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Objective: Establishment of an immunocompetent mouse model representing the typical progressive stages observed in malignant human gliomas for the in vivo evaluation of novel target-specific regimens.
Methods: Isolated clones from tumours that arose spontaneously in GFAP-v-src transgenic mice were used to develop a transplantable brain tumour model in syngeneic B6C3F1 mice. STAT3 protein was knocked down by infection of tumour cells with replication-defective lentivirus encoding STAT3-siRNA. Apoptosis is designed to be induced by soluble recombinant TRAIL + chemical Bcl-2/Bcl-xL inhibitors.
Results: Striatal implantation of 105 mouse tumour cells resulted in the robust development of microscopically (2 – 3 mm) infiltrating malignant gliomas. Immunohistochemically, the gliomas displayed the astroglial marker GFAP and the oncogenic form of STAT3 (Tyr-705-phosphorylated) which is found in many malignancies including gliomas. Phosphorylated STAT3 was particularly prominent in the nucleus but was also found at the plasma membrane of peripherally infiltrating glioma cells. To evaluate the role of STAT3 in tumour progression, we stably expressed siRNA against STAT3 in several murine glioma cell lines. The effect of STAT3 depletion on proliferation, invasion and survival will be first assessed in vitro and subsequently after transplantation in vivo. Upstream and downstream components of the STAT3 signalling pathway as well as possible non-specific side effects of STAT3-siRNA expression after lentiviral infection will be examined, too.
Conclusions: Its high rate of engraftment, its similarity to the malignant glioma of origin, and its rapid locally invasive growth should make this murine model useful in testing novel therapies for malignant gliomas.
Background: In this interdisciplinary project, the biological effects of heavy ions are compared to those of X-rays using tissue slice culture preparations from rodents and humans. Advantages of this biological model are the conservation of an organotypic environment and the independency from genetic immortalization strategies used to generate cell lines. Its open access allows easy treatment and observation via live-imaging microscopy. Materials and methods: Rat brains and human brain tumor tissue are cut into 300 micro m thick tissue slices. These slices are cultivated using a membrane-based culture system and kept in an incubator at 37°C until treatment. The slices are treated with X-rays at the radiation facility of the University Hospital in Frankfurt at doses of up to 40 Gy. The heavy ion irradiations were performed at the UNILAC facility at GSI with different ions of 11.4 A MeV and fluences ranging from 0.5–10 x 106 particles/cm². Using 3D-confocal microscopy, cell-death and immune cell activation of the irradiated slices are analyzed. Planning of the irradiation experiments is done with simulation programs developed at GSI and FIAS. Results: After receiving a single application of either X-rays or heavy ions, slices were kept in culture for up to 9d post irradiation. DNA damage was visualized using gamma H2AXstaining. Here, a dose-dependent increase and time-dependent decrease could clearly be observed for the X-ray irradiation. Slices irradiated with heavy ions showed less gamma H2AX-positive cells distributed evenly throughout the slice, even though particles were calculated to penetrate only 90–100 micro m into the slice. Conclusions: Single irradiations of brain tissue, even at high doses of 40 Gy, will result neither in tissue damage visible on a macroscopic level nor necrosis. This is in line with the view that the brain is highly radio-resistant. However, DNA damage can be detected very well in tissue slices using gamma H2AX-immuno staining. Thus, slice cultures are an excellent tool to study radiation-induced damage and repair mechanisms in living tissues.
Posterior fossa tumor surgery is challenging due to the proximity and exposure of cerebellar structures. A favorable operative approach is unknown. Following lesions to the dentato–rubro–olivary-pathway, a neurodegenerative disease called hypertrophic olivary degeneration (HOD) can occur. This study for the first time demonstrates that paravermal trans-cerebellar approaches are associated with a significantly higher likelihood of HOD on MRI when compared to other approaches. This finding can well be attributed to dentate nucleus (DN) injury. Furthermore, cerebellar mutism syndrome (CMS) was discussed in the literature to be correlated with HOD due to a functional overlap of pathways involved. We found no such correlation in this study, but HOD was shown to be a reliable indicator for surgical disruption of efferent cerebellar pathways involving the DN. Henceforth, neurosurgeons should consider more midline or lateral approaches in posterior fossa surgery to spare the DN whenever feasible, and focus on cerebellar functional anatomy in their preoperative planning.
Transfusion of red blood cells (RBC) in patients undergoing major elective cranial surgery is associated with increased morbidity, mortality and prolonged hospital length of stay (LOS). This retrospective single center study aims to identify the clinical outcome of RBC transfusions on skull base and non-skull base meningioma patients including the identification of risk factors for RBC transfusion. Between October 2009 and October 2016, 423 patients underwent primary meningioma resection. Of these, 68 (16.1%) received RBC transfusion and 355 (83.9%) did not receive RBC units. Preoperative anaemia rate was significantly higher in transfused patients (17.7%) compared to patients without RBC transfusion (6.2%; p = 0.0015). In transfused patients, postoperative complications as well as hospital LOS was significantly higher (p < 0.0001) compared to non-transfused patients. After multivariate analyses, risk factors for RBC transfusion were preoperative American Society of Anaesthesiologists (ASA) physical status score (p = 0.0247), tumor size (p = 0.0006), surgical time (p = 0.0018) and intraoperative blood loss (p < 0.0001). Kaplan-Meier curves revealed significant influence on overall survival by preoperative anaemia, RBC transfusion, smoking, cardiovascular disease, preoperative KPS ≤ 60% and age (elderly ≥ 75 years). We concluded that blood loss due to large tumors or localization near large vessels are the main triggers for RBC transfusion in meningioma patients paired with a potential preselection that masks the effect of preoperative anaemia in multivariate analysis. Further studies evaluating the impact of preoperative anaemia management for reduction of RBC transfusion are needed to improve the clinical outcome of meningioma patients.
Simple Summary
Seizures are among the most common symptoms of meningioma patients even after surgery. This study sought to identify risk factors for early and late seizures in meningioma patients and to evaluate a modified version of a score to predict postoperative seizures on an independent cohort. The data underline that there are distinct factors identifying patients with a high risk of postoperative seizures following meningioma surgery which has been already shown before. We could further show that the high proportion of 43% of postoperative seizures occur as late seizures which are more dangerous because they may happen out of hospital. The modified STAMPE2 score could predict postoperative seizures when reaching very high scores but was not generally transferable to our independent cohort.
Abstract
Seizures are among the most common symptoms of meningioma. This retrospective study sought to identify risk factors for early and late seizures in meningioma patients and to evaluate a modified STAMPE2 score. In 556 patients who underwent meningioma surgery, we correlated different risk factors with the occurrence of postoperative seizures. A modified STAMPE2 score was applied. Risk factors for preoperative seizures were edema (p = 0.039) and temporal location (p = 0.038). For postoperative seizures preoperative tumor size (p < 0.001), sensomotory deficit (p = 0.004) and sphenoid wing location (p = 0.032) were independent risk factors. In terms of postoperative status epilepticus; sphenoid wing location (p = 0.022), tumor volume (p = 0.045) and preoperative seizures (p < 0.001) were independent risk factors. Postoperative seizures lead to a KPS deterioration and thus an impaired quality of life (p < 0.001). Late seizures occurred in 43% of patients with postoperative seizures. The small sub-cohort of patients (2.7%) with a STAMPE2 score of more than six points had a significantly increased risk for seizures (p < 0.001, total risk 70%). We concluded that besides distinct risk factors, high scores of the modified STAMPE2 score could estimate the risk of postoperative seizures. However, it seems not transferable to our cohort
Meningioma surgery in patients ≥70 years of age: clinical outcome and validation of the SKALE score
(2021)
Along with increasing average life expectancy, the number of elderly meningioma patients has grown proportionally. Our aim was to evaluate whether these specific patients benefit from surgery and to investigate a previously published score for decision-making in meningioma patients (SKALE). Of 421 patients who underwent primary intracranial meningioma resection between 2009 and 2015, 71 patients were ≥70 years of age. We compared clinical data including World Health Organization (WHO) grade, MIB-1 proliferation index, Karnofsky Performance Status Scale (KPS), progression free survival (PFS) and mortality rate between elderly and all other meningioma patients. Preoperative SKALE scores (Sex, KPS, ASA score, location and edema) were determined for elderly patients. SKALE ≥8 was set for dichotomization to determine any association with outcome parameters. In 71 elderly patients (male/female 37/34) all data were available. Postoperative KPS was significantly lower in elderly patients (p < 0.0001). Pulmonary complications including pneumonia (10% vs. 3.2%; p = 0.0202) and pulmonary embolism (12.7% vs. 6%; p = 0.0209) occurred more frequently in our elderly cohort. Analyses of the Kaplan Meier curves revealed differences in three-month (5.6% vs. 0.3%; p = 0.0033), six-month (7% vs. 0.3%; p = 0.0006) and one-year mortality (8.5% vs. 0.3%; p < 0.0001) for elderly patients. Statistical analysis showed significant survival benefit in terms of one-year mortality for elderly patients with SKALE scores ≥8 (5.1 vs. 25%; p = 0.0479). According to our data, elderly meningioma patients face higher postoperative morbidity and mortality than younger patients. However, resection is reasonable for selected patients, particularly when reaching a SKALE score ≥ 8.
Patient care in a neurointensive care unit (neuro-ICU) is challenging. Multidrug-resistant organisms (MDROs) are increasingly common in the routine clinical practice. We evaluated the impact of infection with MDROs on outcomes in patients with subarachnoid hemorrhage (SAH). A single-center retrospective analysis of SAH cases involving patients treated in the neuro-ICU was performed. The outcome was assessed 6 months after SAH using the modified Rankin Scale [mRS, favorable (0–2) and unfavorable (3–6)]. Data were compared by matched-pair analysis. Patient characteristics were well matched in the MDRO (n = 61) and control (n = 61) groups. In this center, one nurse was assigned to a two-bed room. If a MDRO was detected, the patient was isolated, and the nurse was assigned to the patient infected with the MDRO. In the MDRO group, 29 patients (48%) had a favorable outcome, while 25 patients (41%) in the control group had a favorable outcome; the difference was not significant (p > 0.05). Independent prognostic factors for unfavorable outcomes were worse status at admission (OR = 3.1), concomitant intracerebral hematoma (ICH) (OR = 3.7), and delayed cerebral ischemia (DCI) (OR = 6.8). Infection with MRDOs did not have a negative impact on the outcome in SAH patients. Slightly better outcomes were observed in SAH patients infected with MDROs, suggesting the benefit of individual care.
Background: New 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. Methods: We 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. Results: Curcumin 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. Conclusions: Curcumin 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.
Purpose: The extent of preoperative peritumoral edema in glioblastoma (GBM) has been negatively correlated with patient outcome. As several ongoing studies are investigating T-cell based immunotherapy in GBM, we conducted this study to assess whether peritumoral edema with potentially increased intracranial pressure, disrupted tissue homeostasis and reduced local blood flow has influence on immune infiltration and affects survival.
Methods: A volumetric analysis of preoperative imaging (gadolinium enhanced T1 weighted MRI sequences for tumor size and T2 weighted sequences for extent of edema (including the infiltrative zone, gliosis etc.) was conducted in 144 patients using the Brainlab® software. Immunohistochemical staining was analyzed for lymphocytic- (CD 3+) and myelocytic (CD15+) tumor infiltration. A retrospective analysis of patient-, surgical-, and molecular characteristics was performed using medical records.
Results: The edema to tumor ratio was neither associated with progression-free nor overall survival (p=0.90, p=0.74). However, GBM patients displaying IDH-1 wildtype had significantly higher edema to tumor ratio than patients displaying an IDH-1 mutation (p=0.01). Immunohistopathological analysis did not show significant differences in lymphocytic or myelocytic tumor infiltration (p=0.78, p=0.74) between these groups.
Conclusion: In our cohort, edema to tumor ratio had no significant correlation with immune infiltration and outcome. However, patients with an IDH-1wildtype GBM had a significantly higher edema to tumor ratio compared to their IDH-1 mutated peer group. Further studies are necessary to elucidate the underlying mechanisms.
