Session N10: Physics in Medicine: Therapy, Imaging, and Modeling

Hypofractionated Brain Radiosurgery Utilizing Quasi Dynamic Dose Painting

The idea of dynamic dose painting for stereotactic radiotherapy was first proposed by us in 2009 via developing a 3D lawn-mowing algorithm (https://pubmed.ncbi.nlm.nih.gov/19229095/).  With the recent advancements in image-guided hypofractionated beam delivery platforms, a high number of isocenters on the order of 500 may be automatically administered.  Such a technical advancement potetially enables a quasi dynamic dose painting (QDDP) approach where a continuous beam trajectory may be mimicked with connected segments of stop-and-shot beam nodes.  In this paper, the first-time clinical implementation of QDDP for hypofractionated radiosurgery of large lesions is presented.  When compared to conventional treatments via a limited isocenters, QDDP drastically improved the dosing quality of a treatment in terms of target coverage, dose conformality and peripheral dose gradient (which was noted to approach the theoretical optimum for some clinical cases).   Technical caveats are plenty for QDDP and will be discussed during the presentation.  In conclusion, the concept of dynamic dose painting was demonstratd to be feasible for the first time in clinics.  QDDP can be espcially advantageous for treating brain tumors large in size, in the eloquent brain or with diffusive characteristics.   

X-ray nanothermometry to improve anticancer thermal therapies

Treatments based on multifunctional thermal-activated nanomaterials have emerged as a promising biomedical strategy to fight cancer [1]. Temperature increments above 42°C were shown to kill cancer cells which has led to the development of nanoparticle-mediated thermo-therapeutic strategies in the fight of oncological diseases. However, these therapeutic effects have been also observed by localized nanoparticle heating without a detectable macroscopic temperature rise [2]. The precise determination of the local temperature reached in the tumour tissue is necessary to evaluate the onset of thermal doses and quantify possible side effects on healthy tissues. In this study, we investigate the potential of X-ray absorption spectroscopy technique to determine in situ the temperature reached in gold and iron oxide-based nanoparticles under therapeutic photoactivated hyperthermia [3, 4]. Experiments were performed at the Au L3-edge in BM25 beamline at the ESRF (France). We will discuss the capabilities and limitations of the technique and explore the induced heating phenomena at the nanoscale.

[1]       A. Espinosa, J. Kolosnjaj-Tabi et al. Adv, Funct. Mater. 28, 1803660 (2018).

[2]       E. Cazares-Cortés, S. Cabana et al. Adv. Drug Deliv. Rev. 138, 233 (2019).

[3]       A. Espinosa, J. Reguera et al., Small, 16, 1904960 (2020).

[4]       A. Espinosa, G. R. Castro et al. Nano Lett. 21, 769 (2021).   

Is 11B(p,α)2α nuclear reaction contributing in proton therapy?

In the last few years proton therapies have been increased exponentially due to the major advantage of protons to deposit most of their energy at the end of the range, forming a well-known Bragg Peak (BP). It has been suggested that ¹¹B accumulation in the tumor volume increases the dose at the BP, thus enhancing the benefits of proton therapy. The mechanism behind this increase is based on the proton-boron fusion that generates alpha particles, deposit their energy in the BP. The question remains on how many alpha particles are needed in order to achieve a significant dose enhancement given the low cross section of protons with ¹¹B. In this study we present a series of simulations in an effort to quantify the enhancement of the dose in the target volume originating from the p + ¹¹B → 3α nuclear reaction. We simulated via TOPAS MC the interaction of 75-250 MeV incident proton beam (10⁷ histories) in a phantom of cylindrical geometry that is filled with water and includes a Boron Uptake Region (BUR) that was placed based on the BP location of the incident energy. The thickness of BUR and boron concentration were varied. The number of produced alpha particles for the different setups was scored and comparisons between the different depth-dose curves will be presented. Work on clinical importance of the ¹¹B(p,α)2α is in progress.   

Evaluation of Dosimetric Uncertainties in Diminutive MLC Fields by “Fixed Virtual Cone Technique” using Measurements and Monte Carlo Simulations

Quantification of dosimetric uncertainties due to variable field sizes in virtual cone technique during stereotactic radiosurgery (SRS) can be challenging. We propose a virtual cone technique defined by a fixed field size to mimic a physical cone. It is characterized by 0.5cm x 0.5cm field, defined by two central leaves of high-definition MLC with a fixed opening of jaws at 100cm SAD. To generate spherical dose distributions equivalent to physical cones and ensure an optimized dose coverage, approximately 12–14 non-coplanar partial arcs to be used. Retrospective measurements (SRS MapCHECK) of 30 SRS cases treated on Varian EDGE system were performed using our virtual cone to quantify dosimetric uncertainties due to gravity or low maintenance of MLC, when the gantry at 90°/270° and the collimator at 90°. Field output factor and dose/MU were compared between measurements (SRS MapCHECK) and Eclipse TPS (Acuros XB) for 6FFF and 10FFF photon beams at two clinical settings (95/5 cm & 90/10 cm). MC study on the EDGE linac verified our method. Preliminary results showed a notable dosimetric variation due to a minute (± 0.5–1.0)mm leaf shift. The 10FFF beam yielded more accurate (≤4%) dosimetric results than the 6FFF beam (≤7%). MC simulations exhibited similar dosimetric results but more consistent than the TPS ones. Overall, the 10FFF beam delivered more accurate and reliable dosimetric results than the 6FFF at different clinical settings, whereas the 90/10cm setting was more effective than the 95/5cm.   

a novel method of quantitative comparison of the benefit and the risk of hydrogen and select heavy ions radiotherapy on breast cancer tumor using SRIM ion transport code.

Charged particle therapy has been an important procedure in non-invasive treatment of tumors. It utilizes the ionization pattern of protons and heavy ions to administer lethal doses of radiation to tumor tissues by destroying their ability to replicate. The use of charged particle therapy to control tumors non-invasively offers numerous advantages such as high Relative Biological Effectiveness (RBE) value. However, in this process, some doses of radiation are given to the healthy cells on the radiation path. This poses some risk. How do we quantify this risk?

In this work, we present a new way of quantifying the relative radiation dose given to cancerous and healthy tissues on the radiation path. The ratio of the average dose rate in Bragg peak (calculated from the FWHM from a gaussian fit do dose rate data) to average dose rate in the plateau region is used to quantify the benefit and potential risk of using Hydrogen, Helium, Carbon, Oxygen, and Neon ions in the treatment of a breast cancer tumor, assumed to be located  at a depth of 62 mm. Stopping and Range of Ion in Matter (SRIM) was used to get the dose rate.

Furthermore, the relative benefits were compared among the four ions with Neon, followed closely by carbon, found to offer the best advantage.   

Development of the Web-based Simulation Platform for gMicroMC

Purpose: Our lab developed an open-source graphical processing unit (GPU)-based microscopic Monte Carlo simulation tool (gMicroMC) for ionizing radiation-induced DNA damage computation. Although the package has gained an increasing interest, the current version requires relatively high coding experience from the user thus hindering its broad application. In this work, we initiated an effort to build a web-based interface to enable a user-friendly simulation environment.

Method: We proposed to establish two servers: a web server for storing static files and an application server for performing GPU-based gMicroMC simulation. We will employ the Django web framework for various tasks such as job submission and implement the Three.js framework to render the 3D graphics at the platform.

Result: We were able to establish a first version of the simulation platform, where the user can setup the simulation parameters and visualize the setup geometry in 3D. We also configured our web server and were able to transfer our codes to it from our local machine.

Conclusion: We laid the foundation for the web-based simulation platform of gMicroMC. Our next steps are to fully accomplish the proposed function of the platform, test it and make it available to the public.   

Signal optimization in mesh-based X-ray phase and dark field imaging

X-ray phase differences imparted by tissue are roughly 1000 times larger than x-ray attenuation differences. Small-angle scatter from tissue microstructure can provide an additional “dark field” signal that is complementary to attenuation and phase. Phase and dark field images can provide enhanced contrast as well as tissue specific information. However, the acquisition of these images requires highly coherent illumination or multiple precisely machined and aligned gratings, which may limit the clinical applicability of these techniques. Our method employs a single, low-cost wire mesh that does not need precise alignment and relaxes the coherence requirement on the source. However, the coarseness of the mesh reduces the strength of the phase and dark field signal compared with grating-based techniques, so it is important to design a system to optimize signal to noise ratio. We performed optimization experiments by adjusting distances between the source, mesh, phantom and detector, varying the x-ray energy and acquiring images with and without a polycapillary optic, which can improve beam coherence. We find optimal ranges for these parameters through simulation and experiment. 

This work was supported in part by the NY State Department of Health (DOH01-C33920GG-3450000).   

Deep high resolution 4D ultrafast ultrasound imaging with 2D matrix arrays

As a non-invasive, non-irradiant and accessible modality, ultrafast ultrasound is more and more favored. Particularly, its role in cancer diagnosis is crucial since a cheap and highly effective imaging modality will allow early and wide screening of patients and considerably enhance the survival rates. In this work, we propose a novel probe design to provide unprecedented spatial resolution in ultrasound imaging, from three spatial dimensions up to 4D (x,y,z,t) when imaging media on ultrafast time scales.

We designed a 1024-transducer array of 64x16 elements, and central frequency 2.5MHz. This rectangular geometry enhances the field of view while still allowing steering capability in both directions. A high-end 1024-channel ultrasound scanner, was used to drive our probe. Importantly, we transmitted and received 2D plane waves with the whole aperture and thus achieved ultrafast imaging rates up to 1kHz at 10 cm depth.

On commercial phantoms, we were able to demonstrate high resolution of 0.5mm at 16 cm depth and contrast-enhanced approaches allow a +9dB gain on microbubbles imaging. Parallel reconstruction algorithms achieved processing times as low as 1ms, being thus real-time. Such capabilities will soon allow soon unveil ultrafast phenomena occurring deep inside the human body.   

Uptake of carbon nanodots into human acute myeloid leukemia (AML) cells in comparison to primary hematopoietic cells

Carbon nanodots (CNDs) are a promising class of nanoparticles. These carbon based, nanometer-sized particles offer a broad spectrum of potential biomedical applications like bioimaging, cancer diagnosis and drug delivery. In context of drug delivery, a selective uptake by malignant cells is crucial. Our aim was to investigate whether there is a differential uptake into AML cells compared to primary hematopoietic cells. CNDs prepared using citric acid and diethylenetriamine were incubated for 24 h with malignant cells from five patients with de novo AML and primary hematopoietic cells from three normal donors. The differential uptake of the CNDs was studied by flow cytometry and monoclonal antibodies. A significant CND uptake was observed in all cell types of the normal and leukemic cells. However, the uptake was significantly smaller for the CD34⁺ and CD33⁺ myeloid subsets of the malignant cell population. T- (CD3⁺) and B- (CD19⁺) lymphoid cells within the leukemic and healthy samples showed a similar uptake. The subcellular distribution was examined on HL-60 cells. Confocal microscopy images show perinuclear accumulation of CNDs in lysosomes. This particular localization could be useful for therapeutical targeting.    

Evaluation of sperm selection efficiency in abnormal semen sample using rheotaxis-based microfluidic device

Semen samples contain a heterogeneous population of spermatozoa, some of which may possess the attributes necessary for successful fertilization. There are several sperm selection techniques that are available for selecting spermatozoa for use in various assisted reproductive technologies (ART). Many reproductive clinics use the conventional density gradient centrifugation techniques to select sperm. These methods are quick and easy to carry out. However, a relatively high centrifugal force can generate reactive oxygen species (ROS). We have developed a rheotaxis-based microfluidic device that washes out the raw semen sample from any dead or less motile sperm. The device consists of a collection and waste chamber. To evaluate the effect of the shape and height of the collection chamber, we measured the sperm motility and velocity parameters after sorting using varying the shape and height of the collection chamber. We verified experimental results using COMSOL simulation, enabling us to assess the importance of the shape and height of the collection chamber in sorting mechanism. Based on the analyses for sperm distribution in the collection chamber, we were able to select sperm with high motility.   

Robustness of diffuse reflectance spectra analysis by the inverse adding-doubling algorithm

Extracting skin properties from diffuse reflectance spectra requires light transport modeling within the tissue. Typically, tissue model parameters defining optical properties are fixed to speed up the fitting process and improve the performance.

We assessed the effect of fixing model parameters on the accuracy and robustness of a GPU-accelerated two-layer inverse adding-doubling (IAD) algorithm by calculating RMSE and MAE for estimated parameters and fitted spectra. Specifically, multiple model parameters in 27 fitting cases were fixed for noiseless simulated skin spectra. Two selected fitting cases were considered for simulated skin spectra with three noise levels added and for in-vivo measured reflectance spectra from hyperspectral images of human hands. Finally, a method was proposed to pre-estimate model parameters from experimental spectra to improve the performance.

Fixing multiple model parameters for simulated spectra reduced SD of estimated parameters up to 10 times to 3%. Pre-estimating parameters improved the agreement of fitted and measured spectra (cumulative RMSE decreased from 0.003 to 0.001) and reduced the fitting time by 0.08 s per spectrum.

Results imply that fixing multiple parameters improves the fitting performance for simulated and experimental skin spectra.   

The Phenomenon Cancer

How does Cancer start to occur behind the scenes? Why does Cancer start at specific locations in the body. What causes cells to replicate in a malign way? What causes cancer to spread to particular locations in the body during particular time points? Cancer, until today a phenomenon, causing often death of living forms. What fundamental force can bring more information about the phenomenon Cancer? The strong force found for the set up of nuclei of atoms, the weak force found as repelling force in nuclei of atoms. Gravitation, the attracting force between entities, stronger with more mass. Electromagnetism the attracting and repelling force of movement of charged entities. The brain organ in living entities produces electromagnetic waves. The cardiac organ in living forms produces electromagnetic waves 5000 times stronger, than the brain organ. The information entering the living system is transformed via four sensory systems into electrical signals, that travels along nerves in the living system. Furthermore, the sensory system called touch, via direct nerve stimulation through e.g. hit/touch of surface locations of living forms can also be found in teeth; seismic waves from entities hitting/touching teeth are transformed into pressure waves in liquid and then transformed into electrical signals. Depending on these incoming signals particular malign occurrences can start in the living system, bacteria, fungi, viruses can take place on the living form/enter the living form. The mathematical representation of a living system can be expressed functional and algebraical. An organ provides a particular function in the living system. Mathematically organs can be represented by functions and algebraically as living system structure. For the phenomenon Cancer it is important to model the phenomenon physically with mathematical expressions. The presentation provides the theoretical part of the research project The Phenomenon Cancer with the King Saud University.