Development of a mathematical model to estimate intra-tumor oxygen concentrations through multi-parametric imaging

Background Tumor hypoxia is involved in every stage of solid tumor development: formation, progression, metastasis, and apoptosis. Two types of hypoxia exist in tumors—chronic hypoxia and acute hypoxia. Recent studies indicate that the regional hypoxia kinetics is closely linked to metastasis and therapeutic responses, but regional hypoxia kinetics is hard to measure. We propose a novel approach to determine the local pO2 by fusing the parameters obtained from in vivo functional imaging through the use of a modified multivariate Krogh model. Methods To test our idea and its potential to translate into an in vivo setting through the use of existing imaging techniques, simulation studies were performed comparing the local partial oxygen pressure (pO2) from the proposed multivariate image fusion model to the referenced pO2 derived by Green’s function, which considers the contribution from every vessel segment of an entire three-dimensional tumor vasculature to profile tumor oxygen with high spatial resolution. Results pO2 derived from our fusion approach were close to the referenced pO2 with regression slope near 1.0 and an r2 higher than 0.8 if the voxel size (or the spatial resolution set by functional imaging modality) was less than 200 μm. The simulation also showed that the metabolic rate, blood perfusion, and hemoglobin concentration were dominant factors in tissue oxygenation. The impact of the measurement error of functional imaging to the pO2 precision and accuracy was simulated. A Gaussian error function with FWHM equal to 20 % of blood perfusion or fractional vascular volume measurement contributed to average 7 % statistical error in pO2. Conclusion The simulation results indicate that the fusion of multiple parametric maps through the biophysically derived mathematical models can monitor the intra-tumor spatial variations of hypoxia in tumors with existing imaging methods, and the potential to further investigate different forms of hypoxia, such as chronic and acute hypoxia, in response to cancer therapies

Development of Follicle-Stimulating Hormone Receptor Binding Probes to Image Ovarian Xenografts

The Follicle-Stimulating Hormone Receptor (FSHR) is used as an imaging biomarker for the detection of ovarian cancer (OC). FSHR is highly expressed on ovarian tumors and involved with cancer development and metastatic signaling pathways. A decapeptide specific to the FSHR extracellular domain is synthesized and conjugated to fluorescent dyes to image OC cells in vitro and tumors xenograft model in vivo. The in vitro binding curve and the average number of FSHR per cell are obtained for OVCAR-3 cells by a high resolution flow cytometer. For the decapeptide, the measured EC50 was 160 μM and the average number of receptors per cell was 1.7 × 10(7). The decapeptide molecular imaging probe reached a maximum tumor to muscle ratio five hours after intravenous injection and a dose-dependent plateau after 24-48 hours. These results indicate the potential application of a small molecular weight imaging probe specific to ovarian cancer through binding to FSHR. Based on these results, multimeric constructs are being developed to optimize binding to ovarian cells and tumors

Validating Hemoglobin Saturation and Dissolved Oxygen in Tumors using the OxyLab Probe and Photoacoustic Imaging

The goal of this experiment is to validate the relationship between hemoglobin saturation (SaO2) and partial pressure of dissolved oxygen (pO2) in breast tumors in mice using photoacoustic computed tomographic (PCT) imaging and OxyLite probe, respectively. In its simplest form, the relationship is described by the dissociation curve, or Hill’s equation, for hemoglobin, and is modeled as a sigmoidal curve that is a function of two parameters – the Hill coefficient, n, and the net association constant of HbO2, K (or pO2 at 50% SaO2). First, a calibration study to validate Hill’s equation in blood was performed by creating a closed circuit phantom to test the SaO2 (co-oximeter) and pO2 (Oxylite probe) relationship (K=23.2mmHg and n=2.26). Next, non-invasive localized measurements of SaO2 in MDA-MD-231 and MCF7 breast tumors using PCT spectroscopic methods were compared to pO2 levels, where pO2 levels were measured in 1mm increments across the central axis of the tumor. The fitted results for MCF7 and MDA-MD-231 were K=17.2mmHg and 20.7mmHg, and n=1.76and 1.63, respectively. The results are consistent with sigmoidal form of Hill’s equation. The lower value of K is indicative of the acidic microenvironment associated with tumors. Ongoing work to correct for photon transport and image artifacts are anticipated to enhance the quality of the results. In conclusion, the results from this study demonstrate photoacoustic can be used to measure tumor oxygenation, and its potential use in investigating the effectiveness of anti-angiogenesis therapy

Monitoring the Effects of Anti-angiogenesis on the Radiation Sensitivity of Pancreatic Cancer Xenografts Using Dynamic Contrast-Enhanced CT

Purpose To image the intra-tumor vascular physiological status of pancreatic tumors xenografts and their response to anti-angiogenic therapy using Dynamic Contrast-Enhanced CT (DCE-CT), and to identify parameters of vascular physiology associated with tumor X-ray sensitivity following anti-angiogenic therapy. Methods and Materials Nude mice bearing human BxPC-3 pancreatic tumor xenografts were treated with 5Gy of radiation therapy (RT), either a low-dose (40mg/kg) or a high-dose (150mg/kg) of DC101, the anti-VEGF receptor-2 anti-angiogenesis antibody, or with combination of low or high dose DC101 and 5Gy RT (DC101-plus-RT). DCE-CT scans were longitudinally acquired over three week period post-DC101 treatment. Parametric maps of tumor perfusion and fractional plasma volume (Fp) were calculated and their averaged values and histogram distributions evaluated and compared to controls, from which a more homogeneous physiological window was observed 1-week post-DC101. Mice receiving a combination of DC101-plus-RT(5Gy) were imaged baseline prior to receiving DC101 and 1-week after DC101 (prior to RT). Changes in perfusion and Fp were compared with alternation in tumor growth delay for RT and DC101-plus-RT(5Gy) treated tumors. Results Pretreatment with low or high doses of DC101 prior to RT significantly delayed tumor growth by an average 7.9 days compared to RT alone (p≤0.01). The increase in tumor growth delay for the DC101-plus-RT treated tumors was strongly associated with changes in tumor perfusion (ΔP>−15%) compared to RT treated tumors alone (p=0.01). In addition, further analysis revealed a trend linking the tumor’s increased growth delay to its tumor volume-to-DC101 dose ratio. Conclusions DCE-CT is capable of monitoring changes in intra-tumor physiological parameter of tumor perfusion in response to anti-angiogenic therapy of a pancreatic human tumor xenograft that was associated with enhanced radiation response

An ultrasound based platform for image-guided radiotherapy in canine bladder cancer patients

Background and purpose: Ultrasound (US) is a non-invasive, non-radiographic imaging technique with high spatial and temporal resolution that can be used for localizing soft-tissue structures and tumors in real-time during radiotherapy (RT) (inter- and intra-fraction). A comprehensive approach incorporating an in-house 3D-US system within RT is presented. This system is easier to adopt into existing treatment protocols than current US based systems, with the aim of providing millimeter intra-fraction alignment errors and sensitivity to track intra-fraction bladder movement. Materials and methods: An in-house integrated US manipulator and platform was designed to relate the computed tomographic (CT) scanner, 3D-US and linear accelerator coordinate systems. An agar-based phantom with measured speed of sound and densities consistent with tissues surrounding the bladder was rotated (0-45°) and translated (up to 55 mm) relative to the US and CT coordinate systems to validate this device. After acquiring and integrating CT and US images into the treatment planning system, US-to-US and US-to-CT images were co-registered to re-align the phantom relative to the linear accelerator. Results: Statistical errors from US-to-US registrations for various patient orientations ranged from 0.1 to 1.7 mm for x, y, and z translation components, and 0.0-1.1° for rotational components. Statistical errors from US-to-CT registrations were 0.3-1.2 mm for the x, y and z translational components and 0.1-2.5° for the rotational components. Conclusions: An ultrasound-based platform was designed, constructed and tested on a CT/US tissue-equivalent phantom to track bladder displacement with a statistical uncertainty to correct and track inter- and intra-fractional displacements of the bladder during radiation treatments

Swarms of uavs and fighter aircraft

This paper describes the successful implementation of a model of swarm dynamics using particle simulation concepts. Several examples of the complex behaviors achieved in a target/interceptor scenario are presented

Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse

As systemic cancer therapies improve and are able to control metastatic disease outside the central nervous system, the brain is increasingly the first site of relapse. The blood–brain barrier (BBB) represents a major challenge to the delivery of therapeutics to the brain. Macrophages originating from circulating monocytes are able to infiltrate brain metastases while the BBB is intact. Here, we show that this ability can be exploited to deliver both diagnostic and therapeutic nanoparticles specifically to experimental brain metastases of breast cancer