Multimodal validation of focal enhancement in intracranial aneurysms as a surrogate marker for aneurysm instability.

PURPOSE: Circumferential enhancement on MR vessel wall imaging has been proposed as a biomarker of a higher risk of rupture in intracranial aneurysms. Focal enhancement is frequently encountered in unruptured aneurysms, but its implication for risk stratification and patient management remains unclear. This study investigates the association of focal wall enhancement with hemodynamic and morphological risk factors and histologic markers of wall inflammation and degeneration. METHODS: Patients with an unruptured middle cerebral artery aneurysm who underwent 3D rotational angiography and 3T MR vessel wall imaging showing focal wall enhancement were included. Hemodynamic parameters were calculated based on flow simulations and compared between enhanced regions and the entire aneurysm surface. Morphological parameters were semiautomatically extracted and quantitatively associated with wall enhancement. Histological analysis included detection of vasa vasorum, CD34, and myeloperoxidase staining in a subset of patients. RESULTS: Twenty-two aneurysms were analyzed. Enhanced regions were significantly associated with lower AWSS, lower maxOSI, and increased LSA. In multivariate analysis, higher ellipticity index was an independent predictor of wall enhancement. Histologic signs of inflammation and degeneration and higher PHASES score were significantly associated with focal enhancement. CONCLUSION: Focal wall enhancement is colocalized with hemodynamic factors that have been related to a higher rupture risk. It is correlated with morphological factors linked to rupture risk, higher PHASES score, and histologic markers of wall destabilization. The results support the hypothesis that focal enhancement could serve as a surrogate marker for aneurysm instability.

NKG2D ligands in glioma stem-like cells: expression in situ and in vitro.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor. Tumor stem cells have a major influence on tumor malignancy, and immunological escape mechanisms, involving the Natural Killer Group 2, member D (NKG2D) receptor-ligand-system, are key elements in tumor immuno-surveillance. We analyzed the expression profile and localization of NKG2D ligands (NKG2DL) and embryonic and neural stem cell markers in solid human GBM and stem-like cells isolated from glioma cell lines by qRT-PCR and immunohistochemistry, including quantitative analysis. We also evaluated the effect of Temozolomide (TMZ), the standard chemotherapeutic agent used in GBM therapy, on NKG2DL expression. NKG2DL-positive cells were mostly found scattered and isolated, were detectable in glial fibrillary acidic protein (GFAP)-positive tumor regions and partly in the penumbra of tumor vessels. NKG2DL were found in a distinct tumor stem-like cell subpopulation and were broadly costained with each other. Quantitative analysis revealed, that dependent on the individual NKG2DL investigated, cell portions costained with different stem cell markers varied between small (Musashi-1) and high (KLf-4) amounts. However, a costaining of NKG2DL with CD3γ, typically found in T cells, was also observable, whereas CD11b as a marker for tumor micoglia cells was only rarely costained with NKG2DL. Stem-like cells derived from the glioma cell lines T98G and U251MG showed a distinct expression pattern of NKG2DL and stem cell markers, which seemed to be balanced in a cell line-specific way. With differentiation, T98G displayed less NKG2DL, whereas in U251MG, only expression of most stem cell markers decreased. In addition, stimulation with TMZ led to a significant upregulation of NKG2DL in stem-like cells of both lines. As stem-like glioma cells tend to show a higher expression of NKG2DL than more differentiated tumor cells and TMZ treatment supports upregulation of NKG2DL, the NKG2D system might play an important role in tumor stem cell survival and in GBM therapy.

Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma.

Tumor-associated microglia and blood-derived macrophages (TAMs) play a central role in modulating the immune suppressive microenvironment in glioma. Here, we show that GPNMB is predominantly expressed by TAMs in human glioblastoma multiforme and the murine RCAS-PDGFb high grade glioma model. Loss of GPNMB in the in vivo tumor microenvironment results in significantly smaller tumor volumes and generates a pro-inflammatory innate and adaptive immune cell microenvironment. The impact of host-derived GPNMB on tumor growth was confirmed in two distinct murine glioma cell lines in organotypic brain slices from GPNMB-KO and control mice. Using published data bases of human glioma, the elevated levels in TAMs could be confirmed and the GPNMB expression correlated with a poorer survival.

Aß38 and Aß43 do not differentiate between Alzheimer's disease and cerebral amyloid angiopathy.

Differential diagnosis between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) using cerebrospinal fluid (CSF) biomarkers is challenging. A recent study suggested that the addition of Aß38 and Aß43 to a standard AD biomarker panel (Aß40, Aß42, t-tau, p-tau) to improve the differential diagnosis. We tested this hypothesis in an independent German cohort of CAA and AD patients and controls using the same analytical techniques. We found excellent discrimination between AD and controls and between CAA and controls, but not between AD and CAA. Adding Aß38 and Aß43 to the panel did not improve the discrimination between AD and CAA.

Frequency of deep-seated cerebral microbleeds in patients with lobar hemorrhages and histopathological evidence for cerebral amyloid angiopathy.

Background: Cerebral amyloid angiopathy (CAA) is a common disease and the most common cause of lobar hemorrhages in the elderly. Usually, deep-seated microhemorrhages preclude the diagnosis of CAA. In this study, we sought to estimate the frequency of deep-seated microbleeds on MRI in patients with lobar hemorrhages and histopathological evidence for cerebral amyloid angiopathy. In addition, we describe a cohort of patients with cortical and deep-seated microbleeds on MRI and a histopathological specimen available from lobar hematoma evacuation. Methods: Retrospective database search for histopathological specimens from lobar hematoma evacuation and review of imaging findings (CT and MRI) and patient charts was performed. Results: Between 1 January 2012 and 31 December 2020, 88 specimens from 88 patients were available. A total of 56 specimens were excluded (no brain tissue in the specimen n = 4, other diagnosis n = 8, no MRI n = 43, and no BOLD-based sequence n = 1). Of the remaining 32 patients, 25 patients (78%) did not harbor deep-seated lesions on MRI, of which 17 patients had histopathological features of CAA. A total of seven patients harbored deep-seated CMB. Of these seven patients, three (3/20, 15%) had histopathological features of CAA. Conclusion: Approximately 15% of patients with histopathologically diagnosed CAA harbor deep-seated microbleeds. This finding may add to the discussion on how to identify patients with CAA and deep-seated CMB.

Intra-cranial aneurysm treatment with contour or WEB - a single center comparison of intervention times and learning curves.

BACKGROUND AND PURPOSE: Treating aneurysms with intra-saccular flow disruption is a feasible alternative to coil-embolization. Besides the established WEB device, the novel Contour Neurovascular System has emerged as a potentially easier alternative regarding sizing and deployment. We report the learning curve experienced at our center from the first 48 patients treated with Contour and compared it with 48 consecutive WEB cases. METHODS: Both groups were compared concerning intervention time, sizing failures leading to device changes and radiation dose. Additionally, we analyzed potential learning effects by comparing the first 24 Contour cases with our last 24 Contour cases and WEB cases respectively. RESULTS: Patient demographics, acute vs. incidental cases and aneurysm localization were comparable in both groups. The deployment time was faster in our 48 Contour cases (median: 22.0 ± 17.0 min), than in the WEB group (median: 27.5 ± 24.0 min). Total intervention time was similar for Contour (median: 68.0 ± 46.9 min) and WEB cases (median: 69.0 ± 38.0 min). Device implantation times in our WEB cases were slightly shorter in the later cases (median: 25.5 ± 24.1 min) than in the earlier (median: 28.0 ± 24.4 min) cases. In the Contour cohort, deployment times were similar for the first 24 cases (median: 22.0 ± 14.5 min) and the final 24 (median: 22.0 ± 19.4 min). Radiation dose was lower in the Contour group (1469.0 ± 1718 mGy*cm2 vs. 1788.0 ± 1506 mGy*cm2 using the WEB device). Less intra-procedural device changes were performed in the Contour cohort (6 of 48 cases, 12.5%), than in the WEB group (8 of 48 cases, 16.7%). CONCLUSION: Aneurysm occlusion times and consequently radiation doses, as well as the amount of device changes were lower in the Contour group. Occlusion times did not differ in the first and last 24 Contour cases, leading to the assumption that the handling of Contour does not require extended training. A short training effect in occlusion times was noted, however, between the first and last WEB cases as shorter procedure times were seen in the latter cases.

Contour device implantation for treatment of intracranial aneurysms in the basilar tip.

INTRODUCTION: Treatment of basilar apex aneurysms will remain challenging regarding the nobility of the parent vessel and their often wide-necked configuration. With endovascular techniques being the treatment approach of choice, novel intrasaccular flow-disruption devices constitute an endovascular embolization option. In this research, we report our experiences in embolizing basilar tip aneurysms with the novel Contour device. MATERIAL AND METHODS: Retrospective analysis of eight patients after Contour implantation into a basilar apex aneurysm. Periprocedural data on intervention times, radiation dose, procedural success and complications were gathered. All patients received follow-up digital subtraction angiography after six months. Further follow-up examination results were analysed given their availability. RESULTS: Contour implantation was successful in all patients. The mean device instrumentation time was 18.8 ± 7.7 min with a mean full intervention time of 100 ± 65.8 min. The mean full procedure radiation dose was 1917 (421-5107) cGy/cm2. After six months, six aneurysms were occluded (Raymond Roy Scale (RRS) 1/2), one showed perfusion inside the device (RRS 3a) and one patient had undergone reintervention due to progression. The aneurysm with constant perfusion at six months was seen to be occluded after 24 months. CONCLUSION: Contour device implantation is a promising feasible alternative endovascular method for embolization of intracranial aneurysms located in the basilar tip with short intervention times and low radiation dosages. Short- and medium-term follow-ups show promising results concerning aneurysm occlusion and reinterventions, however further research is needed to show long-term stability.

Comprehensive Implementation of Shared Decision Making in a Neuromedical Center Using the SHARE TO CARE Program.

Purpose: SHARE TO CARE (S2C) is a comprehensive, multi-module implementation program for shared decision making (SDM). It is currently applied at the University Hospital Schleswig-Holstein in Kiel, Germany, and among general practitioners at the Federal State of Bremen. This study examines the results of the full implementation of S2C in terms of effectiveness within the Kiel Neuromedical Center comprising the departments of neurology and neurosurgery. Method and Design: The S2C program consists of four combined intervention modules: 1) multimodal training of physicians; 2) a patient activation campaign including the ASK-3 method; 3) digital evidence-based patient decision aids; and 4) SDM support by nurses, e.g., as decision coaches. The SDM level before and immediately after implementation was retrospectively assessed in consecutively selected patients on the subscale "Patient Decision Making" of the Perceived Involvement in Care Scale (PICSPDM). Mean scores were compared with t-tests. Results: Eighty-nine percent of all physicians (N = 56) completed the SDM training. We developed a total of 12 evidence-based digital decision aids in the center, educated two decision coaches to support patients' decision processes by using decision aids. Physicians adjusted patients' pathways to incorporate the use of decision aids. Patients (n = 261) reported a significant increase in participation (p<0.001; Hedges' g = 0.49) in medical decision making. Conclusion: The S2C program has been successfully implemented within the entire Neuromedical Center. Patients reported a medium to small increase of perceived involvement in decision making demonstrating the effectiveness of the implementation. For future research, it might be interesting to investigate the sustainability of the effects of S2C. In addition, it seems useful to complement the patient-based evaluation with observer-based data.

Characterizing mixed location hemorrhages/microbleeds with CSF markers.

OBJECTIVE: Cerebral amyloid angiopathy (CAA) is a common cause of lobar and subarachnoid hemorrhages in the elderly. A diagnosis of CAA requires multiple lobar hemorrhagic lesions (intracerebral hemorrhage and/or cerebral microbleeds) and/or cortical superficial siderosis (cSS). In contrast, hemorrhagic lesions located in the deep structures are the hallmark of hypertensive arteriopathy (HTN-A). They are an exclusion criterion for CAA, and when present with lobar hemorrhagic lesions considered a separate entity: mixed location hemorrhages/microbleeds (MLHs). We compared clinical, radiological, and cerebrospinal fluid (CSF) marker data in patients with CAA, MLH, and Alzheimer's disease (AD), and healthy controls (HCs) and used it to position MLH in the disease spectrum. PATIENTS AND METHODS: Retrospective cohort study of consecutive patients with CAA (n = 31), MLH (n = 31), AD (n = 28), and HC (n = 30). Analysis of clinical, radiological, CSF biomarker (Aß42, Aß40, t-tau, and p-tau), and histopathological data in patients each group. RESULTS: cSS was significantly more common in CAA than MLH (45% vs 13%, p = 0.011), and cSS in MLH was associated with intracerebral hemorrhage (ICH) (p = 0.037). Aß42 levels and the Aß42/Aß40 ratio, diagnostic groups followed the order HC > MLH > CAA > AD and the opposite order for t-tau and p-tau. No clear order was apparent forAß40. Aß40 and Aß42 levels as well as the Aß42/Aß40 ratio were lower in both CAA and MLH patients with cSS than in patients without cSS. Aß40 and Aß42 levels were higher in CAA and MLH patients with lacunar infarcts than in those without. CONCLUSION: Our data suggest that MLH and CAA are mutually not exclusive diagnoses, and are part of a spectrum with variable contributions of both CAA and HTN-A.

Reappraisal of Intracerebral Hemorrhages and Intracerebral Hemorrhage Grading Scale Score in Surgically and Medically Managed Cerebellar Intracerebral Hemorrhage.

BACKGROUND: As compared with supratentorial intracerebral hemorrhages (ICH), bleeds that occur within the cerebellum require special consideration given the nature of the posterior fossa. OBJECTIVE: To validate ICH and ICH grading scale (ICH-GS) scores in patients with cerebellar hemorrhage and examine the outcomes of patients managed surgically as compared with those who underwent conservative treatment. METHODS: This observational multicenter study included 475 patients with cerebellar hemorrhage from 9 different neurosurgical departments in Germany between 2005 and 2021. The prognostic accuracy of ICH and ICH-GS scores were calculated by the area under the curve of the receiver operating characteristic curves. Analyzed outcomes were the in-hospital mortality, mortality at 6 months, in-hospital outcome, and outcome at 6 months. RESULTS: Of 403 patients, 252 patients (62.5%) underwent surgical treatment and 151 patients (37.5%) conservative treatment. Both ICH and ICH-GS scores demonstrated good prognostic accuracy regarding both overall mortality and functional outcomes. In those patients presenting with severe cerebellar hemorrhages, ie, ICH score >3 and ICH-GS score >11, overall mortality was significantly lower in surgically treated patients. Mortality was significantly higher in those patients managed surgically who presented with ICH scores 3; in such patients, improved outcomes were noted when the hematoma was treated conservatively. CONCLUSION: ICH and ICH scores are useful tools for prediction of survival and outcome in patients with cerebellar ICH. Surgical management may be beneficial for those who present with severe cerebellar ICH as reflected by ICH scores >3, while conservative management seems reasonable in patients with lower ICH scores.

Erroneous expression of NKG2D on granulocytes detected by phycoerythrin-conjugated clone 149810 antibody.

BACKGROUND: The activating Natural killer group 2 member D (NKG2D) receptor is typically expressed on NK cells, CD8 T lymphocytes, γδ T cells and small subsets of CD4 T lymphocytes. During the course of an extensive flow cytometry phenotyping of immune cells in the peripheral blood of patients with glioblastoma multiforme (GBM) we noticed an unexpected expression of NKG2D receptor on granulocytes using the phycoerythrin (PE)-conjugated clone 149810 antibody. METHODS: Peripheral blood samples from 35 patients with GBM and 22 age-matched healthy control (HC) donors were analyzed using flow cytometry, imaging cytometry and real-time quantitative reverse transcription PCR to validate the observed expression of NKG2D receptor on myeloid cells. RESULTS: Reactivity with PE-149810 was mostly observed on granulocytes from GBM patients on dexamethasone treatment where it correlated with inferior survival rates. Surprisingly, such NKG2D expression on granulocytes was not observed using the allophycocyanin (APC)-conjugate of the same clone 149810 antibody or an indirect staining procedure with unconjugated clone 149810 antibody. Moreover, the PE-conjugate of a different anti-NKG2D clone (1D11) also did not stain granulocytes. Imaging cytometry indicated cell surface and intracellular localization of PE-149810 but not of PE-1D11 in granulocytes. CONCLUSION: Our results uncover an erroneous and false positive reactivity of PE-labeled (but not of APC-labeled or unconjugated) anti-NKG2D antibody 149810 on granulocytes from dexamethasone-treated GBM patients and raise a note of caution for studies of NKG2D expression on non-lymphoid cells.

Microglia/macrophage-derived human CCL18 promotes glioma progression via CCR8-ACP5 axis analyzed in humanized slice model.

Factors released from glioma-associated microglia/macrophages (GAMs) play a crucial role in glioblastoma multiforme (GBM) progression. Here, we study the importance of CCL18, a cytokine expressed in human but not in rodent GAMs, as a modulator of glioma growth. Since CCL18 signaling could not be studied in classical mouse glioma models, we developed an approach by transplanting induced pluripotent stem cell-derived human microglia and human glioma cells into mouse brain slices depleted of their intrinsic microglia. We observe that CCL18 promotes glioma cell growth and invasion. Chemokine (C-C motif) receptor 8 (CCR8) is identified as a functional receptor for CCL18 on glioma cells, and ACP5 (acid phosphatase 5) is revealed as an important part of the downstream signaling cascade for mediating glioma growth. We conclude, based on the results from an in vitro, ex vivo humanized glioma model and an in vivo GBM model that microglia/macrophage-derived CCL18 promotes glioma growth.

Sustainability of large-scale implementation of shared decision making with the SHARE TO CARE program.

Introduction: SHARE TO CARE (S2C) is a comprehensive implementation program for shared decision making (SDM). It is run at the University Hospital Schleswig-Holstein (UKSH) in Kiel, Germany, and consists of four combined intervention modules addressing healthcare professionals and patients: (1) multimodal training of physicians (2) patient activation campaign including the ASK3 method, (3) online evidence-based patient decision aids (4) SDM support by nurses. This study examines the sustainability of the hospital wide SDM implementation by means of the Neuromedical Center comprising the Departments of Neurology and Neurosurgery. Methods: Between 2018 and 2020, the S2C program was applied initially within the Neuromedical Center: We implemented the patient activation campaign, trained 89% of physicians (N = 56), developed 12 patient decision aids and educated two decision coaches. Physicians adjusted the patients' pathways to facilitate the use of decision aids. To maintain the initial implementation, the departments took care that new staff members received training and decision aids were updated. The patient activation campaign was continued. To determine the sustainability of the initial intervention, the SDM level after a maintenance phase of 6-18 months was compared to the baseline level before implementation. Therefore, in- and outpatients received a questionnaire via mail after discharge. The primary endpoint was the "Patient Decision Making" subscale of the Perceived Involvement in Care Scale (PICSPDM). Secondary endpoints were an additional scale measuring SDM (CollaboRATE), and the PrepDM scale, which determines patients' perceived health literacy while preparing for decision making. Mean scale scores were compared using t-tests. Results: Patients reported a significantly increased SDM level (PICSPDM p = 0.02; Hedges' g = 0.33; CollaboRATE p = 0.05; Hedges' g = 0.26) and improved preparation for decision making (PrepDM p = 0.001; Hedges' g = 0.34) 6-18 months after initial implementation of S2C. Discussion: The S2C program demonstrated its sustainability within the Neuromedical Center at UKSH Kiel in terms of increased SDM and health literacy. Maintaining the SDM implementation required a fraction of the initial intensity. The departments took on the responsibility for maintenance. Meanwhile, an additional health insurance-based reimbursement for S2C secures the continued application of the program. Conclusion: SHARE TO CARE promises to be suitable for long-lasting implementation of SDM in hospitals.

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy: New Data and Quantitative Meta-Analysis.

BACKGROUND: To evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with probable cerebral amyloid angiopathy (CAA) according to the modified Boston criteria in a retrospective multicentric cohort. METHODS: Beta-amyloid 1-40 (Aß40), beta-amyloid 1-42 (Aß42), total tau (t-tau), and phosphorylated tau 181 (p-tau181) were measured in 31 patients with probable CAA, 28 patients with Alzheimer's disease (AD), and 30 controls. Receiver-operating characteristics (ROC) analyses were performed for the measured parameters as well as the Aß42/40 ratio to estimate diagnostic parameters. A meta-analysis of all amenable published studies was conducted. RESULTS: In our data Aß42/40 (AUC 0.88) discriminated best between CAA and controls while Aß40 did not perform well (AUC 0.63). Differentiating between CAA and AD, p-tau181 (AUC 0.75) discriminated best in this study while Aß40 (AUC 0.58) and Aß42 (AUC 0.54) provided no discrimination. In the meta-analysis, Aß42/40 (AUC 0.90) showed the best discrimination between CAA and controls followed by t-tau (AUC 0.79), Aß40 (AUC 0.76), and p-tau181 (AUC 0.71). P-tau181 (AUC 0.76), Aß40 (AUC 0.73), and t-tau (AUC 0.71) differentiated comparably between AD and CAA while Aß42 (AUC 0.54) did not. In agreement with studies examining AD biomarkers, Aß42/40 discriminated excellently between AD and controls (AUC 0.92-0.96) in this study as well as the meta-analysis. CONCLUSION: The analyzed parameters differentiate between controls and CAA with clinically useful accuracy (AUC > ∼0.85) but not between CAA and AD. Since there is a neuropathological, clinical and diagnostic continuum between CAA and AD, other diagnostic markers, e.g., novel CSF biomarkers or other parameters might be more successful.

Primidone blocks RIPK1-driven cell death and inflammation.

The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.

TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression.

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression.

Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties.

BACKGROUND: The transcription factor NF-κB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-κB activity can suppress central oncogenic signaling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. METHODS: In a pharmacogenomics study with a panel of transgenic glioma cells, we observed that NF-κB can be converted into a tumor suppressor by the non-psychotropic cannabinoid cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study, we performed pharmacological assays, gene expression profiling, biochemical, and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM datasets. RESULTS: We found that CBD promotes DNA binding of the NF-κB subunit RELA and simultaneously prevents RELA phosphorylation on serine-311, a key residue that permits genetic transactivation. Strikingly, sustained DNA binding by RELA-lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen species (ROS), while high ROS content in other tumors blocked CBD-induced hGSC death. Consequently, ROS levels served as a predictive biomarker for CBD-sensitive tumors. CONCLUSIONS: This evidence demonstrates how a clinically approved drug can convert NF-κB into a tumor suppressor and suggests a promising repurposing option for GBM therapy.

Effectiveness of an Annular Closure Device to Prevent Recurrent Lumbar Disc Herniation: A Secondary Analysis With 5 Years of Follow-up.

Importance: Patients with large annular defects following lumbar microdiscectomy for disc herniation are at increased risk for symptomatic recurrence and reoperation. Objective: To determine whether a bone-anchored annular closure device in addition to lumbar microdiscectomy resulted in lower reherniation and reoperation rates vs lumbar microdiscectomy alone. Design, Setting, and Participants: This secondary analysis of a multicenter randomized clinical trial reports 5-year follow-up for enrolled patients between December 2010 and October 2014 at 21 clinical sites. Patients in this study had a large annular defect (6-10 mm width) following lumbar microdiscectomy for treatment of lumbar disc herniation. Statistical analysis was performed from November to December 2020. Interventions: Lumbar microdiscectomy with additional bone-anchored annular closure device (device group) or lumbar microdiscectomy only (control group). Main Outcomes and Measures: The incidence of symptomatic reherniation, reoperation, and adverse events as well as changes in leg pain, Oswestry Disability Index, and health-related quality of life when comparing the device and control groups over 5 years of follow-up. Results: Among 554 randomized participants (mean [SD] age: 43 [11] years; 327 [59%] were men), 550 were included in the modified intent-to-treat efficacy population (device group: n = 272; 270 [99%] were White); control group: n = 278; 273 [98%] were White) and 550 were included in the as-treated safety population (device group: n = 267; control group: n = 283). The risk of symptomatic reherniation (18.8% [SE, 2.5%] vs 31.6% [SE, 2.9%]; P < .001) and reoperation (16.0% [SE, 2.3%] vs 22.6% [SE, 2.6%]; P = .03) was lower in the device group. There were 53 reoperations in 40 patients in the device group and 82 reoperations in 58 patients in the control group. Scores for leg pain severity, Oswestry Disability Index, and health-related quality of life significantly improved over 5 years of follow-up with no clinically relevant differences between groups. The frequency of serious adverse events was comparable between the treatment groups. Serious adverse events associated with the device or procedure were less frequent in the device group (12.0% vs 20.5%; difference, -8.5%; 95% CI, -14.6% to -2.3%; P = .008). Conclusions and Relevance: In patients who are at high risk of recurrent herniation following lumbar microdiscectomy owing to a large defect in the annulus fibrosus, this study's findings suggest that annular closure with a bone-anchored implant lowers the risk of symptomatic recurrence and reoperation over 5 years of follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT01283438.

Dormancy and NKG2D system in brain metastases: Analysis of immunogenicity.

Patients with breast cancer (BC) and lung cancer (LC) are prone to developing brain metastases, which are associated with devastating prognoses. Dormant tumor cells, a population of non­apoptotic quiescent cells and immunological escape mechanisms, including the Natural Killer Group 2 member D (NKG2D) receptor­ligand system, represent potential mechanisms of tumor recurrence. To date, the immunological characteristics of dormant tumor cells concerning the NKG2D system in cerebral malignancies are mostly unknown. In the present study, an extensive characterization of dormant and NKG2D ligand (NKG2DL)+ cells in cerebral metastases was performed. The expression profiles and localization patterns of various NKG2DL and several dormancy markers were analyzed in solid human brain metastases from patients with BC and LC using immunostaining and reverse transcription­quantitative polymerase chain reaction analyses. Statistical analysis was performed using Student's t­test and Bravais­Pearson correlation analysis. Not only 'peripheral', but also 'central' dormancy markers, which had been previously described in primary brain tumors, were identified in all cerebral metastases at detectable levels at protein and mRNA levels. Notably, the majority of NKG2DL+ cells were also positive for 'central' dormancy markers, but not 'peripheral' dormancy markers in both patient groups. This cell population may represent a promising future therapeutic target.

Visualization of Aneurysm Healing : Enhancement Patterns and Reperfusion in Intracranial Aneurysms after Embolization on 3T Vessel Wall MRI.

PURPOSE: Wall enhancement of intracranial aneurysms in vessel wall magnetic resonance imaging (MRI) has been linked to aneurysm progression. The clinical significance of aneurysm enhancement after embolization has not yet been investigated. The goal of this study was to identify factors associated with aneurysm wall enhancement and reperfusion after embolization. METHODS: Patients who underwent treatment of intracranial aneurysms with coils or the Woven Endobridge (WEB) and follow-up MR vessel wall imaging were included. Enhancement of the treated aneurysms was separately recorded for the following locations: a) wall at the neck, b) wall at the dome, and c) in the aneurysmal cavity. Reperfusion was determined on follow-up digital subtraction angiography (DSA) and MR time of flight (TOF) angiography. RESULTS: In this study 48 patients with 53 aneurysms were included. Wall enhancement at the neck and the dome of the aneurysm was significantly associated with time between embolization and follow-up MRI under 6 months. Enhancement inside the aneurysmal cavity was significantly associated with a follow-up time longer than 6 months, and with stable aneurysms without reperfusion. CONCLUSION: Wall enhancement is a regular feature in intracranial aneurysms after embolization and decreases over time. Enhancement inside the aneurysmal cavity is associated with a stable state and could possibly serve as an imaging marker of completed aneurysm healing.