Israel Gannot

Monitoring tumor state from thermal images in animal and human models

PURPOSE Thermography is a potentially useful method for tumor progress monitoring since it is noninvasive, nonradiative, low-cost, and rapid. Perfusion and metabolism are dominant factors for determining tumor temperature difference and are also correlated to the tumors growth rate. Therefore, estimating them from the tumor thermal image can be a very useful tumor monitoring method, since thermal changes occur before physical changes. The goal of this work was to study the effect of tumor state on the thermal image in different tumor types, using simulations and measurements. METHODS Simulated tumor models, representing flat and extruding tumors, typical to transplantable and natural tumors, respectively, were simulated and the effects of tumor metabolism and perfusion on the temperature difference were analyzed. Data regarding tumor size and measured temperature differences were obtained from the literature, discussing five types of transplantable tumors in mice and rats. The growth rates of all tumors were calculated by fitting tumor size measurements to a tumor growth model and were used as an indicator to tumor aggressiveness. Tumor temperature difference was calculated by taking the effect of its extruding shape into account, according to a previously published method. Tumor state was estimated from the normalized temperature differences using simulations and compared to the calculated aggressiveness rates. Computational models of human breast cancers, both in round and flat breast models, were recreated using a finite-element-method heat transfer simulation. Tumor size and state were simulated according to the results obtained from the animal tumor analysis, representing two different tumor aggressiveness levels. The calculated temperature difference as a function of tumor size was calculated for each test case. RESULTS Perfusion was shown to be highly dominant in determining the tumors temperature difference. Since both metabolism and perfusion were shown to have a linear effect on the temperature difference, a conversion value was defined between them. The analysis of the animal experimental results showed correlations between tumor aggressiveness and the following factors: the normalized temperature difference, the estimated tumor state, and the temperature difference change rate. The simulated human breast cancer models analysis showed highly varying temperature differences between the simulated models. Although for each model there is a clear difference between the temperature differences of the test cases simulated, the large differences between the results might make tumor state estimation difficult. However, reviewing the gradient of the tumor temperature change as a function of tumor size showed that the ratio between the gradients of both test cases was similar for all models. Therefore, the effect of model errors and differences in the simulated tissue structure and properties and the environmental conditions between the different models, can be mitigated. This pattern may be used to estimate tumor state in in vivo experiments. CONCLUSIONS Continuous monitoring of tumor temperature difference produces valuable information on tumor state and aggressiveness that can be used both in the clinic and in the laboratory. Monitoring can be either performed on a single image, or continuous on multiple images, revealing changes in tumor state.

Fluorescent probes concentration estimation in vitro and ex vivo as a model for early detection of Alzheimer’s disease

Abstract. The pathogenic process of Alzheimer’s disease (AD) begins years before clinical diagnosis. Here, we suggest a method that may detect AD several years earlier than current exams. The method is based on previous reports that relate the concentration ratio of biomarkers (amyloid-beta and tau) in the cerebrospinal fluid (CSF) to the development of AD. Our method replaces the lumbar puncture process required for CSF drawing by using fluorescence measurements. The system uses an optical fiber coupled to a laser source and a detector. The laser radiation excites two fluorescent probes which may bond to the CSF biomarkers. Their concentration ratio is extracted from the fluorescence intensities and can be used for future AD detection. First, we present a theoretical model for fluorescence concentration ratio estimation. The method’s feasibility was validated using Monte Carlo simulations. Its accuracy was then tested using multilayered tissue phantoms simulating the epidural fat, CSF, and bone. These phantoms have various optical properties, thicknesses, and fluorescence concentrations in order to simulate human anatomy variations and different fiber locations. The method was further tested using ex vivo chicken tissue. The average errors of the estimated concentration ratios were low both in vitro (4.4%) and ex vivo (10.9%), demonstrating high accuracy.

Magnetic nanoparticles-based acoustical detection and hyperthermic treatment of cancer, in vitro and in vivo studies

Abstract. This paper describes a minimally invasive method for detection and growth inhibition of tumors that utilizes the unique properties of super paramagnetic nanoparticles. To demonstrate the feasibility of this method, dimercaptosuccinic acid-coated magnetite nanoparticles were successfully fabricated and used. Those nanoparticles were simultaneously used for magnetoacoustic detection of tumors and for specific hyperthermia treatment in C57BL/J mice injected with Lewis lung carcinoma cells. The in vivo acoustic signal attributed to the nanoparticles was 4.4 dB, while the single session hyperthermia treatment caused a reduction of 50% in tumor growing rate. In addition, a thermography-based method was applied to monitor the efficacy of the hyperthermia treatment. The presented method has the potential to revolutionize current cancer treatment by enabling diagnosis and treatment under real-time feedback in one session.

The effect of geometry on tumor thermal profile and its use in tumor functional state estimation

Thermal differences between transplanted tumors and tumors in humans prevent the implementation of thermographic methods developed in mice models to human models and vise-versa. Transplantable tumors tend to have an extruding shape, which may affect the thermal patterns. This hypothesis was studied in phantom experiments and simulations. A correlation between tumor dimensions and relative temperature was found and used to estimate tumor functional state from previously published in vivo experiments. A correlation was found between temperature differences and tumor growth rates (tumor aggressiveness) and the effect of tumor treatment was demonstrated, showing the potential for in vivo, non-invasive tumor monitoring.

Multilayer Mie Scattering Model for Investigation of Intracellular Structural Changes in the Nucleolus and Cytoplasm

Light scattering from biological cells has been used for many years as a diagnostic tool. Several simulation methods of the scattering process were developed in the last decades in order to understand and predict the scattering patterns. We developed an analytical model of a multilayer spherical scattering cell. Here, we describe the model and show that the results obtained within this simple method are similar to those obtained with far more complicated methods such as finite-difference time-domain (FDTD). The multilayer model is then used to study the effects of changes in the distribution of internal cell structures like mitochondria distribution or nucleus internal structures that exist in biological cells. Such changes are related with cancerous processes within the cell as well as other cell pathologies. Results show the ability to discriminate between different cell stages related to the mitochondria distributions and to internal structure of the nucleolus.

Quantitative study of optical and mechanical bone status using multispectral photoacoustics

Osteoporosis is a major public health problem worldwide. Here, we present a quantitative multispectral photoacoustic method for the evaluation of bone pathologies which has significant advantages over pure ultrasonic or pure optical methods as it provides both molecular information and bone mechanical status. This is enabled via a simultaneous measurement of the bones optical properties as well as the speed of sound and ultrasonic attenuation in the bone. To test the methods quantitative predictions, a combined ultrasonic and photoacoustic system was developed. Excitation was performed optically via a portable triple laser-diode system and acoustically via a single element transducer. Additional dual transducers were used for detecting the acoustic waves that were generated by the two modalities. Both temporal and spectral parameters were compared between different excitation wavelengths and measurement modalities. Short photoacoustic excitation wavelengths allowed sensing of the cortical layer while longer wavelengths produced results which were compatible with the quantitative ultrasound measurements.

Special Section Guest Editorial: Optical Diagnostic and Biophotonic Methods from Bench to Bedside

This PDF file contains the editorial “Special Section Guest Editorial: Optical Diagnostic and Biophotonic Methods from Bench to Bedside” for JBO Vol. 15 Issue 06

Real-time temperature feedback for nanoparticles based tumor thermal treatment (Conference Presentation)

Systemic hyperthermia therapy exploits the fact that cancer cells are more sensitive to elevated temperatures than healthy tissue. Systemic application of hyperthermia externally usually leads to low efficiency treatment. Recently, our group and others have proposed an antibody conjugated magnetic nanoparticles (MNPs) approach to overcome the limitation of systemic hyperthermia. MNPs can bind specifically to the tumor sites, thus delivering internal highly effective targeted hyperthermia. However, such internal mechanism requires more complicated controls and monitoring. This current work presents a deep tissue temperature monitoring method to control hyperthermia effectiveness and minimize collateral damage to surrounding tissues. A low-frequency narrowband modulation of the RF field used for MNP heating leads to the generation of diffused thermal waves which propagate to the tissue surface and captured by a thermal camera. A Fourier domain, analytical heat transfer model is used for temperature monitoring algorithm. The ill-posed thermal inverse problem is solved efficiently by iterating over the source power until both the amplitude and phase match the recorded thermal image sequence. The narrow bandwidth thermal stimulation enables acquiring deep signals with high SNR. We show that thermal transverse resolution improves as the stimulation frequency increases even slightly above DC, enabling better heat source transverse separation and margin identification in the case of distributed tumors. These results can be used as a part of an overall image and treat system for efficient detection of tumors, manipulation of MNPs and monitoring MNP based hyperthermia.

A tribute to Dr. Ron W. Waynant (Conference Presentation)

Ron, our beloved mentor, friend and colleague has passed away on May 7th, 2016. This presentation will follow his life and remarkable achievements. It will describe his work and original developments in three major fields of his interest: his early inventive work on vacuum ultraviolet laser radiation; specialty fiber-optics for laser transmission, especially high-power short-pulse broadband laser delivery of free-electron laser; and up to his latest work on Photobiomodulation. The authors will share their personal experience working with Ron - a Nobel and creative person, however, very humble.

Proposed method for internal electron therapy based on high-intensity laser acceleration

Abstract. Radiotherapy is one of the main methods to treat cancer. However, due to the propagation pattern of high-energy photons in tissue and their inability to discriminate between healthy and malignant tissues, healthy tissues may also be damaged, causing undesired side effects. A possible method for internal electron therapy, based on laser acceleration of electrons inside the patient’s body, is suggested. In this method, an optical waveguide, optimized for high intensities, is used to transmit the laser radiation and accelerate electrons toward the tumor. The radiation profile can be manipulated in order to create a patient-specific radiation treatment profile by changing the laser characteristics. The propagation pattern of electrons in tissues minimizes the side effects caused to healthy tissues. A simulation was developed to demonstrate the use of this method, calculating the trajectories of the accelerated electron as a function of laser properties. The simulation was validated by comparison to theory, showing a good fit for laser intensities of up to 2×1020  (W/cm2), and was then used to calculate suggested treatment profiles for two tumor test cases (with and without penetration to the tumor). The results show that treatment profiles can be designed to cover tumor area with minimal damage to adjacent tissues.