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The 7D Surgical Machine-vision Image-Guided Surgery (IGS) (MvIGS) system provides surgical guidance to spinal and cranial procedures where high navigation accuracy is required. By leveraging machine vision technologies, the 7D Surgical MvIGS System has the advantage of allowing surgeons to quickly achieve image registration and start navigation without the need for intraoperative radiation-emitting devices or laborious traditional point matching techniques. The 7D Surgical MvIGS System uses an all-optical nonionizing structured light to acquire a three-dimensional (3D) surface scan of the patient. Advanced machine vision algorithms are then used to register the 3D surface to a preoperative scan of the patient. This approach reduces the need for intraoperative X-rays, significantly reducing the surgeon’s, the staff’s, and the patient’s exposure to radiation. By leveraging the intraoperative high-resolution optical surface data acquired from the patient and machine vision algorithms, the 7D Surgical MvIGS System significantly reduces the steps required to set up and operate an IGS system leading to an unprecedentedly fast workflow which we call Flash Registration. Fewer required user interactions with the system also allow for a short learning curve. These innovations have resulted in an IGS system that is more accessible to a broader user base, while providing a radiation-free surgical environment for surgeons, hospital staff, and patients.

Intraoperative image-guided surgical navigation for craniospinal procedures has significantly improved accuracy by providing an avenue for the surgeon to visualize underlying internal structures corresponding to the exposed surface anatomy. Despite the obvious benefits of surgical navigation, surgeon adoption remains relatively low due to long setup and registration times, steep learning curves, and workflow disruptions. We introduce an experimental navigation system utilizing optical topographical imaging (OTI) to acquire the 3D surface anatomy of the surgical cavity, enabling visualization of internal structures relative to exposed surface anatomy from registered preoperative images. Our OTI approach includes near instantaneous and accurate optical measurement of >250,000 surface points, computed at >52,000 points-per-second for considerably faster patient registration than commercially available benchmark systems without compromising spatial accuracy. Our experience of 171 human craniospinal surgical procedures, demonstrated significant workflow improvement (41 s vs. 258 s and 794 s, p

In this paper, we provide an introduction to machine learning tasks that address important problems in genomic medicine. One of the goals of genomic medicine is to determine how variations in the DNA of individuals can affect the risk of different diseases, and to find causal explanations so that targeted therapies can be designed. Here we focus on how machine learning can help to model the relationship between DNA and the quantities of key molecules in the cell, with the premise that these quantities, which we refer to as cell variables, may be associated with disease risks. Modern biology allows high-throughput measurement of many such cell variables, including gene expression, splicing, and proteins binding to nucleic acids, which can all be treated as training targets for predictive models. With the growing availability of large-scale data sets and advanced computational techniques such as deep learning, researchers can help to usher in a new era of effective genomic medicine.

Processing of transcripts at the 3’-end involves cleavage at a polyadenylation site followed by the addition of a poly(A)-tail. By selecting which polyadenylation site is cleaved, alternative polyadenylation enables genes to produce transcript isoforms with different 3’-ends. To facilitate the identification and treatment of disease-causing mutations that affect polyadenylation and to understand the underlying regulatory processes, a computational model that can accurately predict polyadenylation patterns based on genomic features is desirable. Previous works have focused on identifying candidate polyadenylation sites and classifying sites which may be tissue-specific. What is lacking is a predictive model of the underlying mechanism of site selection, competition, and processing efficiency in a tissue-specific manner. We develop a deep learning model that trains on 3’-end sequencing data and predicts tissue-specific site selection among competing polyadenylation sites in the 3’ untranslated region of the human genome.Two neural network architectures are evaluated: one built on hand-engineered features, and another that directly learns from the genomic sequence. The hand-engineered features include polyadenylation signals, cis-regulatory elements, n-mer counts, nucleosome occupancy, and RNA-binding protein motifs. The direct-from-sequence model is inferred without prior knowledge on polyadenylation, based on a convolutional neural network trained with genomic sequences surrounding each polyadenylation site as input. Both models are trained using the TensorFlow library.The proposed polyadenylation code can predict site selection among competing polyadenylation sites in different tissues. Importantly, it does so without relying on evolutionary conservation. The model can distinguish pathogenic from benign variants that appear near annotated polyadenylation sites in ClinVar and inspect the genome to find candidate polyadenylation sites. We also provide an analysis on how different features affect the model’s performance.

Background contextComputer-assisted navigation (CAN) may guide spinal instrumentation, and requires alignment of patient anatomy to imaging. Iterative closest-point (ICP) algorithms register anatomical and imaging surface datasets, which may fail in the presence of geometric symmetry (congruence), leading to failed registration or inaccurate navigation. Here we computationally quantify geometric congruence in posterior spinal exposures, and identify predictors of potential navigation inaccuracy.MethodsMidline posterior exposures were performed from C1-S1 in four human cadavers. An optically-based CAN generated surface maps of the posterior elements at each level. Maps were reconstructed to include bilateral hemilamina, or unilateral hemilamina with/without the base of the spinous process. Maps were fitted to symmetrical geometries (cylindrical/spherical/planar) using computational modelling, and the degree of model fit quantified based on the ratio of model inliers to total points. Geometric congruence was subsequently assessed clinically in 11 patients undergoing midline exposures in the cervical/thoracic/lumbar spine for posterior instrumented fusion.ResultsIn cadaveric testing, increased cylindrical/spherical/planar symmetry was seen in the high-cervical and subaxial cervical spine relative to the thoracolumbar spine (pConclusionsGeometric congruence is most evident at C1 and the subaxial cervical spine, warranting greater vigilance in navigation accuracy verification. At all levels, inclusion of the base of the spinous process in unilateral registration decreases the likelihood of geometric symmetry and navigation error. This work is important to allow the extension of line-of-sight based registration techniques to minimally-invasive unilateral approaches.

This study investigated the secondary electron production from a gold nanoparticle (GNP) irradiated by monoenergetic electron beams using Monte Carlo (MC) simulation. Spherical GNPs with diameters of 2, 50 and 100 nm in water were irradiated by monoenergetic electron beams with energies equal to 50 keV, 250 keV, 1 MeV and 4 MeV. MC simulations were performed using the Geant4 toolkit to determine the energy of the secondary electrons emitted from the GNPs. The mean effective range and deflection angle of the secondary electrons were tracked. Energy depositions inside and outside the nanoparticles due to the secondary electrons were also calculated. For comparisons, simulations were repeated by replacing the GNPs with water. Our results show that the mean effective range of secondary electrons increased with an increase of the GNP size and electron beam energy. For the electron beam energy and GNP size used in this study, the mean effective range was 0.5-15 µm outside the nanoparticle, which is approximately within the dimension of a living cell. The mean deflection angles varied from 78 to 83 degrees as per our MC results. The proportion of energy deposition inside the GNP versus that outside increased with the GNP size. This is different from the results obtained from a previous study using photon beams. The secondary electron energy deposition ratio (energy deposition for GNP/energy deposition for water) was found to be highest for the smallest GNP of 2 nm diameter in this study. For the energy deposited by the secondary electron, we concluded that the addition of GNPs can increase the secondary electron energy deposition in water, though most of the energy was self-absorbed by the large nanoparticles (50 and 100 nm). In addition, an electron source in the presence of GNPs does not seem to be better than photons as the yield of secondary electrons per unit mass of gold is less than water.

Quantum dot (QD) contrast-enhanced molecular imaging has potential for early cancer detection and image guided treatment, but there is a lack of quantitative image contrast data to determine optimum QD administered doses, affecting the feasibility, risk and cost of such procedures, especially in vivo. Vascular fluorescence contrast-enhanced imaging is performed on nude mice bearing dorsal skinfold window chambers, injected with 4 different QD solutions emitting in the visible and near infrared. Linear relationships are observed among the vascular contrast, injected contrast agent volume, and QD concentration in blood. Due primarily to differential light absorption by blood, the vasculature is optimally visualized when exciting in the 435-480 nm region in 81% of the cases (89 out of 110 regions of interest in 22 window chambers). The threshold dose, defined here as the quantity of injected nanoparticles required to yield a vascular target-to-autofluorescence ratio of 2, varies from 10.6 to 0.15 pmol g(-1) depending on the QD emission wavelength. The wavelength optimization maximum and broadband gain, defined as the ratio of threshold doses estimated for optimal and suboptimal (worst wavelength or broadband) spectral illumination, has average values of 4.5 and 1.9, respectively. This study demonstrates, for the first time, optimized QD imaging in vivo. It also proposes and validates a theoretical framework for QD dose estimation and quantifies the effects of blood absorption, QD emission wavelength, and vessel diameter relative to the threshold dose.

Purpose: The aim of this study is to understand the characteristics of secondary electrons generated from the interaction of gold nanoparticles (GNPs) with x-rays as a function of nanoparticle size and beam energy and thereby further the understanding of GNP-enhanced radiotherapy. Methods: The effective range, deflection angle, dose deposition, energy, and interaction processes of electrons produced from the interaction of x-rays with a GNP were calculated by Monte Carlo simulations. The GEANT4 code was used to simulate and track electrons generated from a 2, 50, and 100 nm diameter GNP when it is irradiated with a 50 kVp, 250 kVp, cobalt-60, and 6 MV photon beam in water. Results: When a GNP was present, depending on the beam energies used, secondary electron production was increased by 10- to 2000-fold compared to an absence of a GNP. Low-energy photon beams were much more efficient at interacting with the GNP by two to three orders of magnitude compared to MV energies and increased the deflection angle. GNPs with larger diameters also contributed more dose. The majority of the energy deposition was outside the GNP, rather than self-absorbed by the nanoparticle. The mean effective range of electron tracks for the beams tested rangedmore » from approximately 3 {mu}m to 1 mm. Conclusions: These simulated results yield important insights concerning the spatial distributions and elevated dose in GNP-enhanced radiotherapy. The authors conclude that the irradiation of GNP at lower photon energies will be more efficient for cell killing. This conclusion is consistent with published studies.« less

Purpose: The impact of photon beam energy and tissue heterogeneities on dose distributions and dosimetric characteristics such as point dose, mean dose, and maximum dose was investigated in the context of small-animal irradiation using Monte Carlo simulations based on the EGSnrc code. Methods: Three Monte Carlo mouse phantoms, namely, heterogeneous, homogeneous, and bone homogeneous were generated based on the same mouse computed tomography image set. These phantoms were generated by overriding the tissue type of none of the voxels (heterogeneous), all voxels (homogeneous), and only the bone voxels (bone homogeneous) to that of soft tissue. Phase space files of the 100 and 225 kVp photon beams based on a small-animal irradiator (XRad225Cx, Precision X-Ray Inc., North Branford, CT) were generated using BEAMnrc. A 360 deg. photon arc was simulated and three-dimensional (3D) dose calculations were carried out using the DOSXYZnrc code through DOSCTP in the above three phantoms. For comparison, the 3D dose distributions, dose profiles, mean, maximum, and point doses at different locations such as the isocenter, lung, rib, and spine were determined in the three phantoms. Results: The dose gradient resulting from the 225 kVp arc was found to be steeper than for the 100 kVp arc. Themore » mean dose was found to be 1.29 and 1.14 times higher for the heterogeneous phantom when compared to the mean dose in the homogeneous phantom using the 100 and 225 kVp photon arcs, respectively. The bone doses (rib and spine) in the heterogeneous mouse phantom were about five (100 kVp) and three (225 kVp) times higher when compared to the homogeneous phantom. However, the lung dose did not vary significantly between the heterogeneous, homogeneous, and bone homogeneous phantom for the 225 kVp compared to the 100 kVp photon beams. Conclusions: A significant bone dose enhancement was found when the 100 and 225 kVp photon beams were used in small-animal irradiation. This dosimetric effect, due to the presence of the bone heterogeneity, was more significant than that due to the lung heterogeneity. Hence, for kV photon energies of the range used in small-animal irradiation, the increase of the mean and bone dose due to the photoelectric effect could be a dosimetric concern.« less

This work contributed the following new information to the study of inhomogeneity correction algorithm: (1) Evaluation of lung dose calculation methods as a function of lung relative electron density (rhoe,lung) and treatment geometry and (2) comparison of doses calculated using the collapsed cone convolution (CCC) and adaptive convolution (AC) in lung using the Monte Carlo (MC) simulation with the EGSnrc-based code. The variations of rhoe,lung and geometry such as the position and dimension of the lung were studied with different photon beam energies and field sizes. Three groups of inhomogeneous lung phantoms, namely, "slab," "column," and "cube," with different positions, volumes, and shapes of lung in water as well as clinical computed tomography lung images were used. The rhoe,lung in each group of phantoms vary from 0.05 to 0.7. 6 and 18 MV photon beams with small (4 x 4 cm2) and medium (10 x 10 cm2) field sizes produced by a Varian 21 EX linear accelerator were used. This study reveals that doses in the inhomogeneous lung calculated by the CCC match well with those by AC within +/- 1%, indicating that the AC, with an advantage of shorter computing times (three to four times shorter than CCC), is a good substitute for CCC. Comparing the CCC and AC to MC in general, significant dose deviations are found when the rhoe,lung is 2 mm) occur in the column phantoms, with two lung volumes separated by a unit density column along the CAX in the middle using the 18 MV beam with 4 x 4 cm2 field for rhoe,lung < or =0.1. This study provides new dosimetric data to evaluate the impact of the variations of rhoe,lung and geometry on dose calculations in inhomogeneous media using CCC and AC.

The aim of this study is to investigate the influence of the body of the metal-oxide-semiconductor field effect transistor (MOSFET) dosimeter in measuring the electron backscatter from lead. The electron backscatter factor (EBF), which is defined as the ratio of dose at the tissue-lead interface to the dose at the same point without the presence of backscatter, was calculated by the Monte Carlo simulation using the GEANT4 code. Electron beams with energies of 4, 6, 9, and 12 MeV were used in the simulation. It was found that in the presence of the MOSFET body, the EBFs were underestimated by about 2%-0.9% for electron beam energies of 4-12 MeV, respectively. The trend of the decrease of EBF with an increase of electron energy can be explained by the small MOSFET dosimeter, mainly made of epoxy and silicon, not only attenuated the electron fluence of the electron beam from upstream, but also the electron backscatter generated by the lead underneath the dosimeter. However, this variation of the EBF underestimation is within the same order of the statistical uncertainties as the Monte Carlo simulations, which ranged from 1.3% to 0.8% for the electron energies of 4-12 MeV, due to the small dosimetric volume. Such small EBF deviation is therefore insignificant when the uncertainty of the Monte Carlo simulation is taken into account. Corresponding measurements were carried out and uncertainties compared to Monte Carlo results were within +/- 2%. Spectra of energy deposited by the backscattered electrons in dosimetric volumes with and without the lead and MOSFET were determined by Monte Carlo simulations. It was found that in both cases, when the MOSFET body is either present or absent in the simulation, deviations of electron energy spectra with and without the lead decrease with an increase of the electron beam energy. Moreover, the softer spectrum of the backscattered electron when lead is present can result in a reduction of the MOSFET response due to stronger recombination in the SiO2 gate. It is concluded that the MOSFET dosimeter performed well for measuring the electron backscatter from lead using electron beams. The uncertainty of EBF determined by comparing the results of Monte Carlo simulations and measurements is well within the accuracy of the MOSFET dosimeter (< +/- 4.2%) provided by the manufacturer.

The development of a small animal model for radiotherapy research requires a complete setup of customized imaging equipment, irradiators, and planning software that matches the sizes of the subjects. The purpose of this study is to develop and demonstrate the use of a flexible in-house research environment for treatment planning on small animals. The software package, called DOSCTP, provides a user-friendly platform for DICOM computed tomography-based Monte Carlo dose calculation using the EGSnrcMP-based DOSXYZnrc code. Validation of the treatment planning was performed by comparing the dose distributions for simple photon beam geometries calculated through the Pinnacle3 treatment planning system and measurements. A treatment plan for a mouse based on a CT image set by a 360-deg photon arc is demonstrated. It is shown that it is possible to create 3D conformal treatment plans for small animals with consideration of inhomogeneities using small photon beam field sizes in the diameter range of 0.5-5 cm, with conformal dose covering the target volume while sparing the surrounding critical tissue. It is also found that Monte Carlo simulation is suitable to carry out treatment planning dose calculation for small animal anatomy with voxel size about one order of magnitude smaller than that of the human.

We have successfully integrated previously established Intracranial window (ICW) technology (1-4) with intravital 2-photon confocal microscopy to develop a novel platform that allows for direct long-term visualization of tissue structure changes intracranially. Imaging at a single cell resolution in a real-time fashion provides supplementary dynamic information beyond that provided by standard end-point histological analysis, which looks solely at 'snap-shot' cross sections of tissue. Establishing this intravital imaging technique in fluorescent chimeric mice, we are able to image four fluorescent channels simultaneously. By incorporating fluorescently labeled cells, such as GFP+ bone marrow, it is possible to track the fate of these cells studying their long-term migration, integration and differentiation within tissue. Further integration of a secondary reporter cell, such as an mCherry glioma tumor line, allows for characterization of cell:cell interactions. Structural changes in the tissue microenvironment can be highlighted through the addition of intra-vital dyes and antibodies, for example CD31 tagged antibodies and Dextran molecules. Moreover, we describe the combination of our ICW imaging model with a small animal micro-irradiator that provides stereotactic irradiation, creating a platform through which the dynamic tissue changes that occur following the administration of ionizing irradiation can be assessed. Current limitations of our model include penetrance of the microscope, which is limited to a depth of up to 900 μm from the sub cortical surface, limiting imaging to the dorsal axis of the brain. The presence of the skull bone makes the ICW a more challenging technical procedure, compared to the more established and utilized chamber models currently used to study mammary tissue and fat pads (5-7). In addition, the ICW provides many challenges when optimizing the imaging.

Microvascular detection and quantification with optical coherence tomography is an exciting and growing research field and is the topic of this chapter. Specifically, the fundamental principles of OCT microvascular imaging are described, encompassing phase-resolved and power-based methods, and the use of exogenous contrast agents. Representative biomedical applications of microvascular OCT imaging are presented, with emphasis on treatment monitoring and tissue response assessment. A discussion of outstanding challenges and future outlook concludes the chapter.

The overexpression of α(v) β(3) integrin receptors on tumor cells and tumor vascular endothelium makes it a useful target for imaging, chemotherapy and anti-angiogenic therapy. However integrin-targeted delivery of therapeutics by nanoparticles have provided only marginal, if any, enhancement of therapeutic effect. This work was thus focused on the development of novel α(v) β(3) -targeted near infrared light-emitting solid lipid nanoparticles (SLN) through conjugation to the α(v) β(3) integrin-specific ligand cyclic Arg-Gly-Asp (cRGD), and the assessment of the effects of α(v) β(3) targeting on nanoparticle biodistribution. Since our previously developed non-targeted "stealth" SLN showed little hepatic accumulation, unlike most reported liposomes and micelles, they served as a reference for quantifying the effects of cRGD-conjugation on tumor uptake and whole animal biodistribution of SLN. Non-targeted SLN, actively targeted (RGD-SLN) and blocked RGD-SLN were prepared to contain near infrared quantum dots for live animal imaging. They were injected intravenously to nude mice bearing xenograft orthotopic human breast tumors or dorsal window chamber breast tumors. Tumor micropharmacokinetics of various SLN formulations were determined using intravital microscopy, and whole animal biodistribution was followed over time by optical imaging. The active tumor targeting with cRGD was found to be a "double-edged sword": while the specificity of RGD-SLN accumulation in tumor blood vessels and their tumor residence time increased, their distribution in the liver, spleen, and kidneys was significantly greater than the non-targeted SLN, leaving a smaller amount of nanoparticles in the tumor tissue. Nevertheless the enhanced specificity and retention of RGD-SLN in tumor neovasculature could make this novel formulation useful for tumor neovascular-specific therapies and imaging applications.

Radiotherapy is a widely used cancer treatment. However, understanding how ionizing radiation affects tumor cells and their vasculature, particularly at cellular, subcellular, genetic, and protein levels, has been limited by an inability to visualize the response of these interdependent components within solid tumors over time and in vivo. Here we describe a new preclinical experimental platform combining intravital multimodal optical microscopy for cellular-level longitudinal imaging, a small animal x-ray microirradiator for reproducible spatially-localized millimeter-scale irradiations, and laser-capture microdissection of ex vivo tissues for transcriptomic profiling. Using this platform, we have developed new methods that exploit the power of optically-enabled microscopic imaging techniques to reveal the important role of the tumor microvasculature in radiation response of tumors. Furthermore, we demonstrate the potential of this preclinical platform to study quantitatively - with cellular and sub-cellular details - the spatio-temporal dynamics of the biological response of solid tumors to ionizing radiation in vivo.

The impact of photon beam energy and tissue heterogeneities on dose distributions and dosimetric characteristics such as point dose, mean dose, and maximum dose was investigated in the context of small-animal irradiation using Monte Carlo simulations based on the EGSnrc code.Three Monte Carlo mouse phantoms, namely, heterogeneous, homogeneous, and bone homogeneous were generated based on the same mouse computed tomography image set. These phantoms were generated by overriding the tissue type of none of the voxels (heterogeneous), all voxels (homogeneous), and only the bone voxels (bone homogeneous) to that of soft tissue. Phase space files of the 100 and 225 kVp photon beams based on a small-animal irradiator (XRad225Cx, Precision X-Ray Inc., North Branford, CT) were generated using BEAMnrc. A 360 degrees photon arc was simulated and three-dimensional (3D) dose calculations were carried out using the DOSXYZnrc code through DOSCTP in the above three phantoms. For comparison, the 3D dose distributions, dose profiles, mean, maximum, and point doses at different locations such as the isocenter, lung, rib, and spine were determined in the three phantoms.The dose gradient resulting from the 225 kVp arc was found to be steeper than for the 100 kVp arc. The mean dose was found to be 1.29 and 1.14 times higher for the heterogeneous phantom when compared to the mean dose in the homogeneous phantom using the 100 and 225 kVp photon arcs, respectively. The bone doses (rib and spine) in the heterogeneous mouse phantom were about five (100 kVp) and three (225 kVp) times higher when compared to the homogeneous phantom. However, the lung dose did not vary significantly between the heterogeneous, homogeneous, and bone homogeneous phantom for the 225 kVp compared to the 100 kVp photon beams.A significant bone dose enhancement was found when the 100 and 225 kVp photon beams were used in small-animal irradiation. This dosimetric effect, due to the presence of the bone heterogeneity, was more significant than that due to the lung heterogeneity. Hence, for kV photon energies of the range used in small-animal irradiation, the increase of the mean and bone dose due to the photoelectric effect could be a dosimetric concern.

Although there are many works on evaluating dose calculations of the anisotropic analytical algorithm (AAA) using various homogeneous and heterogeneous phantoms, related work concerning dosimetry due to tangential photon beam is lacking. In this study, dosimetry predicted by the AAA and collapsed cone convolution (CCC) algorithm was evaluated using the tangential photon beam and phantom geometry. The photon beams of 6 and 15 MV with field sizes of 4×4 (or 7×7), 10×10 and 20×20 cm2, produced by a Varian 21 EX linear accelerator, were used to test performances of the AAA and CCC using Monte Carlo (MC) simulation (EGSnrc‐based code) as a benchmark. Horizontal dose profiles at different depths, phantom skin profiles (i.e., vertical dose profiles at a distance of 2 mm from the phantom lateral surface), gamma dose distributions, and dose‐volume histograms (DVHs) of skin slab were determined. For dose profiles at different depths, the CCC agreed better with doses in the air‐phantom region, while both the AAA and CCC agreed well with doses in the penumbra region, when compared to the MC. Gamma evaluations between the AAA/CCC and MC showed that deviations of 2D dose distribution occurred in both beam edges in the phantom and air‐phantom interface. Moreover, the gamma dose deviation is less significant in the air‐phantom interface than the penumbra. DVHs of skin slab showed that both the AAA and CCC underestimated the width of the dose drop‐off region for both the 6 and 15MV photon beams. When the gantry angle was 0°, it was found that both the AAA and CCC overestimated doses in the phantom skin profiles compared to the MC, with various photon beam energies and field sizes. The mean dose differences with doses normalized to the prescription point for the AAA and CCC were respectively:7.6%±2.6% and 2.1%±1.3% for a 10×10 cm2 field, 6 MV; 16.3%±2.1% and 6.7%±2.1% for a 20×20 cm2 field, 6 MV; 5.5%±1.2% and 1.7%±1.4% for a 10×10 cm2, 15 MV; 18.0%±1.3% and 8.3%±1.8% for a 20×20 cm2, 15 MV. However, underestimations of doses in the phantom skin profile were found with small fields of 4×4 and 7×7 cm2 for the 6 and 15 MV photon beams, respectively, when the gantry was turned 5° anticlockwise. As surface dose with tangential photon beam geometry is important in some radiation treatment sites such as breast, chest wall and sarcoma, it is found that neither of the treatment planning system algorithms can predict the dose well at depths shallower than 2 mm. The dosimetry data and beam and phantom geometry in this study provide a better knowledge of a dose calculation algorithm in tangential‐like irradiation. PACS numbers: 87.55.‐x, 87.53.Bn, 87.55.K‐, 87.55.kh, 87.56.jf

A multichannel optical coherence tomography (multi-beam OCT) system and an in vivo endoscopic imaging probe were developed using a swept-source OCT system. The distal optics were micro-machined to produce a high numerical aperture, multi-focus fibre optic array. This combination resulted in a transverse design resolution of10 microm full width half maximum (FWHM) throughout the entire imaging range, while also increasing the signal intensity within the focus of the individual channels. The system was used in a pre-clinical rabbit study to acquire in vivo structural images of the colon and ex vivo images of the oesophagus and trachea. A good correlation between the structural multi-beam OCT images and HE histology was achieved, demonstrating the feasibility of this high-resolution system and its potential for in vivo human endoscopic imaging.

We report a high-power wavelength-swept laser source for multichannel optical coherence tomography (OCT) imaging. Wavelength tuning is performed by a compact telescope-less polygon-based filter in Littman arrangement. High output power is achieved by incorporating two serial semiconductor optical amplifiers in the laser cavity in Fourier domain mode-locked configuration. The measured wavelength tuning range of the laser is 111 nm centered at 1329 nm, coherence length of 5.5 mm, and total average output power of 131 mW at 43 kHz sweeping rate. Multichannel simultaneous OCT imaging at an equivalent A-scan rate of 258 kHz is demonstrated.

This work contributed the following new information to the study of inhomogeneity correction algorithm: (1) Evaluation of lung dose calculation methods as a function of lung relative electron density (rhoe,lung) and treatment geometry and (2) comparison of doses calculated using the collapsed cone convolution (CCC) and adaptive convolution (AC) in lung using the Monte Carlo (MC) simulation with the EGSnrc-based code. The variations of rhoe,lung and geometry such as the position and dimension of the lung were studied with different photon beam energies and field sizes. Three groups of inhomogeneous lung phantoms, namely, "slab," "column," and "cube," with different positions, volumes, and shapes of lung in water as well as clinical computed tomography lung images were used. The rhoe,lung in each group of phantoms vary from 0.05 to 0.7. 6 and 18 MV photon beams with small (4 x 4 cm2) and medium (10 x 10 cm2) field sizes produced by a Varian 21 EX linear accelerator were used. This study reveals that doses in the inhomogeneous lung calculated by the CCC match well with those by AC within +/- 1%, indicating that the AC, with an advantage of shorter computing times (three to four times shorter than CCC), is a good substitute for CCC. Comparing the CCC and AC to MC in general, significant dose deviations are found when the rhoe,lung isor =0.3. The degree of deviation depends on the photon beam energy and field size and is relatively large when high-energy photon beams with small fields are used. For penumbra widths (20%-80%), the CCC and AC agree well with MC for the slab and cube phantoms with the lung volumes at the central beam axis (CAX). However, deviations (2 mm) occur in the column phantoms, with two lung volumes separated by a unit density column along the CAX in the middle using the 18 MV beam with 4 x 4 cm2 field for rhoe,lungor =0.1. This study provides new dosimetric data to evaluate the impact of the variations of rhoe,lung and geometry on dose calculations in inhomogeneous media using CCC and AC.

The aim of this study is to investigate the influence of the body of the metal-oxide-semiconductor field effect transistor (MOSFET) dosimeter in measuring the electron backscatter from lead. The electron backscatter factor (EBF), which is defined as the ratio of dose at the tissue-lead interface to the dose at the same point without the presence of backscatter, was calculated by the Monte Carlo simulation using the GEANT4 code. Electron beams with energies of 4, 6, 9, and 12 MeV were used in the simulation. It was found that in the presence of the MOSFET body, the EBFs were underestimated by about 2%-0.9% for electron beam energies of 4-12 MeV, respectively. The trend of the decrease of EBF with an increase of electron energy can be explained by the small MOSFET dosimeter, mainly made of epoxy and silicon, not only attenuated the electron fluence of the electron beam from upstream, but also the electron backscatter generated by the lead underneath the dosimeter. However, this variation of the EBF underestimation is within the same order of the statistical uncertainties as the Monte Carlo simulations, which ranged from 1.3% to 0.8% for the electron energies of 4-12 MeV, due to the small dosimetric volume. Such small EBF deviation is therefore insignificant when the uncertainty of the Monte Carlo simulation is taken into account. Corresponding measurements were carried out and uncertainties compared to Monte Carlo results were within +/- 2%. Spectra of energy deposited by the backscattered electrons in dosimetric volumes with and without the lead and MOSFET were determined by Monte Carlo simulations. It was found that in both cases, when the MOSFET body is either present or absent in the simulation, deviations of electron energy spectra with and without the lead decrease with an increase of the electron beam energy. Moreover, the softer spectrum of the backscattered electron when lead is present can result in a reduction of the MOSFET response due to stronger recombination in the SiO2 gate. It is concluded that the MOSFET dosimeter performed well for measuring the electron backscatter from lead using electron beams. The uncertainty of EBF determined by comparing the results of Monte Carlo simulations and measurements is well within the accuracy of the MOSFET dosimeter (+/- 4.2%) provided by the manufacturer.

We report on imaging of microcirculation by calculating the speckle variance of optical coherence tomography (OCT) structural images acquired using a Fourier domain mode-locked swept-wavelength laser. The algorithm calculates interframe speckle variance in two-dimensional and three-dimensional OCT data sets and shows little dependence to the Doppler angle ranging from 75 degrees to 90 degrees . We demonstrate in vivo detection of blood flow in vessels as small as 25 microm in diameter in a dorsal skinfold window chamber model with direct comparison with intravital fluorescence confocal microscopy. This technique can visualize vessel-size-dependent vascular shutdown and transient vascular occlusion during Visudyne photodynamic therapy and may provide opportunities for studying therapeutic effects of antivascular treatments without on exogenous contrast agent.

The aim of this study is to evaluate the impact of the patient dose due to the kilovoltage cone beam computed tomography (kV-CBCT) in a prostate intensity-modulated radiation therapy (IMRT). The dose distributions for the five prostate IMRTs were calculated using the Pinnacle treatment planning system. To calculate the patient dose from CBCT, phase-space beams of a CBCT head based on the ELEKTA x-ray volume imaging system were generated using the Monte Carlo BEAMnr code for 100, 120, 130, and 140 kVp energies. An in-house graphical user interface called DOSCTP (DOSXYZnrc-based) developed using MATLAB was used to calculate the dose distributions due to a 360 degrees photon arc from the CBCT beam with the same patient CT image sets as used in Pinnacle. The two calculated dose distributions were added together by setting the CBCT doses equal to 1%, 1.5%, 2%, and 2.5% of the prescription dose of the prostate IMRT. The prostate plan and the summed dose distributions were then processed in the CERR platform to determine the dose-volume histograms (DVHs) of the regions of interest. Moreover, dose profiles along the x- and y-axes crossing the isocenter with and without addition of the CBCT dose were determined. It was found that the added doses due to CBCT are most significant at the femur heads. Higher doses were found at the bones for a relatively low energy CBCT beam such as 100 kVp. Apart from the bones, the CBCT dose was observed to be most concentrated on the anterior and posterior side of the patient anatomy. Analysis of the DVHs for the prostate and other critical tissues showed that they vary only slightly with the added CBCT dose at different beam energies. On the other hand, the changes of the DVHs for the femur heads due to the CBCT dose and beam energy were more significant than those of rectal and bladder wall. By analyzing the vertical and horizontal dose profiles crossing the femur heads and isocenter, with and without the CBCT dose equal to 2% of the prescribed dose, it was found that there is about a 5% increase of dose at the femur head. Still, such an increase in the femur head dose is well below the dose limit of the bone in our IMRT plans. Therefore, under these dose fractionation conditions, it is concluded that, though CBCT causes a higher dose deposited at the bones, there may be no significant effect in the DVHs of critical tissues in the prostate IMRT.

The development of a small animal model for radiotherapy research requires a complete setup of customized imaging equipment, irradiators, and planning software that matches the sizes of the subjects. The purpose of this study is to develop and demonstrate the use of a flexible in-house research environment for treatment planning on small animals. The software package, called DOSCTP, provides a user-friendly platform for DICOM computed tomography-based Monte Carlo dose calculation using the EGSnrcMP-based DOSXYZnrc code. Validation of the treatment planning was performed by comparing the dose distributions for simple photon beam geometries calculated through the Pinnacle3 treatment planning system and measurements. A treatment plan for a mouse based on a CT image set by a 360-deg photon arc is demonstrated. It is shown that it is possible to create 3D conformal treatment plans for small animals with consideration of inhomogeneities using small photon beam field sizes in the diameter range of 0.5-5 cm, with conformal dose covering the target volume while sparing the surrounding critical tissue. It is also found that Monte Carlo simulation is suitable to carry out treatment planning dose calculation for small animal anatomy with voxel size about one order of magnitude smaller than that of the human.

Purpose: To investigate secondary electron production in gold nanoparticle (GNP) aided radiotherapy through Monte Carlo simulations, thereby advance the understanding of dose enhancements and their role in improving cell kill. Methods: Using the Geant4 toolkit, simulations were performed with four polyenergetic sources, namely 50 kVp, 250 kVp, Cobalt‐60, and 6 MV, to irradiate a gold sphere of diameters 2, 50, or 100 nm in water. The energy of the secondary electrons and the frequency and type of physics interaction that created them were tracked. This allowed calculation of the absorbed dose and energy deposition inside and outside of the nanoparticle. Results: The presence of a GNP can enhance the production of electrons by approximately 3 orders of magnitude at kV beam energies. For MV beams, the increase in electron production was approximately 10 folds. Considerable dose enhancement occurred when gold was present, at approximately 1000 folds for kV beams, and between 2 to 7 folds for MV beams. The energy deposited was calculated to compare how many additional electrons were generated and take into account their energies. In the kV beams, the addition of a GNP caused significantly greater deposited energy surrounding the nanoparticle by 2 to 3 orders of magnitude. For the MV beams, the increase was approximately 5 folds. The proportion of energy deposition inside the GNP versus the outside was also analyzed. At greater nanoparticle diameters, a larger portion of the overall deposited energy resided within the nanoparticle. Conclusions: We present simulation results that show the presence of GNP's can considerably increase the dose and energy deposition outside the nanoparticle, especially at kV energies. This enhancement is also present for MV beams, although to a lesser degree.

This study investigated the low-energy electrons (LEEs) produced when a gold nanoparticle (GNP) is irradiated by photon beams. The secondary electrons emitted from a GNP (diameter = 100 nm), interacting with photon beams with energies equal to 35, 73.3 and 600 keV, were simulated using the Geant4 Monte Carlo code. The phase spaces of the secondary electrons were then used to simulate the LEEs in water using the NOREC Monte Carlo code. All secondary electrons emitted by the GNP, and all LEEs produced by each secondary electron were tracked in Monte Carlo simulations. It is found that the energy distributions of the LEEs from the GNP do not vary significantly between different photon beam energies. Moreover, the 660 keV photon beam produced more LEEs travelling to a longer range than photon beams of lower energies (35 and 73.3 keV). This higher energy deposition and longer range LEEs produced by the 660 keV photon beam can enhance the cell kill. Based on our Monte Carlo results, it is concluded that the unexpected close of the radiosensitization enhancement factors of the 35 (1.66) and 660 keV (1.18) photon beams from our previous measurements is because of the cell kill enhancement with the increased LEE yield and range in the 660 keV photon beam.

Purpose: This study evaluated the surfacedosimetry predicted by the anisotropic analytical algorithm (AAA) and collapsed cone convolution (CCC) algorithm using the tangential‐like photon beam and phantom geometry. Monte Carlo(MC) simulation (EGSnrc code) was used as a benchmark for comparison. Methods: The 6 and 15 MV photon beams with field sizes of 4×4 (or 7×7), 10×10 and 20×20 cm2, produced by a Varian 21EX linear accelerator were used. Horizontal dose profiles at different depths, phantom skin profiles (i.e. vertical dose profiles at a distance of 2 mm from the phantom lateral surface), gamma dose distributions, and dose‐volume histograms (DVHs) of skin slab were determined. Results: For dose profiles at different depths, the CCC agreed better with doses in the air‐phantom region, while both the AAA and CCC agreed well with doses in the penumbra region, when compared to the MC. Gamma evaluations between the AAA/CCC and MC revealed that deviations of 2D dose distribution occurred in both beam edges in the phantom and air‐phantom interface. DVHs of skin slab showed that both the AAA and CCC underestimated the width of the slope for both the 6 and 15 MV photon beams. The mean dose differences along the phantom skin profiles for the AAA and CCC were respectively: 7.6±2.6% and 2.1±1.3% for a 10×10 cm2 field, 6 MV; 16.3±2.1% and 6.7±2.1% for a 20×20 cm2 field, 6 MV; 5.5±1.2% and 1.7±1.4% for a 10×10 cm2, 15 MV; 18.0±1.3% and 8.3±1.8% for a 20×20 cm2, 15 MV. Conclusions: As surfacedose with tangential‐like photon beam geometry is important in some radiation treatment sites such as breast, chest wall and sarcoma, the dosimetry data and beam and phantom geometry in this study are worthwhile to be considered, when carrying out quality assurance and commissioning for treatment planning systems.

This study evaluated the effect of tissue heterogeneities due to photon beams in the kilo‐voltage energy range in small‐animal irradiation. Monte Carlo(MC) simulation (EGSnrc code) was used. Three MC mouse phantoms were generated from a single mouse CTimage set. These phantoms were generated by overriding the relative electron density of no voxels (heterogeneous), all voxels (homogeneous) and the bone voxels (bone homogeneous) to one. Phase‐space files of the 100 and 225 kVp photon beams produced by a small animal irradiator were generated using BEAMnrc. A 360 deg photon arc was simulated for treatment of the lung, and 3D dose calculations were carried out for the three phantom geometries. The resulting dose profiles for the different phantoms and beam energies were compared. It was found that the 225 kVp photon beams have a better conformai dose distribution than the 100 kVp. The bone doses in the heterogeneous mouse phantom were about 4 – 5 (100 kVp) and 2 (225 kVp) times higher when compared to the homogeneous phantom. However, the lungdose does not vary significantly between the heterogeneous, homogeneous and bone homogeneous phantoms for either the 100 or 225 kVp photon beams. We concluded that bone dose enhancement was found when 100 and 225 kVp photon beams were used in small‐animal irradiation. This dosimetric effect due to the presence of the bone heterogeneity was more significant than the lung heterogeneity, and such bone dose enhancement does not occur in the typical patient's radiotherapy using the MV photon beams.

We optimize speckle variance optical coherence tomography (svOCT) imaging of microvasculature in high and low bulk tissue motion scenarios. To achieve a significant level of image contrast, frame rates must be optimized such that tissue displacement between frames is less than the beam radius. We demonstrate that higher accuracy estimates of speckle variance can enhance the detection of capillaries. These findings are illustrated in vivo by imaging the dorsal window chamber model (low bulk motion). We also show svOCT imaging of the nonstabilized finger (high bulk motion), using optimized imaging parameters, demonstrating better vessel detection than Doppler OCT.

We demonstrate the potential of a forward-looking Doppler optical coherence tomography (OCT) probe for color flow imaging in several commonly seen narrowed artery morphologies. As a proof of concept, we present imaging results of a surgically exposed thrombotic occlusion model that was imaged superficially to demonstrate that Doppler OCT can identify flow within the recanalization channels of a blocked artery. We present Doppler OCT images in which the flow is nearly antiparallel to the imaging direction. These images are acquired using a flexible 2.2-mm-diam catheter that used electrostatic actuation to scan up to 30 deg ahead of the distal end. Doppler OCT images of physiologically relevant flow phantoms consisting of small channels and tapered entrance geometries are demonstrated.

Purpose: Through Monte Carlo simulations, we investigate the spatial and energy characteristics of electrons formed from interactions of keV photon beams irradiating a goldnanoparticle to understand their role in enhancing cell kill. Methods and Materials: The GEANT4 toolkit was used for Monte Carlo simulation. A goldnanoparticle sphere with a 100 nm diameter was irradiated by x‐rays with energies of 35 to 6000 keV inside a tracking volume of water. For each electron emitted from the irradiatedgoldnanoparticle, the following parameters were tracked: i) the physics process that created the electron, ii) energy distribution of the electron, iii) range, and iv) deflection angle. The same simulations were performed by replacing the goldnanoparticle with water. Results: The energy distribution of the secondary electrons when the goldnanoparticle is irradiated by a monoenergetic photon beam with various energies is calculated. The number of interactions for 35 keV photons is about 157 times more than that for 660 keV, and 683 times more than the 6000 keV beam. When the goldnanoparticle is absent, the probability of creating an electron becomes much lower. Specifically, the ratio of total interactions with and without gold is 812, 137, 10, 7, and 2 for energies 35, 73.3, 660, 1200 and 6000 keV respectively. Furthermore, irradiating the goldnanoparticle at a higher photon energy increases the range over which the election can travel, and decreases the deflection angle. This represents a change in volume over which the electrons can deposit dose. Conclusions: We conclude that for a cell of typical size, a low energy (35 keV) photon beam generates a large number of secondary electrons when a goldnanoparticle is present compared to without, and will have sufficient range to cause damage in the cell in which the nanoparticle is uptaken.

Purpose: This study investigated dosimetric characteristics of goldnanoparticle under a photon beam. A single goldnanoparticle (microscopic) and a mixture of gold and water (macroscopic) were considered using Monte Carlo simulations based on the Geant4‐ and EGSnrc‐based code, respectively. Methods and Materials: A single goldnanoparticle (diameter of 100 nm) was irradiated by photon beams with energies of 35.5keV, 73.3keV, 660keV, 1.2MeV and 6MeV in water. 250 million histories were used in Monte Carlo simulation to record different numbers of interactions (e.g. photoelectric and Compton) with and without the goldnanoparticle in water. Moreover, a mixture of gold and water was irradiated with photon beams. The dose enhancement ratios (dose of gold and water mixture/dose of water) were determined with different photon beam energies and concentrations of gold.Results: With a single goldnanoparticle, the number of photoelectric interaction was about 47 times larger than that of Compton for the 35.5keV photon beams. This was opposite to the 6MeV photon beams, where the number of Compton interaction was about 46.5 times larger than that of the photoelectric. Although the values of ratio were similar, the total number of interactions for the 35.5keV photon beams was in fact 348 times larger than that of the 6MeV. A larger energy deposition was therefore found when the photon beam energy was decreased from the MeV to keV range. This result agreed with that from a gold and water mixture. Moreover, increasing the concentration of gold increased the dose enhancement in water.Conclusions: Both microscopic and macroscopic study on goldnanoparticle agree that more energy deposition is found when the photon beam energy is decreased from MeV to keV range, due to the increase of photoelectric interaction. A higher concentration of gold can increase the dose enhancement in water.

This study provides new information on the evaluation of the lung dose calculation algorithms as a function of the relative electron density of lung, ρe,lung . Doses calculated using the collapsed cone convolution (CCC) and adaptive convolution (AC) algorithm in lung with the Pinnacle3 system were compared to those calculated using the Monte Carlo (MC) simulation (EGSnrc-based code). Three groups of lung phantoms, namely, "Slab", "Column" and "Cube" with different ρe,lung (0.05-0.7), positions, volumes and shapes of lung in water were used. 6 and 18MV photon beams with 4×4 and 10×10cm2 field sizes produced by a Varian 21EX Linac were used in the MC dose calculations. Results show that the CCC algorithm agrees well with AC to within ±1% for doses calculated in the lung phantoms, indicating that the AC, with 3-4 times less computing time required than CCC, is a good substitute for the CCC method. Comparing the CCC and AC with MC, dose deviations are found when ρe,lung are ⩽0.1-0.3. The degree of deviation depends on the photon beam energy and field size, and is relatively large when high-energy photon beams with small field are used. For the penumbra widths (20%-80%), the CCC and AC agree well with MC for the "Slab" and "Cube" phantoms with the lung volumes at the central beam axis (CAX). However, deviations >2mm occur in the "Column" phantoms, with two lung volumes separated by a water column along the CAX, using the 18MV (4×4cm2 ) photon beams with ρe,lung ⩽0.1.

A software graphical user interface (GUI) for calculation of 3D dose distribution using Monte Carlo (MC) simulation is developed using MATLAB. This GUI (DOSCTP) provides a user-friendly platform for DICOM CT-based dose calculation using EGSnrcMP-based DOSXYZnrc code. It offers numerous features not found in DOSXYZnrc, such as the ability to use multiple beams from different phase-space files, and has built-in dose analysis and visualization tools. DOSCTP is written completely in MATLAB, with integrated access to DOSXYZnrc and CTCREATE. The program function may be divided into four subgroups, namely, beam placement, MC simulation with DOSXYZnrc, dose visualization, and export. Each is controlled by separate routines. The verification of DOSCTP was carried out by comparing plans with different beam arrangements (multi-beam/photon arc) on an inhomogeneous phantom as well as patient CT between the GUI and Pinnacle3. DOSCTP was developed and verified with the following features: (1) a built-in voxel editor to modify CT-based DOSXYZnrc phantoms for research purposes; (2) multi-beam placement is possible, which cannot be achieved using the current DOSXYZnrc code; (3) the treatment plan, including the dose distributions, contours and image set can be exported to a commercial treatment planning system such as Pinnacle3 or to CERR using RTOG format for plan evaluation and comparison; (4) a built-in RTOG-compatible dose reviewer for dose visualization and analysis such as finding the volume of hot/cold spots in the 3D dose distributions based on a user threshold. DOSCTP greatly simplifies the use of DOSXYZnrc and CTCREATE, and offers numerous features that not found in the original user-code. Moreover, since phase-space beams can be defined and generated by the user, it is a particularly useful tool to carry out plans using specifically designed irradiators/accelerators that cannot be found in the Linac library of commercial treatment planning systems.