Modulation of the Complement System by Neoplastic Disease of the Central Nervous System.

The complement system is a highly conserved component of innate immunity that is involved in recognizing and responding to pathogens. The system serves as a bridge between innate and adaptive immunity, and modulation of the complement system can affect the entire host immune response to a foreign insult. Neoplastic diseases have been shown to engage the complement system in order to evade the immune system, gain a selective growth advantage, and co-opt the surrounding environment for tumor proliferation. Historically, the central nervous system has been considered to be an immune-privileged environment, but it is now clear that there are active roles for both innate and adaptive immunity within the central nervous system. Much of the research on the role of immunological modulation of neoplastic disease within the central nervous system has focused on adaptive immunity, even though innate immunity still plays a critical role in the natural history of central nervous system neoplasms. Here, we review the modulation of the complement system by a variety of neoplastic diseases of the central nervous system. We also discuss gaps in the current body of knowledge and comment on future directions for investigation.

Permanent Cerebrospinal Fluid Diversion in Adults With Posterior Fossa Tumors: Incidence and Predictors.

BACKGROUND: Posterior fossa tumors (PFTs) can cause hydrocephalus. Hydrocephalus can persist despite resection of PFTs in a subset of patients requiring permanent cerebrospinal fluid (CSF) diversion. Characteristics of this patient subset are not well defined. OBJECTIVE: To define preoperative and postoperative variables that predict the need for postoperative CSF diversion in adult patients with PFTs. METHODS: We surveyed the CNS (Central Nervous System) Tumor Outcomes Registry at Emory (CTORE) for patients who underwent PFT resection at 3 tertiary-care centers between 2006 and 2019. Demographic, radiographic, perioperative, and dispositional data were analyzed using univariate and multivariate models. RESULTS: We included 617 patients undergoing PFT resection for intra-axial (57%) or extra-axial (43%) lesions. Gross total resection was achieved in 62% of resections. Approximately 13% of patients required permanent CSF diversion/shunting. Only 31.5% of patients who required pre- or intraop external ventricular drain (EVD) placement needed permanent CSF diversion. On logistic regression, size, transependymal flow, use of perioperative EVD, postoperative intraventricular hemorrhage (IVH), and surgical complications were predictors of permanent CSF diversion. Preoperative tumor size was only independent predictor of postoperative shunting in patients with subtotal resection. In patients with intra-axial tumors, transependymal flow (P = .014), postoperative IVH (P = .001), surgical complications (P = .013), and extent of resection (P = .03) predicted need for shunting. In extra-axial tumors, surgical complications were the major predictor (P = .022). CONCLUSION: Our study demonstrates that presence of preoperative hydrocephalus in patients with PFT does not necessarily entail the need for permanent CSF diversion. We report the major predictive factors for needing permanent CSF diversion.

Color-coded perfluorocarbon nanodroplets for multiplexed ultrasound and Photoacoustic imaging.

Laser-activated perfluorocarbon nanodroplets are an emerging class of phase change, dual-contrast agents that can be utilized in ultrasound and photoacoustic imaging. Through the ability to differentiate subpopulations of nanodroplets via laser activation at different wavelengths of near-infrared light, optically-triggered color-coded perfluorocarbon nanodroplets present themselves as an attractive tool for multiplexed ultrasound and photoacoustic imaging. In particular, laser-activated droplets can be used to provide quantitative spatiotemporal information regarding distinct biological targets, allowing for their potential use in a wide range of diagnos tic and therapeutic applications. In the work presented, laser-activated color-coded perfluorocarbon nanodroplets are synthesized to selectively respond to laser irradiation at corresponding wavelengths. The dynamic ultrasound and photoacoustic signals produced by laser-activated perfluorocarbon nanodroplets are evaluated in situ prior to implementation in a murine model. In vivo, these particles are used to distinguish unique particle trafficking mechanisms and are shown to provide ultrasound and photoacoustic contrast for up to 72 hours within lymphatics. Overall, the conducted studies show that laser-activated color-coded perfluorocarbon nanodroplets are a promising agent for multiplexed ultrasound and photoacoustic imaging.

Lipid Shell Composition Plays a Critical Role in the Stable Size Reduction of Perfluorocarbon Nanodroplets.

Perfluorocarbon nanodroplets (PFCnDs) are phase-change contrast agents that have the potential to enable extravascular contrast-enhanced ultrasound and photoacoustic (US/PA) imaging. Producing consistently small, monodisperse PFCnDs remains a challenge without resorting to technically challenging methods. We investigated the impact of variable shell composition on PFCnD size and US/PA image properties. Our results suggest that increasing the molar percentage of PEGylated lipid reduces the size and size variance of PFCnDs. Furthermore, our imaging studies revealed that nanodroplets with more PEGylated lipids produce increased US/PA signal compared with those with the standard formulation. Finally, we highlight the ability of this approach to facilitate US/PA imaging in a murine model of breast cancer. These data indicate that, through a facile synthesis process, it is possible to produce monodisperse, small-sized PFCnDs. Novel in their simplicity, these methods may promote the use of PFCnDs among a broader user base to study a variety of extravascular phenomena.

Design and Demonstration of a Configurable Imaging Platform for Combined Laser, Ultrasound, and Elasticity Imaging.

This paper introduces a configurable combined laser, ultrasound, and elasticity (CLUE) imaging platform. The CLUE platform enables imaging sequences capable of simultaneously providing quantitative acoustic, optical, and mechanical contrast for comprehensive diagnosis and monitoring of complex diseases, such as cancer. The CLUE imaging platform was developed on a Verasonics ultrasound scanner integrated with a pulsed laser, and it was designed to be modular and scalable to allow researchers to create their own specific imaging sequences efficiently. The CLUE imaging platform and sequence were demonstrated in a tissue-mimicking phantom containing a stiff inclusion labeled with optically-activated nanodroplets and in an ex vivo mouse spleen. We have shown that CLUE imaging can simultaneously capture multi-functional imaging signals providing quantitative information on tissue.

Contrast-enhanced ultrasound imaging in vivo with laser-activated nanodroplets.

PURPOSE: This study introduces a real-time contrast-enhanced ultrasound imaging method with recently developed laser-activated nanodroplets (LANDs), a new class of phase-change nanometer-scale contrast agents that provides perceptible, sustained high-contrast with ultrasound. METHODS: In response to pulsed laser irradiation, the LANDs-, which contain liquid perfluorohexane and optical fuses-blink (vaporize and recondense). That is, they change their state from liquid nanodroplets to gas microbubbles, and then back to liquid nanodroplets. In their gaseous microbubble state, the LANDs provide high-contrast ultrasound, but the microbubbles formed in situ typically recondense in tens of milliseconds. As a result, LAND visualization by standard, real-time ultrasound is limited. However, the periodic optical triggering of LANDs allows us to observe corresponding transient, periodic changes in ultrasound contrast. This study formulates a probability function that measures how ultrasound temporal signals vary in periodicity. Then, the estimated probability is mapped onto a B-scan image to construct a LAND-localized, contrast-enhanced image. We verified our method through phantom and in vivo experiments using an ultrasound system (Vevo 2100, FUJIFILM VisualSonics, Inc., Toronto, ON, Canada) operating with a 40-MHz linear array and interfaced with a 10 Hz Nd:YAG laser (Phocus, Opotek Inc., Carlsbad, CA, USA) operating at the fundamental 1064 nm wavelength. RESULTS: From the phantom study, the results showed improvements in the contrast-to-noise ratio of our approach over conventional ultrasound ranging from 129% to 267%, with corresponding execution times of 0.10 to 0.29 s, meaning that the developed method is computationally efficient while yielding high-contrast ultrasound. Furthermore, in vivo sentinel lymph node (SLN) imaging results demonstrated that our technique could accurately identify the SLN. CONCLUSIONS: The results indicate that our approach enables efficient and robust LAND localization in real time with substantially improved contrast, which is essential for the successful translation of this contrast agent platform to clinical settings.

A scattering phantom for observing long range order with two-dimensional angle-resolved Low-Coherence Interferometry.

Angle-resolved low coherence interferometry (a/LCI) is an approach for assessing tissue structure based on light scattering data. Recent advances in a/LCI have extended the analysis to study scattering distributions in two dimensions. In order to provide suitable scattering phantoms for 2D a/LCI, we have developed phantoms based on soft lithography which can provide a range of structures including long range order. Here we characterize these phantoms and demonstrate their utility for providing standardized multi-scale structural information for light scattering measurements.