Challenges of nanomedicine in oncology require therapeutic tools to affect metabolic pathways in the target cells. Therapeutic nucleic acids (NAs) are promising instruments as siRNAs target them selectively, while microRNAs can reach several targets. However, oligonucleotides suffer from rapid nuclease degradation in biological media. Cationic dendrimers – highly symmetric hyperbranched molecules – can be efficient vehicles. In the current work we studied challenges of using polycationic phosphorus and carbosilane dendrimers and their complexes with oligonucleotides (dendriplexes). Different tumor models were used: Jurkat (single-cells suspension culture in serum-containing media), BTSC233, JHH520, NCH644, GBM1 (glioblastoma cancer stem cells (GSCs) as neurospheres in serum-free medium), U87 ("standard" glioblastoma culture). Human PBMCs and iPSCs were used as non-tumor controls. We used miR-34, synthetic inhibitor of miR-21 and siRNA against LYN kinase (siLyn) as therapeutics. Such biological effects as internalization, cytotoxicity (incl. comparison to standard chemodrugs), apoptosis induction, expression of surface markers, related to interactions with immune microenvironment (PD-L1, TIM-3, CD47), LYN-expression were investigated. Dendrimers have their own cytotoxic effects on tumor cells, which are comparable or superior to standard chemodrugs; in some models the toxic effect on tumor cells was higher than on non-tumor cells. Moreover, GSCs showed higher sensitivity to molecules. Cationic dendrimers efficiently delivered NAs into tumor cells. Dendriplexes showed antitumor effects: decrease of cell viability, apoptosis induction. Dendrimers and dendriplexes affected the expression of PD-L1 and TIM-3, which could be a sign of cell stress. siLyn-dendriplexes decreased tumor cell viability but did not change significantly LYN expression. Patterns of changes strongly depended on the cell type and cultivation mode. We showed promising antitumor activity of cationic dendrimers and their complexes with therapeutic NAs. However, further investigations of the impact of different cell type and model features in view of pre-clinical testing is to be performed.

s Brain and Spine 1 (2021) 100307 have the lowest risk of bleeding. Nearly all participants (93%) agreed that more evidence is needed concerning AP and AC management in neurosurgery. Conclusion: Worldwide, the perioperative management of antiplatelets and anticoagulation medication is very heterogeneous among neurosurgeons. Interventional trials are needed to further elucidate this clinically important question. BRAIN AND SPINE 1 (2021) 100307 100778 GLOBAL SURGERY, PANDEMICS, MASS CASUALTIES: HOW DO WE ACHIEVE THE UN HEALTHCARE-RELATED SUSTAINABLE DEVELOPMENT GOALS FOR 2030? R. Andrews . 1 NASA Ames Research Center, Nanotechnology & Smart Systems, Los Gatos, United States Background: Lack of surgery causes 1/3 of all deaths globally, with an annual GDP loss of $1.5T by 2030. The trauma suffered by hundreds of thousands of people annually from both natural and man-made mass casualty disasters requires immediate surgery – not the current delay of days to a week or more. Methods: The trauma/stroke center model – with 24/7/365 availability of services (emergency and intensive care, radiology, laboratory, blood bank, etc) – has improved morbidity/mortality for conditions ranging from difficult childbirth to acute abdomen. Integrating healthcare resources from the civilian and military sectors and technological advances (from telemedicine and smart glasses to battery-powered CT scanners and drones) can ameliorate morbidity/mortality during not only day-to-day care and mass casualty events but also during pandemics like COVID-19. The UN and WHO have formulated goals for healthcare by 2030, e.g. the National Surgical, Obstetric, and Anesthesia Plan program that is being followed by many developing countries. Results: The Mass Casualty Center project integrates both healthcare systems (e.g. civilian and military, national and international) and new technologies to improve morbidity/mortality for both day-to-day care and mass casualty events. Examples: Telemedicine is improving outcomes and reducing costs for neurotrauma in Albania; drones are flying lab samples, blood products, antibiotics, and vaccines to remote regions throughout Rwanda; integration of civilian and military emergency response resources are reducing morbidity/mortality in Chile; creation of a full-service healthcare system (from prevention programs to ambulances to hospitals to medical and nursing schools to rehabilitation) is providing services previously unavailable in Peshawar, Pakistan, thanks to the efforts of neurosurgeon Tariq Khan. Conclusion: Through collaboration among healthcare organizations (civilian and military, national and international) and integration of the latest technology – surgeons in general and neurosurgeons in particular can foster programs to reduce the 1/3 of all deaths globally due to lack of surgery. BRAIN AND SPINE 1 (2021) 100307 100779 DELIRIUM IN NEUROSURGERY: A LARGE RETROSPECTIVE COHORT STUDY P. Kappen , C. Dirven , M. Klimek , R. Osse , A. Vincent . 1 Erasmus Medical Center, Neurosurgery, Rotterdam, Netherlands; 2 Erasmus Medical Center, Anesthesiology, Rotterdam, Netherlands; 3 Erasmus Medical Center, Psychiatry, Rotterdam, Netherlands Background: Post-operative delirium (POD), an organically caused acute onset of confusion, is a frequent and severe complication after general surgery. The clinical relevance of POD in neurosurgery is yet to be determined, with limited literature on this topic, while these patients could particularly be vulnerable. Hence, we investigated the incidence, risk factors and health outcomes of POD in neurosurgical patients. Methods: Adult patients undergoing a neurosurgical procedure in the Erasmus Medical Centre in Rotterdam were retrospectively included. POD was defined in case of a Delirium Observation Scale (DOS) 3 or start of antipsychotic treatment for delirium within 10 days after surgery. Multivariate risk factors were identified using logistic regression analysis, after subdividing patients in craniotomy (i.e. bone-flap removal), intracranial surgery (i.e. ventricle drains / stereotactic biopsy) and spinal surgery. Health outcomes associated with the onset of POD were calculated. Results: We included 4292 neurosurgical procedures between June 2017 and September 2020. Overall incidence of POD was 18.6%. Incidence was 24.5% (n 1⁄4 1501) after craniotomy, 22.5% after intracranial surgery (n 1⁄4 1438) and 8% 136 after spinal surgery in 8% (n 1⁄4 1353). Independent pre-operative and intraoperative risk factors for the development of POD were older age, more opioid and dexamethasone consumption, electrolyte disturbances, cognitive problems, prior delirium, emergency operations, blood loss and surgery duration. POD was associated with longer hospitalization (median 13 vs 5 days), more ICU admission (42.1 vs. 15.7%), less discharge towards home (26.5 vs. 64.0%) and increased 30-day mortality (9.9% vs 5.8%) Conclusion: POD is a frequent and severe complication after neurosurgical procedures. We identified several risk factors, few of which modifiable such as medication consumption and electrolyte disturbances, for the development of POD. BRAIN AND SPINE 1 (2021) 100307 100780 EMPHASIZING THE ROLE OF NEUROSURGERY WITHIN GLOBAL HEALTH AND NATIONAL HEALTH SYSTEMS: A CALL TO ACTION S.Z.Y. Ooi , J.W. Lartigue , O.E. Dada , M. Haq , A. Vital , S. Rapaport , L. Sebopelo , W.P. Senyuy , K. Sarpong , T. Khan , C. Karekezi , K.B. Park . 1 Cardiff University School of Medicine, Cardiff, United Kingdom; 2 School of Medicine and Pharmacy, State University of Haiti, Port-au-Prince, Haiti; 3 College of Medicine, University of Ibadan, Ibadan, Nigeria; 4 GKT School of Medical Education, King's College London, London, United Kingdom; 5 Johns Hopkins School of Medicine, Baltimore, United States; 6 University of Botswana, Gaborone, Botswana; 7 Faculty of Health Sciences, University of Buea, Buea, Cameroon; 8 Georgetown University School of Medicine, Washington, United States; 9 North West General Hospital and Research Center, Department of Neurosurgery, Peshawar, Pakistan; 10 Rwanda Military Hospital, Neurosurgery Unit, Department of Surgery, Kigali, Rwanda; 11 Program in Global Surgery and Social Change, Harvard Medical School, Boston, United States Background: Worldwide, neurological disorders are the leading cause of disability-adjusted life years lost and the second leading cause of death. Despite global health capacity-building efforts, each year, 22.6 million individuals worldwide require neurosurgeon’s care due to diseases such as traumatic brain injury and hydrocephalus, and 13.8 million of these individuals require surgery. It is clear that neurosurgical care is indispensable in both national and international public health discussions. The study highlights the role neurosurgeons can play in supporting the global health agenda, national surgical plans, and health strengthening systems (HSS) interventions. Methods:Guided by a literature review, the authors discuss key topics such as: i) the global burden of neurosurgical diseases and the disproportional effect on lowand middle-incomecountries (LMICs); ii) thecurrent stateofneurosurgical carearound the world: the unmet need, workforce deficit, health system priority, and lack of global neurosurgery capacity building in current global health efforts; iii) the inherent benefits of strong neurosurgical capability for health systems; iv) the global neurosurgery movement: a brief history, accomplishments and shared vision. Results: Many neurosurgeons possess the sustained passion, resilience, and leadership needed to advocate for improved neurosurgical care worldwide. Neurosurgical initiatives in mentoring, education, research and capacity building have involved individuals at all stages of training from all over the world. Neurosurgical care has been linked to 14 of the 17 Sustainable Development Goals (SDGs), thus highlighting the tremendous impact neurosurgeons can have upon HSS initiatives. Conclusion: We recommend policymakers and global health actors to: i) increase the involvement of neurosurgeons within the global health dialogue; ii) involve neurosurgeons in the national surgical system strengthening process; iii) integrate neurosurgical care within the global surgery movement; and iv) promote the training and education of neurosurgeons, especially those residing in LMICs, in field of global public health. BRAIN AND SPINE 1 (2021) 100307 100781 SARS-COV-2 INFECTION IS AN INDEPENDENT RISK FACTOR FOR INTRACRANIAL HAEMORRHAGE S. Muhammad , I. Fischer , Z. Hawsawi , D. Khan , J.F. Cornelius , K. Ulf Dietrich , D. H€anggi . 1 Universit€ atsklinikum Düsseldorf, Neurosurgery, Düsseldorf, Germany; 2 King Abdulaziz Hospital, Neurosurgery, Makka, Saudi Arabia Background: Although SARS-CoV-2 primarily attacks the respiratory system, it has been reported to affect other organs as well. Here we investigate on a single centre cohort of patients who were admitted due to concomitant COVID-19 and Abstracts Brain and Spine 1 (2021) 100307s Brain and Spine 1 (2021) 100307 neurological symptoms or with neurological symptoms alone. We aimed to investigate whether CNS complications are related to COVID-19. Methods: We examined 21 patients suffering from stroke and intracranial haemorrhage (ICH). The median age was 53. 11 (52%) of the patients also suffered from Covid-19. 12 (57%) had hypertension, 6 (29%) had diabetes mellitus. 10 (48%) of the patients required ventilation and 4 (19%) died despite treatment. Patients suffering from Covid-19 were younger than the others (45 vs. 59, p1⁄40.044). We compared relative frequencies using Fisher’s exact test. We used principal component analysis (PCA) to reduce data dimensionality. We trained a linear support vector machine (SVM) on the first two PCs of the laboratory data to predict Covid-19. Results: Patients suffering from stroke or ICH either had hypertension or COVID19 infection, but seldom both (OR1⁄40.05, p1⁄40.0075)

Die Schädelbasis stellt eine chirurgisch hochkomplexe Einheit dar und ist häufig nur über kombinierte Zugangswege erreichbar. Neu entwickelte Operationstechniken mit Verwendung von mikrochirurgischen Visualisierungsverfahren und aktiven Instrumenten („powered instruments“) sowie „Multi-Port-Zugänge“ ermöglichen neue, weniger traumatische Operationskorridore. Hierfür ist eine enge interdisziplinäre Zusammenarbeit zwischen dem Chirurgen aus dem Fachgebiet der Hals-Nasen-Ohren-Heilkunde sowie dem Neurochirurgen notwendig. Die aktuell etablierten Zugangsverfahren zur zentralen Schädelbasis werden aufgrund eigener klinischer Erfahrungen und unter Berücksichtigung der Entität systematisiert und in Bezug auf die aktuelle Studienlage erörtert. Es erfolgte eine retrospektive, qualitative und deskriptive Auswertung der Operationsberichte einzelner Patienten, die in der Zeit zwischen 2006 und 2019 mit Pathologien an der zentralen Schädelbasis chirurgisch gemeinsam von der Neurochirurgie und der Hals-Nasen-Ohren-Heilkunde/Kopf- und Halschirurgie behandelt wurden. Die chirurgischen Zugangswege zur zentralen Schädelbasis ließen sich nachfolgend kategorisieren, teilweise auch in Kombination derselben, als sog. Multi-Port-Zugänge: transnasal-transsphenoidal, subfrontal, subtemporal, transzygomatisch, transpterygonal, transpetrös, translabyrinthär und subokzipital. Maßgebend für die Wahl des Zugangswegs waren die Lokalisation und Art der Pathologie, sowie der mögliche Anspruch auf Funktionserhalt und Komplettentfernung. Aufgrund der Komplexität der Strukturen der zentralen Schädelbasis, der unterschiedlichsten Tumorentitäten und der benötigten Fachkompetenz unterschiedlicher Facharztdisziplinen bleibt die Chirurgie der zentralen Schädelbasis eine Herausforderung, der man sich nur an speziellen, nach den Kriterien der Gesellschaft für Schädelbasischirurgie e. V. zertifizierten Kompetenzzentren stellen sollte.

Ein Erratum zu dieser Publikation wurde veröffentlicht: https://doi.org/10.1007/s00115-020-00991-0

Giant cavernous carotid aneurysms (GCCAs) usually exert substantial mass effect on adjacent intracavernous cranial nerves. Since predictors of cranial nerve deficits (CNDs) in patients with GCCA are unknown, we designed a study to identify associations between CND and GCCA morphology and the location of mass effect.

Introduction: Glioblastoma is the most common primary malignant brain tumor in adults. It is highly resistant to available treatment options as the invasiveness of the tumor limits complete resection, as well as the dynamic tumor genome, multiple pathways driving the malignant phenotype, and the blood brain barrier, which limits the availability of drugs to the tumor. Evidence suggests a significant role for NF-κB in the gliomagenesis and the mechanism of treatment resistance in glioblastoma making NF-κB a potentially potent target for treatment. However, increasing evidence suggest a great cellular heterogeneity in glioma, making it important to understand which glioma cell types are dynamically driven by certain molecular pathways, and how that relates to their function in glioma progression and resistance. Therefore, we established an in vivo reporter system based on NF-κB responsive promoter elements driving green fluorescent protein (GFP) to monitor the expression of this transcription factor. Materials and Methods: Ten tandem repeats of the NF-κB transcription responsive element were designed, annealed and ligated into the HIV-1 based lentiviral vector pLVXPuro by replacing the CMV promoter with NF-κB elements. GFP was subcloned into the multiple cloning site of pLVXPuro. The integrity of the plasmid was verified by sequencing analysis. Its reliability as a NF-κB reporter was verified in vivo and in vitro. Using a chronic cranial window mouse model two-photon microscopy allows for consecutive in vivo imaging to observe different biological processes such as tumor growth, angiogenesis, and tumor repair after laser ablation and radiotherapy. Results: While cells grown under stem like conditions in vitro were highly NF-κB reporter positive, only few cells were positive in the established tumor in vivo, and that this changed dynamically depending on distinct states of tumor progression, and in response to lesions in the tumor area that were repopulated - “repaired” - by tumor cells. Furthermore, we were able to show that TNFα induced NF-κB reporter activity significantly in vitro. Radiotherapy led to a significant increase in reporter GFP expression in vivo as well as in vitro, to the extent that most cells became reporter positive. Pre-existing reporter-positive cells differed from reporter negative cells with respect to resistance against cytotoxic stress. NF-κB reporter positivity did not colocalize with established “stem cell” markers Mushashi, Nestin and Sox2 on tumor slices grown in our mouse model. DISCUSSION: Our results suggest a role for NF-κB expression during GBM resistance to treatment and progression after radiation in a heterogeneous manner. We will further analyze cell fate and morphology during irradiation and tumor “repair” with regard to their NF-κB positivity, and will include this data in the presentation, including inhibitory strategies of the NF-κB pathway.

Nimodipine is used throughout the world to improve outcome after aneurysmal subarachnoid hemorrhage (aSAH). Its use, however, is limited by systemic hypotension that occurs in ≤56% of patients. Plasma concentrations can exceed those associated with hypotension, yet cerebrospinal fluid (CSF) concentrations remain below the optimal Background and Purpose—We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. Methods—Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. Results—Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). Conclusions—EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190. (Stroke. 2017;48:145-151. DOI: 10.1161/STROKEAHA.116.014250.)