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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.
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.
Over the past 10 years, the crisis of sepsis has remained a great challenge. According to data from 2016, the sepsis-related mortality rate remains high. In addition, sepsis consumes extensive medical resources in intensive care units, and anti-inflammatory agents fail to improve sepsis-associated hyperinflammation and symptoms of immunosuppression. The specific immune mechanism of sepsis remains to be elucidated. Reactive oxygen species (ROS) are triggered by energy metabolism and respiratory dysfunction in sepsis, which not only cause oxidative damage to tissues and organelles, but also directly and indirectly promote NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. NLRP3 inflammasomes enlarge the inflammatory response and trigger apoptosis of immune cells to exacerbate sepsis progression. Inhibiting the negative effects of ROS and NLRP3 inflammasomes therefore provides the possibility of reversing the excessive inflammation during sepsis. In this review, we describe the interaction of ROS and NLRP3 inflammasomes during sepsis, provide prevention strategies, and identify fields that need further study.
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.
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.
Gas Plasma Exposure of Glioblastoma Is Cytotoxic and Immunomodulatory in Patient-Derived GBM Tissue
(2022)
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.
Purpose
Endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunting are well-established treatments of obstructive hydrocephalus (HCP) in adult and pediatric patients. However, there is a lack of data with regard to the quality of life (QoL) of these patients during long-term follow-up
Methods
Inclusion criteria were pediatric patients with endoscopic treatment of hydrocephalus at the University Medicine Greifswald between 1993 and 2016. Patients older than 14 years at present were assessed with the Short Form-12 (SF-12) questionnaire. Patients younger than 14 years of age were assessed with the KINDL-R questionnaire that was completed by their parents. Patients’ values were compared with the scores of a corresponding age-matched group of the healthy population and with patients who received later shunt treatment. Information about comorbidities, current symptoms, and educational level were gained by an additional part. Comparative analysis between patients with ETV success and failure (defined as shunt implantation after ETV) was performed.
Results
A total of 107 patients (53 m, 54f) were included. Fifty-seven/107 patients (53.3%) were considered as ETV success. Mean age at ETV was 6.9 ± 5.9 years. Fifty-four statements of 89 patients that are still alive were gained (response rate 63%). Of these, 49 questionnaires were complete and evaluable (23 m, 26f; mean age 19.8 ± 10.0 years with an average follow-up period of 13.7 ± 7.2 years). Twenty-six/49 patients (53.1%) are considered ETV success. No statistically significant differences could be obtained between patients with ETV success and ETV failure. Patients older 14 years show QoL within normal range, patients younger than 14 years show significantly lower result regarding their environment of peers and social contacts. Patients younger than 6 months at the time of ETV and patients with posthemorrhagic HCP show significantly lower physical QoL. Gait disturbance, fatigue, and seizures are associated with a lower QoL, and educational level is lower than in the normal population.
Conclusions
Patients who underwent ETV in childhood do not have a lower health-related QoL in general. Subsequent insertions of ventriculoperitoneal (vp) shunts do not lower QoL. Certain subgroups of the patients show lower results compared to the healthy population.
Purpose
Despite being rarely reported, ischemic insults resulting from compromising small brainstem perforators following microvascular decompression (MVD) remain a potential devastating complication. To avoid this complication, we have been using indocyanine green (ICG) angiography intraoperatively to check the flow within the small brainstem perforators. We aim to evaluate the safety and usefulness of ICG videoangiography in MVD.
Methods
We extracted retrospective data of patients who received ICG videoangiography from our prospectively maintained database for microvascular decompression. We noted relevant data including demographics, offending vessels, operative technique, outcome, and complications.
Results
Out of the 438 patients, 15 patients with a mean age (SD) of 53 ± 10.5 years underwent intraoperative ICG angiography. Male:female was 1:1.14. The mean disease duration prior to surgery was 7.7 ± 5.3 years. The mean follow-up (SD) was 50.7 ± 42.0 months. In 14 patients, the offending vessel was an artery, and in one patient, a vein. Intraoperative readjustment of the Teflon pledget or sling was required in 20% (3/15) of the cases. No patient had any sort of brainstem ischemia. Eighty percent of the patients (12/15) experienced complete resolution of the spasms. 86.7% (13/15) of the patients reported a satisfactory outcome with marked improvement of the spasms. Three patients experienced slight hearing affection after surgery, which improved in two patients later. There was no facial or lower cranial nerve affection.
Conclusion
Intraoperative ICG is a safe tool for evaluating the flow within the brain stem perforators and avoiding brainstem ischemia in MVD for hemifacial spasm.