Long-Term Time Series Forecasting and Updates on Survival Analysis of Glioblastoma Multiforme: A 1975-2018 Population-Based Study.

OBJECTIVE: Glioblastomas multiforme (GBMs) are the most common primary CNS tumors. Epidemiologic studies have investigated the effect of demographics on patient survival, but the literature remains inconclusive. METHODS: This study included all adult patients with intracranial GBMs reported in the surveillance epidemiology and end results (SEER)-9 population database (1975-2018). The sample consisted of 32,746 unique entries. We forecast the annual GBM incidence in the US population through the year 2060 using time series analysis with autoregressive moving averages. A survival analysis of the GBM-specific time to death was also performed. Multivariate Cox proportional hazards (PH) regression revealed frank violations of the PH assumption for multiple covariates. Parametric models best described the GBM population's survival pattern; the results were compared to the semi-parametric analysis and the published literature. RESULTS: We predicted an increasing GBM incidence, which demonstrated that by the year 2060, over 1,800 cases will be reported annually in the SEER. All eight demographic variables were significant in the univariable analysis. The calendar year 2005 was the cutoff associated with an increased survival probability. A male survival benefit was eliminated in the year-adjusted Cox. Infratentorial tumors, nonmetropolitan areas, and White patient race were the factors erroneously associated with survival in the multivariate Cox analysis. Accelerated Failure Time (AFT) lognormal regression was the best model to describe the survival pattern in our patient population, identifying age >30 years old as a poor prognostic and patients >70 years old as having the worst survival. Annual income >USD 75,000 and supratentorial tumors had good prognostics, while surgical intervention provided the strongest survival benefit. CONCLUSIONS: Annual GBM incidence rates will continue to increase by almost 50% in the upcoming 30 years. Cox regression analysis should not be utilized for time-to-event predictions in GBM survival statistics. AFT lognormal distribution best describes the GBM-specific survival pattern, and as an inherent population characteristic, it should be implemented by researchers for future studies. Surgical intervention provides the strongest survival benefit, while patient age >70 years old is the worst prognostic. Based on our study, the demographics such as gender, race, and county type should not be considered as meaningful prognostics when designing future trials.

Formation and manipulation of ferrofluid droplets with magnetic fields in a microdevice: a numerical parametric study.

We present a numerical model that describes the microfluidic generation and manipulation of ferrofluid droplets under an external magnetic field. We developed a numerical Computational Fluid Dynamics (CFD) analysis for predicting and optimizing continuous flow generation and processing of ferrofluid droplets with and without the presence of a permanent magnet. More specifically, we explore the dynamics of oil-based ferrofluid droplets within an aqueous continuous phase under an external inhomogeneous magnetic field. The developed model determines the effect of the magnetic field on the droplet generation, which is carried out in a flow-focusing geometry, and its sorting in T-junction channels. Three-channel depths (25 µm, 30 µm, and 40 µm) were investigated to study droplet deformation under magnetic forces. Among the three, the 30 µm channel depth showed the most consistent droplet production for the studied range of flow rates. Ferrofluids with different loadings of magnetic nanoparticles were used to observe the behavior for different ratios of magnetic and hydrodynamic forces. Our results show that the effect of these factors on droplet size and generation rate can be tuned and optimized to produce consistent droplet generation and sorting. This approach involves fully coupled magnetic-fluid mechanics models and can predict critical details of the process including droplet size, shape, trajectory, dispensing rate, and the perturbation of the fluid co-flow for different flow rates. The model enables better understanding of the physical phenomena involved in continuous droplet processing and allows efficient parametric analysis and optimization.

Variants of the elastin (ELN) gene and susceptibility to intracranial aneurysm: a synthesis of genetic association studies using a genetic model-free approach.

BACKGROUND: The presence of an intracranial aneurysm (IA) is thought to have a genetic origin. The genetic association studies (GAS) that investigated the association between IA and elastin gene (ELN) variants have produced contradictory or inconclusive results. MATERIALS AND METHODS: In order to decrease the uncertainty of estimated genetic risk effects, a meta-analysis of published GAS-related variants in the ELN gene (ELN INT20 1315T > C, EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A) with susceptibility to IA was conducted using a genetic model-free approach. The risk effects were estimated using the generalized odds ratio (ORG) metric. RESULTS: The analysis showed significant association for the INT20 1315T > C variant [ORG = 0.66 (0.45-0.95)], indicating a protection effect. For the variants EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A, no statistically significant association with IAs was found. CONCLUSION: There is evidence that the ELN variant INT20 1315T > C is implicated in the development of IA; however, the results should be interpreted with caution since the number of published studies is limited.

Translabyrinthine resection of small intracanalicular acoustic tumor.

This case is an example of a translabyrinthine resection of a small intracanalicular acoustic tumor. The patient is a 69-year-old right-handed woman with complaints of progressive incapacitating vertigo and right-sided hearing loss worsening over the past 3 years. She had normal facial nerve function with imaging demonstrating progressive increase in size of a small right-sided acoustic tumor. A translabyrinthine approach was performed, and the mass was resected completely. Facial nerve function remained normal immediately after surgery. The video can be found here: http://youtu.be/27ARlLLSbKE .

Effect of Polymer and Cell Membrane Coatings on Theranostic Applications of Nanoparticles: A Review.

The recent decade has witnessed a remarkable surge in the field of nanoparticles, from their synthesis, characterization, and functionalization to diverse applications. At the nanoscale, these particles exhibit distinct physicochemical properties compared to their bulk counterparts, enabling a multitude of applications spanning energy, catalysis, environmental remediation, biomedicine, and beyond. This review focuses on specific nanoparticle categories, including magnetic, gold, silver, and quantum dots (QDs), as well as hybrid variants, specifically tailored for biomedical applications. A comprehensive review and comparison of prevalent chemical, physical, and biological synthesis methods are presented. To enhance biocompatibility and colloidal stability, and facilitate surface modification and cargo/agent loading, nanoparticle surfaces are coated with different synthetic polymers and very recently, cell membrane coatings. The utilization of polymer- or cell membrane-coated nanoparticles opens a wide variety of biomedical applications such as magnetic resonance imaging (MRI), hyperthermia, photothermia, sample enrichment, bioassays, drug delivery, etc. With this review, the goal is to provide a comprehensive toolbox of insights into polymer or cell membrane-coated nanoparticles and their biomedical applications, while also addressing the challenges involved in translating such nanoparticles from laboratory benchtops to in vitro and in vivo applications. Furthermore, perspectives on future trends and developments in this rapidly evolving domain are provided.

Petroclival meningiomas: an update on surgical approaches, decision making, and treatment results.

OBJECT: Petroclival meningiomas remain a formidable challenge for neurosurgeons because of their location deep within the skull base and proximity to eloquent neurovascular structures. Various skull base approaches have been used in their treatment, and deciding which is the optimal one remains controversial. Attempts at achieving gross- or near-total resections are associated with an increased rate of morbidity and mortality. As adjunctive treatment options such as stereotactic radiosurgery have been developed and become widely available, there has been a trend toward accepting subtotal resections in an effort to minimize neurological morbidity. This paper reviews a recent series of patients with petroclival meningiomas and highlights current management trends and important considerations useful in surgical decision making. METHODS: The records of patients with large (> 3 cm) petroclival meningiomas surgically treated by the senior author over the past 5 years were reviewed. The clinical results are presented as examples of the surgical approaches available for approaching these tumors, and treatment options are reviewed. RESULTS: Of 196 meningiomas surgically treated during the study period, 8 lesions in 8 patients met the study criteria. Overall clinical results were excellent, with no death or major morbidity. Intracranial gross- or near-total resection (Simpson Grade 1, 2, or 3) was achieved in 5 patients (67%). New cranial nerve deficits occurred in 3 patients (37%) and were more common in patients in whom a subtotal resection was performed (2 of 3 cases). A variety of surgical approaches were used. Important considerations determining the best approach include the location of the tumor relative to the internal auditory canal, the presence of preoperative hearing loss, and the location of the tumor relative to the tentorium. CONCLUSIONS: Achieving gross- or near-total resections of large petroclival meningiomas remains achievable and should be the primary goal of surgical treatment. A retrosigmoid craniotomy remains a workhorse surgical approach for most petroclival tumors of any size. Tumors that are medial to the internal auditory canal and span both middle and posterior cranial fossae are often best treated with a combined transpetrosal approach, which is especially true if there is a preoperative hearing deficit.

Prognostics of Systemic Malignancy ICD-O Topography and Morphology Types on Brain Metastases: An NCDB Time-to-event Cohort.

BACKGROUND: The primary site and histology of systemic malignancy are known predictors of progression to brain metastases (BM). We investigated the combinational interactions of International Classification of Diseases for Oncology (ICD-O) primary topography and morphology types on the survival of BM after adjusting for relevant clinical and demographic prognostic factors. METHODS: The cohort included all adult patients with BM at diagnosis of an invasive malignancy in the National Cancer Database (2010 to 2018). The sample consisted of 180,150 entries out of 14,279,749 cancer patients screened. A survival analysis of the topography-specific and histology-specific time to death was performed. Multivariate Cox regression revealed violations of the proportional hazard assumption for multiple covariates. Parametric models using a log-logistic distribution best described the population survival pattern. RESULTS: The primary topography "prostate" and morphology "choriocarcinoma" provided the strongest survival benefit among ICD-O types, whereas BM from prostate demonstrated a 14-month median overall increase in survival probability. Favorable prognostics were BM from breast, bone/joints, and testis; also, the morphologies of carcinoid tumor, mature B-cell lymphoma, and papillary adenocarcinoma. Poor prognostics were BM from gastrointestinal (liver, biliary tree, pancreas, and gallbladder) and gynecologic malignancies. All morphologies of spindle cell carcinoma, hemangiosarcoma, undifferentiated carcinoma, Ewing sarcoma, pseudosarcomatous carcinoma, renal cell carcinoma/sarcomatoid, signet ring cell carcinoma, spindle cell sarcoma, and squamous cell carcinoma/spindle cell were associated with poor survival. CONCLUSIONS: This is the largest cohort providing an unbiased estimate of the adjusted ICD-O topography and morphology effect sizes. The results can be summarized as a booklet for prognostic classification of disease in patients with BM secondary to systemic malignancy.

Interstitial infusion of erlotinib in the rodent brain.

A critical need exists for the development of novel forms of treatment for high-grade glioma. Molecular characterization of high-grade glioma has shown overexpression of the epidermal growth factor receptor, antagonists to which, including erlotinib, may prevent tumor growth. Interstitial infusion is a mode of local delivery which bypasses the blood-brain barrier and utilizes a pressure-dependent gradient to enhance drug uniformity and volume of distribution. Interstitial infusion of erlotinib was performed to the striatum of 12 rats in increasing, therapeutic doses. No evidence of clinical or histopathologic toxicity was found. In this experimental study we demonstrate that interstitial infusion of erlotinib is safe in the rodent brain, and may have potential applicability for the treatment of high-grade glioma.

Numerical Analysis of Bead Magnetophoresis from Flowing Blood in a Continuous-Flow Microchannel: Implications to the Bead-Fluid Interactions.

In this work, we report a numerical flow-focused study of bead magnetophoresis inside a continuous-flow microchannel in order to provide a detailed analysis of bead motion and its effect on fluid flow. The numerical model involves a Lagrangian approach and predicts the bead separation from blood and their collection into a flowing buffer by the application of a magnetic field generated by a permanent magnet. The following scenarios are modelled: (i) one-way coupling wherein momentum is transferred from the fluid to beads, which are treated as point particles, (ii) two-way coupling wherein the beads are treated as point particles and momentum is transferred from the bead to the fluid and vice versa, and (iii) two-way coupling taking into account the effects of bead volume in fluid displacement. The results indicate that although there is little difference in the bead trajectories for the three scenarios, there is significant variation in the flow fields, especially when high magnetic forces are applied on the beads. Therefore, an accurate full flow-focused model that takes into account the effects of the bead motion and volume on the flow field should be solved when high magnetic forces are employed. Nonetheless, when the beads are subjected to medium or low magnetic forces, computationally inexpensive models can be safely employed to model magnetophoresis.

Laser-Induced Interstitial Thermotherapy of Gliomas.

Laser-induced interstitial thermotherapy (LITT) is a modern minimally invasive treatment modality applied for management of a variety of diseases. Recent developments of techniques for precise targeting of the lesion, accurate delivery of the prescribed therapeutically effective thermal doses, and real-time visualization of the induced tissue damage during the procedure by means of intraoperative MR thermometry have stimulated a number of clinical studies testing LITT in cases of different brain pathologies, including gliomas. This modality is particularly attractive in patients with recurrent, deep-seated, and/or critically located neoplasms refractory to other treatments, where it can effectively demonstrate improvement of prognosis providing high quality of life and eliminating the risks of open tumor resection. Low morbidity rates associated with LITT and short hospital stay result in decreased cost of hospitalization. The effectiveness of thermal therapies, particularly after long-term follow-up, still needs evaluation in carefully planned randomized clinical trials, whereas elucidating the effects of laser treatment at the molecular, cellular, and organic levels will continue to expand the boundaries of its clinical applicability in neuro-oncology.

A Role for Sox2 in the Adult Cerebellum.

The cerebellum, a derivative of the hindbrain, plays a crucial role in balance and posture as well as in higher cognitive and locomotive processes. Cerebellar development is initiated during the segmental phase of hindbrain formation. Here, we describe the phenotype, of a single surviving adult conditional mouse mutant mouse, in which Sox2 function is ablated in embryonic radial glial cells by means of hGFAP-CRE. The single Sox2RGINV/mosaic adult mutant mouse displays motor disability, microsomia, reduced Central Nervous System (CNS) size and cerebellar defects associated with human genetically related congenital abnormalities.

Quantitative pupillometry: normative data in healthy pediatric volunteers.

OBJECT: The authors describe the prospective use of a new hand-held point-and-shoot pupillometer (NeurOptics) to assess pupil function quantitatively. METHODS: Repetitive measurements were made in 90 pediatric participants ranging in age from 1 to 18 years, providing a total of 100 measurements under ambient light conditions. The participants consisted of 45 patients without known intracranial or ophthalmological pathological conditions as well as 45 volunteers in the outpatient setting. Quantitative pupil measurements were reliably replicated in the study participants. The mean resting pupil aperture was 4.11 mm and the minimal diameter after stimulation was 2.65 mm, resulting in a 36% change in pupil size. The mean constriction velocity was 2.34 mm/second, with a mean dilation velocity of 2.2 mm/second. CONCLUSION: Pupil symmetry was impressive in the entire cohort.

Adult paravertebral pleomorphic rhabdomyosarcoma infiltrating diffusely the whole spinal axis. Case report.

The authors report a unique case of diffuse spinal metastatic disease due to a pleomorphic rhabdomyosarcoma (RMS) in an adult. In addition to its overall rarity, peculiar characteristics of the particular tumor included its site of origin, demonstrated radiologically as the lumbar paravertebral musculature (psoas muscle) and the transcanalicular spread into the vertebral canal, resulting in thecal compression at multiple levels. The salient clinicopathological characteristics of RMS, as they related particularly to the spine, are subsequently discussed and a short review of the major therapeutic modalities for these tumors is offered.

Sciatica: a historical perspective on early views of a distinct medical syndrome.

The authors offer a brief overview of early theories and treatments of sciatica. Tracing medical traditions through early Greek, Roman, and Eastern epochs, the authors demonstrate the slow sequential steps that were required to delineate this disease as a uniquely human affliction.

Sox2 acts as a rheostat of epithelial to mesenchymal transition during neural crest development.

Precise control of self-renewal and differentiation of progenitor cells into the cranial neural crest (CNC) pool ensures proper head development, guided by signaling pathways such as BMPs, FGFs, Shh and Notch. Here, we show that murine Sox2 plays an essential role in controlling progenitor cell behavior during craniofacial development. A "Conditional by Inversion" Sox2 allele (Sox2(COIN) ) has been employed to generate an epiblast ablation of Sox2 function (Sox2(EpINV) ). Sox2 (EpINV/+(H)) haploinsufficient and conditional (Sox2(EpINV/mosaic) ) mutant embryos proceed beyond gastrulation and die around E11. These mutant embryos exhibit severe anterior malformations, with hydrocephaly and frontonasal truncations, which could be attributed to the deregulation of CNC progenitor cells during their epithelial to mesenchymal transition. This irregularity results in an exacerbated and aberrant migration of Sox10(+) NCC in the branchial arches and frontonasal process of the Sox2 mutant embryos. These results suggest a novel role for Sox2 as a regulator of the epithelial to mesenchymal transitions (EMT) that are important for the cell flow in the developing head.

Analysis of pulsed laser plasmon-assisted photothermal heating and bubble generation at the nanoscale.

A study is presented of photothermal effects associated with nanosecond-pulsed laser-illuminated subwavelength metallic nanoparticles in aqueous solutions. Computational electromagnetic and fluid analysis are used to model fundamental aspects of the photothermal process taking into account energy conversion within the nanoparticle at plasmon resonance, heat transfer to the fluid, homogeneous bubble nucleation, and the dynamic behaviour of the bubble and surrounding fluid. Various nanoparticle geometries are modelled including spheres, nanorods and tori. The analysis demonstrates that the laser intensity and pulse duration can be tuned to achieve controllable bubble generation without exceeding the melting temperature of the particle. The analysis also shows that the particle geometry can be tuned to optimize photothermal energy conversion for bubble generation at wavelengths that span the UV to NIR spectrum. Multiparticle systems are studied and a cooperative heating effect is demonstrated for particles that are within a few radii of each other. This provides more robust bubble generation using substantially reduced laser energy as compared to single-particle systems. The modelling approach is discussed in detail and should be of considerable use in the development of new photothermal applications.

Improvement of neurological recovery and stimulation of neural progenitor cell proliferation by intrathecal administration of Sonic hedgehog.

OBJECT: Sonic hedgehog (Shh) is a glycoprotein molecule that has been shown to be associated with the proliferative capacity of endogenous neural precursor cells during embryonic development. It has also been shown to regulate the proliferative capacity of neural stem cells in the adult subventricular zone (SVZ), which are also upregulated in animal models of ischemic stroke. In the present study, the effects of exogenous administration of intrathecal Shh protein were examined in the setting of a rodent model of ischemic stroke, with particular attention given to endogenous neural stem cell proliferation and migration as well as inducible differences in behavioral recovery. METHODS: A rodent model of ischemic stroke was created using the intraluminal suture method of reversible middle cerebral artery occlusion. Animals were treated with intrathecal administration of Shh protein at 24 hours after the onset of the stroke. Behavioral testing was performed, and the animals were killed for measurements of infarct volume 7 days after stroke. Immunohistochemical staining was performed and measurements of cellular proliferation were obtained, with a focus on the proportion and distribution of neural progenitor cells in the SVZ. These values were compared across experimental groups. RESULTS: Treatment with intrathecal Shh protein resulted in significant improvement in behavioral function compared with the control group, with a significant reduction of ischemic tissue in the cerebral hemisphere. An increase of nestin immunoreactive cells was observed along the SVZ. CONCLUSIONS: Intrathecal Shh agonist at doses that upregulate spinal cord GLI1 transcription increases the population of neural precursor cells after spinal cord injury in adult rats. Intrathecal administration of Shh protein appears to have a neuroprotective effect in animal models of ischemic stroke and is associated with improved behavioral recovery, which may be related to its effects on neurogenesis in the SVZ and could be associated with improved functional recovery.

Interstitial infusion of glioma-targeted recombinant immunotoxin 8H9scFv-PE38.

Monoclonal antibodies have the potential to target therapy for high-grade gliomas. Monoclonal antibody 8H9 is specific for membrane protein B7H3 and is reactive with most human high-grade gliomas. We tested the 8H9scFv-PE38 recombinant Pseudomonas immunotoxin in a preclinical model of high-grade glioma. The half maximal inhibitory concentration (IC(50)) of 8H9scFv-PE38 in vitro was determined using glioblastoma cell lines U87 and U251. Maximum tolerated infusion dose of 8H9scFv-PE38 following interstitial infusion to the striatum and pons was defined using athymic rats. Maximum tolerated infusion dose of 8H9scFv-PE38 or PBS control were interstitially delivered to athymic rats xenografted with U87 in the striatum or brain stem. Radiographic response and survivals were measured and compared between treatment groups. The in vitro IC(50) of 8H9scFv-PE38 for U87 was 1,265 ng/mL and, for U251, 91 ng/mL. The maximum tolerated infusion doses of interstitially infused 8H9scFv-PE38 to the striatum and brain stem were 0.75 and 1.8 mug, respectively. For rats harboring intracranial U87 xenografts, infusion of 8H9scFv-PE38 increased mean survival (striatum, 43.4 versus 24.6 days; brain stem, 80.6 versus 45.5 days; n = 28 total) and produced three long-term survivors past 120 days. None of the 14 placebo-treated animals survived >54 days. Tumors also showed volumetric response to infusion of 8H9scFv-PE38 by magnetic resonance imaging. Interstitial infusion of 8H9scFv-PE38 shows potential for the treatment of hemispherical and brain stem glioma. Mol Cancer Ther; 9(4); 1039-46. (c)2010 AACR.