Development of a bleeding scale and hemostasis algorithm in cranial neurosurgery.

Effective hemostasis is crucial in neurosurgery as anatomical and functional considerations reduce tolerance for any bleeding. The classification of bleeding severities is a necessary step to enable neurosurgeons to counteract bleeding during surgery. Even though bleeding scales are used for a variety of surgical specialties, they cannot be transferred to cranial neurosurgery without adaption, and no consensus on the nature of such a classification exists to date. Moreover, there is plethora of topical hemostasis products with diverse mechanisms of action and application available. Clinical studies investigating those products used in neurosurgery did not define standardized procedures. This article demonstrates the systematic establishment of both a bleeding scale and a hemostasis algorithm to close this gap in the assessment of intracranial bleeding. The expert panel consisting of 7 members from different neurosurgical centers developed a qualitative bleeding scale with the peculiarities of neurosurgical procedures, based on the experience of each member in daily practice. The hemostasis algorithm is a recommendation for neurosurgeons to aid in the decision-making process to control any sort of bleeding, taking into account the rational use of available hemostatics, depending on type and location of bleeding, as well as the mechanism of action of such agents. Effectiveness of hemostasis, surgery times and economic costs can be optimized by applying the algorithm in daily practice.

Nuclear Glycoprotein A Repetitions Predominant (GARP) Is a Common Trait of Glioblastoma Stem-like Cells and Correlates with Poor Survival in Glioblastoma Patients.

Glioblastoma (GB) is notoriously resistant to therapy. GB genesis and progression are driven by glioblastoma stem-like cells (GSCs). One goal for improving treatment efficacy and patient outcomes is targeting GSCs. Currently, there are no universal markers for GSCs. Glycoprotein A repetitions predominant (GARP), an anti-inflammatory protein expressed by activated regulatory T cells, was identified as a possible marker for GSCs. This study evaluated GARP for the detection of human GSCs utilizing a multidimensional experimental design that replicated several features of GB: (1) intratumoral heterogeneity, (2) cellular hierarchy (GSCs with varied degrees of self-renewal and differentiation), and (3) longitudinal GSC evolution during GB recurrence (GSCs from patient-matched newly diagnosed and recurrent GB). Our results indicate that GARP is expressed by GSCs across various cellular states and disease stages. GSCs with an increased GARP expression had reduced self-renewal but no alterations in proliferative capacity or differentiation commitment. Rather, GARP correlated inversely with the expression of GFAP and PDGFR-α, markers of astrocyte or oligodendrocyte differentiation. GARP had an abnormal nuclear localization (GARPNU+) in GSCs and was negatively associated with patient survival. The uniformity of GARP/GARPNU+ expression across different types of GSCs suggests a potential use of GARP as a marker to identify GSCs.

Open-Label Phase II Evaluation of Imatinib in Primary Inoperable or Incompletely Resected and Recurrent Glioblastoma.

PURPOSE: Preclinical studies indicated that imatinib may have single-agent activity in glioblastoma through inhibition of tyrosine kinase activity and also that it might enhance the efficacy of radiotherapy. We therefore sought to investigate clinical efficacy in patients with newly diagnosed and recurrent glioblastoma in combination with radiotherapy. METHODS: We conducted a nonrandomized, 2-arm, open-label phase II trial including patients aged 18 years or older with an ECOG performance status of 0-2 that were either newly diagnosed (arm A) with a measurable tumor (i.e., after incomplete resection or biopsy) or that were diagnosed with progression of a glioblastoma after initial therapy (arm B). Patients in arm A received 600 mg/day imatinib in combination with hypofractionated radiotherapy (2.5 Gy per fraction, 22 fractions). Patients in arm B received 600 mg/day imatinib alone or in combination with re-irradiation at various doses. In case tumor progression occurred, CCNU was added (2 cycles, 100 mg/m2) to imatinib. The primary end point was progression-free survival (PFS). The secondary end point was safety, defined as per Common Terminology Criteria for Adverse Events (version 2.0). Overall survival (OS) was analyzed as an exploratory end point. RESULTS: Fifty-one patients were enrolled, of which 19 were included in arm A and 32 in arm B. The median follow-up was 4 (0.5-30) months in arm A and 6.5 (0.3-51.5) months in arm B. The median PFS was 2.8 months (95% CI 0-8.7) in arm A and 2.1 months (95% CI 0-11.8) in arm B. The median OS was 5.0 (0.8-30) months (95% CI 0-24.1) in arm A and 6.5 (0.3-51.5) months (95% CI 0-32.5) in arm B. The major grade 3 events were seizure (present in 17 patients), pneumonia (11 patients), and vigilance decrease (7 patients). CONCLUSIONS: Imatinib showed no measurable activity in patients with newly diagnosed or recurrent glioblastoma.

GARP as an Immune Regulatory Molecule in the Tumor Microenvironment of Glioblastoma Multiforme.

Glycoprotein A repetition predominant (GARP), a specific surface molecule of activated regulatory T cells, has been demonstrated to significantly contribute to tolerance in humans by induction of peripheral Treg and regulatory M2-macrophages and by inhibition of (tumorantigen-specific) T effector cells. Previous work identified GARP on Treg, and also GARP on the surface of several malignant tumors, as well as in a soluble form being shedded from their surface, contributing to tumor immune escape. Preliminary results also showed GARP expression on brain metastases of malignant melanoma. On the basis of these findings, we investigated whether GARP is also expressed on primary brain tumors. We showed GARP expression on glioblastoma (GB) cell lines and primary GB tissue, as well as on low-grade glioma, suggesting an important influence on the tumor micromilieu and the regulation of immune responses also in primary cerebral tumors. This was supported by the finding that GB cells led to a reduced, in part GARP-dependent effector T cell function (reduced proliferation and reduced cytokine secretion) in coculture experiments. Interestingly, GARP was localized not only on the cell surface but also in the cytoplasmatic, as well as nuclear compartments in tumor cells. Our findings reveal that GARP, as an immunoregulatory molecule, is located on, as well as in, tumor cells of GB and low-grade glioma, inhibiting effector T cell function, and thus contributing to the immunosuppressive tumor microenvironment of primary brain tumors. As GARP is expressed on activated Treg, as well as on brain tumors, it may be an interesting target for new immunotherapeutic approaches using antibody-based strategies as this indication.

Long-Term Reduction of Sacroiliac Joint Pain With Peripheral Nerve Stimulation.

BACKGROUND: We recently demonstrated that 86% of the patients treated with peripheral nerve stimulation (PNS) for therapy-refractory sacroiliac joint (SIJ) pain were satisfied with the result after 1 year of treatment. OBJECTIVE: To investigate the long-term (up to 4 years) response rate of this novel treatment. METHODS: Sixteen consecutive patients with therapy-refractory SIJ pain were treated with PNS and followed for 4 years in 3 patients, 3 years in 6 patients, and 2 years in 1 patient. Quality of life, pain, and patient satisfaction were assessed using the Oswestry Disability Index 2.0, Visual Analog Scale (VAS), and International Patient Satisfaction Index. RESULTS: Patients reported a pain reduction from 8.8 to 1.6 (VAS) at 1 year ( P < .001), and 13 of 14 patients (92.9%) rated the therapy as effective (International Patient Satisfaction Index score ≤ 2). At 2 years, average pain score was 1.9 ( P < .001), and 9 of 10 patients (90.0%) considered the treatment a success. At 3 years, 8 of 9 patients (88.9%) were satisfied with the treatment results, reporting an average VAS of 2.0 ( P < .005). At 4 years, 2 of 3 patients were satisfied with the treatment results. CONCLUSION: We have shown for the first time that PNS is a successful long-term therapy for SIJ pain.

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.

The chemokine receptor CXCR7 influences prognosis in human glioma in an IDH1-dependent manner.

AIMS: The chemokine receptor CXCR7 is found on glioma cells and glioma-associated vessels and dependent upon its localisation on tumour or endothelial cells the CXCR7 receptor can mediate glioma cell invasion and tumour angiogenesis. Its expression predicts survival in several types of cancers. METHODS: We immunohistochemically studied the expression of CXCR7 and its ligand SDF1α in a cohort of 354 human patients with glioma. In an in vivo glioma model, we studied the effect of selective CXCR7 inhibition on mean vascular density. RESULTS: Here we show that expression of either mutant isocitrate dehydrogenase (IDH) 1 or podoplanin (PDPN), two proteins present in basically non-overlapping glioma populations, predicts the prognostic significance of CXCR7. Specifically, expression of CXCR7 on endothelial cells in IDH1 mutant cases predicted poor outcome. Surprisingly, in PDPN expressing gliomas, one of the marker genes for the recently identified mesenchymal subgroup, expression of CXCR7 predicts diminished prognosis on tumour cells and better prognosis on endothelial cells. CONCLUSIONS: Since CXCR7 is expressed on migrating cells our data suggest that, although ubiquitously present, angiogenesis and invasion are outcome-relevant events in specific glioma subgroups, providing a potentially important tool for targeted therapy assignment.

Technical Note: Treatment of Sacroiliac Joint Pain with Peripheral Nerve Stimulation.

INTRODUCTION: Sacroiliac joint (SIJ) pain affects older adults with a prevalence of up to 20% among patients with chronic low back pain. While pain medication, joint blocks and denervation procedures achieve pain relief in most patients, some cases fail to improve. Our goal was to determine the effectiveness of SIJ peripheral nerve stimulation in patients with severe conservative therapy-refractory SIJ pain. MATERIALS AND METHODS: Here we present 12 patients with severe conservative therapy-refractory pain receiving an SIJ peripheral nerve stimulation. Patient satisfaction, pain, and quality of life were evaluated by means of the International Patient Satisfaction Index (IPSI), visual analog scale (VAS), and Oswestry Disability Index 2.0 (ODI) using standard questionnaires. For stimulation we placed an eight-pole peripheral nerve electrode parallel to the SIJ. RESULTS: Two weeks postoperatively, our patients reported an average ODI reduction from 57% to 32% and VAS from 9 to 2.1. IPSI was 1.1. After six months, the therapy was rated as effective in seven out of eight patients reporting at that period. The average ODI was low at 34% (p = 0.0006), while the VAS index rose to 3.8 (p < 0.0001) and IPSI to 1.9. Twelve months after stimulation, six out of seven patients considered their treatment a success with an average ODI of 21% (p < 0.0005), VAS 1.7 (p < 0.0001), and IPSI 1.3. CONCLUSIONS: We conclude that SIJ stimulation is a promising therapeutic strategy in the treatment of intractable SIJ pain. Further studies are required to determine the precise target group and long-term effect of this novel treatment method.

Mutant IDH1 inhibits PI3K/Akt signaling in human glioma.

BACKGROUND: Recently, isocitrate dehydrogenase 1 (IDH1) was identified as a major participant in glioma pathogenesis. At present, the enzymatic activity of the protein has been the main topic in investigating its physiological function, but its signaling pathway allocation was unsuccessful. Interestingly, proteins regulated by phosphoinositide 3-kinase (PI3K)/Akt signaling, are among the top downregulated genes in gliomas associated with high percentage of IDH1 and IDH2 mutations. The aim of this study was to investigate a hypothetical relation between IDH1 and PI3K signaling. METHODS: The presence of mutant IDH1 and markers for active PI3K/Akt signaling, present as phosphorylated Akt and podoplanin (PDPN), were investigated in a discovery cohort of 354 patients with glioma. In vitro experiments were used to confirm functional links. RESULTS: This study shows an inverse correlation between mutant IDH1 and markers for active PI3K/Akt signaling. In support of a functional link between these molecules, in vitro expression of mutant IDH1 inhibited Akt phosphorylation in a 2-hydroxyglutarate-dependent manner. CONCLUSIONS: This study provides patient tumor and in vitro evidence suggesting that mutant IDH1 inhibits PI3K/Akt signaling.

Ligamentum flavum hematomas of the cervical and thoracic spine.

OBJECTIVE: To report extremely rare cases of ligamentum flavum hematomas in the cervical and thoracic spine. Only six cases of thoracic ligamentum flavum hematomas and three cases of cervical ligamentum flavum hematomas have been reported so far. METHODS: Two patients presented with tetraparesis and one patient presented with radicular pain and paresthesias in the T3 dermatome. MRI was performed in two patients, which showed a posterior intraspinal mass, continuous with the ligamentum flavum. The mass was moderately hypointense on T2-weighted images and hyperintense on T1-weighted images with no contrast enhancement. The third patient underwent cervical myelography because of a cardiac pacemaker. The myelography showed an intraspinal posterior mass with compression of the dural sac at C3/C4. RESULTS: All patients underwent a hemilaminectomy to resect the ligamentum flavum hematoma and recovered completely afterwords, and did not experience a recurrence during follow-up of at least 2 years. CONCLUSION: This case series shows rare cases of ligamentum flavum hematomas in the cervical and thoracic spine. Surgery achieved complete recovery of the preoperative symptoms in all patients within days.

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.

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.

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.

Blockade of TGF-ß signaling by the TGFßR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-ß is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-ß receptor (TGFßR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFßR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFßR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma.

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.

Detection of IDH1 mutations in gliomatosis cerebri, but only in tumors with additional solid component: evidence for molecular subtypes.

The current WHO classification of brain tumors defines gliomatosis cerebri (GC) as an extensively infiltrating astrocytic glioma involving at least three cerebral lobes. The relation of GC to diffuse astrocytomas and glioblastoma is uncertain. Due to malignant biological behavior, GC is allotted to WHO grade III. Recent reports showed IDH1 mutations in astrocytic and oligodendroglial tumors WHO grades II and III and in secondary glioblastomas with a frequency of up to 90%, whereas IDH1 mutations occurred in only 5% of primary glioblastomas. Here, we examined the frequency of IDH1 mutations in 35 GC samples by direct sequencing, derived cleaved amplified polymorphic sequence analysis and immunohistochemistry. We identified IDH1 mutations in 10/24 (42%) cases, which also included a solid tumor portion (type 2 GC), but not in 11 "classical" cases without solid tumor mass (type 1 GC). TP53 mutations were revealed in two type 2 GC, but not in any type 1 GC, while combined chromosomal losses of 1p and 19q were not found at all. Our data suggest that GC consists of two histological/molecular subtypes, type 1 being clearly distinct from diffuse astrocytoma, and type 2 sharing features with diffuse astrocytoma.

Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma.

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m(2) twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-L-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8-12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.

Far-distant metastases along the CSF pathway of glioblastoma multiforme during continuous low-dose chemotherapy with temozolomide and celecoxib.

Glioblastoma multiforme is the most common and most malignant primary brain tumour. Prognosis after diagnosis remains poor despite recent advances in adjuvant therapy. Treatment of choice is gross surgical resection and combined radio-chemotherapy with temozolomide as chemotherapeutic agent. Experimental continuous low-dose chemotherapy with temozolomide in combination with a cyclooxygenase-2 inhibitor has shown encouraging effects on progression-free survival and overall survival in patients, but leads to a high proportion of distant recurrences. Here, we describe extreme far-distant metastases along the neural axis of glioblastoma multiforme in four patients receiving metronomic antiangiogenic chemotherapy and review the literature to discuss possible mechanisms.

Long-term adjuvant administration of temozolomide in patients with glioblastoma multiforme: experience of a single institution.

PURPOSE: Long-term administration of adjuvant temozolomide is common practice in many institutions, especially when treatment is well tolerated and stable disease is achieved. In this study, we evaluate the feasibility and efficacy of long-term temozolomide in patients with glioblastoma multiforme treated at a single institution. METHODS: One hundred and fourteen patients with newly diagnosed glioblastoma were followed for the course of their disease. Treatment consisted of surgery [gross total resection (GTR) subtotal resection (STR) or biopsy] followed by radiotherapy and concomitant temozolomide. Adjuvant temozolomide was administered until evidence for progressive disease or serious side effects occurred. Follow-up was routinely performed every 3 months. RESULTS: One hundred and fourteen patients with glioblastoma multiforme received a median of 6 cycles of adjuvant first-line temozolomide (range 1-57). For patients with less than 6 cycles, chemotherapy was stopped in 60% for reasons other than progression, while only in 17% of patients receiving 6 or more (P < 0.0001). Median TTP was 7 months (95% CI: 6-10 months). PFS after 6 months was 53%. Median OS in all patients was 15 months (95% CI: 13-18 months). TTP and OS directly correlate with the amount of chemotherapy cycles (each P < 0.0001). No significant influence of the extent of surgical treatment on PFS (P = 0.2141) and OS (P = 0.4308) could be detected. CONCLUSION: This data set suggests that long-term administration of temozolomide is safe and efficacious. Side effects occur more frequently in the early phase of drug administration (<6 cycles). There is a strong correlation of long-term temozolomide on PFS and OS regardless of the extent of surgery and other factors.

Circulating endothelial progenitor cells in malignant gliomas.

OBJECT: Recent experimental work suggests that circulating endothelial progenitor cells (cEPCs) are recruited to the angiogenic vascular system of malignant gliomas. Consequently, the level of cEPCs has been proposed as a novel biomarker for the diagnosis and monitoring of these lesions. The aim of the present study was to examine the level of cEPCs and the level of EPC mobilizing mediators in the blood of patients with malignant gliomas. The authors were also interested in whether a correlation could be observed between the level of cEPCs and the extent of glioma angiogenesis determined by conventional methods. METHODS: Peripheral blood mononuclear cells from the whole blood of 12 patients with malignant gliomas (all glioblastomas multiforme [GBMs]), 10 with metastases to the brain, and 10 healthy volunteers were isolated using Ficoll density gradient centrifugation. The number of cEPCs was quantified by fluorescence-activated cell sorting analysis using antibodies against CD34, CD133, and VEGFR-2. Serum concentrations of VEGF and granulocyte-macrophage colony-stimulating factor (GM-CSF) were determined using the enzyme-linked immunosorbent assay. Histological analysis of tumor blood vessel density was performed by CD34 immunohistochemical staining. RESULTS: The number of cEPCs was significantly higher in patients with GBMs than in those with metastases (p < 0.04) or in the healthy volunteers (p < 0.004). The serum VEGF concentrations in patients with GBMs and metastases were significantly higher than in the healthy volunteers (p < 0.0001). Similar findings were observed for concentrations of GM-CSF. In addition, the patients in the GBM group with higher levels of cEPCs had significantly higher tumor blood vessel densities (1.71 +/- 1.17% of total area) compared with patients who had low levels of cEPCs (0.62 +/- 0.28% of total area; p < 0.02). CONCLUSIONS: Endothelial progenitor cells are increasingly mobilized in patients with malignant gliomas, and their levels correlate with tumor angiogenic activity. Therefore, the authors' results suggest that cEPCs may have the potential to serve as a novel biomarker for the identification of patients who would benefit from antiangiogenic therapy for GBM.