal Vessel Analysis (RVA) in the Context of Subarachnoid Hemorrhage - A Proof of Concept Study.

BACKGROUND: Timely detection of impending delayed cerebral ischemia after subarachnoid hemorrhage (SAH) is essential to improve outcome, but poses a diagnostic challenge. Retinal vessels as an embryological part of the intracranial vasculature are easily accessible for analysis and may hold the key to a new and non-invasive monitoring technique. This investigation aims to determine the feasibility of standardized retinal vessel analysis (RVA) in the context of SAH. METHODS: In a prospective pilot study, we performed RVA in six patients awake and cooperative with SAH in the acute phase (day 2-14) and eight patients at the time of follow-up (mean 4.6±1.7months after SAH), and included 33 age-matched healthy controls. Data was acquired using a manoeuvrable Dynamic Vessel Analyzer (Imedos Systems UG, Jena) for examination of retinal vessel dimension and neurovascular coupling. RESULTS: Image quality was satisfactory in the majority of cases (93.3%). In the acute phase after SAH, retinal arteries were significantly dilated when compared to the control group (124.2±4.3MU vs 110.9±11.4MU, p<0.01), a difference that persisted to a lesser extent in the later stage of the disease (122.7±17.2MU, p<0.05). Testing for neurovascular coupling showed a trend towards impaired primary vasodilation and secondary vasoconstriction (p = 0.08, p = 0.09 resp.) initially and partial recovery at the time of follow-up, indicating a relative improvement in a time-dependent fashion. CONCLUSION: RVA is technically feasible in patients with SAH and can detect fluctuations in vessel diameter and autoregulation even in less severely affected patients. Preliminary data suggests potential for RVA as a new and non-invasive tool for advanced SAH monitoring, but clinical relevance and prognostic value will have to be determined in a larger cohort.

A Sandwich Technique for Prevention of Cerebrospinal Fluid Rhinorrhea and Reconstruction of the Sellar Floor after Microsurgical Transsphenoidal Pituitary Surgery.

BACKGROUND: Cerebrospinal fluid (CSF) leaks are a well-known complication of transsphenoidal surgery. Several autologous and artificial grafts have been used to close the sellar floor in an attempt to prevent postoperative CSF rhinorrhea. OBJECTIVE: To evaluate and describe a sandwich technique to close the sellar floor using autologous bone, absorbable gelatin sponge, and coated collagen fleece. METHODS: We reviewed 50 consecutive patients between April 2010 and August 2011 who underwent transsphenoidal surgery ending with reconstruction of the sellar floor with a particular sandwich technique. Patients with an intraoperative CSF leak received an additional lumbar drain. RESULTS: There were no cases of CSF rhinorrhea at postoperative follow-up after 6 weeks and no revision surgery. CONCLUSION: The proposed sandwich technique for closure of the sellar floor to the sphenoid sinus is a suitable alternative to autologous grafts and seems to be effective in preventing CSF rhinorrhea.

Dual Anti-angiogenic Chemotherapy with Temozolomide and Celecoxib in Selected Patients with Malignant Glioma Not Eligible for Standard Treatment.

AIM: Due to their high rate of neo-angiogenesis, malignant gliomas may qualify for treatment with anti-angiogenic substances. We report on a series of patients with malignant glioma not eligible for standard postoperative combined radiochemotherapy due to decreased health status. PATIENTS AND METHODS: A total of nine patients with malignant glioma, postoperatively presenting with a Karnofsky performance score (KPS) below 70, were treated with standalone metronomic low-dose chemotherapy with temozolomide and celecoxib (cyclo-oxygenase-2 inhibitor). Overall survival was defined as the primary end-point and the functional status (KPS) and time to progression as secondary end-points of our analysis. RESULTS: The median KPS after surgery was 60. Treatment achieved a decrease in tumor and edema volume and, more importantly, preserved the functional status defined as the ability to care for self (KPS 70%) until disease progression. No notable side-effects were recorded. CONCLUSION: In patients with decreased general condition (KPS <70), not eligible for standard treatment, anti-angiogenic therapy offers a reasonable alternative approach. Our results indicate prolonged survival and preserved quality of life in comparison to best supportive care.

An intra-individual comparison of MRI, [18F]-FET and [18F]-FLT PET in patients with high-grade gliomas.

OBJECTIVES: Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [18F]-FET and the nucleoside PET tracer [18F]-FLT in high-grade gliomas (HGG). METHODS: MRI, [18F]-FET and [18F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for [18F]-FET and [18F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearman's rank correlation coefficient and the Mann-Whitney U test. RESULTS: [18F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [18F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [18F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [18F]-FET PET detected 22 of 23 (96%) HGG. [18F]-FET uptake beyond areas of cT1 was found in 61% of cases and [18F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [18F]-FET compared to [18F]-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001). CONCLUSION: In HGG [18F]-FET but not [18F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [18F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [18F]-FLT tracer uptake.

Perfusion characteristics of Moyamoya disease: an anatomically and clinically oriented analysis and comparison.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is characterized by unique angiographic features of collateralization. However, a detailed quantification as well as comparative analysis with cerebrovascular atherosclerotic disease (CAD) and healthy controls have not been performed to date. METHODS: We reviewed 67 patients with MMD undergoing Xenon-enhanced computed tomography, as well as 108 patients with CAD and 5 controls. In addition to cortical, central, and infratentorial regions of interest, particular emphasis was put on regions that are typically involved in MMD (pericallosal territory, basal ganglia). Cerebral blood flow (CBF), cerebrovascular reserve capacity (CVRC), and hemodynamic stress distribution were calculated. RESULTS: MMD is characterized by a significant, ubiquitous decrease in CVRC and a cortical but not pericallosal decrease in CBF when compared with controls. Baseline perfusion is maintained within the basal ganglia, and hemodynamic stress distribution confirmed a relative preservation of central regions of interest in MMD, indicative for its characteristic proximal collateralization pattern. In MMD and CAD, cortical and central CBF decreased significantly with age, whereas CVRC and hemodynamic stress distribution are relatively unaffected by age. No difference in CVRC of comparable regions of interest was seen between MMD and CAD, but stress distribution was significantly higher in MMD, illustrating the functionality of the characteristic rete mirabilis. CONCLUSIONS: Our data provide quantitative support for a territory-specific perfusion pattern that is unique for MMD, including central preservation of CBF compared with controls and patients with CAD. This correlates well with its characteristic feature of proximal collateralization. CVRC and hemodynamic stress distribution seem to be more robust parameters than CBF alone for assessment of disease severity.

A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07).

BACKGROUND: Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. METHODS: This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. RESULTS: Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. CONCLUSION: Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.

Risk profile in extracranial/intracranial bypass surgery--the role of antiplatelet agents, disease pathology, and surgical technique in 168 direct revascularization procedures.

OBJECTIVE: Cerebral revascularization procedures are a treatment option in moyamoya disease patients, but recent studies failed to show an immediate benefit in cerebrovascular atherosclerotic disease. To facilitate optimal efficacy of the procedure, a detailed characterization of a representative perioperative complication rate and the role of potential risk factors such as underlying pathology, antiplatelet therapy, and the type of surgery performed is warranted and the purpose of this study. METHODS: We included 158 consecutive patients with moyamoya disease or cerebrovascular atherosclerotic disease undergoing 168 direct revascularization procedures. Type of disease, antiplatelet therapy, coagulation disorders, surgical technique, intraoperative complications, postoperative imaging, the need for revision, and outcome at time of discharge were analyzed. RESULTS: Complication rate was low, with a high patency rate of 97%. Six hemispheres (3.6%) needed to undergo surgical revision; early morbidity was 10.7% with no mortality, with evidence of ischemia in 6.9% of patients. Type of pathology treated and surgical technique did not influence outcome. Antiplatelet treatment was not associated with an increased risk for hemorrhage or revision, but improved outcome (P < 0.05). Ischemia, hemorrhage, and the need for revision aggravated outcome at time of discharge. CONCLUSION: Extra-/intracranial bypass surgery remains a treatment option in patients with moyamoya disease, although its use in the context of atherosclerotic disease was recently put into question. Regardless, a detailed characterization of perioperative risk factors is needed to optimize a potential long-term benefit of surgery. At a high-volume center, the complication rate is low independent from the underlying pathology with a high patency rate. Antiplatelet treatment does not increase the risk of hemorrhagic complications, but may improve outcome. Longer follow-up is required to adequately assess the true efficacy of revascularization on stroke prevention.

Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system.

Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2 mutations (p < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution.

Routine postoperative imaging early after lumbar decompression surgery: a prospective evaluation.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To determine the value of routine postoperative magnetic resonance imaging early after lumbar decompression in patients with nonspecific symptoms. SUMMARY OF BACKGROUND DATA: Imaging after lumbar surgery may be performed more readily in patients even with nonspecific symptoms and without neurological deficit. METHODS: Patients undergoing elective lumbar decompression surgery completed standardized questionnaires, were assessed neurologically on admission, and underwent magnetic resonance scanning within 72 hours after surgery. Residual stenosis was graded as absent or mild (outcome A) or moderate to severe (outcome B). Surgical technique and intraoperative complications and postoperative neurological status were recorded. RESULTS: We recruited 28 consecutive patients who reported significant improvement in preoperative symptoms. In two-thirds of all patients, postoperative images showed at least one segment with moderate or severe residual stenosis (outcome B). Radiological outcome did not correlate with postoperative pain. Patient satisfaction index was comparable in groups A and B. The cross section of the spinal canal was significantly wider with a drain in situ. This did not, however, translate into a difference in overall visual analogue scale score or wound discomfort. Patients tended to report more back and leg pain with drains and were less satisfied with the result of the operation. CONCLUSION: Early postoperative magnetic resonance scans in patients with nonspecific symptoms frequently show radiologically relevant stenosis, which is associated with neither outcome nor patient satisfaction. Drain placement is associated with less radiological narrowing but with lower patient satisfaction. Imaging without clinical correlate may yield nondiscriminatory information likely to unsettle and puzzle both patients and health care providers. LEVEL OF EVIDENCE: 3.

[18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma.

BACKGROUND: To assess the sensitivity and specificity of [(18)F]-fluoro-ethyl-l-tyrosine ((18)F-FET) PET in brain tumors and various non-neoplastic neurologic diseases. METHODS: We retrospectively evaluated (18)F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). (18)F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense). RESULTS: Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed (18)F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher (18)F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). (18)F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions. CONCLUSIONS: (18)F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood-brain barrier and (18)F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.

Distance to the neurooncological center: a negative prognostic factor in patients with glioblastoma multiforme. An epidemiological study.

BACKGROUND: Regardless of current multimodal treatment strategies, the prognosis of patients harboring glioblastoma multiforme (GBM) is still dismal. The introduction of concomitant radiochemotherapy and adjuvant cyclic temozolomide has significantly improved the overall survival, compared to postoperative radiotherapy-alone. Furthermore this regimen shows a lower toxicity profile compared to previous nitrosourea-based chemotherapy and can easily be applied on an outpatient basis, thus potentially facilitating chemotherapy in rural and more remote areas. The distance to the oncological center has been shown to be a negative prognostic parameter in other types of cancer. Therefore, we aimed to investigate whether the introduction of temozolomide as the standard regimen in the treatment of GBM has influenced the administration of chemotherapy and the prognosis of patients depending on the distance to our neurooncological center. PATIENTS AND METHODS: A total of 208 patients diagnosed with GBM (M:F=1.4:1), surgically resected between 1990 and 2009, thus covering the pre-temozolomide and the temozolomide-era, were included retrospectively in this analysis. The distance from the patients' residences to the neurooncological center was determined and statistical analysis was performed to assess its influence on overall survival and administration of adjuvant treatment (radiotherapy-only, nitrosourea-based chemotherapy and adjuvant temozolomide). RESULTS: Overall, 41.3% of the cohort underwent subtotal surgical resection, whereas a gross total resection was accomplished in 57.2%. The median distance to the neurooncological center was 75 km (range=1-870 km). Postoperatively, 68 patients (32.7%) received concomitant and adjuvant radiochemotherapy with temozolomide, 31 (14.9%) were treated with nitrosourea other than the Procarbazin, Lomustin, Vincristin (PCV), 34 (16.3%) with PCV, and 71 patients (34.1%) had radiotherapy-alone. The distance to the neurooncological center had a significant influence on overall survival for the whole cohort (p=0.027) and patients with increasing distances, were significantly less often treated with chemotherapy (p=0.05). With the introduction of temozolomide this relation was lost (overall survival, temozolomide and other agents: p=0.685/p=0.007; administration of adjuvant chemotherapy in the temozolomide-era/whole cohort: p=0.612/p=0.05). CONCLUSION: The distance to the neurooncological center negatively-influenced the prognosis of patients with GBM. Patients were less often treated with adjuvant chemotherapy in the pre-temozolomide era with increasing distance to the neurooncological center. Although the introduction of temozolomide as the standard chemotherapeutic agent in GBM treatment changed this fact, the influence of the distance to the specialized center should be kept in mind as a prognostic factor for this disease.

Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients.

APG101 is a glycosylated fusion protein consisting of the extracellular domain of human CD95 (APO-1/Fas) and the Fc domain of human IgG1. Administration of APG101 blocks the interaction between CD95 and its cognate ligand CD95L, thereby inhibiting various pathways involved in e.g. proliferation, migration, differentiation and apoptosis induction. The safety and tolerability of ascending single doses of intravenously applied APG101 was examined in a randomized, double-blind, placebo-controlled, mono-centre "first in man" dose escalation study in 34 healthy male volunteers. Pharmacokinetics and pharmacodynamics were also assessed. The maximum serum concentration of 460 µg/ml was achieved following 1h infusion of the highest dose of 20 mg/kg. The systemic clearance was low (0.4 to 0.5 ml/hkg). Mean terminal elimination half-life was 12 to 15 days. Two patients suffering from malignant glioma received APG101 intravenously under compassionate use conditions. They received doses ranging from 5mg to 600 mg APG101. No adverse events and no clinical significant changes in laboratory parameters related to APG101 were reported. The presence of anti-drug-antibodies (ADA) was investigated and revealed no detectable levels of ADA. Overall, single ascending doses of APG101 up to 20 mg/kgbody weight (bw) administered as infusion over 1h were considered as safe and well tolerated in healthy volunteers. After the application of multiple doses of 400 mg in two glioma patients, steady state for APG101 seemed to be reached. These results support further clinical evaluation of APG101 at a dose of 400 mg per week in glioblastoma patients.

Aneurysmal subarachnoid hemorrhage (aSAH) results in low prevalence of neuro-endocrine dysfunction and NOT deficiency.

Neuro-endocrine deficiencies have been argued to be common sequelae after aneurysmal subarachnoid hemorrhage (aSAH). As this, however, does not resemble our clinical experience, we studied the incidence of neuro-endocrine and neuropsychological deficits after aSAH. Twenty-six patients (20 females) were prospectively screened for neuro-endocrine and neuropsychological deficits 3, 6 and 12 months after aSAH. GH, IGF-1, prolactin, LH, FSH, estradiol, testosterone, ACTH as well as cortisol during ACTH-stimulation were assessed. Neuropsychological analysis covered verbal comprehension, short term and working memory, visuospatial construction, figural memory, psychomotor speed, attention, and concentration. During the study period 5 individuals demonstrated neuro-endocrine dysfunction. Hypogonadotrophic hypogonadism resolved spontaneously in 2 patients and central hypothyroidism in one of these patients during the study. After 12 months three patients presented low IGF-1 levels. 73.9% of our cohort was affected by neuropsychological deficits during follow-up. At 3, 6 and 12 months the prevalences were 56.5, 52.6 and 42.1%, respectively. Interestingly, all patients with neuro-endocrine dysfunction presented impaired clinical outcome with a GOS 4 at some time point of the study (GOS 4 vs. 5, 45.5% vs. 0, P = 0.007). We found a low prevalence of neuro-endocrine and a high prevalence of neuropsychological deficits in patients 3, 6 and 12 months after aSAH without significant interrelation. Spontaneous recovery of neuro-endocrine alterations most likely presents an adaption to or dysfunction after severe illness. This hypothesis is strengthened by the fact that only patients with inferior clinical outcome after aSAH as assessed by GOS demonstrated neuro-endocrine dysfunction.

Correlation of the Ga-68-bombesin analog Ga-68-BZH3 with receptors expression in gliomas as measured by quantitative dynamic positron emission tomography (dPET) and gene arrays.

PURPOSE: The kinetics of Ga-68-BZH3, a Ga-68-bombesin analog, was compared to molecular biological data obtained from gene arrays in seven patients with a recurrent glioma. The primary aim of this study was the correlation of receptor expression and tracer kinetics. PROCEDURES: Dynamic positron emission tomography studies were performed and the data were analyzed by a volume-of-interest technique using a two-tissue compartment model as well as a non-compartment model. Gene array data were obtained from gene array analysis of tumor tissue samples. RESULTS: The correlation analysis revealed a significant nonlinear correlation of r = 0.89 (p < 0.03) for k1 and BB(2) (gastrin-releasing peptide receptor). BB(1) and BB(3) were not significantly correlated with k1. vb and k3 were not significantly correlated with the expression data of the receptors on the p < 0.05 level. CONCLUSIONS: The parameter k1 is correlated with the expression of BB(2) based on gene array data. The quantitative analysis of the Ga-68-BZH3 kinetics can be used to predict the receptor expression of BB(2) in gliomas based on k1 of the compartment analysis. However, this study is limited to the expression data on the mRNA level and further studies are needed to assess the correlation of gene expression on the protein level.

Perfusion Characteristics in Chronic Cerebrovascular Insufficiency : An Anatomically and Clinically Oriented XeCT Analysis of Cerebrovascular Atherosclerotic Disease.

Xenon-enhanced computed tomography (XeCT) allows quantification of hemodynamic insufficiency in the setting of cerebrovascular atherosclerotic disease (CAD). However, data regarding the relationship between hemodynamic indices [cerebral blood flow (CBF) and cerebrovascular reserve capacity (CVRC)] and normal subjects (with aging) and pathology (progression of CAD or development of stroke symptoms) are limited. In this study, we analyzed 103 consecutive patients undergoing XeCT according to age, anatomical location and disease severity. We stratified anatomically defined ROIs according to a classification system that observes the presence of proximal stenosis (class I vs. class II/III) as well as the presence of neurological symptoms (class II vs. III); CBF, CVRC and hemodynamic stress distribution were calculated. Supratentorial CBF decreases significantly with age, but not infratentorially. Cortical CVRC remains stable over time. Our classification of disease severity correlated highly significantly with a decrease in supratentorial CBF and CVRC, though CVRC is less sensitive to age-related changes. Regression analysis delineated a CVRC of 34% to discriminate between ROI classes. Age-dependent perfusion characteristics in normal vascular territories were characterized. In CAD, CVRC remains the most sensitive parameter. A simplified classification of ROIs according to disease severity correlates well with established markers for hemodynamic insufficiency. It may facilitate comparison of different pathologies such as CAD and Moyamoya disease and will be the focus of further studies.

Feasibility of intraventricular nicardipine prolonged release implants in patients following aneurysmal subarachnoid haemorrhage.

OBJECTIVE: Intracisternal nicardipine prolonged release implants (NPRI) have been shown to be effective in the prophylaxis of cerebral vasospasm (VS). However, they cannot be used in patients following coil occlusion of the aneurysm. As a certain dissemination of nicardipine within the cerebrospinal fluid (CSF) has been described, we examined the feasibility of intraventricular use of NPRI in patients that underwent clip and coil occlusion of their aneurysms following aneurysmal subarachnoid haemorrhage (aSAH). By comparison with an historical control group, an estimation of their effectivity in regard to angiographic vasospasm and the development of cerebral infarction has been performed. METHODS: Thirty-one patients suffering from aSAH were prospectively included in this trial. Study participants received prior to clipping (n = 17) or coiling (n = 14) 6 (n = 15) or 10 NPRI (n = 16) into the lateral ventricles. Physiological data were collected, proximal and global VS were determined using pre-operative and day 8 ± 1 angiography, and incidence of hydrocephalus and VS related infarcts were evaluated and compared to a historical control group consisting of 16 operated patients without NPRI implantation. RESULTS: Intraventricular NPRI were tolerated well. There were no adverse side effects detectable, physiological variables such as heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP) and electrolytes showed no difference compared to control. There was no difference in the proportion of patients that required CSF shunting. A significant positive angiographic effect could only be observed in clipped patients (proximal vessel diameters: control, 80 ± 30%; NPRI 90 ± 24%; incidence of moderate/severe global VS: control, 73%; NPRI, 41%). CONCLUSIONS: The use of intraventricular NPRI seems to be safe and tolerated well. There is preliminary evidence for effectivity on angiographic VS for clipped patients only. A further increase of the effective dose might also exert efficacy in the subset of patients following coil occlusion.

Pharmacokinetic studies of 68Ga-labeled Bombesin (68Ga-BZH3) and F-18 FDG PET in patients with recurrent gliomas and comparison to grading: preliminary results.

PURPOSE: Dynamic PET studies with a 68Ga-Bombesin analog, the 68Ga-BZH3, were performed in patients with highly suspected recurrent gliomas to investigate the effect of the receptor scintigraphy on tumor grading. Furthermore, dynamic F-18 Fluorodeoxyglucose (FDG) studies were performed for comparison. METHODS: The study consisted of 15 patients with histologically confirmed recurrent gliomas. Dynamic PET scans using 68Ga-BZH3 and FDG were obtained on 2 different days within 1 week. Multivariate analysis was used for the evaluation of the kinetic data. Standardized uptake values were calculated and a compartment (2-tissue) as well as a noncompartment model was used for data evaluation of both tracers. RESULTS: The evaluation includes 6 patients with a WHO II, 6 patients with a WHO III, and 3 patients with a WHO IV recurrent gliomas. Of the 15 patients, 10 patients demonstrated an increased 68Ga-BZH3 uptake visually, 3 of them with a WHO II, 4 with a WHO III, and 3 with a WHO IV tumor. Of the 15 patients, 6 patients revealed an enhanced FDG metabolism visually, 3 of them with a WHO II, and 3 with a WHO III. None of the 3 patients with WHO IV tumor demonstrated an enhanced FDG-uptake. Discriminant analysis based on a combination of FDG influx and binding potential of 68Ga-BZH3 best discriminated between low- and high-grade gliomas with a correct classification rate of 100%. CONCLUSIONS: 68Ga-BZH3 seems to be helpful in patients with recurrent gliomas for the differentiation between low- and high-grade gliomas. Overall, the quantitative evaluation was superior to the visual analysis and the parameters of the 68Ga-BZH3 kinetics were more helpful than those of FDG for the differentiation between low- and high-grade gliomas.