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- ACT-209905 (2)
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- Klinik und Poliklinik für Neurochirurgie (5) (remove)
Background: High resolution three-dimensional (3-D) magnetic resonance imaging (MRI) is widely used to predict the neurovascular anatomy within the cerebellopontine angle. Objective: To assess value of 3-D three-dimensional Steady-state free precession imaging (SSFP) and Time-of-flight magnetic resonance angiography (TOF MRA) and in detecting the offending vessels in hemifacial spasm by comparison to intraoperative endoscopic visualization. Methods: 42 patients underwent endoscope-assisted microvascular decompression (MVD). All available preoperative 3-D SSFP and TOF MRA images were checked. Intraoperative videos were captured by a high definition endoscopic camera attached to endoscopes while exploring the area of facial nerve root exit zone (REZ). Evaluation of the 3-D images was performed by two independent groups of observers and compared with the operative findings. Results: 3-D MRI had an average positive predictive value (PPV) of 89.1% in differentiating between simple and complex compression. Mean accuracy of the before mentioned images in detection of the offending vessels was 83.3% and 77% according to the first and second group of observers respectively. Averaged inter-observer agreement between the two groups of observers was substantial with an averaged Kappa coefficient (K) of 0.56. In simple compression group, mean accuracy was 97% and 89.4% according to the first and second group of observers respectively. Averaged K for agreement was substantial (K=0.65). Conclusion: According to endoscopic visualisation, 3-D SSFP and TOF MRA images are accurate in detecting the offending vessels in simple compression of the facial nerve, and in predicting presence of a complex compression with variable sensitivity in identifying all offending vessels.
Background: Microvascular Decompression represents an effective treatment for hemifacial spasm. The use of lateral spread responses (LSRs) monitoring remains a useful intraoperative tool to ensure adequate decompression of the facial nerve. Objective: To assess the value of LSRs intraoperative monitoring as a prognostic indicator for the outcome of microvascular decompression in hemifacial spasm. Methods: Our study included 100 patients prospectively. The patients were classified into 4 groups whether LSRs were totally, partially, not relieved or not detected from the start. According to clinical outcome, the patients were classified into 4 groups depending on the clinical course after surgery and the residual symptoms if any. Then, correlations were made between LSRs events and treatment outcome to detect its reliability as a prognostic indicator. Results: LSRs were relieved totally in 56% of the patients, partially relieved in 14%, not relieved in 10% and were not detected in 20% of the patients from the start. HFS was relieved directly after operation in 62% with clinical improvement of 90-100%. 31% described 50-90% improvement over the next 3 months after surgery. Almost all of these 31% (28 out of 31 patients) reported further clinical improvement of 90-100% within one year after surgery. 3% suffered from a relapse after a HFS-free period and 4% reported minimal or no improvement describing 0-50% of the preoperative state. The percentage of the satisfied patients with the clinical outcome who reported after one year a clinical improvement of 90-100% was 90%. Statistical analysis did not find a significant correlation between the relief of LSRs and clinical outcome. Conclusion: LSRs may only represent an intraoperative tool to guide for an adequate decompression but failed to represent a reliable prognostic indicator for treatment outcome.
Glioblastoma multiforme (GBM) is the most common and most aggressive malignant tumor of the central nervous system in adults. The median survival time of patients suffering from GBM is only 14-15 months. Despite a great progress in the technique of resection, radiation therapy, and chemotherapeutic drugs, survival time has not been significantly prolonged. Interestingly, the progression of GBM has been associated with intratumoral immune dysfunction states, and the GBM tissue represents a complex formation of tumor cells itself and diverse non-malignant cells such as endothelial cells, microglia or immunocompetent cells from peripheral blood. In that regard, accumulating evidence supports that Sphingosine 1-phosphate (S1P) acts as a key signal in the cancer extracellular milieu. S1P has been intensively discussed to be an important pro-tumoral molecule, since it is involved in proliferation, migration and invasion of both healthy and malignant cells. An increase in S1P has been associated with proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. S1P binds to five different cell surface G protein-coupled receptors called S1P receptor 1-5 (S1PR1-5), it has been shown in previous studies that particularly the S1PR1 and 2 are involved in regulating proliferation, metastasis, invasion, vascular angiogenesis and maturation of GBM cells and thus play an important role in tumorigenesis. Therefore, we used S1PR1 (ACT-209905, W146) and S1PR2 modulators/antagonists (Compound 16, JTE013) to investigate the role of these S1P receptor subtypes in the growth of human (prGBM, LN18) and murine (GL261) GBM cells to gain insight into the molecular processes of the pro-tumorigenic S1P signaling cascade in GBM cells. Further, we analyzed the influence of the human monocytic cell line THP-1 on GBM cell growth by co-culture experiments together with simultaneous application of S1PR1/S1PR2 modulators/antagonists to determine the role played by S1PR1 and S1PR2 signaling pathways in the interaction between tumor and immune cells. We found that all tested S1PR1/2 modulators (ACT-209905, W146, Compound 16, JTE013) significantly reduced the viability (Resazurine assay) and vitality (Crystal violet assay) as well as the migration and invasion of prGBM, LN18 and GL261 cells in a concentration dependent manner. The growth inhibitory effect of S1PR1 blocking by ACT-209905 was accompanied by the induction of apoptosis in GBM cells seen by increased caspase 3 activity. When S1PR1 antagonist (ACT-209905, W146) was co-administered with S1PR2 antagonist (Compound 16, JTE013) the inhibitory effect was much stronger compared to the single administration. Further, single and dual application of S1PR1 modulator and S1PR2 antagonist caused a stronger inhibition of GBM cell viability and vitality compared to 100 μM Temozolomide (TMZ) as the standard chemotherapeutic for GBM. These results suggest that both S1PR1 and S1PR2 are involved in the growth of GBM cells and that a simultaneous inhibition of both receptors has synergistic effects. In addition, the influence of THP-1 cells as a model for human monocytes/macrophages on GBM cell growth was analyzed since it has been shown that S1P signaling polarizes macrophages to the pro-tumoral M2 phenotype and S1PR1 has been linked to macrophage activation. Co-culture of GBM cells with THP-1 cells or THP-1 conditioned medium significantly enhanced the viability and vitality as well as the migration and invasion of GBM cells in a cell number dependent manner suggesting that THP-1 cells might secrete to date unknown pro-tumoral molecules which stimulate the pro-invasive growth of GBM cells. Our FACS analyses showed that THP-1 cells express not only the CD11b macrophage marker but also CD163 and CD206 as marker for the pro-tumorigenic M2 phenotype. Interestingly, the concomitant application of the S1PR1 modulator ACT-209905 had a significant inhibitory effect on the THP-1 induced increase of GBM cell growth and migration, which argues for a role of S1PR1 in the pro-tumoral characteristic of THP-1 on GBM cells. Immunoblot analyses further showed that blocking of the S1PR1 pathway leads to a reduced activation of several kinases including p38, AKT1 and ERK1/2 whereas THP-1 cells and THP-1 conditioned medium caused an activation of these kinases. To clarify the role of p38, AKT1 and ERK1/2 in the inhibitory effects of S1PR1 antagonists on GBM proliferation and migration in detail further studies are needed. Beside an impact on growth promoting kinases, S1PR1 blocking by ACT-209905 diminished surface expression (Median Fluorescence Intensity measured by FACS) of the pro-migratory molecules CD54 (ICAM-1) and CD166 (ALCAM), and reduced the percentage of CD62P (P-Selectin) positive GBM cells. In contrast, co-culture with THP-1 cells increased ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905 arguing for a role of ICAM-1 and P-Selectin in the migration of GBM cells. In conclusion, our study suggests a role of S1PR1 and S1PR2 signaling pathways in the growth and progression of GBM, improves our understanding of the complex mechanisms of S1P signaling in GBM cells, and gives at least a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells combined with potential underlying mechanisms. Thus, this study argues for a further preclinical and clinical evaluation of a pharmacological modulation of S1PR1 and S1PR2 as a new or adjunctive therapeutic principle in GBM.
The glioblastoma multiforme (GBM) not only presents the most common tumor of the central nervous system in adults, it is also the most aggressive brain tumor. Although patients suffering from GBM standardly receive a combination of multiple treatments including surgery, radiotherapy and chemotherapy, its prognosis is still poor with a median survival time of only 12-15 months. Therefore, new and effective treatment methods are urgently needed.
A signaling molecule which is both involved in proliferation, migration and invasion of a broad range of healthy and malignant cells is the lipid mediator sphingosine-1-phosphate (S1P). Previous studies have confirmed that sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) is involved in the regulation of proliferation, invasion, metastasis, vascular maturation and angiogenesis of GBM cells, and is closely related to the occurrence and development of tumors. Thus, ACT-209905 (provided by Actelion Pharmaceuticals) as a selective S1PR1 modulator was applied to gain insights into the molecular processes activated by S1PR1 in GBM cells using two human (LN18, U87MG) and one murine (GL261) GBM cell line.
In our in vitro cell viability analyses, we found that ACT-209905 significantly reduced viability of LN18 cells in a concentration dependent manner. A combined administration of ACT-209905 with S1PR2 inhibitors (Compound 16, Compound 16ME – both provided by ONO Pharmaceuticals, and JTE-013 – commercially available) showed a stronger effect than the single administration demonstrating that both S1PR1 and S1PR2 are involved in growth of GBM cells and may interact with each other. Our results also demonstrated that ACT-209905 can induce apoptosis in GBM cells since caspase 3 activity was induced by the S1PR1 modulator which might therefore play an important role in inhibiting the proliferation of GBM cells. Further, we found a significant inhibitory effect of ACT-209905 on the migration and invasion of LN18 and U87MG GBM cells arguing for a participation of S1PR1 signaling in migration and invasion of GBM cells, too. Stimulation of S1P receptors results in the activation of several kinases such as AKT1 and ERK1/2, correspondingly our immunoblot analyses showed a strong activation of both kinases by S1P which was reduced by ACT-209905 in LN18 cells but not in GL261 cells suggesting that different pathways are activated by S1P in these GBM cell lines. Further studies have to be performed to clarify the role of AKT1 and ERK1/2 in the inhibitory effects of ACT-209905 on GBM proliferation, migration and invasion.
Currently, GBM stem cells are discussed as a reason for resistance against the radiochemotherapy and the recurrence of the tumor. Our immunoblot analyses showed that Nestin and CD133, two marker proteins for GBM stem cells, were higher expressed in GBM cells treated with ACT-209905 compared to control or S1P treated LN18 cells. Further investigations in the future might contribute to the elucidation of an involvement of the S1P receptors in the stem cell behavior of GBM cells. Paradoxically to the up-regulation of CD133 and Nestin by ACT-209905, treatment of LN18 stem-like neurospheres with ACT-209905 showed a significant cytotoxic effect of the compound which was even more pronounced in the stem-like neurosphere cells compared to the adherent parental LN18 cells.
Overall, the studies of this work improve our understanding of the complex mechanisms of S1P signaling in GBM cells and might drive the development of its pharmacological modulation as a new therapeutic principle in GBM. Furthermore, an extended knowledge about the molecular effects of ACT-209905 on GBM cells will broaden the understanding for possible future applications and clinical indications.
Background:
Microvascular decompression (MVD) success rates exceed 90% in hemifacial spasm (HFS).
However, postoperative recovery patterns and durations are variable.
Objective:
We aim to study factors that might influence the postoperative patterns and duration needed until
final recovery.
Method:
Only patients following de-novo MVD with a minimum follow-up of 6 months were included.
Overall trend of recovery was modeled. Patients were grouped according to recognizable clinical
recovery patterns. Uni- and multivariable analyses were used to identify the factors affecting
allocation to the identified patterns and time needed to final recovery.
Results:
323(92.6%) patients had >90% symptom improvement and 269(77.1%) patients had complete
resolution at the last follow–up. The overall trend of recovery showed steep remission within the
first 6 months, followed by relapse peaking around 8 months with a second remission ~16
months. Five main recovery patterns were identified.
Patterns analysis showed that evident proximal indentation of the facial nerve at REZ, males and
facial palsy are associated with earlier recovery at multivariable and univariable levels. AICA,
AICA/VA compressions and shorter disease durations are related to immediate resolution of the
symptoms only on the univariable level. Time analysis showed that proximal indentation (vs.
distal indentation), males and facial palsy witnessed significantly earlier recoveries.
Conclusion:
Our main finding is that in contrast to peripheral indentation, proximal indentation of the facial
nerve at REZ is associated with earlier recovery. Postoperative facial palsy and AICA
compressions are associated with earlier recoveries. We recommend a minimum of 1 year before
evaluating the final outcome of MVD for HFS.