The Evolving Classification of Meningiomas: Integration of Molecular Discoveries to Inform Patient Care.

Meningioma classification and treatment have evolved over the past eight decades. Since Bailey, Cushing, and Eisenhart's description of meningiomas in the 1920s and 1930s, there have been continual advances in clinical stratification by histopathology, radiography and, most recently, molecular profiling, to improve prognostication and predict response to therapy. Precise and accurate classification is essential to optimizing management for patients with meningioma, which involves surveillance imaging, surgery, primary or adjuvant radiotherapy, and consideration for clinical trials. Currently, the World Health Organization (WHO) grade, extent of resection (EOR), and patient characteristics are used to guide management. While these have demonstrated reliability, a substantial number of seemingly benign lesions recur, suggesting opportunities for improvement of risk stratification. Furthermore, the role of adjuvant radiotherapy for grade 1 and 2 meningioma remains controversial. Over the last decade, numerous studies investigating the molecular drivers of clinical aggressiveness have been reported, with the identification of molecular markers that carry clinical implications as well as biomarkers of radiotherapy response. Here, we review the historical context of current practices, highlight recent molecular discoveries, and discuss the challenges of translating these findings into clinical practice.

Plasminogen Degradation by Neutrophil Elastase in Pleural Infection, Not High Plasminogen Activator Inhibitor-1 (PAI-1), is the Cause of Intrapleural Lytic Failure.

BACKGROUND: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue-plasminogen activator(tPA) and deoxyribonuclease(DNase), with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would have high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation. RESEARCH QUESTION: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure? STUDY DESIGN AND METHODS: We obtained infected pleural fluid and circulating plasma from hospitalized adults(n=10) with IRB approval from a randomized trial evaluating intrapleural fibrinolytics versus surgery for initial management of pleural space infections. Samples were collected pre-intervention, post-intervention day-1(PID1), PID2, and PID3. Activity assays, enzyme-linked immunosorbent assays, and western blot(WB) analysis were performed, and turbidometric measurements of fibrinolysis were performed on pleural fluid +/- exogenous plasminogen supplementation. Results are reported as median(Q1, Q3) or n(%) as appropriate, with alpha set at 0.05. RESULTS: Pleural fluid elastase activity was >4-fold higher(p=0.02) and plasminogen antigen levels >3-fold lower(p=0.04) than their corresponding plasma. Pleural fluid WB analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen-activator inhibitor-1(PAI-1), the native tPA inhibitor, had high antigen levels pre-intervention but the overwhelming majority of this PAI-1(82%) was not active(p=0.003), and all PAI-1 activity was lost by PID2 in patients receiving intrapleural tPA/DNase. Finally, using turbidity clot lysis assays we found that 9 of 10 patients' pleural fluid was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients. INTERPRETATION: Inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure.

Prohibitin Expression in Antigen-Presenting Cells: Implications for Inciting Trigger in CNS IgG4-Related Disease.

Immunoglobulin G4-related disease (IgG4-RD) is a rare autoimmune disorder with an unknown etiology. Using orthogonal immune profiling and automated sequential multiplexing, we found an enhanced frequency of activated circulating B cells, antigen-presenting myeloid cells in peripheral blood, and a distinct distribution of immune cells within the CNS lesions. Prohibitin-expressing CD138+ plasma B cells and CD11c+ dendritic cells have been found interacting with T cells resulting in irmnune cell activation within the lesion. The data implicate prohibitin as a potential triggering antigen in the pathogenesis of IgG4-RD and shed light on the cellular dynamics and interactions driving IgG4-RD in the central nervous system, emphasizing the need for further studies corroborating these findings.

Predictors of salvage therapy for parasagittal meningiomas treated with primary surgery, radiosurgery, or surgery plus adjuvant radiotherapy.

OBJECTIVE: Parasagittal meningiomas (PM) are treated with primary microsurgery, radiosurgery (SRS), or surgery with adjuvant radiation. We investigated predictors of tumor progression requiring salvage surgery or radiation treatment. We sought to determine whether primary treatment modality, or radiologic, histologic, and clinical variables were associated with tumor progression requiring salvage treatment. METHODS: Retrospective study of 109 consecutive patients with PMs treated with primary surgery, radiation (RT), or surgery plus adjuvant RT (2000-2017) and minimum 5 years follow-up. Patient, radiologic, histologic, and treatment data were analyzed using standard statistical methods. RESULTS: Median follow up was 8.5 years. Primary treatment for PM was surgery in 76 patients, radiation in 16 patients, and surgery plus adjuvant radiation in 17 patients. Forty percent of parasagittal meningiomas in our cohort required some form of salvage treatment. On univariate analysis, brain invasion (OR: 6.93, p < 0.01), WHO grade 2/3 (OR: 4.54, p < 0.01), peritumoral edema (OR: 2.81, p = 0.01), sagittal sinus invasion (OR: 6.36, p < 0.01), sagittal sinus occlusion (OR: 4.86, p < 0.01), and non-spherical shape (OR: 3.89, p < 0.01) were significantly associated with receiving salvage treatment. On multivariate analysis, superior sagittal sinus invasion (OR: 8.22, p = 0.01) and WHO grade 2&3 (OR: 7.58, p < 0.01) were independently associated with receiving salvage treatment. There was no difference in time to salvage therapy (p = 0.11) or time to progression (p = 0.43) between patients receiving primary surgery alone, RT alone, or surgery plus adjuvant RT. Patients who had initial surgery were more likely to have peritumoral edema on preoperative imaging (p = 0.01). Median tumor volume was 19.0 cm3 in patients receiving primary surgery, 5.3 cm3 for RT, and 24.4 cm3 for surgery plus adjuvant RT (p < 0.01). CONCLUSION: Superior sagittal sinus invasion and WHO grade 2/3 are independently associated with PM progression requiring salvage therapy regardless of extent of resection or primary treatment modality. Parasagittal meningiomas have a high rate of recurrence with 80.0% of patients with WHO grade 2/3 tumors with sinus invasion requiring salvage treatment whereas only 13.6% of the WHO grade 1 tumors without sinus invasion required salvage treatment. This information is useful when counseling patients about disease management and setting expectations.

Obesity and meningioma: a US population-based study paired with analysis of a multi-institutional cohort.

OBJECTIVE: Whether obesity is associated with meningioma and the impact of obesity by gender has been debated. The primary objective of this study was to investigate differences in BMI between male and female patients undergoing craniotomy for meningioma and compare those with patients undergoing craniotomy for other intracranial tumors. The secondary objective was to compare meningioma location and progression-free survival (PFS) between obese and nonobese patients in a multi-institutional cohort. METHODS: National data were obtained from the National Surgical Quality Improvement Program (NSQIP) database. Male and female patients were analyzed separately. Patients undergoing craniotomies for meningioma were compared with patients of the same sex undergoing craniotomies for other intracranial tumors. Institutional data from two academic centers were collected for all male and an equivalent number of female meningioma patients undergoing meningioma resection. Multivariate regression controlling for age was used to determine differences in meningioma location. Kaplan-Meier curves and log-rank tests were computed to investigate differences in PFS. RESULTS: From NSQIP, 4163 male meningioma patients were compared with 24,266 controls, and 9372 female meningioma patients were compared with 21,538 controls. Male and female patients undergoing meningioma resection were more likely to be overweight or obese compared with patients undergoing craniotomy for other tumors, with the odds ratio increasing with increasing weight class (all p < 0.0001). In the multi-institutional cohort, meningiomas were more common along the skull base in male patients (p = 0.0123), but not in female patients (p = 0.1246). There was no difference in PFS between obese and nonobese male (p = 0.4104) or female (p = 0.5504) patients. Obesity was associated with increased risk of pulmonary embolism in both male and female patients undergoing meningioma resection (p = 0.0043). CONCLUSIONS: Male and female patients undergoing meningioma resection are more likely to be obese than patients undergoing craniotomy for other intracranial tumors. Obese males are more likely to have meningiomas in the skull base compared with other locations, but this association was not found in females. There was no significant difference in PFS among obese patients. The mechanism by which obesity increases meningioma incidence remains to be determined.

Surgical Outcome of Patients With Supratentorial Meningiomas Aged 80 Years or Older-Retrospective International Multicenter Study.

BACKGROUND AND OBJECTIVES: Demographic changes will lead to an increase in old patients, a population with significant risk of postoperative morbidity and mortality, requiring neurosurgery for meningiomas. This multicenter study aims to report neurofunctional status after resection of patients with supratentorial meningioma aged 80 years or older, to identify factors associated with outcome, and to validate a previously proposed decision support tool. METHODS: Neurofunctional status was assessed by the Karnofsky Performance Scale (KPS). Patients were categorized in poor (KPS ≤40), intermediate (KPS 50-70), and good (KPS ≥80) preoperative subgroups. Volumetric analyses of tumor and peritumoral brain edema (PTBE) were performed; volumes were scored as small (<10 cm 3 ), medium (10-50 cm 3 ), and large (>50 cm 3 ). RESULTS: The study population consisted of 262 patients, and the median age at surgery was 83.0 years. The median preoperative KPS was 70; 117 (44.7%) patients were allotted to the good, 113 (43.1%) to the intermediate, and 32 (12.2%) to the poor subgroup. The median tumor and PTBE volumes were 30.2 cm 3 and 27.3 cm 3 ; large PTBE volume correlated with poor preoperative KPS status ( P = .008). The 90-day and 1-year mortality rates were 9.0% and 13.2%, respectively. Within the first postoperative year, 101 (38.5%) patients improved, 87 (33.2%) were unchanged, and 74 (28.2%) were functionally worse (including deaths). Each year increase of age associated with 44% (23%-70%) increased risk of 90-day and 1-year mortality. In total, 111 (42.4%) patients suffered from surgery-associated complications. Maximum tumor diameter ≥5 cm (odds ratio 1.87 [1.12-3.13]) and large tumor volume (odds ratio 2.35 [1.01-5.50]) associated with increased risk of complications. Among patients with poor preoperative status and large PTBE, most (58.3%) benefited from surgery. CONCLUSION: Patients with poor preoperative neurofunctional status and large PTBE most often showed postoperative improvements. The decision support tool may be of help in identifying cases that most likely benefit from surgery.

Reservoir Stratification Modulates the Influence of Impoundments on Fish Mercury Concentrations along an Arid Land River System.

Impoundment is among the most common hydrologic alterations with impacts on aquatic ecosystems that can include effects on mercury (Hg) cycling. However, landscape-scale differences in Hg bioaccumulation between reservoirs and other habitats are not well characterized nor are the processes driving these differences. We examined total Hg (THg) concentrations of Smallmouth Bass (Micropterus dolomieu) collected from reservoir, tailrace, and free-flowing reaches along an 863 km segment of the Snake River, USA, a semiarid river with 22 impoundments along its course. Across three size-classes (putative 1-year-old, first reproductive, and harvestable sized fish), THg concentrations in reservoirs and tailraces averaged 76% higher than those in free-flowing segments. Among reservoirs, THg concentrations were highest in reservoirs with inconsistent stratification patterns, 47% higher than annually stratified, and 144% higher than unstratified reservoirs. Fish THg concentrations in tailraces immediately downstream of stratified reservoirs were higher than those below unstratified (38-130%) or inconsistently stratified (32-79%) reservoirs. Stratification regimes influenced the exceedance of fish and human health benchmarks, with 52-80% of fish from stratifying reservoirs and downstream tailraces exceeding a human consumption benchmark, compared to 6-17% where stratification did not occur. These findings suggest that impoundment and stratification play important roles in determining the patterns of Hg exposure risk across the landscape.

Combination of aspirin and rosuvastatin for reduction of venous thromboembolism in severely injured patients: a double-blind, placebo-controlled, pragmatic randomized phase II clinical trial (The STAT Trial).

INTRODUCTION: Venous thromboembolism (VTE) remains a significant source of postinjury morbidity and mortality. Beta-hydroxy beta-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (rosuvastatin) significantly reduced pathologic clotting events in healthy populations in a prior trial. Furthermore, acetylsalicylic acid (ASA) has been shown to be noninferior to prophylactic heparinoids for VTE prevention following orthopedic surgery. We hypothesized that a combination of rosuvastatin/ASA, in addition to standard VTE chemoprophylaxis, would reduce VTE in critically ill trauma patients. METHODS: This was a double-blind, placebo-controlled, randomized trial, evaluating VTE rates in two groups: ASA + statin (Experimental) and identical placebos (Control). Injured adults, 18-65 years old, admitted to the surgical intensive care unit without contraindications for VTE prophylaxis were eligible. Upon initiation of routine VTE chemoprophylaxis (i.e. heparin/heparin-derivatives), they were randomized to the Experimental or Control group. VTE was the primary outcome. RESULTS: Of 112 potentially eligible patients, 33% (n = 37, median new injury severity scale = 27) were successfully randomized, of whom 11% had VTEs. The Experimental group had no VTEs, while the Control group had 6 VTEs (4 PEs and 2 DVTs) in 4 (22%) patients (P = 0.046). The Experimental treatment was not associated with any serious adverse events. Due to the COVID-19 pandemic, the study was interrupted at the second interim analysis at <10% of the planned enrollment, with significance declared at P < 0.012 at that stage. DISCUSSION: The combination of ASA and rosuvastatin with standard VTE prophylaxis showed a favorable trend toward reducing VTEs with no serious adverse events. An appropriately powered phase III multicenter trial is needed to further investigate this therapeutic approach. LEVEL OF EVIDENCE: Level II, Therapeutic.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Cost-effectiveness of decellularised bone allograft compared with fresh-frozen bone allograft for acetabular impaction bone grafting during a revision hip arthroplasty in the UK.

OBJECTIVES: Fresh-frozen allograft is the gold-standard bone graft material used during revision hip arthroplasty. However, new technology has been developed to manufacture decellularised bone with potentially better graft incorporation. As these grafts cost more to manufacture, the aim of this cost-effectiveness study was to estimate whether the potential health benefit of decellularised bone allograft outweighs their increased cost. STUDY DESIGN: A Markov model was constructed to estimate the costs and the quality-adjusted life years of impaction bone grafting during a revision hip arthroplasty. SETTING: This study took the perspective of the National Health Service in the UK. PARTICIPANTS: The Markov model includes patients undergoing a revision hip arthroplasty in the UK. INTERVENTION: Impaction bone grafting during a revision hip arthroplasty using either decellularised bone allograft or fresh-frozen allograft. MEASURES: Outcome measures included: total costs and quality-adjusted life years of both interventions over the lifetime of the model; and incremental cost-effectiveness ratios for both graft types, using base case parameters, univariate sensitivity analysis and probabilistic analysis. RESULTS: The incremental cost-effectiveness ratio for the base case model was found to be £270 059 per quality-adjusted life year. Univariate sensitivity analysis found that changing the discount rate, the decellularised bone graft cost, age of the patient cohort and the revision rate all had a significant effect on the incremental cost-effectiveness ratio. CONCLUSIONS: As there are no clinical studies of impaction bone grafting using a decellularised bone allograft, there is a high level of uncertainty around the costs of producing a decellularised bone allograft and the potential health benefits. However, if a decellularised bone graft was manufactured for £2887 and lowered the re-revision rate to less than 64 cases per year per 10 000 revision patients, then it would most likely be cost-effective compared with fresh-frozen allograft.

Repeat Surgery for Vestibular Schwannomas: An Institutional Case Series.

Introduction Vestibular schwannomas (VSs) are treated with microsurgery and/or radiosurgery. Repeat resection is rare, and few studies have reported postoperative outcomes. The objective of this study was to describe clinical characteristics and outcomes in patients undergoing repeat surgery for VS. Methods All adult (≥ 18 years) patients undergoing VS resection between 2003 and 2022 at our institution were retrospectively reviewed to identify patients who underwent repeat surgery of an ipsilateral VS following prior gross-total (GTR) or subtotal resection. Patient, radiographic, and clinical characteristics were reviewed. Primary outcomes were postoperative tumor volume, extent of resection, postoperative cranial nerve deficits, and time to further tumor progression. Results Of 102 patients undergoing VS resection, 6 (5.9%) had undergone repeat surgery. Median (range) follow-up was 20 (5-117) months. Three patients were female. Median age was 56 (36-60) years. Median pre- and postoperative tumor volumes were 8.2 (1.8-28.2) cm 3 and 0.4 (0-3.8) cm 3 . GTR was achieved in two patients. Four patients had higher House-Brackmann scores at last follow-up, but none had tumor progression. Conclusion In this small cohort of patients, repeat resection of recurrent or progressive VS can effectively reduce tumor volume with acceptable perioperative outcomes.

Outcomes following surgical resection of trigeminal schwannomas: a systematic review and meta-analysis.

Although typically benign, trigeminal schwannomas (TS) may require surgical resection when large or symptomatic and can cause significant morbidity. This study aims to summarize the literature and synthesize outcomes following surgical resection of TS. A systematic review was performed according to PRISMA guidelines. Data extracted included patient and tumor characteristics, surgical approaches, and postoperative outcomes. Odds ratios (OR) with corresponding 95% confidence intervals (CI) were used for outcome analysis. The initial search yielded 1838 results, of which 26 studies with 974 patients undergoing surgical resection of TS were included. The mean age was 42.9 years and 58.0% were female. The mean tumor diameter was 4.7 cm, with Samii type A, B, C, and D tumors corresponding to 33.4%, 15.8%, 37.2%, and 13.6%, respectively. Over a mean symptom duration of 29 months, patients presented with trigeminal hypesthesia (58.7%), headache (32.8%), trigeminal motor weakness (22.8%), facial pain (21.3%), ataxia (19.4%), diplopia (18.7%), and visual impairment (12.0%). Surgical approaches included supratentorial (61.4%), infratentorial (15.0%), endoscopic (8.6%), combined/staged (5.3%), and anterior (5.7%) or posterior (4.0%) petrosectomy. Postoperative improvement of facial pain (83.9%) was significantly greater than trigeminal motor weakness (33.0%) or hypesthesia (29.4%). The extent of resection (EOR) was reported as gross total (GTR), near total, and subtotal in 77.7%, 7.7%, and 14.6% of cases, respectively. Over a mean follow-up time of 62.6 months, recurrence/progression was noted in 7.4% of patients at a mean time to recurrence of 44.9 months. Patients with GTR had statistically significantly lower odds of recurrence/progression (OR: 0.07; 95% CI: 0.04-0.15) compared to patients with non-GTR. This systematic review and meta-analysis report patient outcomes following surgical resection of TS. EOR was found to be an important predictor of the risk of recurrence. Facial pain was more likely to improve postoperatively than facial hypesthesia. This work reports baseline rates of post-operative complications across studies, establishing benchmarks for neurosurgeons innovating and working to improve surgical outcomes for TS patients.

Validating the VS-5 Score for Predicting Outcomes After Vestibular Schwannoma Resection in an Institutional Cohort.

BACKGROUND: The VS-5 index was recently proposed to predict complications, nonroutine discharge, length of stay (LOS), and cost after vestibular schwannoma (VS) resection. The VS-5 ranges from 0-17.86, and a score ≥2 was proposed as being predictive of postoperative adverse events. We sought to determine whether the VS-5 is predictive of nonroutine discharge and length of stay in an institutional cohort. METHODS: This is a retrospective study of 100 patients undergoing VS resection. For each patient, a VS-5 score was calculated. Bivariate analyses were conducted to determine differences in postoperative outcomes between high- and low-risk subgroups. Area under the receiver operating characteristic curve sensitivity/specificity analysis using Youden's Index was conducted to evaluate the optimal cutoff. RESULTS: Fifty-one (51%) patients were classified as high risk (VS-5 ≥ 2). Patients with VS-5 ≥ 2 had higher frequency of nonroutine discharge (22% vs. 4%, P = 0.0150) and no significant difference in postoperative LOS. The area under the receiver operating characteristic curve for predicting nonroutine discharge was 0.78 ± 0.15 (P < 0.0001). The optimal cutoff for nonroutine discharge was ≥6, higher than the published cutoff of ≥ 2. The new cutoff was predictive of nonroutine discharge (47% vs. 6%, P = 0 < 0.0001) and LOS (6 [3-11] days vs. 3 [1-28] days, P = 0.0001). CONCLUSIONS: The VS-5 frailty index predicted nonroutine discharge but not LOS. Youden's index indicates that a cutoff of 6, not 2, is optimal for predicting nonroutine discharge and LOS.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Background: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods: Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results: The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07-0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37-0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions: A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Clinical outcomes for pleomorphic xanthoastrocytoma patients: an institutional experience.

Purpose: Report our institutional experience with pleomorphic xanthoastrocytoma (PXA) to contribute to limited data on optimal management. Methods: Patients with pathologically confirmed PXA treated at our institution between 1990 and 2019 were identified. Demographic information, tumor grade, treatment variables, and clinical outcomes were collected from patient charts. Kaplan-Meier estimates were used to summarize two primary outcome measurements: progression-free survival (PFS) and overall survival (OS). Outcomes were stratified by tumor grade and extent of resection. Cox regression and log-rank testing were performed. Results: We identified 17 patients with pathologically confirmed PXA. Two patients were excluded due to incomplete treatment information or < 6m of follow-up; 15 patients were analyzed (median follow-up 4.4y). Six patients had grade 2 PXA and 9 had grade 3 anaplastic PXA. The 2-year and 5-year PFS for the cohort was 57% and 33%, respectively; 2-year and 5-year OS was 93% and 75%, respectively. Patients with grade 2 tumors exhibited superior PFS compared to those with grade 3 tumors (2-year PFS: 100% vs. 28%, 5-year PFS: 60% vs. 14%), hazard ratio, 5.09 (95% CI:1.06-24.50), p = 0.02. Undergoing a GTR also yielded improved outcomes (hazard ratio: 0.38, p = 0.15). All but one (89%) of the grade 3 patients underwent RT. Conclusion: The poor survival of the cohort, especially with grade 3 tumors, suggests the need for more aggressive treatment, including maximal resection followed by intensive adjuvant therapy. Better prognostics of tumor recurrence are needed to guide the use of adjuvant therapy.

Robust endoscopic image mosaicking via fusion of multimodal estimation.

We propose an endoscopic image mosaicking algorithm that is robust to light conditioning changes, specular reflections, and feature-less scenes. These conditions are especially common in minimally invasive surgery where the light source moves with the camera to dynamically illuminate close range scenes. This makes it difficult for a single image registration method to robustly track camera motion and then generate consistent mosaics of the expanded surgical scene across different and heterogeneous environments. Instead of relying on one specialised feature extractor or image registration method, we propose to fuse different image registration algorithms according to their uncertainties, formulating the problem as affine pose graph optimisation. This allows to combine landmarks, dense intensity registration, and learning-based approaches in a single framework. To demonstrate our application we consider deep learning-based optical flow, hand-crafted features, and intensity-based registration, however, the framework is general and could take as input other sources of motion estimation, including other sensor modalities. We validate the performance of our approach on three datasets with very different characteristics to highlighting its generalisability, demonstrating the advantages of our proposed fusion framework. While each individual registration algorithm eventually fails drastically on certain surgical scenes, the fusion approach flexibly determines which algorithms to use and in which proportion to more robustly obtain consistent mosaics.

Beyond uterine atony: characterizing postpartum hemorrhage coagulopathy.

BACKGROUND: Postpartum hemorrhage is a leading cause of morbidity and mortality worldwide, yet the associated early coagulopathy is not well defined. OBJECTIVE: We hypothesized that women who develop postpartum hemorrhage have a distinct derangement of thrombin generation and coagulation factors compared with postpartum women without postpartum hemorrhage. STUDY DESIGN: This prospective study of pregnant patients with postpartum hemorrhage was completed at a single urban hospital. Blood was drawn on postpartum hemorrhage diagnosis and 2 and 4 hours later. Assays of patients with postpartum hemorrhage included thrombelastography, whole blood thrombin generation, coagulation factor activity, tissue factor levels and activity, and tissue factor pathway inhibitor levels, which were compared with that of patients without postpartum hemorrhage. RESULTS: A total of 81 patients were included in this study. Of those patients, 66 had postpartum hemorrhage, and 15 served as controls. Compared with patients without PPH, patients with postpartum hemorrhage had lower fibrinogen levels (469.0 mg/dL vs 411.0 mg/dL; P=.02), increased tissue plasminogen activator resistance (fibrinolysis 30 minutes after maximal clot strength: 8.7% vs 4.2%; P=.02), decreased peak thrombin concentration (150.2 nM vs 40.7 nM; P=.01), and decreased maximal rate of thrombin generation (60.1 nM/minute vs 2.8 nM/minute; P=.02). Furthermore, compared with patients without postpartum hemorrhage, patients with postpartum hemorrhage had decreased tissue factor levels (444.3 pg/mL vs 267.1 pg/mL; P=.02) and increased tissue factor pathway inhibitor levels (0.6 U/mL vs 0.8 U/mL; P=.04), with decreased tissue factor pathway inhibitor ratios (624 vs 299; P=.01). CONCLUSION: PPH is not only an issue of uterine tone and mechanical bleeding but also a distinct coagulopathy that is characterized by decreased fibrinogen level, clot breakdown resistance, and markedly low thrombin generation. This pathology seemed to be driven by low tissue factor and high tissue factor pathway inhibitor levels.

Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.

BACKGROUND: Meningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions, we sought to determine whether any existing chemotherapies might be effective against meningiomas with high-risk methylation profiles. METHODS: A previously published dataset of meningioma methylation profiles was used to screen for clinically significant CpG methylation events and associated cellular pathways. Based on these results, patient-derived meningioma cell lines were used to test candidate drugs in vitro and in vivo, including efficacy in conjunction with radiotherapy. RESULTS: We identified 981 genes for which methylation of mapped CpG sites was related to progression-free survival in meningiomas. Associated molecular pathways were cross-referenced with FDA-approved cancer drugs, which nominated Docetaxel as a promising candidate for further preclinical analyses. Docetaxel arrested growth in 17 meningioma cell sources, representing all tumor grades, with a clinically favorable IC50 values ranging from 0.3 nM to 10.7 mM. The inhibitory effects of this medication scaled with tumor doubling time, with maximal benefit in fast-growing lesions. The combination of Docetaxel and radiation therapy increased markers of apoptosis and double-stranded DNA breaks, and extended the survival of mice engrafted with meningioma cells relative to either modality alone. CONCLUSIONS: Global patterns of DNA methylation may be informative for the selection of chemotherapies against meningiomas, and existing drugs may enhance radiation sensitivity in high-risk cases.

Clinical Management of Supratentorial Non-Skull Base Meningiomas.

Supratentorial non-skull base meningiomas are the most common primary central nervous system tumor subtype. An understanding of their pathophysiology, imaging characteristics, and clinical management options will prove of substantial value to the multi-disciplinary team which may be involved in their care. Extensive review of the broad literature on the topic is conducted. Narrowing the scope to meningiomas located in the supratentorial non-skull base anatomic location highlights nuances specific to this tumor subtype. Advances in our understanding of the natural history of the disease and how findings from both molecular pathology and neuroimaging have impacted our understanding are discussed. Clinical management and the rationale underlying specific approaches including observation, surgery, radiation, and investigational systemic therapies is covered in detail. Future directions for probable advances in the near and intermediate term are reviewed.

Optimization and fabrication of programmable domains for soft magnetic robots: A review.

Driven by the aim of realizing functional robotic systems at the milli- and submillimetre scale for biomedical applications, the area of magnetically driven soft devices has received significant recent attention. This has resulted in a new generation of magnetically controlled soft robots with patterns of embedded, programmable domains throughout their structures. This type of programmable magnetic profiling equips magnetic soft robots with shape programmable memory and can be achieved through the distribution of discrete domains (voxels) with variable magnetic densities and magnetization directions. This approach has produced highly compliant, and often bio-inspired structures that are well suited to biomedical applications at small scales, including microfluidic transport and shape-forming surgical catheters. However, to unlock the full potential of magnetic soft robots with improved designs and control, significant challenges remain in their compositional optimization and fabrication. This review considers recent advances and challenges in the interlinked optimization and fabrication aspects of programmable domains within magnetic soft robots. Through a combination of improvements in the computational capacity of novel optimization methods with advances in the resolution, material selection and automation of existing and novel fabrication methods, significant further developments in programmable magnetic soft robots may be realized.