Christian Senft

Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial.

BACKGROUND Intraoperative MRI is increasingly used in neurosurgery, although there is little evidence for its use. We aimed to assess efficacy of intraoperative MRI guidance on extent of resection in patients with glioma. METHODS In our prospective, randomised, parallel-group trial, we enrolled adults (≥18 years) with contrast enhancing gliomas amenable to radiologically complete resection who presented to Goethe University (Frankfurt, Germany). We randomly assigned patients (1:1) with computer-generated blocks of four and a sealed-envelope design to undergo intraoperative MRI-guided surgery or conventional microsurgery (control group). Surgeons and patients were unmasked to treatment group allocation, but an independent neuroradiologist was masked during analysis of all preoperative and postoperative imaging data. The primary endpoint was rate of complete resections as established by early postoperative high-field MRI (1·5 T or 3·0 T). Analysis was done per protocol. This study is registered with ClinicalTrials.gov, number NCT01394692. FINDINGS We enrolled 58 patients between Oct 1, 2007, and July 1, 2010. 24 (83%) of 29 patients randomly allocated to the intraoperative MRI group and 25 (86%) of 29 controls were eligible for analysis (four patients in each group had metastasis and one patient in the intraoperative MRI group withdrew consent after randomisation). More patients in the intraoperative MRI group had complete tumour resection (23 [96%] of 24 patients) than did in the control group (17 [68%] of 25, p=0·023). Postoperative rates of new neurological deficits did not differ between patients in the intraoperative MRI group (three [13%] of 24) and controls (two [8%] of 25, p=1·0). No patient for whom use of intraoperative MRI led to continued resection of residual tumour had neurological deterioration. One patient in the control group died before 6 months. INTERPRETATION Our study provides evidence for the use of intraoperative MRI guidance in glioma surgery: such imaging helps surgeons provide the optimum extent of resection. FUNDING None.

The Pan-Bcl-2 Inhibitor ()-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2′, and ABT-737, whereas the pan-Bcl-2 inhibitor (−)-gossypol efficiently induced cell death. Furthermore, (−)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O6-methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (−)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (−)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1. Mol Cancer Res; 8(7); 1002–16. ©2010 AACR.

Navigated transcranial magnetic stimulation and functional magnetic resonance imaging: advanced adjuncts in preoperative planning for central region tumors.

BACKGROUND:Tumor resection in the vicinity of the motor cortex poses a challenge to all neurosurgeons. For preoperative assessment of eloquent cortical areas, functional magnetic resonance imaging (fMRI) is used, whereas intraoperatively, direct cortical stimulation (DCS) is performed. Navigated transcranial magnetic stimulation (nTMS) is comparable to DCS in activating cortical pyramidal neurons. OBJECTIVE:To evaluate the reliability of nTMS compared with fMRI and DCS for preoperative resection planning of centrally located tumors. METHODS:In a prospective series, 11 patients (ages, 20-63 years; mean, 41.9 ± 14.9 years, 2 women) with tumors located in or adjacent to the motor cortex were evaluated for surgery. fMRI and nTMS were applied for preoperative assessment of the extent of tumor resection. A 3-dimensional anatomic data set with superimposed fMRI data was integrated in the eXimia Navigated Brain Stimulation station for ensuing motor cortex mapping by nTMS. Responses from nTMS were evaluated by electromyographic response. During surgery, the coordinates of each DCS site were unambiguously defined and integrated into neuronavigation. A post hoc comparison of the coordinates of nTMS, fMRI, and DCS was performed. RESULTS:Distances from nTMS to DCS (10.5 ± 5.67 mm) were significantly smaller than those from fMRI to DCS (15.0 ± 7.6 mm). CONCLUSION:nTMS anticipates information usually only enabled by DCS and therefore allows surgical planning in eloquent cortex surgery.

Glioblastoma therapy in the elderly and the importance of the extent of resection regardless of age

OBJECT The objective of this study was to analyze whether age influences the outcome of patients with glioblastoma and whether elderly patients with glioblastoma can tolerate the same aggressive treatment as younger patients. METHODS Data from 361 consecutive patients with newly diagnosed cerebral glioblastoma (2000-2006) who underwent regular follow-up evaluation from initial diagnosis until death were prospectively entered into a database. Patients underwent resection (complete, subtotal, or partial) or biopsy, depending on tumor size, location, and Karnofsky Performance Scale score. Following surgery, all patients underwent adjuvant treatment consisting of radiotherapy, chemotherapy, or combined treatment. Patients older than 65 years of age were defined as elderly (146 total). RESULTS Two hundred thirty-four patients underwent tumor resection (complete 26%, subtotal 29%, and partial 45%). One hundred twenty-seven underwent biopsy. Mean patient age was 61 years, and overall survival was 11.6 ± 12.1 months. The overall survival of elderly patients (9.1 ± 11.6 months) was significantly lower than that of younger patients (14.9 ± 16.7 months; p = 0.0001). Stratifying between resection or biopsy, age was a negative prognostic factor in patients undergoing biopsy (4.0 ± 7.1 vs 7.9 ± 8.7 months; p = 0.007), but not in patients undergoing tumor resection (13.0 ± 8.5 vs 13.3 ± 14.5 months; p = 0.86). Survival of elderly patients undergoing complete tumor resection was 17.7 ± 8.1 months. CONCLUSIONS In this series of patients with glioblastoma, age was a prognostic factor in patients undergoing biopsy, but not in patients undergoing resection. Tumor location and patient clinical status may prohibit extensive resection, but resection should not be withheld from patients only on the basis of age. In elderly patients with glioblastoma, undergoing resection to the extent feasible, followed by adjuvant therapies, is warranted.

Usefulness of intraoperative ultra low-field magnetic resonance imaging in glioma surgery.

OBJECTIVE The aim of this study was to demonstrate the usefulness of a mobile, intraoperative 0.15-T magnetic resonance imaging (MRI) scanner in glioma surgery. METHODS We analyzed our prospectively collected database of patients with glial tumors who underwent tumor resection with the use of an intraoperative ultra low-field MRI scanner (PoleStar N-20; Odin Medical Technologies, Yokneam, Israel/Medtronic, Louisville, CO). Sixty-three patients with World Health Organization Grade II to IV tumors were included in the study. All patients were subjected to postoperative 1.5-T imaging to confirm the extent of resection. RESULTS Intraoperative image quality was sufficient for navigation and resection control in both high- and low-grade tumors. Primarily enhancing tumors were best detected on T1-weighted imaging, whereas fluid-attenuated inversion recovery sequences proved best for nonenhancing tumors. Intraoperative resection control led to further tumor resection in 12 (28.6%) of 42 patients with contrast-enhancing tumors and in 10 (47.6%) of 21 patients with noncontrast-enhancing tumors. In contrast-enhancing tumors, further resection led to an increased rate of complete tumor resection (71.2 versus 52.4%), and the surgical goal of gross total removal or subtotal resection was achieved in all cases (100.0%). In patients with noncontrast-enhancing tumors, the surgical goal was achieved in 19 (90.5%) of 21 cases, as intraoperative MRI findings were inconsistent with postoperative high-field imaging in 2 cases. CONCLUSION The use of the PoleStar N-20 intraoperative ultra low-field MRI scanner helps to evaluate the extent of resection in glioma surgery. Further tumor resection after intraoperative scanning leads to an increased rate of complete tumor resection, especially in patients with contrast-enhancing tumors. However, in noncontrast- enhancing tumors, the intraoperative visualization of a complete resection seems less specific, when compared with postoperative 1.5-T MRI.

Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells

The objective of current treatment strategies for glioblastoma (GBM) is cytoreduction. Unfortunately, the deleterious migratory and invasive behavior of glial tumors remains largely unattended. The transcription factor signal transducer and activator of transcription (STAT) 3 is known to be involved in the development and progression of many different tumor types, including malignant gliomas. Beside other biological effects, STAT3 controls cell proliferation and tissue remodeling, processes common to both wound healing and tumor dissemination. Here, we report on impeded migratory and invasive potential of five different glioblastoma cell lines after treatment with AG490, a pharmacological inhibitor of the upstream STAT3 activator Janus kinase (JAK) 2. STAT3 was constitutively activated in all the cell lines tested, and treatment with AG490 eliminated the biologically active, tyrosine705-phosphorylated form of STAT3 in a dose-dependent fashion, as determined by Western blot analysis. Inhibition of activated STAT3 was paralleled by a decrease in transcriptional expression of the STAT3 target genes MMP-2 and MMP-9, and led to reduced proteolytic activity, as determined by zymography. Accordingly, the migratory behavior of all five GBM cell lines was impeded in monolayer wound-healing assays; invasive capacity in matrigel-coated trans-well assays was also hampered by treatment with AG490. The proliferative activity of the cell lines was also significantly reduced after treatment with AG490. The effects elicited by STAT3 inhibition were observed in both PTEN-expressing and PTEN-deficient cells. Because pharmacological inhibition of the JAK-2/STAT3 signaling pathway affects not only tumor cell proliferation but also the characteristic features of malignant gliomas, i.e. migration and invasion pertinent to invariable tumor recurrence and high morbidity, our findings support the idea that STAT3 is a suitable target in the treatment of brain tumors.

The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas

BackgroundNew drugs are constantly sought after to improve the survival of patients with malignant gliomas. The ideal substance would selectively target tumor cells without eliciting toxic side effects. Here, we report on the anti-proliferative, anti-migratory, and anti-invasive properties of the natural, nontoxic compound Curcumin observed in five human glioblastoma (GBM) cell lines in vitro.MethodsWe used monolayer wound healing assays, modified Boyden chamber trans-well assays, and cell growth assays to quantify cell migration, invasion, and proliferation in the absence or presence of Curcumin at various concentrations. Levels of the transcription factor phospho-STAT3, a potential target of Curcumin, were determined by sandwich-ELISA. Subsequent effects on transcription of genes regulating the cell cycle were analyzed by quantitative real-time PCR. Effects on apoptosis were determined by caspase assays.ResultsCurcumin potently inhibited GBM cell proliferation as well as migration and invasion in all cell lines contingent on dose. Simultaneously, levels of the biologically active phospho-STAT3 were decreased and correlated with reduced transcription of the cell cycle regulating gene c-Myc and proliferation marking Ki-67, pointing to a potential mechanism by which Curcumin slows tumor growth.ConclusionsCurcumin is part of the diet of millions of people every day and is without known toxic side effects. Our data show that Curcumin bears anti-proliferative, anti-migratory, and anti-invasive properties against GBM cells in vitro. These results warrant further in vivo analyses and indicate a potential role of Curcumin in the treatment of malignant gliomas.

Low field intraoperative MRI-guided surgery of gliomas: A single center experience

INTRODUCTION The aim of this article is to report on our experience in using a low field intraoperative MRI (iMRI) system in glioma surgery and to summarize the hitherto use and benefits of iMRI in glioma surgery. PATIENTS AND METHODS Between July 2004 and May 2009, a total of 103 patients harboring gliomas underwent tumor resection with the use of a mobile low field iMRI in our institution. Surgeries were performed as standard micro-neurosurgical procedures using regular instrumentarium. All patients underwent early postoperative high field MRI to determine the extent of resection. Adjuvant treatment was conducted according to histopathological grading and standard of care. RESULTS All tumors could be reliably visualized on intraoperative imaging. Intraoperative imaging revealed residual tumor tissue in 51 patients (49.5%), leading to further tumor resection in 31 patients (30.1%). Extended resection did not translate into a higher rate of neurological deficits. When analyzing survival of patients with glioblastoma, patients undergoing complete tumor resection did significantly better than patients with residual tumor (50% survival rate at 57.8 weeks vs. 33.8 weeks, log rank test p=0.003), while younger age did not influence survival (p=0.12). CONCLUSION Low field iMRI is a helpful tool in modern neurosurgery and facilitates brain tumor resection to a maximum safe extent. Its use translates into a better prognosis for these patients with devastating tumors. Future studies covering the use of iMRI will need to be conducted in a prospective, randomized fashion to prove the true benefit of iMRI in glioma surgery.

Influence of iMRI-guidance on the extent of resection and survival of patients with glioblastoma multiforme.

Intraoperative MRI (iMRI) is used in glioma surgery mainly to determine the extent of resection, allowing surgeons to immediately continue resection in case of residual tumor tissue. The aim of this study is to report on the influence of the use of iMRI on the extent of resection and survival of patients with glioblastoma multiforme (GBM). We analyzed our prospectively collected database of patients with GBM operated upon during the initial period after installation of an iMRI; between July 2004 and December 2005, all patients with GBM undergoing intended complete tumor resection were included in this study, while patients undergoing mere tumor biopsy or intended incomplete resection were not. In total, 43 Patients met the inclusion criteria. Of these, 10 patients (23.3%) were operated upon with the help of iMRI while 33 underwent conventional tumor resection. All patients underwent postoperative high-field MR imaging at 1.5 Tesla to determine the extent of resection. Subsequently, all patients received adjuvant treatment. Median patient age was 60.0 years; median overall survival was 70.7 weeks. Radiologically complete tumor resection (P < 0.001) and the administration of temozolomide chemotherapy (P < 0.01) were statistically significant prognostic factors in a multivariate analysis. The rate of complete tumor resections was significantly higher in the iMRI group than in the conventional surgery group (P < 0.05). Patient age was not a prognostic factor in our series of patients (P = 0.22). Intraoperative MRI is a helpful tool to increase the extent of resection in GBM surgery and thereby improve patient survival.

The influence of preoperative anticoagulation on outcome and quality of life after surgical treatment of chronic subdural hematoma

The main aim of this study was to investigate the influence of perioperative anticoagulation on the clinical course and outcome of 144 patients who underwent surgery for chronic subdural hematoma (CSDH). The outcome was categorized according to the modified Rankin Scale (mRS), Barthel Index and postoperative quality of life (QoL) scale. There was a significant correlation between preoperative aspirin medication and reoperation (Mann-Whitney U-test, p<0.05). Moreover, dosage and duration of postoperative low-molecular-weight heparin (LMWH) administration were associated with a higher risk of reoperation (Mann-Whitney U-test, p<0.01) and a worse outcome on the mRS (Mann-Whitney U-test, p<0.05). Intraoperative treatment with prothrombin complex concentrate led to a poor outcome on the mRS (Craddock-Flood test, p<0.05). Reoperation is the strongest predictive factor of a poor QoL after surgical treatment of CSDH. Both preoperative and postoperative anticoagulation treatment may affect reoperation rate and, thus, postoperative QoL.