The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Grading meningioma resections: the Simpson classification and beyond.

Technological (and also methodological) advances in neurosurgery and neuroimaging have prompted a reappraisal of Simpson's grading of the extent of meningioma resections. To the authors, the published evidence supports the tenets of this classification. Meningioma is an often surgically curable dura-based disease. An extent of meningioma resection classification needs to account for a clinically meaningful variation of the risk of recurrence depending on the aggressiveness of the management of the (dural) tumor origin.Nevertheless, the 1957 Simpson classification undoubtedly suffers from many limitations. Important issues include substantial problems with the applicability of the grading paradigm in different locations. Most notably, tumor location and growth pattern often determine the eventual extent of resection, i.e., the Simpson grading does not reflect what is surgically achievable. Another very significant problem is the inherent subjectivity of relying on individual intraoperative assessments. Neuroimaging advances such as the use of somatostatin receptor PET scanning may help to overcome this central problem. Tumor malignancy and biology in general certainly influence the role of the extent of resection but may not need to be incorporated in an actual extent of resection grading scheme as long as one does not aim at developing a prognostic score. Finally, all attempts at grading meningioma resections use tumor recurrence as the endpoint. However, especially in view of radiosurgery/radiotherapy options, the clinical significance of recurrent tumor growth varies greatly between cases.In summary, while the extent of resection certainly matters in meningioma surgery, grading resections remains controversial. Given the everyday clinical relevance of this issue, a multicenter prospective register or study effort is probably warranted (including a prominent focus on advanced neuroimaging).

Stroke-derived neutrophils demonstrate higher formation potential and impaired resolution of CD66b + driven neutrophil extracellular traps.

BACKGROUND: Recent evidence suggests a merging role of immunothrombosis in the formation of arterial thrombosis. Our study aims to investigate its relevance in stroke patients. METHODS: We compared the peripheral immunological profile of stroke patients vs. healthy controls. Serum samples were functionally analyzed for their formation and clearance of Neutrophil-Extracellular-Traps. The composition of retrieved thrombi has been immunologically analyzed. RESULTS: Peripheral blood of stroke patients showed significantly elevated levels of DNAse-I (p < 0.001), LDG (p = 0.003), CD4 (p = 0.005) as well as the pro-inflammatory cytokines IL-17 (p < 0.001), INF-γ (p < 0.001) and IL-22 (p < 0.001) compared to controls, reflecting a TH1/TH17 response. Increased counts of DNAse-I in sera (p = 0.045) and Neutrophil-Extracellular-Traps in thrombi (p = 0.032) have been observed in patients with onset time of symptoms longer than 4,5 h. Lower values of CD66b in thrombi were independently associated with greater improvement of NIHSS after mechanical thrombectomy (p = 0.045). Stroke-derived neutrophils show higher potential for Neutrophil-Extracellular-Traps formation after stimulation and worse resolution under DNAse-I treatment compared to neutrophils derived from healthy individuals. CONCLUSIONS: Our data provide new insight in the role of activated neutrophils and Neutrophil-Extracellular-Traps in ischemic stroke. Future larger studies are warranted to further investigate the role of immunothrombosis in the cascades of stroke. TRIAL REGISTRATION: DRKS, DRKS00013278, Registered 15 November 2017, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013278.

The rupture of an anterior communicating artery aneurysm does not associate with an asymmetry in the A1 or A2 arteries: a retrospective study of radiological features.

BACKGROUND AND OBJECTIVES: Although the formation and rupture risk of an anterior communicating artery (ACoA) aneurysm has been the subject of many studies, no previous study has primarily searched for the relationship of the parent and daughter vessels and the impact of their size/diameter ratio on the potential rupture risk of an AcoA aneurysm. The objective of this study is to explore this link and to further analyse the surrounding vasculature of the anterior communicating artery aneurysm. MATERIALS AND METHODS: We conducted a retrospective analysis of 434 patients: 284 patients with an ACoA aneurysm (121 unruptured and 162 ruptured) and 150 control patients without an ΑCoA aneurysm. Radiological angiography investigations were used to assess the diameter ratios of the parent vessels in addition to ACoA aneurysm morphology parameters. RESULTS: When comparing the ruptured to the unruptured cases, we observed no significant difference in the parent or daughter vessel diameter ratios. Younger patient age (OR 0.96, p = 0.00) and a higher aneurysm size ratio (OR 1.10, p = 0.02) were of prognostic importance concerning the rupture risk of the aneurysm. The A1 diameter ratio and the A2 diameter were not statistically significant (OR 1.00, p = 0.99, and OR 3.38, p = 0.25 respectively). CONCLUSIONS: In our study, we focused on asymmetry in the parent and daughter vessels as well as traditional ACoA aneurysm morphological characteristics. We were able to label younger patient age and a greater size ratio as independent prognostic factors for ACoA aneurysm rupture. We were unable to label parent and daughter vessel asymmetry as prognostic factors. To validate our findings, parent and daughter vessel asymmetry should be subjected to future prospective studies.

Deciphering the 8q24.21 association for glioma.

We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.

Karyopherin a2 and chromosome region maintenance protein 1 expression in meningiomas: novel biomarkers for recurrence and malignant progression.

The karyopherin protein family comprises importins and exportins which are nucleocytoplasmic shuttling receptors. Increased levels of karyopherin a2 and chromosome region maintenance protein 1 correlate with a higher WHO grade and a poorer prognosis in patients with infiltrative astrocytomas. The aim of this study was to evaluate representative members of importins and exportins (i.e. karyopherin a2 and chromosome region maintenance protein 1) as novel biomarkers for meningiomas of WHO grades I-III. We semiquantitatively analyzed nuclear expression of karyopherin a2, chromosome region maintenance protein 1 and the MIB1 labeling index using immunohistochemistry in 108 primary (44 meningiomas WHO grade I, 48 meningiomas WHO grade II, 16 meningiomas WHO grade III) and 13 recurrent meningiomas. Statistical analysis was performed using standard techniques. Karyopherin a2 (p < 0.001) and chromosome region maintenance protein 1 (p = 0.002) expression correlated significantly with the histological grade. Karyopherin a2 expression correlated with proliferative activity as assessed by the MIB1 index (p < 0.001). Recurrent tumors expressed significantly higher levels of karyopherin a2 (p = 0.045) when compared to primary growths. Multivariate analysis of the overall series as well as of patients with atypical meningiomas identified higher karyopherin a2 (≥ 5 vs. <5%) and chromosome region maintenance protein 1 (≥ 60 vs. 60%) expression as independent predictors of tumor recurrence. Karyopherin a2 and chromosome region maintenance protein 1 expression may have potential as novel biomarkers for meningiomas.

Extent of resection and survival in supratentorial infiltrative low-grade gliomas: analysis of and adjustment for treatment bias.

BACKGROUND: Any correlation between the extent of resection and the prognosis of patients with supratentorial infiltrative low-grade gliomas may well be related to biased treatment allocation. Patients with an intrinsically better prognosis may undergo more aggressive resections, and better survival may then be falsely attributed to the surgery rather than the biology of the disease. The present study investigates the potential impact of this type of treatment bias on survival in a series of patients with low-grade gliomas treated at the authors' institution. METHODS: We conducted a retrospective study of 148 patients with low-grade gliomas undergoing primary treatment at our institution from 1996-2011. Potential prognostic factors were studied in order to identify treatment bias and to adjust survival analyses accordingly. RESULTS: Eloquence of tumor location proved the most powerful predictor of the extent of resection, i.e., the principal source of treatment bias. Univariate as well as multivariate Cox regression analyses identified the extent of resection and the presence of a preoperative neurodeficit as the most important predictors of overall survival, tumor recurrence and malignant progression. After stratification for eloquence of tumor location in order to correct for treatment bias, Kaplan-Meier estimates showed a consistent association between the degree of resection and improved survival. CONCLUSION: Treatment bias was not responsible for the correlation between extent of resection and survival observed in the present series. Our data seem to provide further support for a strategy of maximum safe resections for low-grade gliomas.

FIFA Initiatives Improved Survival After Loss of Consciousness During Football Games.

Loss of consciousness (LOC) during football games is associated with very high mortality rates. In order to address football medical emergencies, in 2013 FIFA implemented the "FIFA 11 steps to prevent sudden cardiac death" program and distributed the FIFA Medical Emergency Bag. The purpose of this work was to identify independent survival factors after LOC on the pitch and to investigate the effectiveness of the FIFA initiatives. An internet search was performed to identify football players suffering LOC on the pitch between 1990 and 2021. A total of 268 cases could be identified and were dichotomized according to the implementation date of the FIFA medical emergency bag. There was 55% mortality after LOC, while cardiogenic LOC was more often (82% vs. 20%) fatal than traumatic LOC. Mortality in developing countries was higher than in developed countries. From the year 2013 survival improved significantly for both traumatic and cardiogenic cases. The location of the LOC significantly influenced survival (OR: 0.20 and p<0.001). LOC on the football field is associated with increased mortality and requires separate monitoring based on a traumatic vs. non-traumatic cause. FIFA initiatives significantly reduced mortality after LOC but significant differences were identified between developed and developing countries.

Chromosome 7p11.2 (EGFR) variation influences glioma risk.

While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.

Prognostic impact of the isocitrate dehydrogenase 1 single-nucleotide polymorphism rs11554137 in malignant gliomas.

BACKGROUND: The IDH1 gene, which encodes isocitrate dehydrogenase 1, is frequently mutated in gliomas and acute myeloid leukemia. The single-nucleotide polymorphism (SNP) (reference SNP no. rs11554137:C>T) located on IDH1 codon 105 has been associated with a poor outcome in patients with acute myeloid leukemia but has not been investigated in patients with gliomas. METHODS: The IDH1 codon 105 SNP was genotyped first in a series of 952 patients with grade 2 through 4 gliomas and was correlated with outcomes and tumor genomic profile. Then, it was genotyped in 2 validations sets of 306 patients with glioblastoma (GBM) and 591 patients with glioma. RESULTS: The minor allele codon 105 glycine (GGT) SNP (IDH1(105GGT) ) was identified in 98 of 952 patients (10.3%) and was not associated with the codon 132 (IDH1(132) ) mutation. Patients who had GMB with the IDH1(105GGT) variant had a poorer outcome than patients without the variant (median overall survival [OS], 10.7 months vs 15.5 months; P = .001; median progression-free survival [PFS], 6.4 months vs 8.5 months; P = .003). The prognostic impact was confirmed in an independent validation set of 306 GBMs from the same center (median PFS, 6.8 months vs 9.7 months; P = .006; median OS, 13.9 months vs 18.8 months; P = .0187). In the second validation cohort (591 grade 2-4 gliomas), a significant association was observed between IDH1(105GGT) and an adverse prognosis for the overall series and for patients with World Health Organization grade 3 gliomas, but the difference did not reach significance in patients with GBM. CONCLUSIONS: Taken together, the current data strongly suggested an association between the SNP rs11554137:C>T polymorphism and adverse outcomes in patients with malignant glioma. A single-nucleotide polymorphism (SNP) located on codon 105 of the isocitrate dehydrogenase 1 (IDH1) gene (reference SNP rs11554137) is analyzed in 3 independent series of patients with gliomas. The SNP rs11554137 is independent of the occurrence of somatic mutation on IDH1 codon 132, but, per se, has a prognostic impact in malignant gliomas.

Meningiomas with CNS invasion.

CNS invasion has been included as an independent criterion for the diagnosis of a high-grade (WHO and CNS grade 2 and 3) meningioma in the 2016 and more recently in the 2021 WHO classification. However, the prognostic role of brain invasion has recently been questioned. Also, surgical treatment for brain invasive meningiomas may pose specific challenges. We conducted a systematic review of the 2016-2022 literature on brain invasive meningiomas in Pubmed, Scopus, Web of Science and the Cochrane Library. The prognostic relevance of brain invasion as a stand-alone criterion is still unclear. Additional and larger studies using robust definitions of histological brain invasion and addressing the issue of sampling errors are clearly warranted. Although the necessity of molecular profiling in meningioma grading, prognostication and decision making in the future is obvious, specific markers for brain invasion are lacking for the time being. Advanced neuroimaging may predict CNS invasion preoperatively. The extent of resection (e.g., the Simpson grading) is an important predictor of tumor recurrence especially in higher grade meningiomas, but also - although likely to a lesser degree - in benign tumors, and therefore also in brain invasive meningiomas with and without other histological features of atypia or malignancy. Hence, surgery for brain invasive meningiomas should follow the principles of maximal but safe resections. There are some data to suggest that safety and functional outcomes in such cases may benefit from the armamentarium of surgical adjuncts commonly used for surgery of eloquent gliomas such as intraoperative monitoring, awake craniotomy, DTI tractography and further advanced intraoperative brain tumor visualization.

Explanted Skull Flaps after Decompressive Hemicraniectomy Demonstrate Relevant Bone Avitality-Is Their Reimplantation Worth the Risk?

BACKGROUND: Reimplantations of autologous skull flaps after decompressive hemicraniectomies (DHs) are associated with high rates of postoperative bone flap resorption (BFR). We histologically assessed the cell viability of explanted bone flaps in certain periods of time after DH, in order to conclude whether precursors of BRF may be developed during their storage. METHODS: Skull bone flaps explanted during a DH between 2019 and 2020 were stored in a freezer at either -23 °C or -80 °C. After their thawing process, the skulls were collected. Parameters of bone metabolism, namely PTH1 and OPG, were analyzed via immunohistochemistry. H&E stain was used to assess the degree of avital bone tissue, whereas the repeated assays were performed after 6 months. RESULTS: A total of 17 stored skull flaps (8 at -23 °C; 9 at -80 °C) were analyzed. The duration of cryopreservation varied between 2 and 17 months. A relevant degree of bone avitality was observed in all skull flaps, which significantly increased at the repeated evaluation after 6 months (p < 0.001). Preservation at -23 °C (p = 0.006) as well as longer storage times (p < 0.001) were identified as prognostic factors for higher rates of bone avitality in a linear mixed regression model. CONCLUSIONS: Our novel finding shows a clear benefit from storage at -80° C, which should be carefully considered for the future management and storage of explanted skull flaps. Our analysis also further revealed a significant degree of bone avitality, a potential precursor of BFR, in skull flaps stored for several weeks. To this end, we should reconsider whether the reimplantation of autologous skull flaps instead of synthetic skull flaps is still justified.

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms.

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including 31P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by 1H and 31P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by 31P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure-function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood-brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms.

Mechanisms of Cell Cycle Arrest and Apoptosis in Glioblastoma.

Cells of glioblastoma, the most frequent primary malignant brain tumor, are characterized by their rapid growth and infiltration of adjacent healthy brain parenchyma, which reflects their aggressive biological behavior. In order to maintain their excessive proliferation and invasion, glioblastomas exploit the innate biological capacities of the patients suffering from this tumor. The pathways involved in cell cycle regulation and apoptosis are the mechanisms most commonly affected. The following work reviews the regulatory pathways of cell growth in general as well as the dysregulated cell cycle and apoptosis relevant mechanisms observed in glioblastomas. We then describe the molecular targeting of the current established adjuvant therapy and present ongoing trials or completed studies on specific promising therapeutic agents that induce cell cycle arrest and apoptosis of glioblastoma cells.

[Perforator-based keystone flap in the reconstruction of extensive tissue defects after lumbosacral spondylodesis]. / Perforatorbasierte Keystone-Lappenplastik in der Rekonstruktion ausgedehnter Gewebedefekte nach lumbosakraler Spondylodese.

BACKGROUND: Prolonged surgical site infections after spinal fusion surgery may lead to exposure of the implant due to the formation of extensive tissue defects and endanger the clinical outcome. OBJECTIVE: This study aims to enlighten the role of the keystone perforator flap method in the reconstruction of lumbar soft tissue defects. MATERIAL AND METHODS: The retrospective study included 11 consecutive patients with a wound dehiscence of over 6â€¯× 6 cm defect area persisting for 2 weeks after spinal fusion. The keystone perforator flap was applied for the reconstruction of tissue defects, whereas the arterial blood supply of the flaps was based on the intramuscular and intermuscular perforating branches of the dorsal branches of the lumbar arteries. RESULTS: The median age of our cohort was 58 years. The median body mass index (BMI) and Charlson comorbidity index (CCI) were 29.9 and 3.4, respectively. In eight cases a lumbosacral was carried out whereas in the remaining series a lumbar fusion was performed. In the course of the subsequent wound revision, on average 4 applications of negative pressure wound therapy (NPWT) were performed. The average defect size was 7.5 cm in width and 16.5 cm in length. The microbiological analysis of the tissue samples obtained intraoperatively after repeated NPWT revealed positive evidence of pathogenic bacteria in all cases. The average duration of inpatient treatment after flap surgery was 15 days, which was significantly shorter than the NPWT management of the open defect wounds (15.5 ± 2.5 vs. 37 ± 16.5, p < 0.05). CONCLUSION: The keystone perforator flap offers a stable coverage for soft tissue defects and supports infection control after spinal fusion.

Distinct Behavior of Traumatic versus Nontraumatic Intracerebral Hematomas: Different Biology or Impact of Age?

BACKGROUND AND STUDY AIMS: Patients with large intracerebral hematomas (ICH) may demonstrate different demographics and underlying brain and systemic diseases, as well as different radiologic courses and distinct outcomes. It remains unclear whether their different behavior attributes to a different biology of the ICH or to the asymmetric characteristics of the two populations. To analyze and adjust for potential sources of selection and treatment bias, our study compared age-matched patients with traumatic and nontraumatic ICH in a single cohort diagnosed and treated in the same surgical department. MATERIAL AND METHODS: We analyzed 135 consecutive patients with traumatic (n = 90) or spontaneous ICH (n = 45) undergoing treatment at a surgical intensive care unit of an urban university hospital. We documented their differences before and after adjustment for age in terms of demographics, the therapies applied, their radiologic (i.e., volume and rate of ICH expansion [HE]) and clinical (patients' outcome at 30 days) course, the length of hospital and ICU stay, as well as the hospital costs. RESULTS: Patients with traumatic ICH demonstrated more favorable clinical and radiologic characteristics at admission, that is, higher Glasgow Coma Scale score (p < 0.001), less frequently dilated pupil (p = 0.028), lower Charlson Comorbidity Index (p < 0.001), smaller ICH volume (p < 0.001), noneloquent (p < 0.001) or nonintraventricular (p = 0.003) ICH locations, as well as underwent fewer neurosurgical interventions (p < 0.001) and showed a better outcome (p = 0.041), defined as Glasgow Outcome Scale 4 and 5. After adjustment for age, no different outcomes were observed. Of note, elderly patients on novel oral anticoagulants (NOACs) were more likely to develop an HE compared with those on vitamin K antagonists (VKAs, p = 0.05) after traumatic brain injury (TBI) but not after spontaneous ICH. CONCLUSION: Our data reveal a significant heterogeneity within the traumatic series. Whereas younger patients show an excellent outcome, the elderly population of the traumatic cases demonstrates a poor outcome similar to that of the nontraumatic cohort. HE under NOACs rather than under VKAs is more likely in the elderly after TBI. Larger prospective trials are warranted to elucidate the potential individual underlying molecular mechanisms for the development of an ICH and HE in these diseases.

Prognostic Factors for Functional Outcome of Patients with Optic Nerve Sheath Meningiomas Treated with Stereotactic Radiotherapy-Evaluation of Own and Meta-Analysis of Published Data.

OBJECTIVE: To evaluate prognostic factors for a favorable outcome (improvement of the visual acuity or visual fields) after fractionated stereotactic radiotherapy (fSRT) of optic nerve sheath meningioma (ONSM). METHODS: We performed a database search for ONSM treatments during the period from April 2008 to September 2019 in the prospective database for stereotactic radiosurgery/radiotherapy (SRS/SRT) of the Robert Janker Clinic Bonn (Department of Radiotherapy) and performed a literature review and meta-analysis of published data on ONSM between 2010 and 2019. Ophthalmic status before and after treatment was evaluated and the collective was dichotomized into two groups: functional improvement (FI; improvement of either visual acuity or visual fields) and non functional improvement (NFI; with stable or deteriorating visual acuity or visual fields). The two groups were compared regarding different variables: pretreatment visual acuity, age, gender, gross tumor volume (GTV), follow up (FU) time, tumor localization, and maximal retina dose. RESULTS: Overall, 13 stereotactic radiotherapies were performed for ONSM (12 × fSRT, 1 × SRS). Mean follow up was 3 years (range: 1-5 years). The total dose was 50.4 Gy (5 × 1.8 Gy/week) in 12 patients treated with fSRT and 1 × 14 Gy in one SRS case. Mean GTV was 1.13 ccm (range: 0.44-2.20 ccm). During follow up, all tumors were stable or showed shrinkage of tumor volume (100% tumor control), no adverse events were observed, 53% of the patients achieved either better visual acuity or visual fields. Pretreatment visual acuity was significantly different between the FI and the NFI group (0.17 vs. 0.63, p = 0.03) in our series and in the meta analysis (p < 0.01). Moreover, shorter FU time and lower retinal dose were significantly linked (p < 0.05 and p < 0.01, respectively) with a better outcome in the meta-analysis but not in our patient cohort. Intracranial tumor localization, gender, and age were not significantly different between the two outcome groups. CONCLUSION: FSRT for ONSM achieves in over 50% of cases an improvement of the ophthalmic status with low morbidity and excellent tumor control in our series and the meta analysis. Patients with a favorable outcome had in all analysis a significantly higher visual acuity before treatment start. Therefore, we advocate using fSRT as early as possible before vision deterioration occurs.

Intake of NOAC is associated with hematoma expansion of intracerebral hematomas after traumatic brain injury.

PURPOSE: Novel oral anticoagulants are increasingly replacing vitamin K antagonists in the prophylaxis of thromboembolism as they are associated with lower incidence of spontaneous intracerebral hematomas and they do not require drug level monitoring. However, management dilemmas are apparent in patients on novel oral anticoagulants who have developed intracerebral hematomas after traumatic brain injury, since clinical experience with their reversal strategies is limited. METHODS: We retrospectively studied 90 patients with traumatic intracerebral hematomas undergoing treatment at the surgical intensive care unit of the BG University Clinic Bergmannsheil in Bochum between 2015 and 2018. We analyzed potential prognostic factors for their radiological (expansion of intracerebral hematoma) and clinical (patients' outcome) course, in particular the role of novel oral anticoagulants. RESULTS: 71.1% of patients were male; mean age was 67.3 years. Hematoma's expansion occurred in 35.9% of our patients, whereas 62.2% of our cohort showed a favorable outcome, defined as Glasgow Outcome Scale 4 and 5. Intake of novel oral anticoagulants was associated with a higher rate of hematoma's expansion compared to patients on vitamin K antagonists (p = 0.05) or to patients with normal coagulation status (p = 0.002). A younger age (p < 0.001) was identified as the sole independent prognostic factor for a more favorable outcome, after excluding our cases, who underwent a cardiopulmonary resuscitation. CONCLUSIONS: Our data showed a higher rate of hematoma's expansion in patients with traumatic intracerebral hematomas on novel oral anticoagulants vs. vitamin K antagonists and recommend the consideration of prophylactic reversal of the novel oral anticoagulants at admission. Larger prospective trials are warranted to conclude whether the current specific reversal protocols are safe and effective.

Evidence for Quantum Chemical Effects in Receptor-Ligand Binding Between Integrin and Collagen Fragments - A Computational Investigation With an Impact on Tissue Repair, Neurooncolgy and Glycobiology.

The collagen-integrin interactions are mediated by the doubly charged Mg2+ cation. In nature this cation seems to have the optimal binding strength to stabilize this complex. It is essential that the binding is not too weak so that the complex becomes unstable, however, it is also of importance that the ligand-receptor binding is still labile enough so that the ligand can separate from the receptor in a suited environment. In the case of crystal growing for experimentally useful integrin-collagen fragment complexes it turned out that Co2+ cations are ideal mediators to form stable complexes for such experiments. Although, one can argue that Co2+ is in this context an artificial cation, however, it is now of special interest to test the impact of this cation in cell-culture experiments focusing on integrin-ligand interactions. In order to examine, in particular, the role cobalt ions we have studied a Co2+ based model system using quantum chemical calculations. Thereby, we have shown that hybrid and long-range corrected functional, which are approximations provide already a sufficient level of accuracy. It is of interest to study a potential impact of cations on the binding of collagen-fragments including collagens from various species because different integrins have numerous biological functions (e.g. Integrin - NCAM (Neural cell adhesion molecule) interactions) and are triggered by intact and degraded collagen fragments. Since integrin-carbohydrate interactions play a key role when bio-medical problems such as tumor cell adhesion and virus-host cell infections have to be addressed on a sub-molecular level it is essential to understand the interactions with heavy-metal ions also at the sub-atomic level. Our findings open new routes, especially, in the fields of tissue repair and neuro-oncology for example for cell-culture experiments with different ions. Since Co2+ ions seem to bind stronger to integrin than Mg2+ ions it should be feasible to exchange these cations in suited tumor tissues although different cations are present in other metalloproteins which are active in such tissues. Various staining methods can be applied to document the interactions of integrins with carbohydrate chains and other target structures. Thereby, it is possible to study a potential impact of these interactions on biological functions. It was therefore necessary to figure out first which histological-glycobiological experimental settings of tumor cells are suited for our purpose. Since the interactions of several metalloproteins (integrin, ADAM12) with polysialic acid and the HNK-1 epitope play a crucial role in tumor tissues selected staining methods are proper tools to obtain essential information about the impact of the metal ions under study.