Klinische Aspekte der Moyamoya-Vaskulopathie in Europa

Hintergrund: Die Moyamoya Vaskulopathie (MMV) ist eine seltene cerebrovaskuläre Erkrankung, welche häufig bei Kindern und Erwachsenen im mittleren Alter Schlaganfälle verursacht. Aufgrund der niedrigen Inzidenz, insbesondere außerhalb von Asien, sind die klinischen Merkmale dieser Erkrankung lückenhaft und standardisierte Algorithmen für die Behandlung fehlen. Das Ziel unserer Arbeit war für die MMV in Europa die klinischen und diagnostischen Merkmale dieser Erkrankung zu erarbeiten. Methodik: Eine retrospektive Analyse unserer MMV-Patienten erfolgte mit Fokus auf den klinischen Symptomen, der Diagnostik, den Revaskularisierungen und deren Komplikationen. Wir führten des Weiteren eine getrennte Analyse zu Schwangerschaften in unserer Kohorte durch. Ergebnisse: Unsere kaukasische MME-Serie mit 153 Patienten bestätigte die interethnischen Unterschiede insbesondere im Vergleich zu den asiatischen Serien. Insgesamt zeigten sich die Charakteristika vergleichbar zu den nordamerikanischen Serien. Allerdings gab es einen wichtigen Unterschied für die juvenilen MMV-Patienten mit mehr hämorrhagischer Manifestation in unserer Serie (12%). Die Analyse für die bildmorphologische Beteiligung der hinteren Blutzirkulation ergab eine deutlich höhere Steno-Okklusion der Arteria cerebri posterior bei den pädiatrischen Patienten. Die Ergebnisse der Charakterisierung der 61 kaukasischen MMS-Patienten zeigten ebenso deutliche Unterschiede zu den asiatischen MMS-Patienten. Die wichtigsten Differenzen im Vergleich zu der japanischen Serie waren weniger unilaterale Fälle, mehr weibliche Beteiligung sowie eine umgekehrte bimodale Altersverteilung. Bei einem Vergleich zwischen kaukasischen MME- und MMS-Patienten war die fehlende hämorrhagische Manifestation in juvenilen MMS-Patienten der deutlichste Unterschied. Die Bewertung der Revaskularisierung in kaukasischen MMS-Patienten zeigte mit 88% an funktionstüchtigen Bypassgefäßen in der Langzeitkontrolle ein zufriedenstellendes Ergebnis. Der direkte Vergleich von zwei nuklearmedizinischen Methoden (Tc-99m-HMPAO SPECT versus O-15-Wasser-PET) für Patienten mit klinischem Verdacht auf eine reduzierte CVRK verdeutlichte die Nachteile der SPECT-Untersuchung mit Bedarf für weitere Diagnostik bei begründetem klinischen Verdacht. O-15-Wasser PET zeigte in 44% der Patienten und in einem Drittel der betroffenen Gehirnhemisphären eine beeinträchtigte CVRK trotz erhaltener CVRK in SPECT. Die Bewertung verschiedener Schnittführungen für die direkten oder kombinierten Revaskularisierungsoperationen wies auf mehr Wundheilungsstörungen bei einem kompletten Y-Schnitt im Vergleich zu den übrigen Inzisionen hin. Die Analyse der Schwangerschaften in unserer Kohorte ergab 60 Schwangerschaften und 48 Geburten, wo 81% der Patientinnen ihre Schwangerschaft bereits vor der MMV-Diagnose erlebt hatten. Für die kleine Kohorte mit einer Schwangerschaft bei bereits bekannter MMV-Diagnose schien eine Revaskularisierung vor ischämischen Ereignissen zu schützen. Schlussfolgerung: Unsere Studien verdeutlichen die interethnischen Differenzen der MMV und stellen eine Grundlage für den Vergleich kaukasischer Patienten in Europa mit anderen Serien dar. Diese klinischen Unterschiede sollten bei der Diagnosestellung und beim Management dieser Erkrankung von Nutzen sein. Für die Diagnostik sollte O-15-Wasser PET einer SPECT-Untersuchung, wenn möglich, vorgezogen werden oder zumindest in ausgewählten Fällen durchgeführt werden. Unsere Studien ermutigen zur Erstellung einer europaweiten prospektiven Datenbank dieser seltenen Erkrankung

Adjuvant radiotherapy improves progression-free survival in intracranial atypical meningioma

BACKGROUND: Meningiomas are the most common primary tumors of the central nervous system. In patients with WHO grade I meningiomas no adjuvant therapy is recommended after resection. In case of anaplastic meningiomas (WHO grade III), adjuvant fractionated radiotherapy is generally recommended, regardless of the extent of surgical resection. For atypical meningiomas (WHO grade II) optimal postoperative management has not been clearly defined yet. METHODS: We conducted a retrospective analysis of patients treated for intracranial atypical meningioma at Charité Universitätsmedizin Berlin from March 1999 to October 2018. Considering the individual circumstances (risk of recurrence, anatomical location, etc.), patients were either advised to follow a wait-and-see approach or to undergo adjuvant radiotherapy. Primary endpoint was progression-free survival (PFS). RESULTS: This analysis included 99 patients with atypical meningioma (WHO grade II). Nineteen patients received adjuvant RT after primary tumor resection (intervention group). The remaining 80 patients did not receive any further adjuvant therapy after surgical resection (control group). Median follow-up was 37 months. Median PFS after primary resection was significantly longer in the intervention group than in the control group (64 m vs. 37 m, p = 0.009, HR = 0.204, 95% CI = 0.062-0.668). The influence of adjuvant RT was confirmed in multivariable analysis (p = 0.041, HR = 0.192, 95% CI = 0.039-0.932). CONCLUSIONS: Our study adds to the evidence that RT can improve PFS in patients with atypical meningioma

Decision Making in Patients With Metastatic Spine. The Role of Minimally Invasive Treatment Modalities

Spine metastases affect more than 70% of terminal cancer patients that eventually suffer from severe pain and neurological symptoms. Nevertheless, in the overwhelming majority of the cases, a spinal metastasis represents just one location of a diffuse systemic disease. Therefore, the best practice for treatment of spinal metastases depends on many different aspects of an oncological disease, including the assessment of neurological status, pain, location, and dissemination of the disease as well as the ability to predict the risk of disease progression with neurological worsening, benefits and risks associated to treatment and, eventually, expected survival. To address this need for a framework and algorithm that takes all aspects of care into consideration, we reviewed available evidence on the multidisciplinary management of spinal metastases. According to the latest evidence, the use of stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) for spinal metastatic disease is rapidly increasing. Indeed, aggressive surgical resection may provide the best results in terms of local control, but carries a significant rate of post-surgical morbidity whose incidence and severity appears to be correlated to the extent of resection. The multidisciplinary management represents, according to current evidence, the best option for the treatment of spinal metastases. Noteworthy, according to the recent literature evidence, cases that once required radical surgical resection followed by low-dose conventional radiotherapy, can now be more effectively treated by minimally invasive spinal surgery (MISS) followed by spine SRS with decreased morbidity, improved local control, and more durable pain control. This combination allows also extending this standard of care to patients that would be too sick for an aggressive surgical treatment

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

Shortened Tracer Uptake Time in GA-68-DOTATOC-PET of Meningiomas Does Not Impair Diagnostic Accuracy and PET Volume Definition

Ga-68-DOTATOC-PET/MRI can affect the planning target volume (PTV) definition of meningiomas before radiosurgery. A shorter tracer uptake time before image acquisition could allow the examination of more patients. The aim of this study was to investigate if shortening uptake time is possible without compromising diagnostic accuracy and PET volume. Fifteen patients (f = 12; mean age 52 years (34-80 years)) with meningiomas were prospectively examined with dynamic [68Ga]Ga-68-labeled [DOTA0-Phe1-Tyr3] octreotide (Ga-68-DOTATOC)-PET/MRI over 70 min before radiosurgery planning. Meningiomas were delineated manually in the PET dataset. PET volumes at each time point were compared to the reference standard 60 min post tracer injection (p.i.) using the Friedman test followed by a Wilcoxon signed-rank test and Bonferroni correction. In all patients, the earliest time point with 100% lesion detection compared to 60 min p.i. was identified. PET volumes did not change significantly from 15 min p.i. (p = 1.0) compared to 60 min p.i. The earliest time point with 100% lesion detection in all patients was 10 min p.i. In patients with meningiomas undergoing Ga-68-DOTATOC-PET, the tracer uptake time can safely be reduced to 15 min p.i. with comparable PET volume and 100% lesion detection compared to 60 min p.i

Analysis of different vascular targeting strategies via intravital microscopy in treatment of glioblastoma

Einleitung: Das Glioblastoma multiforme (GBM) ist der häufigste und bösartigste astrogliale Hirntumor, dessen Prognose trotz Fortschritten in der Forschung weiterhin sehr schlecht ist. Die Angiogenese dieser Tumore spielt in diesem Zusammenhang eine bedeutende Rolle und stellt somit ein vielversprechendes Therapieziel dar. Der Erfolg der antiangiogenen Therapie ist durch verschiedene Resistenzmechanismen limitiert. Einer dieser Resistenzmechanismen ist die myeloidzell-induzierte Vaskulogenese. Als neue Therapieversuche gelten zum einen antikörper-vermittelte vaskuläre Targetingstrategien sowie zum anderen die Kombination antiangiogener Therapien mit Chemotherapeutika. Der Antikörper L19 ist einer der am besten charakterisierten Antikörper spezifisch für den neoangiogenen Marker Fibronektin B. Unser Ziel war, die mikrovaskuläre Biodistribution der „vascular accessory cells“ (VACs) und des Antikörpers L19 sowie die mikrohämodynamischen Effekte einer kombinierten Temozolomid- und Sunitinibtherapie (TMZ/SU) in vivo zu untersuchen. Methodik: Als Methode setzten wir ein Gliommodell in der chronischen Rückenhautkammer in vivo ein und führten Mikrohämodynamik- und Biodistributionsanalysen mittels Intravitalmikroskopie durch. Ergebnisse: Unsere Ergebnisse zeigten, dass die antiangiogene Therapie mit Sunitinib zu einer verbesserten Mikrohämodynamik der therapieresistenten Tumorgefäße und zu einer Reduktion der perivaskulären Akkumulation der VACs führte. Eine kombinierte Therapie mit TMZ/SU resultierte in einer Reduktion der Gefäßpermeabilität von therapieresistenten Gefäßen, was auf eine zusätzliche Resistenzentwicklung hinweisen könnte. Unsere Studie demonstrierte, dass die spezifische Bindung des L19 Antikörpers an die Tumorgefäße zeitabhängig ist und zusätzlich eine subsequente Extravasation in das Tumorinterstitium stattfindet. Darüber hinaus zeigten wir, dass die Sunitinibtherapie zu einer verstärkten Bindung des Antikörpers führte. Schlussfolgerung: Zusammenfassend lässt sich schlussfolgern, dass VACs keine Rolle in der Resistenzentwicklung der antiangiogenen Therapie mit Sunitinib spielen sondern ein zusätzliches Ziel dieser Therapie darstellen könnten. Auf der anderen Seite führte eine kombinierte Therapie mit TMZ/SU zusätzlich zu einem additiven Therapieeffekt sowie vermutlich zu einer Resistenzentwicklung durch die Perizyten-Endothelzell-Interaktionen an therapieresistenten Tumorgefäßen, was eine Therapielimitierung mit sich bringen könnte. Das vaskuläre Targeting stellt eine vielversprechende Therapiemodalität auch in Kombination mit antiangiogener Therapie dar und benötigt in der Zukunft eine genauere Validierung.Introduction: GBM is the most common and most malignant astroglial brain tumor. Despite recent progress in the research the prognosis of this disease remains very poor. High angiogenesis of these tumors is one of the causes of their malignancy, thus angiogenesis represents one of the promising therapy targets. However, the therapeutic effect of the antiangiogenic treatments is limited by diverse resistance mechanisms. Myeloid cell induced vasculogenesis is one the discussed mechanisms. On the other hand, vascular targeting strategies and combination of antiangiogenic therapies with chemotherapeutics represent new promising therapy modalities to overcome therapy resistance. L19 antibody is one of the best characterized antibodies specific to a neoangiogenesis marker fibronectin B. Our aim was to analyze microvascular biodistribution of VACs, L19 antibody and microhemodynamic effects of the combination therapy with TMZ/SU in vivo. Methods: We used a glioma-model in dorsal skinfold chamber in vivo and analyzed biodistribution and microhemodynamics by intravitalmicroscopy. Results: Our results showed that antiangiogenic treatment with sunitinib led to better microhemodynamics of therapy resistant tumor blood vessels and to reduced accumulation of VACs in perivascular niche. The combination therapy with TMZ/SU resulted in diminished permeability of therapy resistant tumor vessels, which may represent an additional resistance development. Our study demonstrated that specific binding of L19 antibody to tumor vessels was time dependent and there was also a subsequential extravasation of the antibody in tumor tissue. Additionally, L19 antibody`s binding increased after antiangiogenic treatment. Conclusion: In conclusion, we postulate that VACs do not play a role in resistance of antiangiogenic treatment but might even represent an additional target of this therapy. On the other hand, the combination therapy with TMZ/SU led not only to additive therapeutic benefits but also probably to resistance development by pericyte/endothelial cell interaction of resistant blood vessels limiting therapeutic effects. Vascular targeting strategies represent a promising era alone or in combination with antiangiogenic treatments and should be more investigated in the future

Surgical Management of Failed Revascularization in Moyamoya Vasculopathy

Objectives: Moyamoya vasculopathy (MMV) is a rare stenoocclusive cerebrovascular disease associated with increased risk of ischemic and hemorrhagic stroke, which can be treated using surgical revascularization techniques. Despite well-established neurosurgical procedures performed in experienced centers, bypass failure associated with neurological symptoms can occur. The current study therefore aims at characterizing the cases of bypass failure and repeat revascularization at a single center. Methods: A single-center retrospective analysis of all patients treated with revascularization surgery for MMV between January 2007 and December 2019 was performed. Angiographic data, cerebral blood flow analysis [H2O PET or single-photon emission CT (SPECT)], MRI, and clinical/operative data including follow-up assessments were reviewed. Results: We identified 308 MMV patients with 405 surgically treated hemispheres. Of the 405 hemispheres treated, 15 patients (3.7%) underwent repeat revascularization (median age 38, time to repeat revascularization in 60% of patients was within 1 year of first surgery). The most common cause of repeat revascularization was a symptomatic bypass occlusion (80%). New ischemic lesions were found in 13% of patients prior to repeat revascularization. Persistence of reduced or progressive worsening of cerebrovascular reserve capacity (CVRC) compared with preoperative status was observed in 85% of repeat revascularization cases. Intermediate-flow bypass using a radial artery graft was most commonly used for repeat revascularization (60%) followed by re-superficial temporal artery to middle cerebral artery (re-STA-MCA) bypass (26%). High-flow bypass using a saphenous vein graft and using an occipital artery to MCA bypass was each used once. Following repeat revascularization, no new ischemic events were recorded. Conclusion: Overall, repeat revascularization is needed only in a small percentage of the cases in MMV. A rescue surgery should be considered in those with neurological symptoms and decreased CVRC. Intermediate-flow bypass using a radial artery graft is a reliable technique for patients requiring repeat revascularization. Based on our institutional experience, we propose an algorithm for guiding the decision process in cases of bypass failure

The CXCL2/IL8/CXCR2 Pathway Is Relevant for Brain Tumor Malignancy and Endothelial Cell Function

We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma

The CXCL2/IL8/CXCR2 Pathway Is Relevant for Brain Tumor Malignancy and Endothelial Cell Function

We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma

CD13 expression affects glioma patient survival and influences key functions of human glioblastoma cell lines in vitro

Abstract CD13 (APN) is an Alanyl-Aminopeptidase with diverse functions. The role of CD13 for gliomas is still unknown. In this study, data of glioma patients obtained by TCGA and CGGA databases were used to evaluate the survival rate and prognostic value of CD13 expression level. Protein expression of CD13 was confirmed by immunofluorescence staining of fresh patient tissues. Eight human glioblastoma cell lines were studied by RT-PCR, Western Blot, immunofluorescence staining and flow cytometry to define CD13 expression. Cell lines with different CD13 expression status were treated with a CD13 inhibitor, bestatin, and examined by MTT, scratch and colony formation assaysas well as by apoptosis assay and Western Blots. Bioinformatics analysis indicated that patients with high expression of CD13 had poor survival and prognosis. Additionally, CD13 protein expression was positively associated with clinical malignant characteristics. Investigated glioblastoma cell lines showed distinct expression levels and subcellular localization of CD13 with intracellular enrichment. Bestatin treatment reduced proliferation, migration and colony formation of glioma cells in a CD13-dependent manner while apoptosis was increased. In summary, CD13 has an impact on glioma patient survival and is important for the main function of specific glioma cells