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.

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.

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.

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.

Interferon-gamma down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells.

NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alphabeta CD8(+) T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-gamma (IFN-gamma) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-gamma treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-gamma, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells.

Clinical evaluation of the safety and efficacy of lumbar cerebrospinal fluid drainage for the treatment of refractory increased intracranial pressure.

OBJECT: Several approaches have been established for the treatment of intracranial hypertension; however, a considerable number of patients remain unresponsive to even aggressive therapeutic strategies. Lumbar CSF drainage has been contraindicated in the setting of increased intracranial pressure (ICP) because of possible cerebral herniation. The authors of this study investigated the efficacy and safety of controlled lumbar CSF drainage in patients suffering from intracranial hypertension following severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH). METHODS: The authors prospectively evaluated 100 patients-45 with TBI and 55 with SAH-having a mean age of 43.7 +/- 15.7 years (mean +/- SD) and suffering from refractory intracranial hypertension (ICP > 20 mm Hg). Intracranial pressure and cerebral perfusion pressure (CPP) before and after the initiation of lumbar CSF drainage as well as related complications were documented. Patient outcomes were assessed 6 months after injury. RESULTS: The application of lumbar CSF drainage led to a significant reduction in ICP from 32.7 +/- 10.9 to 13.4 +/- 5.9 mm Hg (p < 0.05) and an increase in CPP from 70.6 +/- 18.2 to 86.2 +/- 15.4 mm Hg (p < 0.05). Cerebral herniation with a lethal outcome occurred in 6% of patients. Thirty-six patients had a favorable outcome, 12 were severely disabled, 7 remained in a persistent vegetative state, and 45 died. CONCLUSIONS: Lumbar drainage of CSF led to a significant and clinically relevant reduction in ICP. The risk of cerebral herniation can be minimized by performing lumbar drainage only in cases with discernible basal cisterns.

Differentiation between malignant transformation and tumour recurrence by (68)Ga-bombesin and (18)F-FDG-PET, in patients with low grade gliomas.

Treatment of gliomas is multimodal. Magnetic resonance imaging (MRI) in the posttreatment course is of limited value due to therapy-induced changes. In low-grade gliomas (LGG) malignant transformation is of special interest. Our patients and methods were as follows: In nine consecutive patients with LGG we examined the role of bombesin labelled with gallium-68 ((68)Ga-bombesin) studied with positron emission tomography (PET), in addition to fluoro-18-fluorodeoxyglucose ((18)F-FDG) in the differential diagnosis of tumour recurrence versus malignant transformation. We used (68)Ga-bombesin combined with (18)F-FDG-PET in these patients with suspicious new contrast enhancement at the original tumour site or resection cavity in MRI. Eight patients were operated. In one patient, tumour recurrence was most likely as shown by the PET findings and chemotherapy was administered. Our results have shown that in this last mentioned patient after the follow-up period, MRI contrast enhancement was definitively regressive. In the operated patients the tumour was graded as glioblastoma multiforme, gliosarcoma and WHO grade III tumour. In two patients histological grading confirmed the PET findings without malignant transformation. In all of the 9 patients the combination of (68)Ga-bombesin and (18)F-FDG-PET predicted correctly malignant transformation or recurrence of the initial tumour grade which shows that (68)Ga-bombesin-PET can provide additional important information to detect a malignant transformation. In conclusion it is crucial for the patient to differentiate the nature of the new lesion in order to endorse an aggressive or non-aggressive treatment.

Preoperative thrombocytosis predicts poor survival in patients with glioblastoma.

Thrombocytosis, which is defined as a platelet count greater than 400 platelets/nl, has been found to be an independent predictor of shorter survival in various tumors. Release of growth factors from tumors has been proposed to increase platelet counts. Preoperative platelet counts and other clinical and hematological parameters were reviewed from the records of 153 patients diagnosed between 1999 and 2004 with histologically confirmed glioblastoma in order to evaluate the prognostic significance of preoperative thrombocytosis in these patients. The relationship between thrombocytosis and survival was initially analyzed in all patients regardless of further therapy. Univariate log-rank tests showed that the median survival time of 29 patients with preoperative thrombocytosis (19%) was significantly shorter (4 months; 95% confidence interval [95% CI], 3-6 months) compared to 124 patients with normal platelet counts (11 months; 95% CI, 8-13 months; p = 0.0006). Multivariate analysis (Cox proportional hazards model) confirmed preoperative platelet count, age, prothrombin time, and activated partial thromboplastin time to be prognostic factors of survival (all p < 0.05). In a subset of patients (only operated patients with radiation therapy with or without additional chemotherapy), survival was likewise significantly shorter when preoperative thrombocytosis was diagnosed (6 months; 95% CI, 4-12 months) compared to patients with normal platelet count (13 months; 95% CI, 11-15 months; p = 0.0359). In multivariate analysis, age, platelet count, preoperative prothrombin time, and degree of tumor resection retained significance as prognostic factors of survival (all p < 0.05). The results of our study demonstrate preoperative thrombocytosis to be a prognostic factor associated with shorter survival time in patients with glioblastoma.

Efficacy of different regimens of adjuvant radiochemotherapy for treatment of glioblastoma.

AIMS AND BACKGROUND: We retrospectively analyzed the impact of different adjuvant chemotherapy regimens in a group of patients treated for glioblastoma compared to patients receiving only postoperative radiotherapy. MATERIAL AND METHODS: Eighty-six consecutive patients underwent radiotherapy between January 2000 and December 2003: 52 patients received radiotherapy alone, 17 patients radiochemotherapy with low-dose temozolomide (20 mg/m(2)) + cyclooxygenase-2-inhibitors (200 mg), 6 patients radiochemotherapy with high-dose temozolomide (50 mg/m2). Eleven patients, with unfavorable prognostic factors, were treated with imatinib and 55/2.5 Gy. RESULTS: The groups treated with high- and low-dose temozolomide showed the longest overall survival (median, 21 months and 17 months, respectively). Median overall survival was 9 months for radiation alone and 4 months for the imatinib-treated group. The same positive trend of temozolomide on prolonged overall survival was confirmed when only patients submitted to maximally radical resection or patients with KPS >70 were considered. Differences in progression-free survival were not statistically significant. CONCLUSIONS: Patients treated with adjuvant temozolomide either inside or outside of study protocols had survival times similar to other reports or randomized studies. The absence of a significant influence of temozolomide on progression-free survival could depend on the unavoidable drawbacks and biases of retrospective investigations or on the definition of relapse used. The unsatisfactory results of radiotherapy plus imatinib may have been due to a high prevalence of unfavorable prognostic factors in the respective patients. The ongoing controlled trial will further define the efficacy of adjuvant/concomitant imatinib.

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.

Persistent postpartum headache from a chronic subdural hematoma after peridural anesthesia.

BACKGROUND: Postpartum headache after peridural anesthesia is usually attributed to accidental perforation of the dura causing postlumbar puncture headache. CASE: In a patient with persistent headache after peridural anesthesia for labor, a chronic subdural hematoma was diagnosed 5 weeks postpartum. CONCLUSION: Caution is warranted in patients with peridural anesthesia for labor who present with unusually persistent headache.

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.

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.

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.

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.