Stephan Dützmann

Inhibition of tissue factor/protease-activated receptor-2 signaling limits proliferation, migration and invasion of malignant glioma cells

Tissue factor (TF) is upregulated in several malignant diseases, including gliomas. Here, we demonstrate pronounced differences in the expression of TF and its interactors factor VII and protease-activated receptor 2 (PAR-2) in nine human glioma cell lines (U87, U251, U343, U373, MZ-18, MZ-54, MZ-256, MZ-304, Hs 683) as detected by RT-PCR and Western blot analysis. Inhibition of TF signaling by a neutralizing monoclonal antibody (mAb TF9-10H10) led to significantly reduced proliferation in high-grade astroglial (MZ-18 and MZ-304) and oligodendroglial (Hs 683) cell lines abundantly expressing TF, but not in U373 cells expressing low amounts of TF. Scratch migration assays and Boyden chamber assays indicated that mAb TF9-10H10 and lentiviral knockdown of TF significantly reduced cell migration and invasion of MZ-18, MZ-304 and Hs 683 cells, both under normoxic and hypoxic conditions. Of note, all three cell lines displayed increased cell migration and invasion under hypoxic conditions (1% O(2)), which was associated with enhanced expression of TF and increased phosphorylation of p44/42 mitogen-activated protein kinase (ERK1/2). Silencing of TF blocked activation of the ERK pathway, induction of TF expression and the potentiating effect of hypoxia on cell migration and invasion. RNA interference against PAR-2 abrogated the autocrine effects of TF on cell proliferation, migration and invasion, indicating that TF signals via PAR-2 in glioma cells. Our results suggest an important role for the TF/FVIIa/PAR-2/ERK axis in tumor growth and invasion of glioma and suggest that TF may be a suitable target for the development of novel therapies against high-grade glioma.

Open vs retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome: a retrospective cohort study.

BACKGROUND Both open ulnar nerve decompression and retractor-endoscopic ulnar nerve decompression have been shown to yield good results. However, a comparative evaluation of the techniques is lacking. OBJECTIVE To compare the results of open and endoscopic surgery in cubital tunnel syndrome. METHODS One hundred fourteen patients undergoing open (n = 59) or endoscopic (n = 55) decompression of the ulnar nerve for cubital tunnel syndrome were retrospectively compared. The long- and short-term outcomes were compared with respect to the time until return to full activity and the duration of postoperative pain. Additionally, matched pairs between the 2 groups were chosen for analysis (n = 34). RESULTS Long-term results in the open vs endoscopic groups were as follows: excellent results, 54.2% vs 56.4%; good results, 23.8% vs 32.7%; fair results, 20.3% vs 9.1%; and poor results, 1.7% vs 1.8%, respectively. For the matched pairs, the results had similar significance levels (P = .84). The times until return to full activity in the open vs the endoscopic groups were as follows: 2 to 7 days, 18.6% vs 76.4%; 7 to 14 days, 55.9% vs 10.9%; and > 14 days, 25.4% vs 12.7% (P < .001 between nonmatched and matched pairs). The durations of postoperative pain in the open vs the endoscopic groups were as follows: 1 to 3 days, 45.8% vs 67.3%; 3 to 10 days, 42.5% vs 25.4%; and > 10 days, 11.7% vs 7.3% (P =.04 for nonmatched and P = .05 for matched pairs). CONCLUSION There are no significant differences in long-term outcomes after open and retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome. The short-term results are significantly better in endoscopic surgery.

Anti-tissue factor (TF9-10H10) treatment reduces tumor cell invasiveness in a novel migratory glioma model

In vitro and descriptive studies of human tissue samples revealed the pro‐coagulant glycoprotein tissue factor (TF) as a potent player in glioma cell infiltration that is activated by hypoxia and has also been shown to be upregulated by mutations of TP53 or PTEN. Here we present the morphological and genetic characterization of a novel glioblastoma in vivo model and provide evidence that treatment with an antibody targeting TF leads to reduced glioma cell invasiveness. Therefore, we established a murine xenograft treatment model by transplanting the angiogenic and diffusely infiltrating human glioma cell line MZ‐18 with endogenous TF expression into nude mice brains and treating these mice with an intracranial osmotic pump system continuously infusing a monoclonal antibody against TF (mAb TF9‐10H10). The human MZ‐18 cell line harbors two TP53 mutations resulting in a strong nuclear accumulation of p53, thereby facilitating the unambiguous identification of tumor cells in the xenograft model. Intracranial application of TF9‐10H10 significantly reduced invasion of MZ‐18 cells compared to mock‐treated control animals. The extent of activated blood vessels was also reduced upon anti‐TF treatment. Thus, targeting the TF pathway might be a promising treatment strategy for future glioblastoma therapies, by affecting both invading tumor cells and tumor vasculature.

Retractor-Endoscopic Nerve Decompression in Carpal and Cubital Tunnel Syndromes: Outcomes in a Small Series

OBJECTIVE To present midterm to long-term results obtained in carpal tunnel release, in situ decompression, and anterior transposition of the ulnar nerve using the retractor integrated endoscope. METHODS During the period 2000-2010, 145 patients underwent endoscopic carpal tunnel releases (n = 47), endoscopic in situ decompression of the ulnar nerve (n = 55), and endoscopic anterior transposition of the ulnar nerve (n = 52). Bilateral surgery was performed in 9 patients. Independent examinations at 24 months after surgery were used for objective results (Bishop score). Subjective results were procured using a questionnaire. RESULTS After endoscopic carpal tunnel release, 59.6% of patients showed excellent results, 21.2% showed good results, 12.8% showed fair results, and 6.4% showed poor results according to objective scoring. In 85% of patients, subjective improvement was noted after surgery; symptoms were the same as before surgery in 12.8% of patients and were worse in 2.1% of patients after surgery. After endoscopic in situ decompression, 56.4% of patients showed excellent results on objective scoring, 32.7% showed good results, 9.1% showed fair results, and 1.8% showed poor results. On subjective questioning, 72.7% of patients reported improvement, 20% reported no change in symptoms, and 7.3% reported worse symptoms. After endoscopic anterior transposition of the ulnar nerve, 48.1% of patients showed excellent results on objective scoring, 26.9% showed good results, 23.1% showed fair results, and 1.9% showed poor results. Subjectively, 65.4% of patients reported improvement, 26.9% reported no change in symptoms, and 7.7% reported worse symptoms. Patients with symptom duration of <9 months before surgery showed better results than patients with symptom duration of >9 months. CONCLUSIONS The retractor-endoscopic technique provides good long-term results after carpal tunnel release, in situ decompression, and anterior subcutaneous transposition of the ulnar nerve. Outcomes showed some correlation to the duration of preoperative symptoms.

The pro-migratory and pro-invasive role of the procoagulant tissue factor in malignant gliomas

During the infiltration process, glioma cells are known to migrate along preexisting anatomical structures such as blood vessels, axonal fiber tracts and the subependymal space, thereby widely invading surrounding CNS tissue. This phenomenon represents a major obstacle for the clinical treatment of these tumours. Several extracellular key factors and intracellular signaling pathways have been previously linked to the highly aggressive, invasive phenotype observed in malignant gliomas. The glioblastoma (GBM) which is the most malignant form of these tumors, is histologically characterized by areas of tumor necroses and pseudopalisading cells, the latter likely representing tumor cells actively migrating away from the hypoxic-ischemic core of the tumor. It is believed that intravascular thromboses play a major role in the emergence of hypoxia and intratumoral necroses in GBMs. One of the most highly upregulated prothrombotic factor in malignant gliomas is tissue factor (TF), a 47 kDa type I transmembrane protein belonging to the cytokine receptor superfamily. In a recent study, we provided evidence that TF/FVIIa signaling via the protease-activated receptor 2 (PAR-2) promotes cell growth, migration and invasion of glioma cells. In this point of view article we outline the key molecular players involved in migration and invasion of gliomas, highlight the potential role of TF for the pro-migratory and pro-invasive phenotype of these tumors and discuss the underlying mechanisms on the cellular level and in the tumor microenvironment.

Intratumoral Concentrations and Effects of Orally Administered Micellar Curcuminoids in Glioblastoma Patients

ABSTRACT Background: The oral bioavailability of curcuminoids is low, but can be enhanced by incorporation into micelles. The major curcuminoid curcumin has antitumor effects on glioblastoma cells in vitro and in vivo. We therefore aimed to determine intratumoral concentrations and the clinical tolerance of highly bioavailable micellar curcuminoids in glioblastoma patients. Methods: Thirteen glioblastoma patients ingested 70 mg micellar curcuminoids [57.4 mg curcumin, 11.2 mg demethoxycurcumin (DMC), and 1.4 mg bis-demethoxycurcumin (BDMC)] three times per day for 4 days (total amount of 689 mg curcumin, 134 mg DMC, and 17 mg BDMC) prior to planned resection of their respective brain tumors. Tumor and blood samples were taken during the surgery and analyzed for total curcuminoid concentrations. 31P magnetic resonance spectroscopic imaging was performed before and after curcuminoid consumption. Results: Ten patients completed the study. The mean intratumoral concentration of curcumin was 56 pg/mg of tissue (range 9–151), and the mean serum concentration was 253 ng/ml (range 129–364). Inorganic phosphate was significantly increased within the tumor (P = 0.034). The mean ratio of phosphocreatine to inorganic phosphate decreased, and the mean intratumoral pH increased (P = 0.08) after curcuminoid intervention. Conclusion: Oral treatment with micellar curcuminoids led to quantifiable concentrations of total curcuminoids in glioblastomas and may alter intratumoral energy metabolism.

Management, risk factors and outcome of cranial dural arteriovenous fistulae: a single-center experience

BackgroundThe role of endovascular interventions in managing dural arteriovenous fistulas (DAVFs) is increasing. Furthermore, in patients with aggressive DAVFs, different surgical interventions are required for complete obliteration or disconnection. Our objective was to evaluate the management of patients with intracranial DAVFs treated in our institution to identify the parameters that may help guide the long-term management of these lesions.MethodsThe hospital records of 53 patients with intracranial DAVFs were reviewed. We then conducted a systematic telephone interview to obtain long-term follow-up information.ResultsThe main presenting symptoms were tinnitus and headache. Nineteen (35%) patients presented with intracranial bleeding, 84% of patients scored between 0 and 2 using a modified Rankin Scale at the last follow-up visit. Twenty-four patients were treated surgically. Overall postoperative complications occurred in seven (29%) surgically treated patients, but only two patients permanently worsened. For patients with Borden type II and III fistulas, the annual incidence of hemorrhage was 30%. Two patients had late recurrences of surgically and endovascularly occluded DAVFs. Long-term follow-up showed that compared with spinal DAVFs, only 50% of intracranial DAVFs showed complete remission of symptoms, 41% partial remission, 6% no remission and 4% deterioration of symptoms that led to treatment of the DAVF.ConclusionIn general, intracranial DAVFs can be successfully surgically managed by simple venous disconnection in many cases. However, half of the patients do not show complete remission of symptoms. Age and the occurrence of perioperative complication were the most important determinants of outcome.

Is Postoperative Imaging Mandatory after Meningioma Removal? Results of a Prospective Study

Background Routine postoperative imaging (PI) following surgery for intracranial meningiomas is common practice in most neurosurgical departments. The purpose of this study was to determine the role of routine PI and its impact on clinical decision making after resection of meningioma. Methods Patient and tumor characteristics, details of radiographic scans, symptoms and alteration of treatment courses were prospectively collected for patients undergoing removal of a supratentorial meningioma of the convexity, falx, tentorium, or lateral sphenoid wing at the authors’ institution between January 1st, 2010 and March 31st, 2012. Patients with infratentorial manifestations or meningiomas of the skull base known to be surgically difficult (e.g. olfactory groove, petroclival, medial sphenoid wing) were not included. Maximum tumor diameter was divided into groups of < 3cm (small), 3 to 6 cm (medium), and > 6 cm (large). Results 206 patients with meningiomas were operated between January 2010 and March 2012. Of these, 113 patients met the inclusion criteria and were analyzed in this study. 83 patients (73.5%) did not present new neurological deficits, whereas 30 patients (26.5%) became clinically symptomatic. Symptomatic patients had a change in treatment after PI in 21 cases (70%), while PI was without consequence in 9 patients (30%). PI did not result in a change of treatment in all asymptomatic patients (p<0.001) irrespective of tumor size (p<0.001) or localization (p<0.001). Conclusions PI is mandatory for clinically symptomatic patients but it is safe to waive it in clinically asymptomatic patients, even if the meningioma was large in size.

Transmuscular approach to the sciatic nerve using the SynFrame system.

Lesions of the sciatic nerve are most commonly of traumatic and tumorous nature, the latter being predominant. The exposure of the sciatic nerve is rarely required in daily surgical practice and is usually restricted to specialized centers. The standard approach is the infragluteal exposure, which has been successfully employed in the largest series of sciatic nerve surgery reported so far. However, the infragluteal approach is a relatively traumatic exposure, causing [transient] postoperative morbidity. In this letter we describe our modified transmuscular approach to the sciatic nerve in the gluteal region using the SynFrame retractor system, which makes this surgical approach almost a single surgeon procedure.

Predictors of neurological recovery after surgery of metastatic epidural spinal cord compression

Objective: The aim of this study was to identify potential preoperative predictors (inclusive time between onset of motor weakness and surgical decompression) of neurological function and ambulation in a consecutive series of patients with MESCC treated with urgent spinal cord decompression. Material/Methods: 327 patients with MESCC who underwent emergency laminectomy were reviewed retrospectively. Variables evaluated were: age, gender, site of primary tumor, location of spinal cord compression, location and number of affected segments, time between onset of neurological deficits to surgical decompression, the preand early postoperative ASIA scores, preand postoperative ability to walk and to ambulate and the preand postoperative quality of walking. Variables were analyzed with uniand multivariate methods. A backward stepwise binary logistic regression analysis was performed to determine the effect of the evaluated variables in a multivariate model. Results: The majority of the patients were assigned to ASIA impairment scale grade D. At admission 49.5 % of the patients could walk and 50.5% of the patients were not able to walk. The mean time between onset of neurological deficits and decompression was 114.72 hours +/173.41 (range 2 – 1800 hours). Univariate analyses identified preoperative ASIA impairment scale grades, the ability to walk preoperatively, tumor localization, age and duration of symptom (time interval between onset of motor weakness and surgical decompression) as predictors for neurological improvement and outcome. In a multivariate model time between onset of motor weakness and surgical decompression (p<0,05) and the ability to walk preoperatively (p<0.0001) were significant independent predictors for improvement of the ability to walk. Conclusion: Early surgical decompression is important for neurological recovery in patients with MESCC especially with rapid neurological deterioration. Correspondence to: Privatdozent Dr. Matthias Setzer, Neurosurgical Department, Neurocenter, University Hospital Frankfurt, Goethe University, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. Tel: +49 69 63015295, E-mail: Matthias.Setzer@kgu.de