_Applied_  
_sciences_  
_Imaging the Human Thyroid Using Three-Dimensional Diffuse Optical Tomography: A Preliminary Study_  
**[PERSON] 1, [PERSON] 2, [PERSON] 3, [PERSON] 3\({}^{\text{\textregistered}}\) and [PERSON] 1,*_**  
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penetration into the tumor capsule by lesional cells is indicative of malignancy, while others argue that infiltration of tumor cells into the surrounding thyroid parenchyma through the entire thickness of the capsule is capsular invasion [5; 6]. Thus, noninvasive and more sensitive diagnostic approaches to FTC would be helpful. X-ray CT (computed tomography) and MRI (magnetic resonance imaging) are common diagnostic imaging techniques. Since, however, the ability to characterize thyroid nodules and detect small carcinomas is inferior to ultrasound scanning, X-ray CT and MRI are mainly used to evaluate extrathyroid carcinoma extensions [7]. With 18 FDG PET/CT (fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography) it is possible to detect solid tumors but not thyroid cancers, as there is uptake of 18 FDG in chronic thyroiditis [8]. Thyroid cancer is accompanied by functional changes, including angiogenesis [9] and its related molecular responses [10; 11], as well as structural changes. Optical imaging with near-infrared light, including photoacoustic imaging (PAI), diffuse optical spectroscopy (DOS), and diffuse optical tomography (DOT), can noninvasively evaluate hemodynamic and metabolic changes associated with thyroid cancer, and offers the potential for a diagnostic approach to FTC. To date, PAI has been applied to the detection of angiogenesis in thyroid cancer. [PERSON] et al. demonstrated that PAI detected small blood vessels that color Doppler flow imaging (CDFI) could not, whereas it has also been reported that acoustic reflection at large impedance-mismatched boundaries at the trachea caused artifacts in PAI images [12]. This approach could be useful in diagnosing PTC but not for FTC, because FTC is not accompanied by angiogenesis [9]. It has also been suggested that two members of the matrix metalloproteinase family (MMP-2, MMP-9) are biomarkers for FTC [10]. Using an MMP-activatable photoacoustic probe, [PERSON] et al. demonstrated that molecular PAI offers great promise for the diagnosis of FTC, but clinical application appears difficult [13]. [PERSON] et al. employed custom time-resolved spectroscopy and a diffuse correlation spectroscopic system to the measurements of total hemoglobin (Hb) concentrations, tissue oxygen saturation (StO\({}_{2}\)), and blood flow indexes in the thyroid and also in muscles [14]. Several studies have suggested that hypoxia contributes to the progression of thyroid cancer, especially via the hypoxia-inducible factor-1\(\alpha\) (HIF1-\(\alpha\)) [11; 15], and a lower StO\({}_{2}\) has the potential to be an indicator of malignancy. However, with the DOS system of [PERSON] et al., it is difficult to measure the thyroid separately from muscles, while it would be possible with DOT. Diffuse optical tomography is an imaging modality that reconstructs absorption (\(\mu_{a}\)) and reduced scattering (\(\mu_{s}\)') coefficients from boundary measurements [16]. From the reconstructed \(\mu_{a}\), the Hb concentration and StO\({}_{2}\) can be calculated. The \(\mu_{s}\)' reflects morphological and structural changes, such as cell swelling caused by cell injuries, whereas it is unlikely that \(\mu_{s}\)' is altered by capsular and/or vascular invasion by FTC. Cytochrome c oxidase (cyt. ox.) in mitochondria is also a biological chromophore that can be measured by DOT. The redox state of cyt. ox. is dependent on the intracellular oxygen concentration, and its reduction occurs under severe hypoxic conditions [17]. From this, it may be expected that DOT will be able detect FTC by measuring the StO\({}_{2}\) and cyt. ox. in the thyroid. To the best of our knowledge, DOT images of the human thyroid have not been reported, except for those in our simulation study [18].