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BackgroundMoyamoya disease (MMD) is a cerebrovascular disorder characterized by fragile vascular system. Previous studies suggested that the blood-brain barrier (BBB) destabilizing cytokine angiopoietin-2 plays a critical role in increasing vascular plasticity and endothelial disintegration in MMD. The aim of this study was to assess cerebrovascular integrity in vivo in patients affected by MMD.MethodsWe retrospectively analyzed 11 patients that underwent bypass for MMD (MMD group), 11 patients that underwent bypass for atherosclerotic cerebrovascular disease (ACVD—control group I), and 5 patients that underwent clipping for unruptured aneurysms (non-ischemic—control group II). Sodium fluorescein (NaFL) extravasation was evaluated during videoangiography when checking for bypass patency. A grading system (0, +, ++, +++) was used to define the extent of extravasation. Frequency and intensity of leakage was compared among different groups.ResultsNaFL extravasation appeared in 10/11 (91%) patients with MMD and in 8/11 (73%) patients with ACVD during bypass procedures. Extravasation was observed in none of the patients undergoing clipping for unruptured aneurysms. Although both chronic ischemic patient groups showed a comparably high incidence of NaFL extravasation, the MMD group was characterized by a much greater intensity of NaFL extravasation (grade +++ in 82%) than the ACVD group (grade +++ in 27%, p < 0.05).ConclusionsWe demonstrate blood-brain barrier impairment in MMD patients for the first time in vivo. This may be due to mechanisms intrinsic to the unique pathology of MMD, probably explaining the higher association with hemorrhage and post-operative hyperperfusion.

Background Craniopharyngiomas are rare, mostly benign brain tumors, and their management remains challenging due to the limited data from large cohorts. This study evaluates the practice patterns and outcomes for craniopharyngioma patients managed at a tertiary care center. Methods This retrospective cohort study included patients with histologically confirmed craniopharyngioma treated between 1996 and 2022. Patient, tumor, and treatment variables were analyzed for their association with local control (LC), progression-free survival (PFS), and overall survival (OS) using multivariable Cox regression models. Results A total of 88 patients were analyzed. The median clinical and radiographic follow-up periods were 62.0 and 42.5 months, respectively. Fifty-three recurrences and twelve deaths were observed. After primary treatment, the 2-, 4, and 6-year LC and PFS rates were 69.1, 50.7, 37.7% and 71.5, 55.4, and 47.3%, respectively. For patients undergoing primary treatment, multivariable Cox regression showed an association between the extent of resection, i.e., gross total resection (GTR), and PFS (hazard ratio (HR): 0.36, p  = 0.01) with weaker evidence for LC (HR: 0.40, p  = 0.053). Age was the only variable associated with OS (HR: 1.05, p  = 0.01). Seventeen patients received radiotherapy, which was not formally associated with LC, PFS, and OS. The majority of patients required hormone replacement therapy after treatment. Conclusions This study underlines the role of GTR in delaying disease progression and the need for hormone replacement after treatment. While radiotherapy was not formally associated with any benefit in this series, its use might be helpful in candidates after subtotal resection and for treating recurrences. Further prospective research is needed to refine treatment algorithms, improve long-term outcomes, and optimize the quality of life of affected patients.

Metastatic spine disease (MSD) is a severe event in cancer patients. Experimental data indicate that bone metastasis is mostly mediated by blood flow-dependent, passive arrest of circulating tumor cells to the bone metastatic niche (BMN). Here, we have set out to test these experimental observations in a clinical, human setting to improve our understanding of MSD. 507 patients, treated on spinal metastases in our institution from 2005 to  2015 were retrospectively evaluated. We identified 259 patients with accessible staging reports of the skeleton before and at initial diagnosis of MSD. Data analysis comprised localizations of bone metastases, underlying malignancy and time to development of MSD. Dissemination pattern of bone metastasis was correlated with red bone marrow (RBM) content of the respective bone as a measure of blood flow. Spinal metastases occurred most frequently in lung cancer (21%), prostate cancer (19%), and breast cancer (12%). At the diagnosis of MSD, majority of patients have multiple extra-spinal bone metastases (2/3). The distribution of metastases to extra-spinal bones and to the spine is mostly proportional to the RBM content of the involved bone. Corresponding to the high RBM content, thoracic spine, pelvic bones and ribs represent a predilection site for bone metastasis. We confirm a distinct preference of cancer types to metastasize to bones. When it comes to bone metastases all primaries show uniform distribution pattern, which supports the hypothesis of a predominantly blood flow-dependent distribution of tumor cells and passive arrest to the BMN rather than a spine-specific homing mechanism.

Three-dimensional exoscopes have been designed to overcome certain insufficiencies of operative microscopes. We aimed to explore the clinical use in various spinal surgeries. We performed surgery on patients with different spine entities in a neurosurgical department according to the current standard operating procedures over a 4-week period of time. The microsurgical part has been performed with Aesculap AEOS 3D microscope. Three neurosurgeons with different degree of surgical expertise completed a questionnaire with 43 items based on intraoperative handling and feasibility after the procedures. We collected and analyzed data from seventeen patients (35% male/65% female) with a median age of 70 years [CI 47–86] and median BMI of 25.8 kg/m 2 [range 21–33]. We included a variety of spinal pathologies (10 degenerative, 4 tumor and 3 infectious cases) with different level of complexity. Regarding setup conflicts we observed issues with adjustment of the monitor position or while using additional equipment (e.g. fluoroscopy in fusion surgery) ( p  = 0.007/ p  = 0.001). However image resolution and sharpness as well as 3D-depth perception were completely satisfactory for all surgeons in all procedures. The utilization of the exoscopic arm was easy for 76.5% of the surgeons, and all of them declared a significant improvement of the surgical corridor. The 3D-exoscope implementation appears to achieve very satisfactory results in spinal procedures especially with minimally invasive approaches.

PurposeThoracic disc herniations are uncommon and carry a high risk for neurological deterioration. Traditional surgical approaches include thoracotomy, costotransversectomy or posterior approaches with considerable morbidity. In this technical note with case series, we describe a minimally invasive tubular retractor–assisted retropleural approach for simple and less invasive microsurgical exploration of thoracic disc herniations from a lateral angle.MethodsSurgical technique consisted of partial rib resection and retropleural dissection followed by the placement of a tubular retractor (METRx Tubes, Medtronic) for an anterior-lateral exposure of the disc and neuroforamen. Epidemiological, clinical and surgical patient data were acquired.ResultsBetween 2017 and 2020, six patients were surgically treated using the minimally invasive tubular retractor–assisted retropleural approach. Microsurgical exposure of the disc and neural structures was achieved from a lateral direction without requiring thoracotomy or lung deflation. Control imaging confirmed resection in all cases without relevant residuum. As postoperative complications, one dural injury and one postoperative pneumothorax occured. No neurologic deterioration or recurrence occurred during a median follow-up of 3 months.ConclusionThe described tubular retractor–assisted retropleural exposure serves as a feasible minimally invasive microsurgical approach to the anterior-lateral thoracic spine.

An inverse association between the use of platelet inhibitors and the risk of cancer has been reported by numerous epidemiological studies in the past. The effects of antiplatelet agents on the cerebral metastasis formation of non-small cell lung cancer (NSCLC) are largely unknown. We therefore, investigated the effect of platelet inhibition in NSCLC patients at the time of the first diagnosis of cerebral metastases. We retrospectively investigated the clinical course of 417 NSCLC patients with cerebral metastases who underwent craniotomy for metastasis resection during the course of their disease. The presence of platelet inhibition prior to cerebral metastases diagnosis was used to dichotomize the cohort. Relevant clinical parameters, time to neurosurgical intervention for cerebral metastases, overall survival, and the incidence of intracranial hemorrhage or hemorrhagic transformation of metastases, were compared between the two groups. The presence of platelet inhibitor intake was associated with a significantly prolonged time to neurosurgical intervention for cerebral metastases in non-small cell lung cancer 63 vs. 47 months; ( p  = 0.001). Furthermore, platelet inhibitor intake was also associated with an increased overall survival of 12 vs. 10 months ( p  = 0.02). Statistically, no increased risk of hemorrhagic transformation of the metastasis or intracranial hemorrhage was found ( p  = 0.635 and p  = 1.000), respectively. In this retrospective study, the use of platelet inhibitors was not associated with an increased risk of intracranial hemorrhage, the use of platelet inhibitors was associated with delayed need for neurosurgical treatment for cerebral metastases and improved overall survival in NSCLC patients.

Background Surgically accessible brain metastases are treated through microsurgical removal followed by radiation therapy, resulting in improved progression-free and overall survival. Some patients experience recurrence, prompting the need for effective management strategies. Despite the prevalence of recurrence, there remains a gap in the literature regarding the outcomes of patients undergoing re-resection of brain metastases. Objectives This study aims to comprehensively characterize clinical, radiological, histopathological, and treatment-related aspects, along with outcomes, for patients undergoing re-resection of locally and distantly recurrent brain metastases. Methods We conducted a single-center retrospective cohort study, including patients who underwent secondary brain metastasis resection following prior primary brain metastasis resection and irradiation. Results Among 60 patients, 41 (68.3%) had local recurrences, and 19 (31.7%) had distant recurrences. Median intracranial progression-free survival was 7.7 months [95% CI: 6.5–11.2], time to re-resection was 11.6 months [95% CI: 9.1–15.3], and overall survival was 30.8 months [95% CI: 20.4–49.5]. Non-small cell lung cancer (NSCLC) was the most common primary tumor. Post-initial resection treatments included radiation alone (31.7%), radiation plus chemotherapy (25.0%), radiation plus targeted therapy (15.0%), and radiation plus immunotherapy (28.3%). Cavity irradiation was performed in 46 patients (76.7%) and whole brain radiation in 14 (23.3%). Post-re-resection treatments varied: 21 patients (35.0%) received best supportive care, 15 (25.0%) radiation only, 12 (20.0%) systemic therapy only, and 12 (20.0%) both radiation and systemic therapy. Independent risk factors for shorter overall survival included non-breast cancer histology, pre-re-resection tumor volume > 9 mL, pre-re-resection Karnofsky Performance Status ≤ 60%, and presence of vital tumor cells at re-resection. Conclusion Brain metastasis resection of local and distant recurrences is feasible and a treatment option for selected patients with good clinical performance status. This study underscores the potential role of re-resection in brain metastasis. Further research to improve patient selection and treatment algorithms is warranted.

Synaptic mechanisms that contribute to human memory consolidation remain largely unexplored. Consolidation critically relies on sleep. During slow wave sleep, neurons exhibit characteristic membrane potential oscillations known as UP and DOWN states. Coupling of memory reactivation to these slow oscillations promotes consolidation, though the underlying mechanisms remain elusive. Here, we performed axonal and multineuron patch-clamp recordings in acute human brain slices, obtained from neurosurgeries, to show that sleep-like UP and DOWN states modulate axonal action potentials and temporarily enhance synaptic transmission between neocortical pyramidal neurons. Synaptic enhancement by UP and DOWN state sequences facilitates recruitment of postsynaptic action potentials, which in turn results in long-term stabilization of synaptic strength. In contrast, synapses undergo lasting depression if presynaptic neurons fail to recruit postsynaptic action potentials. Our study offers a mechanistic explanation for how coupling of neural activity to slow waves can cause synaptic consolidation, with potential implications for brain stimulation strategies targeting memory performance. Whether and how slow wave activity (SWA) and the underlying membrane potential UP and DOWN states initiate mechanisms that augment memory functions in humans are not fully understood. Here authors used multineuron patch-clamp in alive human brain tissue, resected during neurosurgeries, to show that membrane potential UP/DOWN states, which mimic neural sleep activity, modulate axonal action potentials to boost synaptic strength and plasticity.

Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K + efflux as a key signaling event, suggesting that K + -permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K + channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K + conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K + efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K + conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K + -independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. Graphical Abstract

Melanoma brain metastases (MBM) variably respond to therapeutic interventions; thus determining patient’s prognosis. However, the mechanisms that govern therapy response are poorly understood. Here, we use a multi-OMICS approach and targeted sequencing (TargetSeq) to unravel the programs that potentially control the development of progressive intracranial disease. Molecularly, the expression of E-cadherin (Ecad) or NGFR, the BRAF mutation state and level of immune cell infiltration subdivides tumors into proliferative/pigmented and invasive/stem-like/therapy-resistant irrespective of the intracranial location. The analysis of MAPK inhibitor-naive and refractory MBM reveals switching from Ecad-associated into NGFR-associated programs during progression. NGFR-associated programs control cell migration and proliferation via downstream transcription factors such as SOX4. Moreover, global methylome profiling uncovers 46 differentially methylated regions that discriminate BRAF mut and wildtype MBM. In summary, we propose that the expression of Ecad and NGFR sub- classifies MBM and suggest that the Ecad-to-NGFR phenotype switch is a rate-limiting process which potentially indicates drug-response and intracranial progression states in melanoma patients. Melanoma brain metastases (MBM) show heterogeneous therapeutic response determined by incompletely understood mechanisms. Here, the authors use a multi-OMICS approach and targeted sequencing (TargetSeq) to decipher programs that may define molecular subsets of MBM and their response to therapy.