bioRxiv preprint doi: https://doi.org/10.1101/2021.08.16.456538; this version posted August 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. Application of components analysis in dynamic thermal breast imaging to identify pathophysiologic mechanisms of heat transfer Meir Gershensona*, Jonathan Gershensonb aRetired, Merida, Mexico bWest Los Angeles VA Medical Center, Los Angeles CA components analysis resulted in three corresponding Abstract images: 1. Minimum change as a function of applied temperature or time (suggests correlation with the cancer generated heat), 2. Moderate temperature Significance: Of the most compelling unsolved dependence (suggests correlation with veins affected issues in the paradigm to create success in the field of by vasomodulation) and 3. Complex time behavior breast cancer infrared imaging is localization of (suggests correlation with heat absorption due to high direct internal heat of the tumor. The contribution of tumor perfusion). All components appear clear and differential heat production related to metabolism distinct. versus perfusion is not understood. Previous work until now has not shown progress beyond identifying Conclusions: Applying signal processing methods to veins which are fed by the ‘hot’ cancer. Employing the dynamic infrared data, we found three distinct signal analysis techniques, we probe important components with correspondence to understood questions which may lead to further understanding physiologic processes. The two cases shown are self- pathophysiology of heat transfer occurring in the evident of the capability of the method but are setting of malignancy. lacking supporting ground truth that is unavailable with such a limited data set. Validation of this proposed paradigm and studying furthering clinical Aim: When using thermal imaging to detect breast applications has potential to create significant cancer, the dominant heat signature is that of indirect achievement for IR modality in diagnostic imaging. heat transported in gradient away from the tumor location. Unprocessed images strikingly display Keywords:, components analysis, dynamic vasculature which acts to direct excess heat thermogram, metabolic activity, vasomodulation, superficially towards the skin surface before veins. dissipating. In current clinical use, interpretation of thermogram images considers abnormal vascular *Meir Gershenson, E-mail: patterns and overall temperature as indicators of [email protected] disease. The goal of this work is to present a processing method for dynamic external stimulus thermogram images to isolate and separate the 1 Introduction indirect vascular heat while revealing the desired direct heat from the tumor. 1.1 Breast cancer screening Breast cancer is the most diagnosed cancer among Approach: In dynamic thermal imaging of the women. Early detection is thought to be crucial to breast, a timed series of images are taken following improve outcomes. The most common clinically application of external temperature stimulus (most used modalities for screening and diagnostic imaging often cooled air). While the tumor heat response is of breast carcinomas are mammography, ultrasound thought to be independent of the external stimulus, the secondary heat of the veins is known to be and MRI. Mammography is regarded as the gold affected by vasomodulation. The recorded data is standard for screening and guidance of tissue analyzed using independent component analysis sampling for suspected neoplasms. However, certain (ICA) and principal component analysis (PCA) limitations exist: decreased sensitivity in dense breast methods. ICA separates the image sequence into new tissue (more common among younger women), independent images having a common characteristic ionizing radiation dose to the patient (with modest time behavior. Resulting individual components are expectation to result in new cancers among screening analyzed for correspondence to the presence or lack of vasomodulation. population), and inhibitive cost for use in developing, low-income countries. Results: Using the Brazilian visual lab mastology data set containing dynamic thermograms, applying 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.16.456538; this version posted August 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. 1.2 Breast thermography and anatomical tumor location. Use of IR imaging to identify neovascularization has some utility. Novel Thermography is an emission scan of medium or thermal imaging techniques use what is called long wave infrared (IR) electromagnetic radiation “thermal challenge”, “cold-stress” or “dynamic emitted via the body, dependent upon the imaging” where either the breast or some other part temperature. Thus, the IR image of the body is of the body is cooled while taking the thermogram, equivalent to an overall map of external temperature limited success was demonstrated by Y Ohashi and I contained from individual pixels. While Uchida5 who subtract the later cold series images thermography was approved by the FDA as an from initial images taken prior to cold stress. Later adjunct method to mammography in 1982, its’ utility studies6 failed to see an advantage in cold challenge is very limited due to low sensitivity and poor ability using visual interpretation. to distinguish between healthy and diseased tissue. Characteristically, cancer is differentiated by an The authors8,9 in previous work demonstrated use of increased rate of metabolism (imaged directly in equivalent wave field transform (EWFT) applied to FDG PET imaging) and this may be at least partially dynamic data to detect increased perfusion associated responsible for the increase in temperature. with the tumor. EWFT was developed as Additionally, carcinomas are characteristic for nondestructive testing tool and has shown success in increased blood supply via angiogenesis (used in solving the ill-posed, inverse problem associated with contrast imaging techniques, via ‘enhancement’). heat transfer. EWFT mathematically can be described This increase of blood flow to/surrounding the as a linear transform which converts thermal cancerous site is associated with increased ability of diffusive propagation into a wave like propagation. tissues to absorb heat. The bio heat transfer equation The work showing heat absorbing, high perfusion describing thermal propagation is given by1. In vivo regions can act as a high contrast, negative total measurements establishing tumor hyperthermia were reflector. established by Gautherie3, observing typical 1.50C Some success in interpreting breast thermograms was temperature difference between the tissue and the achieved lately using artificial intelligence. Bardia9 average temperature of the blood or similarly the at al used principal component analysis (PCA) temperature difference between the incoming blood applied to dynamic data to identify the veins as to the outgoing blood. It is a consensus among all the preprocessing for AI interpretation. The results are modeling based on the bioheat equation3,4,5 that the very similar to direct application of AI to the raw IR large majority of the heat generate by tumor is absorb images. It appears that AI detection is based on by the perfusion term. None of the models account observing neovascularization. A major disadvantage what happens to this heat when it carries away by the of any methods based on neovascularization is its veins. As we will show this heat will dominate the inability to locate the cancer but only indicates appearance of the diseased breast. As a result, the existence of cancer which requires additional testing heat signature will appear away from the cancerous to localize it. tissue where the blood flows superficially towards the skin surface, where it is dissipated to the surrounding 2 Method environment. Attempts to use thermography as a signature of 2.1Goal cancer has limited success. The temperature of the blood pool within the arterial vascular system defines The goal is to identify cancer by mapping the the body core temperature, assumedly unform temperature of the surface of the breast as a response distribution throughout the body. Thus, we can detect to external temperature change and identify the areas of higher heat signal than the core temperature signature of the cancer. The problem is that most of revealed as contrast within the image, most evident as the internal heat is carried away by the veins, thus the ‘hot veins’ carrying heat from high metabolic activity true location of the heat source is obscured by heat area. There are no publications to show evidence of dissipating through the venous system close to the correspondence between heat signature localization skin. By identifying heat associate with the venous 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.16.456538; this version posted August 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. and removing it we are left with heat