Biomedical subjects

Peter Vajkoczy

Publications and source records attributed to Peter Vajkoczy.

At least 19 recordsLinked to original sources

PubMed2007

High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells.

Endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. Integrins contribute to EPC homing. High-mobility group box 1 (HMGB1) is a nuclear protein that is released extracellularly on cell necrosis and tissue damage, eliciting a proinflammatory response and stimulating tissue repair. In the present study, we investigated the effects of HMGB1 on EPC homing. EPCs express the HMGB1 receptors RAGE (receptor for advanced glycation end products) and TLR2 (Toll-like receptor 2). EPC migration was stimulated by HMGB1 in a RAGE-dependent manner. In addition, the HMGB1-induced migration of EPCs on fibronectin and fibrinogen was significantly inhibited by antibodies against beta1 and beta2 integrins, respectively. Short-term prestimulation of EPCs with HMGB1 also increased EPC adhesion to endothelial cell monolayers, and this effect was blocked by antibodies to beta2 integrins or RAGE. HMGB1 increased EPC adhesion to the immobilized integrin ligands intercellular adhesion molecule-1 and fibronectin in a RAGE-dependent manner. Strikingly, HMGB1 rapidly increased integrin affinity and induced integrin polarization. Using intravital microscopy in a tumor model of neovascularization, prestimulation of EPCs with HMGB1 enhanced the initial in vivo adhesion of EPCs to microvessels and the recruitment of EPCs in the tumor tissue. In addition, prestimulation of EPCs with HMGB1 increased the homing of EPCs to ischemic muscles. In conclusion, these data represent a link between HMGB1 and integrin functions of EPCs and demonstrate that HMGB1 stimulates EPC homing to ischemic tissues. These results may provide a platform for the development of novel therapeutic approaches to improve EPC homing.

Animals↗

PubMed2006

Effect of nicardipine prolonged-release implants on cerebral vasospasm and clinical outcome after severe aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind phase IIa study.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the effect of nicardipine prolonged-release implants (NPRIs) on cerebral vasospasm and clinical outcome after severe subarachnoid hemorrhage. METHODS: Thirty-two patients with severe subarachnoid hemorrhage and undergoing aneurysm clipping were included into this single center, randomized, double-blind trial. Sixteen patients received NPRIs implanted into the basal cisterns in direct contact to the exposed proximal blood vessels; in 16 control patients, the basal cisterns were opened and washed out only without leaving implants. Angiography was performed preoperatively and at day 8+/-1. Computed tomography imaging was analyzed for the incidence of territorial infarcts unrelated to surgery. Patient outcome was assessed using the modified Rankin and National Institute of Health Stroke scales. RESULTS: The incidence of angiographic vasospasm in proximal vessel segments was significantly reduced after implantation of NPRIs (73% control versus 7% NPRIs). Significant differences occurred also for the majority of distal vessel segments. Computed tomography scans revealed a lower incidence of delayed ischemic lesions (47% control versus 14% NPRIs). The NPRI group demonstrated more favorable modified Rankin and National Institute of Health Stroke scales as well as a significantly lower incidence of deaths (38% control versus 6% NPRIs). CONCLUSIONS: Implantation of NPRIs reduces the incidence of cerebral vasospasm and delayed ischemic deficits and improves clinical outcome after severe subarachnoid hemorrhage.

Adult↗

PubMed2006

Increased vessel diameter of leptomeningeal anastomoses after hypoxic preconditioning.

Recently, cerebral blood flow changes were re-discussed to contribute to tissue protection after preconditioning. In the present study, we demonstrate increased vessel diameters of the leptomeningeal anastomoses after hypoxic preconditioning by visualization of the brain angioarchitecture using the latex perfusion technique. This finding may display the anatomical correlate to previously described perfusion changes after preconditioning.

Animals↗

PubMed2006

Cortical perfusion measurement by indocyanine-green videoangiography in patients undergoing hemicraniectomy for malignant stroke.

BACKGROUND AND PURPOSE: Assessment of cerebral perfusion during neurosurgical procedures would be beneficial to identify areas at risk and to guide placement of monitoring probes. Therefore, we have adapted near-infrared indocyanine-green (ICG) videoangiography to assess cortical perfusion intraoperatively. METHODS: ICG videoangiography was performed intraoperatively in 6 patients after decompressive hemicraniectomy for middle cerebral artery stroke. Flow maps of cortical perfusion were generated with IC-CALC 1.1 software by calculating the ratio of difference in fluorescence intensity and rise time. RESULTS: Excellent visualization of cerebral arteries, cortical perfusion and collateral circulation via leptomeningeal anastomoses could be demonstrated in all cases. Flow maps revealed high spatial resolution and showed heterogeneous maple-leaf-shaped hypoperfusion. 26.5+/-13.7% and 29.0+/-9.1% of the exposed cortical surface (141+/-18 cm2) demonstrated core and penumbral flow, respectively. CONCLUSIONS: ICG videoangiography appears to be a valuable tool to precisely detect relative cortical tissue perfusion. Thus, it may provide useful research data on the pathophysiology of human stroke, help surgeons to maintain adequate brain perfusion intraoperatively, and simplify adequate placement of tissue probes to monitor critically hypoperfused brain tissue.

Adult↗

PubMed2006

Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival.

Malignant gliomas remain incurable brain tumors because of their diffuse-invasive growth. So far, the genetic and molecular events underlying gliomagenesis are poorly understood. In this study, we have identified the receptor tyrosine kinase Axl as a mediator of glioma growth and invasion. We demonstrate that Axl and its ligand Gas6 are overexpressed in human glioma cell lines and that Axl is activated under baseline conditions. Furthermore, Axl is expressed at high levels in human malignant glioma. Inhibition of Axl signaling by overexpression of a dominant-negative receptor mutant (AXL-DN) suppressed experimental gliomagenesis (growth inhibition >85%, P < 0.05) and resulted in long-term survival of mice after intracerebral glioma cell implantation when compared with Axl wild-type (AXL-WT) transfected tumor cells (survival times: AXL-WT, 10 days; AXL-DN, >72 days). A detailed analysis of the distinct hallmarks of glioma pathology, such as cell proliferation, migration, and invasion and tumor angiogenesis, revealed that inhibition of Axl signaling interfered with cell proliferation (inhibition 30% versus AXL-WT), glioma cell migration (inhibition 90% versus mock and AXL-WT, P < 0.05), and invasion (inhibition 62% and 79% versus mock and AXL-WT, respectively; P < 0.05). This study describes the identification, functional manipulation, in vitro and in vivo validation, and preclinical therapeutic inhibition of a target receptor tyrosine kinase mediating glioma growth and invasion. Our findings implicate Axl in gliomagenesis and validate it as a promising target for the development of approaches toward a therapy of these highly aggressive but, as yet, therapy-refractory, tumors.

Animals↗

PubMed2006

Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

Angiopoietin-1↗

PubMed2006

EphB4 controls blood vascular morphogenesis during postnatal angiogenesis.

Guidance molecules have attracted interest by demonstration that they regulate patterning of the blood vascular system during development. However, their significance during postnatal angiogenesis has remained unknown. Here, we demonstrate that endothelial cells of human malignant brain tumors also express guidance molecules, such as EphB4 and its ligand ephrinB2. To study their function, EphB4 variants were overexpressed in blood vessels of tumor xenografts. Our studies revealed that EphB4 acts as a negative regulator of blood vessel branching and vascular network formation, switching the vascularization program from sprouting angiogenesis to circumferential vessel growth. In parallel, EphB4 reduces the permeability of the tumor vascular system via activation of the angiopoietin-1/Tie2 system at the endothelium/pericyte interface. Furthermore, overexpression of EphB4 variants in blood vessels during (i) vascularization of non-neoplastic cell grafts and (ii) retinal vascularization revealed that these functions of EphB4 apply to postnatal, non-neoplastic angiogenesis in general. This implies that both neoplastic and non-neoplastic vascularization is driven not only by a vascular initiation program but also by a vascular patterning program mediated by guidance molecules.

Angiopoietin-1↗

PubMed2006

Current advances in the diagnosis of vasospasm.

Symptomatic vasospasm leading to delayed ischemia and neurological deficits is one of the most serious complications after aneurysmal subarachnoid hemorrhage (SAH). Reliable and early detection of symptomatic vasospasm is one of the major goals in the management of patients with SAH. In awake patients, the close clinical neurological examination still remains the most important diagnostic measure. In comatous or sedated patients, cerebral angiography remains the mainstay of the diagnostic workup for vasospasm. However, angiography does not allow assessing the hemodynamic relevance of vasospasm and is not suited for early identification of cerebral hypoperfusion and ischemia. Therefore, a large panel of new monitoring techniques for the assessment of regional cerebral perfusion has been recently introduced into the clinical management of SAH patients. This article briefly reviews the most relevant methods for monitoring cerebral perfusion and discusses their clinical predictive value for the diagnosis of vasospasm. On the basis of the currently available monitoring technologies, an algorithm for the diagnosis of vasospasm is presented.

Algorithms↗

PubMed2005

Cathepsin L is required for endothelial progenitor cell-induced neovascularization.

Infusion of endothelial progenitor cells (EPC), but not of mature endothelial cells, promotes neovascularization after ischemia. We performed gene expression profiling of EPC and endothelial cells to identify genes that might be important for the neovascularization capacity of EPC. Notably, the protease cathepsin L (CathL) was highly expressed in EPC as opposed to endothelial cells and was essential for matrix degradation and invasion by EPC in vitro. CathL-deficient mice showed impaired functional recovery following hind limb ischemia, supporting the concept of a crucial role for CathL in postnatal neovascularization. Infused CathL-deficient progenitor cells neither homed to sites of ischemia nor augmented neovascularization. Forced expression of CathL in mature endothelial cells considerably enhanced their invasive activity and sufficed to confer their capacity for neovascularization in vivo. We concluded that CathL has a critical role in the integration of circulating EPC into ischemic tissue and is required for EPC-mediated neovascularization.

Animals↗

PubMed2005

Hemodynamic reserve and high-intensity transient signals in moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) as a rare obstructive cerebrovascular disease is assumed to present with ischemic symptoms due to hemodynamic compromise. However, alternative mechanisms, such as cerebral embolism in low-flow territories, may also contribute to clinical symptoms. The incidence of high-intensity transient signals (HITS) and the degree of hemodynamic compromise were studied in symptomatic patients with MMD. METHODS: Twenty-four patients (17 female, 7 male; mean age 33 +/- 13 years) with clinical symptoms attributable to cerebral ischemia and the angiographic features of MMD (21 definite form, 3 probable MMD; 22 patients 'late stage' MMD, 2 patients 'early stage' MMD) in 45 affected hemispheres were enrolled in the present study. Patients underwent parallel estimation of hemodynamic compromise by means of functional blood flow (rCBF) studies using SPECT, PET or xenon-CT and HITS detection by TCD. RESULTS: Hemodynamic compromise was observed in 37/40 (92%) hemispheres studied. During TCD monitoring, HITS were detected in 3 patients (12.5%), with a total frequency of 3 (6.6%) in the 45 hemispheres investigated. All patients with HITS showed hemodynamic compromise in functional rCBF studies. In these patients, HITS were recorded ipsilateral to the symptomatic hemisphere. HITS occurred in late stage MMD patients only once, while both cases with early stage MMD demonstrated multiple HITS. CONCLUSIONS: The incidence of HITS in patients with MMD appears to be lower compared to patients with atherosclerotic or atherothrombotic arterial obstructions. In addition, ischemia-related symptoms in 'late stage' MMD seem to be caused by hemodynamic compromise in the majority of these patients.

Adult↗

PubMed2005

ELANA: Excimer Laser-Assisted Nonocclusive Anastomosis for extracranial-to-intracranial and intracranial-to-intracranial bypass: a review.

ELANA, excimer laser-assisted nonocclusive anastomosis, is a technique using an excimer laser/catheter system for intracranial bypass surgery of the brain. The technique has been developed over the past 12 years by Tulleken and colleagues at UMC Utrecht in The Netherlands for treatment of primarily untreatable giant aneurysms. We review here the emergence of transplanted conduit bypass as a valuable technique for managing these lesions and the subsequent development of ELANA bypass. The ELANA technique allows the operating surgeon to perform an extracranial-to-intracranial or intracranial-to-intracranial bypass using a transplanted large caliber conduit without occlusion of the recipient artery, thus eliminating intraoperative ischemic insult related to temporary occlusion time. We describe the ELANA technique, illustrate it with intraoperative photos, and review the relevant literature. ELANA is shown to be safe; we discuss its advantages over conventional techniques.

Journal Article↗

PubMed2005

Effects of positive end-expiratory pressure on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation.

OBJECTIVE: Acute respiratory dysfunction frequently occurs following severe aneurysmal subarachnoid hemorrhage requiring positive end-expiratory pressure (PEEP) ventilation to maintain adequate oxygenation. High PEEP levels, however, may negatively affect cerebral perfusion. The goal of this study was, to examine the influence of various PEEP levels on intracranial pressure, brain tissue oxygen tension, regional cerebral blood flow, and systemic hemodynamic variables. DESIGN: Animal research and clinical intervention study. SETTING: Surgical intensive care unit of a university hospital. SUBJECTS AND PATIENTS: Experiments were carried out in five healthy pigs, followed by a clinical investigation of ten patients suffering subarachnoid hemorrhage. INTERVENTIONS: Under continuous monitoring of intracranial pressure, brain tissue oxygen tension, regional cerebral blood flow, mean arterial pressure, and cardiac output, PEEP was applied in increments of 5 cm H2O from 5 to 25 cm H2O in the experimental part and from baseline to 20 cm H2O in the clinical part. MEASUREMENTS AND MAIN RESULTS: In animals, high PEEP levels had no adverse effect on intracranial pressure, brain tissue oxygen tension, or regional cerebral blood flow. In patients with severe subarachnoid hemorrhage, stepwise elevation of PEEP resulted in a significant decrease of mean arterial pressure and regional cerebral blood flow. Analyses of covariance revealed that these changes of regional cerebral blood flow depended on mean arterial pressure changes as a result of a disturbed cerebrovascular autoregulation. Consequently, normalization of mean arterial pressure restored regional cerebral blood flow to baseline values. CONCLUSIONS: Application of high PEEP does not impair intracranial pressure or regional cerebral blood flow per se but may indirectly affect cerebral perfusion via its negative effect on macrohemodynamic variables in case of a disturbed cerebrovascular autoregulation. Therefore, following severe subarachnoid hemorrhage, a PEEP-induced decrease of mean arterial pressure should be reversed to maintain cerebral perfusion.

Adult↗

PubMed2005

Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas.

OBJECT: The goal of this study was to determine the effects of SU6668, a polyvalent receptor tyrosine kinase inhibitor against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and fibroblast growth factor-1 on tumor growth, angiogenesis, and microcirculation in an orthotopic malignant glioma model. METHODS: Fluorescently labeled C6 malignant glioma cells were implanted into a long-term cranial window, which had been prepared in nude mice. The animals were treated with intraperitoneal injections of SU6668 (75 mg/kg/day) immediately (five animals) or 7 days (five animals) following tumor implantation. Control mice received intraperitoneal injections of vehicle (50 microl dimethylsulfoxide) immediately (five animals) or 7 days (four animals) after tumor implantation. Tumor growth, angiogenesis, and microcirculation were assessed by performing intravital fluorescence videomicroscopy over a 14-day observation period. To assess the effects of SU6668 on overall survival, C6 glioma cells were implanted stereotactically into the brains of 24 additional animals and treatment was initiated on Day 7. In both the immediate and delayed experimental setting, SU6668 treatment resulted in a significant reduction of total and functional tumor vessel densities (both p < 0.05), reflecting a suppression of angiogenesis and impairment of tumor perfusion. As a consequence, tumor growth was significantly inhibited (p < 0.05). Histological analysis demonstrated reduced tumor growth and less mass effect on the adjacent brain of treated animals. The survival experiments confirmed the importance of our results in that survival was significantly prolonged following SU6668 therapy (p < 0.05). CONCLUSIONS: Targeting of multiple angiogenic signaling pathways by polyvalent tyrosine kinase inhibitors represents a promising strategy to interfere with the vascularization, microcirculation, and growth of angiogenesis-dependent tumors. This also applies to malignant gliomas, despite the uniqueness of the cerebral microenvironment and the singular pathobiology of this tumor entity.

Animals↗

PubMed2005

Intraoperative control of extracranial-intracranial bypass patency by near-infrared indocyanine green videoangiography.

OBJECT: Recently, intraoperative fluorescence angiography in which indocyanine green (ICG) is used as a tracer has been introduced as a novel technique to confirm successful aneurysm clipping. The aim of the present study was to assess whether ICG videoangiography is also suitable for intraoperative confirmation of extracranial-intracranial bypass patency. METHODS: Forty patients undergoing cerebral revascularization for hemodynamic cerebral ischemia (11 patients), moya-moya disease (18 patients), or complex intracranial aneurysms (11 patients) were included. Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass surgery was performed 35 times in 30 patients (five patients with moyamoya underwent bilateral procedures), STA-posterior cerebral artery bypass surgery in two patients, and saphenous vein (SV) high-flow bypass surgery in eight patients. In each patient, following the completion of the anastomosis, ICG (0.3 mg/kg body weight) was given systemically via an intravenous bolus injection. A near-infrared light emitted by laser diodes was used to illuminate the operating field and the intravascular fluorescence was recorded using an optical filter-equipped video camera. The findings of ICG videoangiography were compared with those of postoperative digital subtraction (DS) or computerized tomography (CT) angiography. In all cases excellent visualization of cerebral arteries, the bypass graft, and brain perfusion was noted. Indocyanine green videoangiography was used to identify four nonfunctioning STA-MCA bypasses, which could be revised successfully in all cases. In two cases of SV high-flow bypasses, ICG videoangiography revealed stenosis at the proximal anastomotic site, which was also revised successfully. In all cases the final findings of ICG videoangiography could be positively validated during the postoperative course by performing DS or CT angiography. CONCLUSIONS: Indocyanine green videoangiography provides a reliable and rapid intraoperative assessment of bypass patency. Thus, ICG videoangiography may help reduce the incidence of early bypass graft failure.

Adolescent↗

PubMed2005

Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study.

OBJECTIVE: The goal of this study was to investigate the safety and tolerability of the novel endothelin A (ETA) receptor antagonist clazosentan in patients with subarachnoid hemorrhage (SAH) and its potential to reduce the incidence and severity of cerebral vasospasm following surgical clipping of the aneurysm. METHODS: This Phase IIa multicenter study had two parts: a double-blind, randomized Part A (some patients given clazosentan [0.2 mg/kg/hr] and others given placebo), in which statistical inference was performed, and an open-label Part B (patients with established vasospasm given clazosentan [0.4 mg/kg/hr for 12 hours followed by 0.2 mg/kg/hr]) for exploratory purposes only. Primary end points were the incidence and severity of angiographic vasospasm on Day 8 after SAH and the safety and tolerability of the drug. Thirty-four patients (Hunt and Hess Grades III and IV and Fisher Grade > or = 3) were recruited and 32 (15 in the clazosentan group and 17 in the placebo group) were retained in the intent-to-treat population; 19 patients entered Part B. In Part A, treatment with clazosentan resulted in a reduced incidence of angiographically evident cerebral vasospasm (40% compared with 88% of patients, p = 0.008). In addition, the severity of vasospasm was reduced in the clazosentan group (p = 0.012). In Part B of the study, in 50% of assessable patients who were initially treated with placebo reversal of vasospasm was observed following the initiation of clazosentan therapy. The incidence of new infarctions was 15% in the clazosentan group and 44% in the placebo group (p = 0.130). There was no adverse event pattern indicating a specific organ toxicity of clazosentan. CONCLUSIONS: This study indicates that clazosentan reduces the frequency and severity of cerebral vasospasm following severe aneurysmal SAH with the incidence and severity of adverse events comparable to that of placebo.

Adult↗

PubMed2005

Power Doppler imaging in detection of surgically induced indirect neoangiogenesis in adult moyamoya disease.

OBJECT: Moyamoya is a rare, chronic disease that leads to the progressive narrowing and/or occlusion of the distal internal carotid and proximal cerebral arteries. Chronic cerebral ischemia ensues due to insufficient collateral blood supply. One potential treatment consists of the restoration of regional cerebral blood flow by direct or indirect revascularization surgery. The extent of neovascularization, especially in indirect procedures such as encephalomyosynangiosis (EMS), is currently evaluated with conventional angiography. Because this method is invasive and carries some risks, the authors investigated power Doppler imaging as an alternative noninvasive bedside procedure that can be used to assess surgically induced indirect revascularization in adult patients with moyamoya disease. METHODS: Twelve symptomatic patients with adult moyamoya disease (seven women and five men, mean age 38 +/- 17 years) underwent combined (direct and indirect) revascularization. They were then examined using conventional angiography and power Doppler imaging to assess the extent of revascularization within 120 days postsurgery. According to the number of intracranial vessels demonstrating opacification on conventional angiography and power Doppler imaging studies, EMS was graded as follows: 1, absent (0 vessels); 2, moderate (one-four vessels); and 3, extensive (> four vessels) for both methods. Examiners were blinded to the classification results for the procedure that they did not grade. All 24 hemispheres were examined. The visual grading of EMS revealed a highly significant agreement between conventional angiography and power Doppler imaging (Spearman rank coefficient, r = 0.92; p < 0.001) and there was 100% agreement of patency of the bypass between the direct and indirect methods. CONCLUSIONS: The authors found excellent agreement between the two methods. Therefore, power Doppler imaging is a valid noninvasive alternative to carotid artery angiography in evaluating direct and indirect revascularization.

Adult↗

PubMed2004

Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme.

PURPOSE: Glioblastoma multiforme (GBM) represents the prototype of an angiogenic tumor. Recently, the continuous low-dose scheduling of chemotherapeutic drugs in combination with an inhibition of cyclooxygenase-2 (COX-2) has been suggested as a novel anti-angiogenic approach. The aim of this study was to evaluate the safety and activity of continuous low-dose temozolomide (TMZ) plus the COX-2 inhibitor rofecoxib in patients with newly diagnosed GBM. METHODS: In vitro, endothelial cells were characterized by a tenfold higher sensitivity to TMZ than glioma cells. Consequently, a subgroup of patients with incompletely resected GBM (n=13) was divided into three groups aiming at a dose escalation to 1/10 of the daily MTD for TMZ: (A) TMZ 10 mg/m2 every third day and rofecoxib 25 mg/d; (B) TMZ 10 mg/m2/d and rofecoxib 25 mg/d; (C) TMZ 5 mg/m2 twice a day and rofecoxib 12.5 mg twice a day. COX-2, VEGF, VEGF Receptor-2, and CD34 were assessed immunohistochemically, in the clinical setting. RESULTS: The mean follow-up period was 15 months. We observed no severe toxicity attributable to the therapy. Quality of life was not impaired. For the whole study population, median time to progression and overall survival were 8 months and 16 months, respectively. Immunohistochemistry suggested that tumors with higher vessel densities were characterized by a significantly better control than those with lower vessel densities. CONCLUSIONS: Continuous low-dose TMZ plus rofecoxib is feasible, safe, and maintains good quality of life. This study is indicative of an anti-angiogenic efficacy of continuous low-dose TMZ plus rofecoxib in GBMs, especially in those tumors that are characterized by a high angiogenic activity.

Adult↗

PubMed2004

Influence of moderate and profound hyperventilation on cerebral blood flow, oxygenation and metabolism.

OBJECTIVE: The aim of the present study was to examine the impact of moderate and profound hyperventilation on regional cerebral blood flow (rCBF), oxygenation and metabolism. MATERIALS AND METHODS: Twelve anesthetized pigs were subjected to moderate (mHV) and profound (pHV) hyperventilation (target arterial pO(2): 30 and 20 mmHg, respectively) for 30 min each, after baseline normoventilation (BL) for 1 h. Local cerebral extracellular fluid (ECF) concentrations of glucose, lactate, pyruvate and glutamate as well as brain tissue oxygenation (p(ti)O(2)) were monitored using microdialysis and a Licox oxygen sensor, respectively. In nine pigs, regional cerebral blood flow (rCBF) was also continuously measured via a thermal diffusion system. RESULTS: Both moderate and profound hyperventilation resulted in a significant decrease in rCBF (BL: 37.9+/-4.3 ml/100 g/min; mHV: 29.4+/-3.6 ml/100 g/min; pHV: 23.6+/-4.7 ml/100 g/min; p<0.05) and p(ti)O(2) (BL: 22.7+/-4.1 mmHg; mHV: 18.9+/-4.9 mmHg; pHV: 13.0+/-2.2 mmHg; p<0.05). A p(ti)O(2) decrease below the critical threshold of 10 mmHg was induced in three animals by moderate hyperventilation and in five animals by profound hyperventilation. Furthermore, significant increases in lactate (BL: 1.06+/-0.18 mmol/l; mHV: 1.36+/-0.20 mmol/l; pHV: 1.67+/-0.17 mmol/l; p<0.005), pyruvate (BL: 46.4+/-7.8 micromol/l; mHV: 58.0+/-10.3 micromol/l; pHV: 66.1+/-12.7 micromol/l; p<0.05), and lactate/glucose ratio were observed during hyperventilation. (Data are presented as mean+/-S.E.M.) CONCLUSIONS: Both moderate and profound hyperventilation may result in insufficient regional oxygen supply and anaerobic metabolism, even in the uninjured brain. Therefore, the use of hyperventilation cannot be considered as a safe procedure and should either be avoided or used with extreme caution.

Animals↗