Open Access

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.

Background: This randomized controlled trial investigated if uni- and bihemispheric transcranial direct current stimulation (tDCS) of the motor cortex can enhance the effects of visuo-motor grip force tracking task training and transfer to clinical assessments of upper extremity motor function. Methods: In a randomized, double-blind, sham-controlled trial, 40 chronic stroke patients underwent 5 days of visuo-motor grip force tracking task training of the paretic hand with either unilateral or bilateral (N = 15/group) or placebo tDCS (N = 10). Immediate and long-term (3 months) effects on training outcome and motor recovery (Upper Extremity Fugl-Meyer, UE-FM, Wolf Motor Function Test, and WMFT) were investigated. Results: Trained task performance significantly improved independently of tDCS in a curvilinear fashion. In the anodal stimulation group UE-FM scores were higher than in the sham group at day 5 (adjusted mean difference: 2.6, 95%CI: 0.6–4.5, p = 0.010) and at 3 months follow up (adjusted mean difference: 2.8, 95%CI: 0.8–4.7, p = 0.006). Neither training alone, nor the combination of training and tDCS improved WMFT performance. Conclusions: Visuo-motor grip force tracking task training can facilitate recovery of upper extremity function. Only minimal add-on effects of anodal but not dual tDCS were observed. Clinical Trial Registration: https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=NCT01969097&cntry=&state=&city=&dist=, identifier: NCT01969097, retrospectively registered on 25/10/2013.

Simple Summary Despite treatment advances, glioblastoma multiforme (GBM) remains an often-fatal disease, motivating novel therapeutic avenues. Gas plasma is a technology that has been recently employed in preclinical oncology research and acts primarily via reactive oxygen-species-induced cell death. In addition, the modulation of immune processes and inflammation have been ascribed to gas plasma exposure. This is the first study that extends those observations from in vitro investigations to a set of 16 patient-derived GBM tumor biopsies analyzed after gas plasma treatment ex vivo. Besides cell culture results showing cell cycle arrest and apoptosis induction, an immunomodulatory potential was identified for gas plasma exposure in vitro and cultured GBM tissues. The proapoptotic action shown in this study might be an important step forward to the first clinical observational studies on the future discovery of gas plasma technology’s potential in neurosurgery and neuro-oncology. Abstract Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Therapeutic options for glioblastoma are maximal surgical resection, chemotherapy, and radiotherapy. Therapy resistance and tumor recurrence demand, however, new strategies. Several experimental studies have suggested gas plasma technology, a partially ionized gas that generates a potent mixture of reactive oxygen species (ROS), as a future complement to the existing treatment arsenal. However, aspects such as immunomodulation, inflammatory consequences, and feasibility studies using GBM tissue have not been addressed so far. In vitro, gas plasma generated ROS that oxidized cells and led to a treatment time-dependent metabolic activity decline and G2 cell cycle arrest. In addition, peripheral blood-derived monocytes were co-cultured with glioblastoma cells, and immunomodulatory surface expression markers and cytokine release were screened. Gas plasma treatment of either cell type, for instance, decreased the expression of the M2-macrophage marker CD163 and the tolerogenic molecule SIGLEC1 (CD169). In patient-derived GBM tissue samples exposed to the plasma jet kINPen ex vivo, apoptosis was significantly increased. Quantitative chemokine/cytokine release screening revealed gas plasma exposure to significantly decrease 5 out of 11 tested chemokines and cytokines, namely IL-6, TGF-β, sTREM-2, b-NGF, and TNF-α involved in GBM apoptosis and immunomodulation. In summary, the immuno-modulatory and proapoptotic action shown in this study might be an important step forward to first clinical observational studies on the future discovery of gas plasma technology’s potential in neurosurgery and neuro-oncology especially in putative adjuvant or combinatory GBM treatment settings.

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.

Objective: To develop an instrument for the observation of therapeutic communication interactions during rehabilitation sessions and test its inter-rater reliability. Methods: The new instrument THER-I-ACT (THERapy–related Inter-ACTion) has been designed to assess both the frequency and timing of therapeutic interactions in the thematic fields information provision, feedback, other motivational interaction, and bonding. For this inter-rater reliability study, a sample of stroke survivors received arm rehabilitation as either arm ability training, arm basis training, or mirror therapy, or neglect training as individually indicated. Therapy sessions were video-recorded (one for each participant) and therapeutic interactions rated by two independent raters using THER-I-ACT. Results: With regard to the instrument's comprehensiveness to document therapeutic interactions with pre-defined categories the data from 29 sessions suggested almost complete coverage. Inter-rater reliability was very high both for individual categories of therapeutic interaction (frequency and time used for interaction) (intraclass correlation coefficient, ICC 0.91–1.00) and summary scores for the thematic fields of interaction (again for frequency and time used for interaction) (ICC 0.98–1.00). The inter-rater reliability for rating engagement and being focussed for both the therapist and patient was substantial (ICC 0.71 and 0.86). Conclusions: The observational study documented that by use of the newly designed THER-I-ACT various types of therapy-related communication interactions performed by therapists can be assessed with a very high inter-rater reliability. In addition, the thematic fields and categories of therapeutic interaction as defined by the instrument comprehensively covered the type of interaction that occurred in the therapeutic sessions observed.