Minimally Invasive Approaches to Anterior Skull Base Meningiomas.

Objective Anterior skull base meningiomas include olfactory groove, planum sphenoidale, and tuberculum sellae lesions. Traditionally, standard craniotomy approaches have been used to access meningiomas in these locations. More recently, minimally invasive techniques including supraorbital and endonasal endoscopic approaches have gained favor; however there are limited published series comparing the use of these two techniques for these meningiomas. Using our patent database, we identified patients who underwent these two approaches, and conducted a retrospective chart review to compare outcomes between these two techniques. Methods A total of 32 patients who underwent minimally invasive approaches were identified: 20 supraorbital and 11 endoscopic endonasal. Radiographic images, presenting complaints and outcomes, were analyzed retrospectively. The safety of each approach was evaluated. Results The mean extent of resection through a supraorbital approach was significantly greater than that of the endoscopic endonasal approach, 88.1 vs. 57.9%, respectively ( p = 0.016). Overall, preoperative visual acuity and anopsia deficits were more frequent in the endonasal group that persisted postoperatively (visual acuity: p = 0.004; anopsia: p = 0.011). No major complications including cerebrospinal fluid (CSF) leaks or wound-related complications were identified in the supraorbital craniotomy group, while the endonasal group had two CSF leaks requiring lumbar drain placement. Length of stay was shorter in the supraorbital group (3.4 vs. 6.1 days, p < 0.001). Conclusion Anterior skull base meningiomas can be successfully managed by both supraorbital and endoscopic endonasal approaches. Both approaches provide excellent direct access to tumor in carefully selected patients and are safe and efficient, but patient factors and symptoms should dictate the approach selected.

Selective and caspase-independent cytotoxicity of bioactive glasses towards giant cell tumor of bone derived neoplastic stromal cells but not to bone marrow derived stromal cells.

Semi-malignant giant cell tumors of bone (GCTB) are associated with large osteolytic defects and significant bone destructions. Surgical resection remains the standard therapy that is, however, associated with very high recurrence rates. Bioactive glasses (BGs) that are osteogenic but under certain conditions also cytotoxic might be suitable to achieve biological reconstruction with simultaneous reduction of tumor recurrence in GCTB. In this study, a concentration and time dependent cytotoxic effect of five different BG compositions towards neoplastic GCTB cells was identified while bone marrow derived mesenchymal stromal cells were mostly unaffected. Time course and extent of the cytotoxic effect were dependent on the BG composition and were not associated with caspases activation, indicating that apoptotic mechanisms are not involved. Rather, detection of BG-induced disruption of the cell membranes and a rapid drop of intracellular HMG1 (High Mobility Group Box 1 protein) levels suggest a necrotic cell death. Notably, the cytotoxic effects were dependent on a direct contact of cells and BGs and could not be observed using indirect cultivation settings. Our data suggest that BGs might represent promising materials for the treatment of GCTB in order to reduce tumor recurrence with simultaneous enhancement of bone regeneration.

Meningioma surgical outcomes and complications in patients aged 75 years and older.

OBJECTIVE: Meningioma incidence increases with age, yet limited data exist on how comorbidities impact complication rates in elderly patients undergoing meningioma resection. The objective of this study was to report surgical outcomes and identify risk factors for perioperative complications. METHODS: We performed a retrospective study of patients 75 years and older undergoing meningioma resection. Outcomes included survival and complications. Major complications were those requiring surgical intervention or causing permanent neurological deficit. Recursive partitioning, Kaplan-Meier survival, univariate and multi-variate (MVA) analyses were performed. RESULTS: From 1996 to 2014, 103 patients with a median age of 79 years (IQR 77-83 years) underwent cranial meningioma resection. Median follow-up was 5.8 years (IQR 1.7-8.7 years). Median actuarial survival was 10.5 years. Complications occurred in 32 patients (31.1%), and 13 patients (12.6%) had multiple complications. Major complications occurred in 16 patients (15.5%). Increasing age was not a significant predictor of any (p = 0.6408) or major complication (p = 0.8081). On univariate analysis, male sex, Charlson Comorbidity Index greater than 8, and cardiovascular comorbidities were significantly associated with major complications. On MVA only cardiovascular comorbidities (OR 3.94, 95% CI 1.05-14.76, p = 0.0238) were significantly associated with any complication. All patients with major complications had cardiovascular comorbidities, and on MVA male gender (OR 3.78, 95%CI 1.20-11.93, p = 0.0212) was associated with major complications. CONCLUSIONS: Cardiovascular comorbidities and male gender are significant risk factors for complications after meningioma resection in patients aged 75 years and older. While there is morbidity associated with meningioma resection in this cohort, there is also excellent long-term survival.

Effect of manganese, zinc, and copper on the biological and osteogenic properties of mesoporous bioactive glass nanoparticles.

Mesoporous bioactive glass nanoparticles (MBGNs) have demonstrated promising properties for the local delivery of therapeutically active ions with the aim to improve their osteogenic properties. Manganese (Mn), zinc (Zn), and copper (Cu) ions have already shown promising pro-osteogenic properties. Therefore, the concentration-dependent impact of MBGNs (composition in mol%: 70 SiO2 , 30 CaO) and MBGNs containing 5 mol% of either Mn, Zn, or Cu (composition in mol%: 70 SiO2 , 25 CaO, 5 MnO/ZnO/CuO) on the viability and osteogenic differentiation of human marrow-derived mesenchymal stromal cells (BMSCs) was assessed in this study. Mn-doped MBGNs (5Mn-MBGNs) showed a small "therapeutic window" with a dose-dependent negative impact on cell viability but increasing pro-osteogenic features alongside increasing Mn concentrations. Due to a constant release of Zn, 5Zn-MBGNs showed good cytocompatibility and upregulated the expression of genes encoding for relevant members of the osseous extracellular matrix during the later stages of cultivation. In contrast to all other groups, BMSC viability increased with increasing concentration of Cu-doped MBGNs (5Cu-MBGNs). Furthermore, 5Cu-MBGNs induced an increase in alkaline phosphatase activity. In conclusion, doping with Mn, Zn, or Cu can enhance the biological properties of MBGNs in different ways for their potential use in bone regeneration approaches.

Pleural Cryobiopsy: A Systematic Review and Meta-Analysis.

BACKGROUND: Pleural biopsy using either video-assisted thoracoscopic surgery or medical pleuroscopy is the current diagnostic criterion standard for pleural pathology with a high, yet imperfect, diagnostic yield. Cryobiopsy may provide greater tissue, increase depth of sampled tissue, and/or reduce crush artifact. However, its impact on diagnostic yield remains uncertain, and there are potential concerns regarding its safety too. We performed a systematic review and meta-analysis to investigate the same. METHODS: We performed a systematic search of MEDLINE, Embase, and Google Scholar for studies evaluating the performance of pleural cryobiopsy, assessing the quality of each study using the Quality Assessment, Data Abstraction and Synthesis-2 tool. Using inverse variance weighting, we performed a meta-analysis of diagnostic yield estimations. We also reviewed specimen characteristics and complications related to the procedure. RESULTS: Seven observational studies involving 586 pleural biopsies (311 cryobiopsies and 275 flexible forceps biopsies) were evaluated. All but one study used a semi-rigid thoracoscope. Meta-analysis generated a diagnostic yield of 96.5% for cryobiopsy and 93.1% for forceps biopsy with an inverse variance-weighted OR of 1.61 (95% CI, 0.71-3.66) and an I2 of 16%. No instances of moderate to severe bleeding were reported with cryobiopsy. A funnel plot illustrated no major publication bias. CONCLUSIONS: Based on analysis of relatively homogenous observational data, pleural cryobiopsy is safe but does not increase diagnostic yield over flexible forceps biopsy. Adequately powered multicenter randomized trials are needed for further investigation.

Are Transbronchial Cryobiopsies Ready for Prime Time?: A Systematic Review and Meta-Analysis.

BACKGROUND: There is a lack of consensus regarding the yield and safety of transbronchial cryobiopsies for diagnosing diffuse parenchymal lung diseases (DPLD). The purpose of this study was to perform a systematic review and meta-analysis assessing the diagnostic yield and safety profile of transbronchial cryobiopsies in DPLD. METHODS: A literature search of MEDLINE, EMBASE databases, and Google Scholar was performed in August 2017. The quality of included studies was assessed using Quality Assessment, Data Abstraction and Synthesis-2 tool. Meta-analysis was performed using MedCalc (version 17.2). Inverse variance weighting was used to aggregate diagnostic yield proportions across studies, with the number of subjects in each study representing its weight. Random effects model was used when significant heterogeneity was observed (I>40%). RESULTS: A total of 31 studies were included in the review. Of these, 27 studies with 1443 patients reported data on the performance of cryobiopsies for diagnosing DPLD. The diagnostic yield was 72.9% [95% confidence interval (CI), 67.9%-77.7%]. The pooled mean specimen size obtained by cryobiopsies was 23.4 mm (95% CI, 9.6-37.3 mm). The overall complication rate was 23.1% with bleeding and pneumothoraces being the most commonly reported complications. The incidence of significant bleeding was 14.2% (95% CI, 7.9%-21.9%), whereas pneumothorax was seen in 9.4% (95% CI, 6.7%-12.5%) of patients. Overall reported mortality was 0.3%. CONCLUSION: Our meta-analysis shows that cryobiopsies have a good diagnostic yield but a significant risk for complications. Cryobiopsy outcomes vary markedly among different centers. Further research is needed to standardize the procedure and improve its safety profile.

Synthesis, Urease Inhibition and Molecular Modelling Studies of Novel Derivatives of the Naturally Occurring ß-Amyrenone.

Urease enzyme (UE) has been reported to be a potent virulence factor for Helicobacter pylori (HP) bacteria indicated to be responsible for various gastrointestinal diseases. Therefore, the spread of HP, currently regarded by the World Health Organization as a class 1 carcinogen, could be better controlled by targeting UE. It is in this line that we have synthesized three new derivatives (2-4) of the naturally occurring olean-12-en-3-one (1), which was previously isolated from the figs of Ficus vallis-choudae Delile (Moraceae). Among the synthesized compounds, 3 and 4 contain an indole moiety. Their structures were unambiguously assigned by spectroscopic and spectrometric techniques (1D-NMR, 2D-NMR and MS). The starting material and the synthesized compounds were screened for UE inhibition activity, and showed significant activities with IC50 values ranging from 14.5 to 24.6 µM, with compound (1) being the most potent as compared to the positive control thiourea (IC50 = 21.6 µM). Amongst the synthetic derivatives, compound 4 was the most potent (IC50 = 17.9 µM), while the others showed activities close to that of the control. In addition, molecular docking study of target compounds 2-4 was performed in an attempt to explore their binding mode for the design of more potent UE inhibitors.

Computed Tomography Bronchus Sign and the Diagnostic Yield of Guided Bronchoscopy for Peripheral Pulmonary Lesions. A Systematic Review and Meta-Analysis.

RATIONALE: Indeterminate peripheral pulmonary lesions (PPLs) often require tissue diagnosis. If nonsurgical biopsy techniques are considered, deciding between bronchoscopic transbronchial versus computed tomography-guided transthoracic biopsy can be difficult. The former has a low diagnostic yield with a low complication risk, whereas the latter has a better diagnostic yield but a higher complication rate. Investigators have looked at various lesion characteristics that can predict the diagnostic yield of guided bronchoscopic biopsies. Although consensus exists that larger size and proximity to the hilum increase the diagnostic yield, there is ongoing debate about the association between computed tomography bronchus sign (air-filled bronchus in close proximity of the lesion as seen on computed tomography imaging) and the diagnostic yield of guided bronchoscopic modalities. OBJECTIVES: To perform a meta-analysis and systematic review, determining the association between computed tomography bronchus sign and the diagnostic yield of guided bronchoscopy for PPLs. METHODS: MEDLINE, Embase, Scopus, and Google Scholar were searched in January 2018 for guided bronchoscopy studies that had assessed the impact of computed tomography bronchus sign on the diagnostic yield. The quality of included studies was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 tool. Meta-analysis was performed using MedCalc (version 18). Odds ratios were used to compare yield of lesions with and without bronchus sign. Random effects model was used when significant heterogeneity was observed (I2 > 40%). RESULTS: For 2,199 lesions with computed tomography bronchus sign, the overall weighted diagnostic yield was 74.1% (95% confidence interval, 68.3-79.5%). For 971 lesions without computed tomography bronchus sign, the overall weighted diagnostic yield was 49.6% (95% confidence interval, 39.6-59.5%). The odds ratio for successfully diagnosing a lesion with computed tomography bronchus sign was 3.4 (95% confidence interval, 2.4-5.0). Possible sources of heterogeneity in the meta-analysis included differences in study designs, guidance modalities, and cancer prevalence. The odds ratio for successfully diagnosing a lesion with computed tomography bronchus sign was relatively lower for prospective studies. CONCLUSIONS: PPLs with computed tomography bronchus sign are more likely to be diagnosed with guided bronchoscopy than the lesions without computed tomography bronchus sign. Clinicians should consider this, along with the lesion size and distance from the hilum, when contemplating guided bronchoscopy for PPLs.

Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

OBJECTIVE: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture. APPROACH AND RESULTS: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1ß, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs. CONCLUSIONS: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies.

Radial endobronchial ultrasound for the diagnosis of peripheral pulmonary lesions: A systematic review and meta-analysis.

Tissue diagnosis of peripheral pulmonary lesions (PPLs) can be challenging. In the past, flexible bronchoscopy was commonly performed for this purpose but its diagnostic yield is suboptimal. This has led to the development of new bronchoscopic modalities such as radial endobronchial ultrasound (R-EBUS), electromagnetic navigation bronchoscopy (ENB) and virtual bronchoscopy (VB). We performed this meta-analysis using data from previously published R-EBUS studies, to determine its diagnostic yield and other performance characteristics. Ovid MEDLINE and PubMed databases were searched for R-EBUS studies in September 2016. Diagnostic yield was calculated by dividing the number of successful diagnoses by the total number of lesions. Meta-analysis was performed using MedCalc (Version 16.8). Inverse variance weighting was used to aggregate diagnostic yield proportions across studies. Publication bias was assessed using funnel plot and Duval and Tweedie's test. 57 studies with a total of 7872 lesions were included in the meta-analysis. These were published between October 2002 and August 2016. Overall weighted diagnostic yield for R-EBUS was 70.6% (95% CI: 68-73.1%). The diagnostic yield was significantly higher for lesions >2 cm in size, malignant in nature and those associated with a bronchus sign on computerized tomography (CT) scan. Diagnostic yield was also higher when R-EBUS probe was within the lesion as opposed to being adjacent to it. Overall complication rate was 2.8%. This is the largest meta-analysis performed to date, assessing the performance of R-EBUS for diagnosing PPLs. R-EBUS has a high diagnostic yield (70.6%) with a very low complication rate.

Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease.

BACKGROUND: The role of smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation and pathogenesis of stroke has not been determined. Cigarette smoke is a major risk factor for atherosclerosis, but potential mechanisms are unclear, and its role in SMC phenotypic modulation has not been established. METHODS AND RESULTS: In cultured cerebral vascular SMCs, exposure to cigarette smoke extract (CSE) resulted in decreased promoter activity and mRNA expression of key SMC contractile genes (SM-α-actin, SM-22α, SM-MHC) and the transcription factor myocardin in a dose-dependent manner. CSE also induced pro-inflammatory/matrix remodeling genes (MCP-1, MMPs, TNF-α, IL-1ß, NF-κB). CSE increased expression of KLF4, a known regulator of SMC differentiation, and siKLF4 inhibited CSE induced suppression of SMC contractile genes and myocardin and activation of inflammatory genes. These mechanisms were confirmed in vivo following exposure of rat carotid arteries to CSE. Chromatin immune-precipitation assays in vivo and in vitro demonstrated that CSE promotes epigenetic changes with binding of KLF4 to the promoter regions of myocardin and SMC marker genes and alterations in promoter acetylation and methylation. CONCLUSION: CSE exposure results in phenotypic modulation of cerebral SMC through myocardin and KLF4 dependent mechanisms. These results provides a mechanism by which cigarette smoke induces a pro-inflammatory/matrix remodeling phenotype in SMC and an important pathway for cigarette smoke to contribute to atherosclerosis and stroke.

TNF-α induces phenotypic modulation in cerebral vascular smooth muscle cells: implications for cerebral aneurysm pathology.

Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF-α) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-α-actin, SM-22α, smooth muscle myosin heavy chain), while dominant-negative cells suppressed expression. Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased expression of KLF4, a known regulator of SMC differentiation. Kruppel-like transcription factor 4 (KLF4) small interfering RNA abrogated TNF-α activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF-α and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF-α inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays in vivo and in vitro demonstrated that TNF-α promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF-α induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF-α in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.

Endovascular treatment of very small ruptured intracranial aneurysms: complications, occlusion rates and prediction of outcome.

OBJECTIVE: To assess predictors of outcome following endovascular treatment of small ruptured intracranial aneurysms (SRA). METHODS: Between 2004 and 2011, 91 patients with SRA (≤3 mm) were treated at our institution. Multivariate analysis was carried out to assess predictors of endovascular-related complications, aneurysm obliteration (>95%), recanalization and favorable outcome (Glasgow Outcome Scale 3-5). RESULTS: Endovascular treatment was aborted in nine of 91 patients (9.9%). Procedure-related complications occurred in eight of 82 patients (9.8%) of which five were transient and three were permanent. Three patients (3.7%) undergoing endovascular treatment experienced an intraprocedural aneurysm rupture. Three of nine patients (33.3%) treated with stent- or balloon-assisted coiling experienced periprocedural complications compared with five of 73 patients (6.8%) receiving only coils or Onyx (p=0.039). There were no procedural deaths or rehemorrhages. Rates of recanalization and retreatment were 18.2% and 12.7%, respectively. No factors predicted initial occlusion or recanalization. In multivariate analysis, pretreatment factors predictive of a favorable outcome included younger age (OR 0.94; 95% CI 0.91 to 0.99, p=0.017), larger aneurysm size (OR 3.4; 95% CI 1.02 to 11.11, p=0.045), Hunt and Hess grade (OR 0.38; 95% CI 0.19 to 0.75, p=0.005) and location (OR 5.12; 95% CI 1.29 to 20.25, p=0.02). When assessing treatment and post-treatment variables, vasospasm was the only additional covariate predictive of a poor outcome (OR 5.90; 95% CI 1.34 to 25.93,p=0.019). CONCLUSIONS: Most patients with SRA can be treated with endovascular therapy and have limited complications. Overall predictors of outcome for patients undergoing endovascular treatment of SRA include age, aneurysm size, Hunt and Hess grade, location and post-treatment vasospasm.

Cigarette smoke and inflammation: role in cerebral aneurysm formation and rupture.

Smoking is an established risk factor for subarachnoid hemorrhage yet the underlying mechanisms are largely unknown. Recent data has implicated a role of inflammation in the development of cerebral aneurysms. Inflammation accompanying cigarette smoke exposure may thus be a critical pathway underlying the development, progression, and rupture of cerebral aneurysms. Various constituents of the inflammatory response appear to be involved including adhesion molecules, cytokines, reactive oxygen species, leukocytes, matrix metalloproteinases, and vascular smooth muscle cells. Characterization of the molecular basis of the inflammatory response accompanying cigarette smoke exposure will provide a rational approach for future targeted therapy. In this paper, we review the current body of knowledge implicating cigarette smoke-induced inflammation in cerebral aneurysm formation/rupture and attempt to highlight important avenues for future investigation.