Role of mTOR and VEGFR Inhibition in Prevention of Metastatic Tumor Growth in the Spine

Objective: Spinal metastatic disease remains a major problem of oncological diseases. Patients affectedmay suffer pain, spinal instability, and severe neurological deficits. Today, palliative surgery and radiotherapy are the mainstays of therapy. In contrast, preventive treatment strategies or treatment concepts for an early stage are lacking. Here, we have used a syngeneic, experimental spine metastases model in the mouse to test the efficacy of mTOR inhibition and anti-angiogenesis on the formation and progression of spinal melanoma metastases. Methods: We used our previously established syngeneic spinal metastases mouse model by injecting luciferin-transfected B16 melanoma cells into the common carotid artery. Following injection, mice were treated with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) complex, axitinib, a tyrosine kinase inhibitor, that blocks vascular endothelial growth factor receptors (VEGFR) 1-3, as well as placebo. Animals were followed-up daily by neurological assessment and by repeat in vivo bioluminescence imaging. With occurrence of neurological deficits, a spinal MRI was performed, and mice were sacrificed. The whole spine was dissected free and analyzed by immunohistochemical techniques. Results: Overall survival was 23 days in the control group, significantly prolonged to 30 days (p = 0.04) in the everolimus group, and to 28 days (p = 0.04) in the axitinib group. While 78% of mice in the placebo group developed symptomatic metastatic epidural spinal cord compression, only 50% did so in the treatment groups. The mean time to manifestation of paralysis was 22 days in the control group, 26 days (p = 0.10) in the everolimus group, and 27 days (p = 0.06) in the axitinib group. Screening for spinal metastases by bioluminescence imaging on two different time points showed a decrease in metastatic tumor formation in the treatment groups compared to the controls. Immunohistochemical analysis confirmed the bioactivity of the two compounds: The Ki67 proliferation labeling index was reduced in the everolimus group and numbers of CD31 positive endothelial cells were reduced in the axitinib group. Conclusion: Both, the mTOR inhibitor everolimus as well as antiangiogenetic effects by the VEGFR inhibitor axitinib showed potential to prevent and retard formation of symptomatic spinal metastases. However, the therapeutic efficacy was only mild in this experimental model

Junctional Adhesion Molecule-C Mediates the Recruitment of Embryonic-Endothelial Progenitor Cells to the Perivascular Niche during Tumor Angiogenesis

The homing of Endothelial Progenitor Cells (EPCs) to tumor angiogenic sites has been described as a multistep process, involving adhesion, migration, incorporation and sprouting, for which the underlying molecular and cellular mechanisms are yet to be fully defined. Here, we studied the expression of Junctional Adhesion Molecule-C (JAM-C) by EPCs and its role in EPC homing to tumor angiogenic vessels. For this, we used mouse embryonic-Endothelial Progenitor Cells (e-EPCs), intravital multi-fluorescence microscopy techniques and the dorsal skin-fold chamber model. JAM-C was found to be expressed by e-EPCs and endothelial cells. Blocking JAM-C did not affect adhesion of e-EPCs to endothelial monolayers in vitro but, interestingly, it did reduce their adhesion to tumor endothelium in vivo. The most striking effect of JAM-C blocking was on tube formation on matrigel in vitro and the incorporation and sprouting of e-EPCs to tumor endothelium in vivo. Our results demonstrate that JAM-C mediates e-EPC recruitment to tumor angiogenic sites, i.e., coordinated homing of EPCs to the perivascular niche, where they cluster and interact with tumor blood vessels. This suggests that JAM-C plays a critical role in the process of vascular assembly and may represent a potential therapeutic target to control tumor angiogenesis

Predictors of clinical outcomes in space-occupying cerebellar infarction undergoing suboccipital decompressive craniectomy

IntroductionDespite current clinical guidelines recommending suboccipital decompressive craniectomy (SDC) in cerebellar infarction when patients present with neurological deterioration, the precise definition of neurological deterioration remains unclear and accurate timing of SDC can be challenging. The current study aimed at characterizing whether clinical outcomes can be predicted by the GCS score immediately prior to SDC and whether higher GCS scores are associated with better clinical outcomes.MethodsIn a single-center, retrospective analysis of 51 patients treated with SDC for space-occupying cerebellar infarction, clinical and imaging data were evaluated at the time points of symptom onset, hospital admission, and preoperatively. Clinical outcomes were measured by the mRS. Preoperative GCS scores were stratified into three groups (GCS, 3–8, 9–11, and 12–15). Univariate and multivariate Cox regression analyses were performed using clinical and radiological parameters as predictors of clinical outcomes.ResultsIn cox regression analysis GCS scores of 12–15 at surgery were significant predictors of positive clinical outcomes (mRS, 1–2). For GCS scores of 3–8 and 9–11, no significant increase in proportional hazard ratios was observed. Negative clinical outcomes (mRS, 3–6) were associated with infarct volume above 6.0 cm3, tonsillar herniation, brainstem compression, and a preoperative GCS score of 3–8 [HR, 2.386 (CI, 1.160–4.906); p = 0.018].ConclusionOur preliminary findings suggest that SDC should be considered in patients with infarct volumes above 6.0 cm3 and with GCS between 12 and 15, as these patients may show better long-term outcomes than those in whom surgery is delayed until a GCS score below 11

Navigation accuracy and assessability of carbon fiber-reinforced PEEK instrumentation with multimodal intraoperative imaging in spinal oncology

Radiolucent carbon-fiber reinforced PEEK (CFRP) implants have helped improve oncological follow-up and radiation therapy. Here, we investigated the performance of 3D intraoperative imaging and navigation systems for instrumentation and precision assessment of CFRP pedicle screws across the thoraco-lumbar spine. Thirty-three patients with spinal tumors underwent navigated CFRP instrumentation with intraoperative CT (iCT), robotic cone-beam CT (rCBCT) or cone-beam CT (CBCT) imaging. Two different navigation systems were used for iCT-/rCBCT- and CBCT-based navigation. Demographic, clinical and outcome data was assessed. Four blinded observers rated image quality, assessability and accuracy of CFRP pedicle screws. Inter-observer reliability was determined with Fleiss` Kappa analysis. Between 2018 and 2021, 243 CFRP screws were implanted (iCT:93, rCBCT: 99, CBCT: 51), of which 13 were non-assessable (iCT: 1, rCBCT: 9, CBCT: 3; *p = 0.0475; iCT vs. rCBCT). Navigation accuracy was highest using iCT (74%), followed by rCBCT (69%) and CBCT (49%) (*p = 0.0064; iCT vs. CBCT and rCBCT vs. CBCT). All observers rated iCT image quality higher than rCBCT/CBCT image quality (*p < 0.01) but relevant pedicle breaches were reliably identified with substantial agreement between all observers regardless of the imaging modality. Navigation accuracy for CFRP pedicle screws was considerably lower than expected from reports on titanium implants and CT may be best for reliable assessment of CFRP materials

Current state of social media utilization in neurosurgery amongst European Association of Neurosurgical Societies (EANS) member countries.

BACKGROUND Social Media (SoMe) is becoming increasingly used in the medical community, and its use has been related with academic productivity. However, utilization of SoMe in the European neurosurgical community has not been assessed systematically. METHODS An online search was undertaken to discover SoMe accounts of (1) national and related neurosurgical societies listed on the EANS website, (2) neurosurgical journals present on EANS website, (3) neurosurgery centers within EANS member countries, as listed on their website. SoMe accounts of Facebook, Twitter, YouTube, and Instagram were searched for journals and societies, and Twitter, Instagram, and Facebook for neurosurgery departments. The number of likes/followers/subscribers was recorded. RESULTS Five (31%) neurosurgery journals had a SoMe presence. The highest number of followers, likes, and tweets was found for JNNP, and Journal of Neurological Surgery Part B had the most subscribers and video views. SoMe usage was identified for 11 national (28.2%) and 2 multi-national neurosurgical societies. From these, the French Society of Neurosurgery had the largest number of Facebook followers (> 2800) and Likes (> 2700), the Society of British Neurological Surgeons had the largest number of Twitter followers (> 2850), whereas EANS overall had the most followers on Twitter > 5100 and Facebook > 5450. A total of 87 SoMe neurosurgery center accounts were found on either Facebook, Instagram or Twitter, for 64 of 1000 centers (6.4%) in 22 of 40 different countries (55%). Of these 67% (n = 43/64) arose from 6 countries (England, Germany, Italy, Romania, Turkey, Ukraine). There were more Facebook accounts (n = 42) than Instagram accounts (n = 23) or Twitter accounts (n = 22). CONCLUSION SoMe use amongst neurosurgical societies and departments in Europe is very limited. From our perspective, explanations are lacking for the correlated numbers to the market shares of SoMe in the respective countries. Further research, including a survey, to follow up on this important topic should be undertaken among EANS members

Clinical implementation of a 3D4K-exoscope (Orbeye) in microneurosurgery

Exoscopic surgery promises alleviation of physical strain, improved intraoperative visualization and facilitation of the clinical workflow. In this prospective observational study, we investigate the clinical usability of a novel 3D4K-exoscope in routine neurosurgical interventions. Questionnaires on the use of the exoscope were carried out. Exemplary cases were additionally video-documented. All participating neurosurgeons (n = 10) received initial device training. Changing to a conventional microscope was possible at all times. A linear mixed model was used to analyse the impact of time on the switchover rate. For further analysis, we dichotomized the surgeons in a frequent (n = 1) and an infrequent (n = 9) user group. A one-sample Wilcoxon signed rank test was used to evaluate, if the number of surgeries differed between the two groups. Thirty-nine operations were included. No intraoperative complications occurred. In 69.2% of the procedures, the surgeon switched to the conventional microscope. While during the first half of the study the conversion rate was 90%, it decreased to 52.6% in the second half (p = 0.003). The number of interventions between the frequent and the infrequent user group differed significantly (p = 0.007). Main reasons for switching to ocular-based surgery were impaired hand-eye coordination and poor depth perception. The exoscope investigated in this study can be easily integrated in established neurosurgical workflows. Surgical ergonomics improved compared to standard microsurgical setups. Excellent image quality and precise control of the camera added to overall user satisfaction. For experienced surgeons, the incentive to switch from ocular-based to exoscopic surgery greatly varies

PrImary decompressive Craniectomy in AneurySmal Subarachnoid hemOrrhage (PICASSO) trial: study protocol for a randomized controlled trial

BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (SAH) is associated with poor neurological outcome and high mortality. A major factor influencing morbidity and mortality is brain swelling in the acute phase. Decompressive craniectomy (DC) is currently used as an option in order to reduce intractably elevated intracranial pressure (ICP). However, execution and optimal timing of DC remain unclear. METHODS: PICASSO resembles a multicentric, prospective, 1:1 randomized standard treatment-controlled trial which analyzes whether primary DC (pDC) performed within 24 h combined with the best medical treatment in patients with poor-grade SAH reduces mortality and severe disability in comparison to best medical treatment alone and secondary craniectomy as ultima ratio therapy for elevated ICP. Consecutive patients presenting with poor-grade SAH, defined as grade 4–5 according to the World Federation of Neurosurgical Societies (WFNS), will be screened for eligibility. Two hundred sixteen patients will be randomized to receive either pDC additional to best medical treatment or best medical treatment alone. The primary outcome is the clinical outcome according to the modified Rankin Scale (mRS) at 12 months, which is dichotomized to favorable (mRS 0–4) and unfavorable (mRS 5–6). Secondary outcomes include morbidity and mortality, time to death, length of intensive care unit (ICU) stay and hospital stay, quality of life, rate of secondary DC due to intractably elevated ICP, effect of size of DC on outcome, use of duraplasty, and complications of DC. DISCUSSION: This multicenter trial aims to generate the first confirmatory data in a controlled randomized fashion that pDC improves the outcome in a clinically relevant endpoint in poor-grade SAH patients. TRIAL REGISTRATION: DRKS DRKS00017650. Registered on 09 June 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06969-4

Diagnostic reliability of the Berlin classification for complex MCA aneurysms—usability in a series of only giant aneurysms

Background and objective The main challenge of bypass surgery of complex MCA aneurysms is not the selection of the bypass type but the initial decision-making of how to exclude the affected vessel segment from circulation. To this end, we have previously proposed a classification for complex MCA aneurysms based on the preoperative angiography. The current study aimed to validate this new classification and assess its diagnostic reliability using the giant aneurysm registry as an independent data set. Methods We reviewed the pretreatment neuroimaging of 51 patients with giant (> 2.5 cm) MCA aneurysms from 18 centers, prospectively entered into the international giant aneurysm registry. We classified the aneurysms according to our previously proposed Berlin classification for complex MCA aneurysms. To test for interrater diagnostic reliability, the data set was reviewed by four independent observers. Results We were able to classify all 51 aneurysms according to the Berlin classification for complex MCA aneurysms. Eight percent of the aneurysm were classified as type 1a, 14% as type 1b, 14% as type 2a, 24% as type 2b, 33% as type 2c, and 8% as type 3. The interrater reliability was moderate with Fleiss's Kappa of 0.419. Conclusion The recently published Berlin classification for complex MCA aneurysms showed diagnostic reliability, independent of the observer when applied to the MCA aneurysms of the international giant aneurysm registry.Peer reviewe

Junctional Adhesion Molecule-C Mediates the Recruitment of Embryonic-Endothelial Progenitor Cells to the Perivascular Niche during Tumor Angiogenesis

The homing of Endothelial Progenitor Cells (EPCs) to tumor angiogenic sites has been described as a multistep process, involving adhesion, migration, incorporation and sprouting, for which the underlying molecular and cellular mechanisms are yet to be fully defined. Here, we studied the expression of Junctional Adhesion Molecule-C (JAM-C) by EPCs and its role in EPC homing to tumor angiogenic vessels. For this, we used mouse embryonic-Endothelial Progenitor Cells (e-EPCs), intravital multi-fluorescence microscopy techniques and the dorsal skin-fold chamber model. JAM-C was found to be expressed by e-EPCs and endothelial cells. Blocking JAM-C did not affect adhesion of e-EPCs to endothelial monolayers in vitro but, interestingly, it did reduce their adhesion to tumor endothelium in vivo. The most striking effect of JAM-C blocking was on tube formation on matrigel in vitro and the incorporation and sprouting of e-EPCs to tumor endothelium in vivo. Our results demonstrate that JAM-C mediates e-EPC recruitment to tumor angiogenic sites, i.e., coordinated homing of EPCs to the perivascular niche, where they cluster and interact with tumor blood vessels. This suggests that JAM-C plays a critical role in the process of vascular assembly and may represent a potential therapeutic target to control tumor angiogenesis

Plastic vascular systems in glioblastoma multiforme and Moyamoya vasculopathy

In der Neurochirurgie steht eine pathologisch veränderte Neoangiogenese vor allem im Rahmen des Glioblastoma multiforme und der Moyamoya Erkrankung im Vordergrund. Das Ziel dieser Arbeit war es die Bedeutung der Neoangiogenese für die Pathophysiologie und Therapie dieser beiden neurochirurgischen Modellkrankheiten darzulegen. Zu diesem Zweck wurden sowohl experimentelle als auch klinische Untersuchungsmethoden herangezogen. Während beim Glioblastoma multiforme die therapeutische Bedeutung der Tumorangiogenese durch verschiedene präklinische Experimente mit einem Schwerpunkt auf der Intravitalmikroskopie untersucht wurde, rückte bei der Moyamoya Vaskulopathie die Analyse der zerebralen Mikrozirkulation mittels intraoperativer Videoangiographie in den Vordergrund. Darüberhinaus wurden die vaskulären und klinischen Konsequenzen operativer Revaskularisierungstechniken untersucht. Die Ergebnisse dieser Arbeit zeigen, dass die Tank-binding Kinase 1 sowohl proangiogene als auch proinflammatorische Wirkungen besitzt und damit als neues Therapieziel zur Behandlung von Tumoren (wie z.B. dem Glioblastoma multiforme) herangezogen werden kann. Darüberhinaus wird verdeutlicht, dass eine antiangiogene Therapie nicht nur eine Reduktion der Gefäßdichte induziert, sondern dass therapieresistente Tumorgefäße durch Alterationen der Gefäßmorphologie und Gefäßfunktion gekennzeichnet sind, welche die vaskuläre Anflutung einer chemotherapeutischen Substanz verbessern. In diesem Zusammenhang dient das Gefäßsystem des Glioblastoma multiforme nicht nur als vielversprechendes antiangiogenes Therapieziel, sondern auch als Ziel antikörpervermittelter Therapiestrategien. Hier zeigt das Biodistributionsverhalten des neoangiogenen gefäßspezifischen Fibronektinantikörpers L19-SIP eine verstärkte Bindung an gut perfundierte und unreife Gliomgefäße mit anschließender sekundärer Extravasation. Unter einer antiangiogenen Therapie kann die Bindung des Antikörpers in therapieresistenten Gefäßen gesteigert werden, so dass der Antikörper sowohl für gezielte diagnostische als auch therapeutische Interventionen verwendet werden kann. Bei der Moyamoya Erkrankung spielt die kortikale Mikrozirkulation eine zentrale Rolle. Eine Moyamoya spezifische Erhöhung der kortikalen Gefäßdichte führt zu einer deutlichen Reduktion des peripheren Gefäßwiderstandes und kann als Kompensationsmechanismus für die zerebrale Minderdurchblutung angesehen werden. Dementsprechend sind Moyamoya Patienten ohne neurologisches Defizit durch eine effizientere kortikale Mikrozirkulation gekennzeichnet als Patienten, die im Verlauf ihrer Erkrankung bereits klinisch manifeste Ischämien entwickelt haben. Basierend auf diesem Wissen kann die Moyamoya Vaskulopathie anhand des angiographischen Erscheinungsbildes, der Präsenz manifester Ischämien und der zerebrovaskulären Reservekapazität in drei Erkrankungsschweregrade eingeteilt werden, die eine Vorhersage klinisch manifester Ischämien erlauben. Nicht zuletzt spielt das Moyamoya spezifische neoangiogene Potential eine wichtige Rolle bei der chirurgischen Revaskularisierung. Bei pädiatrischen Moyamoya Patienten ist die Stimulation der Gefäßneubildung aus einer Encephalomyosynangiose suffizient um eine klinisch ausreichende Revaskularisierung zu induzieren. Bei adulten Moyamoya- Patienten ist ein direkter extra-intrakranieller Bypass der Anlage einer indirekten Revaskularisierung bezüglich der Widerherstellung der zerebralen Durchblutung überlegen. Bei diesen Patienten ist das neoangiogene Potential nicht ausreichend um eine Restitution der zerebrovaskulären Reservekapazität basierend auf einer indirekten Revaskularisierung zu erreichen. Zusammenfassend zeigt diese Arbeit, dass sowohl beim Glioblastoma multiforme als auch bei der Moyamoya Vaskulopathie die Neubildung von Blutgefäßen eine zentrale Rolle bei der Entstehung und Therapie spielt. Ein tieferes Verständnis der assoziierten Gefäßbiologie und der molekularen Grundlagen wird die Therapie dieser Erkrankungen in Zukunft verbessern.Pathologically altered neoangiogenesis plays a pivotal role in different neurosurgical pathologies. A special neurosurgical focus on angiogenesis exists in glioblastoma multiforme als well as in Moyamoya vasculopathy. Therefore, it was the aim of this work to investigate the importance of pathologic neovascularization for the pathophysiology and treatment of glioblastoma multiforme and Moyamoya vasculopathy. Different clinical and experimental methods were used to investigate microcirculation in glioblastoma and Moyamoya vasculopathy. Especially in malignant glioma the focus was on preclinical experimental therapy models using intravital microscopy investigating the effects of different antiangiogenic and vascular targeting strategies. In Moyamoya vasculopathy, intraoperative indocyanine green videoangiography was used to assess cortical microcirculation. Additionally, digital subtraction angiography was used to assess angiographic effects of different revascularization techniques. The results of this work demonstrate, that Tank-Binding-Kinase 1 represents a proangiogenic and proinflammatory mediator in tumor angiogenesis and therefore may represent a novel therapy target e.g. for the treatment of malignant glioma. Moreover, antiangiogenic therapy in glioblastoma multiforme leads to a significant reduction of vascular density, but at the same time induces vascular resistance mechanisms that lead to significant anatomic and functional alterations of microcirculation that enhance vascular delivery of chemotherapeutic substances. In this therapeutic context, glioblastoma multiforme microcirculation represents a very suitable target for vascular targeting strategies using the fibronectin extradomain B antibody fragment L19-SIP. L19-SIP preferentially binds to high perfusion microvessels and immature microvessels with a special focus on vascular sprouts. Vascular binding is followed by a secondary extravasation process into tumor interstitium. After antiangiogenic therapy, L19-SIP shows a significantly enhanced binding in therapy-resistant, high-flow tumor vessels. This opens specific diagnostic and therapeutic possibilities for L19-SIP mediated therapy strategies. In Moyamoya vasculopathy, cortical microcirculation is significantly altered in comparison to patients suffering from atherosclerotic cerebrovascular compromise. Moyamoya patients are characterized by significantly increased cortical microvascular density leading to reduced peripheral vascular resistance compensating for reduced cerebral blood flow due to stenoocclusion of the basal cerebral arteries. Consequently, patients without neurological symptoms show higher cortical microvascular density and improved hemodynamics as compared to patients with clinically evident cerebral ischemia. Based on this knowledge, Moyamoya vasculopathy may be divided into 3 different grades (using digital subtraction angiography, cerebral MRI and assessment of hemodynamic reserve) that allow the prediction of the stroke risk of each individual hemisphere. Moyamoya specific neoangiogenic potential also exerts a significant effect on different revascularization techniques. In adult Moyamoya vasculopathy patients, a combined revascularization technique (STA- MCA bypass + encephalomyosynangiosis) is superior in restoring cerebrovascular reserve capacity compared to an indirect procedure (encephalomyosynangiosis). In conclusion, the results of this work demonstrate, that neovascularization plays a pivotal role for the pathophysiology and treatment of glioblastoma multiforme and Moyamoya vasculopathy