This PDF file contains the front matter associated with SPIE Proceedings Volume 10851, including the Title Page, Copyright information, Table of Contents, Author and Conference Committee lists.

Background & objective: Skin cancer is a very common malignancy that occurs more frequently in fair skin and older individuals. Raman spectroscopy is a non-invasive optical technique that can be used as an adjunct for skin cancer diagnosis. The objective of this study is to evaluate whether incorporating patient demographics can improve skin cancer diagnosis based on Raman spectroscopy. Patients & Methods: Raman spectra of 731 lesions and their respective adjacent normal skin were measured in vivo using a real-time Raman spectrometer. The lesions were divided into skin cancers (including malignant melanoma, basal cell carcinoma, squamous cell carcinoma and precancerous lesion - actinic keratosis, n = 340) and benign skin lesions (including pigmented nevi and seborrheic keratosis, n = 391). Patient age, gender, skin type and location of the lesion were incorporated into the analysis. Multivariate statistical analysis including principal component and general discriminant analysis (PC-GDA) and partial least squares (PLS) are used for skin cancer discrimination based on leave-one-out cross-validation. Results: The posterior probability of being a cancer is significantly dependent on gender, age and location of the lesion (p<0.05) but independent of skin type (p>0.05). The area under the receiver operating characteristic curve (ROC) is increased from 0.905 (95%CI: 0.884-0.927) to 0.932 (95%CI: 0.919-0.945) after taking into account demographics. Correspondingly, the specificity is increased from 43.2% to 50.1% at sensitivity of 99%; and from 73.4% to 77.5% at sensitivity of 90%. Conclusions: The specificity is increased after incorporating demographics into the algorithm for skin cancer diagnosis based on Raman spectroscopy.

Traditional clinical diagnosis and research on skin lesions, performed by visual examination, dermoscopy, biopsy, and pathology, are complemented with newer noninvasive optical imaging approaches, including reflectance confocal microscopy (RCM) and optical coherence tomography (OCT). Limitations such as single contrast (gray-scale) (RCM, OCT), limited structure-specific contrast (RCM, OCT), en face orientation (RCM), relatively low resolution (OCT), and spatially variable speckle noise (RCM, OCT), contrary to the orthogonal orientation, purple and pink color contrast and noise-free appearance of pathology. Interpreting nuclear, cellular and morphologic patterns at different magnifications and scales are mostly manual, qualitative and subjective, with consequent intra- and inter-observer variability among experts and extensive training requirements for novices. These new / developing approaches need quantitative, accurate and repeatable image reading and analysis tools, which may be created with machine learning (ML) and associated methods. Recent advances in ML offer an intellectually rich "sandbox," which can be simply and naively applied as "off the shelf" solutions. However, we contend that for longer-term success, it is critical to avoid such off-the-shelf solutions and instead design novel, specialized, microscopy-specific ML algorithms. The "sandbox" provides ideas, concepts, developments, low-level feature extraction tools and higher-level ML tools. Recent work has focused on using ML for detection of the dermal-epidermal junction in image-stacks (RCM, OCT), classification of cellular patterns in image-mosaics of melanocytic lesions (RCM), basal cell carcinoma detection (OCT), and videomosaicking (RCM). In this presentation, we provide a tutorial on applying ML to skin microscopy in the context of our experience developing novel learning models for RCM skin image analysis.

Multiphoton microscopy imaging techniques provide molecule specific contrast and can produce in vivo histopathology with clearly recognizable features such as cellular and nuclear morphology, collagen, etc. Despite this advantage, high cost, risk of damage from high-intensity pulses, and lack of FDA approval prevents widespread adoption of multiphoton microscopy techniques in conventional clinical scenario. Reflectance confocal microscopy, on the other hand, is much more affordable for clinical scenario, as it is FDA approved, can perform in vivo, non-invasive imaging of specimens with less risk of DNA damage, and even has been granted insurance reimbursement codes. However, the images obtained by reflectance confocal have little resemblance to traditional histopathology due to graininess in the images, and lack molecule specific contrast which makes the images more challenging to interpret and determine a diagnosis,. We propose brining multiphoton-like contrast to confocal instruments by a neural network trained on a set of co-registered reflectance confocal and multiphoton images. We assume that the local reflectance texture of cytoplasm, nuclei, melanin and cytoplasm are distinct within a cell. Once the neural network has been trained, it would be able to distinguish these structures, and produce clear histology-like images from the grainy confocal reflectance data. Our preliminary training results show a successful estimation of multiphoton images from reflectance confocal images by training a 3 layer neural network on a set of 1000 32x32 image patches.

We have recently introduced a novel methodology for noninvasive assessment of structure and composition of human skin in vivo. The approach combines pulsed photothermal radiometry (PPTR), involving time-resolved measurements of mid-infrared emission after irradiation with a millisecond light pulse, and diffuse reflectance spectroscopy (DRS) in visible part of the spectrum (400–600 nm). The experimental data are fitted simultaneously with respective predictions from a four-layer Monte Carlo (MC) model of light transport in human skin. The described approach allows assessment of the contents of specific chromophores (melanin, oxy-, and deoxyhemoglobin), as well as scattering properties and thicknesses of the epidermis and dermis. However, the involved multidimensional optimization with a numerical forward model (i.e., inverse MC) is computationally very expensive. In addition, each optimization task is repeated several times to control the inevitable numerical noise and facilitate escape from local minima. Thus, assessment of 14 free parameters from each radiometric transient and DRS spectrum takes several hours despite massive parallelization using CUDA technology and a high-performance graphics card. To alleviate this limitation, we have constructed a computationally very efficient predictive model (PM) based on machine learning. The PM is an ensemble of decision trees (random forest), trained using ~11,000 "pairs" of various skin parameter combinations and the corresponding PPTR signals and DRS spectra, computed using our forward MC model. We analyze the performance of such a PM by means of cross-validation and comparison with the inverse MC approach.

Assessment of burn severity is critical for wound treatment. Spatial frequency domain imaging (SFDI) has been previously used to characterize burns based on the relationships between histology and tissue optical properties. Recently, multispectral and hyperspectral imaging optical features have been combined with machine learning to classify burn severity. Here, we investigated the use of SFDI reflectance data at multiple wavelengths and spatial frequencies, with a support vector machine (SVM), to predict severity in a porcine model of graded burns. Burn severity predictions using SVM were compared to burn grade determined using histology techniques. Results suggest that the combination of spatial frequency data with machine learning models has the potential for accurately predicting burn severity at the 24 hr postburn time point.

Skin cancers are a world wide deathly health problem, where significant life and cost savings could be achieved if detection of cancer can be done in early phase. Hypespectral imaging is prominent tool for non-invasive screening. In this study we compare how use of both spectral and spatial domain increase classification performance of convolutional neural networks. We compare five different neural network architectures for real patient data. Our models gain same or slightly better positive predictive value as clinicians. Towards more general and reliable model more data is needed and collection of training data should be systematic.

One of the barriers to the widespread use of blue and red light for the treatment of acne has been the availability of a simple to use hands-free portable light delivery system which conforms to the tissue surface and delivers clinically effective dosage without impairing vision, while providing a hands-free wearable delivery system. Our team focused on the development of a printed micro LED flexible substrate to provide 450 nm and red 640 nm pulsed light in a flexible skin adhering re-useable light patch, powered by a small Bluetooth enabled controller.

The dosage and treatment schedules using blue light therapy in the treatment of P.acnes have not been optimized leading to less than satisfactory results and patient compliance. Our team has been developing optimized protocols using pulsed blue light with a novel wearable flexible printed LED substrate to suppress P.acnes bacterial growth. Aim: To optimize antimicrobial protocols using 450 nm pulsed light against P. acnes and correlate optimal bacterial suppression with fluorescence intensity of bacterial absorbing pigments. Methods: Printed 450 nm light substrates in 33% pulsed mode and irradiance of 2 mW/cm2, at various time points were used. The protocol involved multiple exposures (0, 3, and 6 hours) of 450 nm, pulsed 33% at an irradiance of 2 mW/cm2. The change in fluorescence intensity was evaluated after irradiation with 5, 3.6 and 3 J/cm2 on days one, two and three; 5 and 3.6 J/cm2 on day four and 5 J/cm2 on day five. Spectroscopic data, digital images and percent survival were obtained. Results: Optimal bacterial suppression of 100% was obtained using the protocol. Spectroscopic data correlated with the three-hour time interval frame, before the next exposure. The protocol involved a sequential reduction in fluence over a five-day period, correlating with the “depletion and replenishment” of fluorescence intensities of the excited photosensitizers in P. acnes. Conclusion: Both bacterial survival and fluorescence intensity data supports our hypothesis that irradiation of P. acnes three-hours interval produces maximum bacterial suppression. This optimization advances our knowledge towards the use of this protocol in clinical settings.

The terahertz (THz) band lies between the infrared and microwave regions of the electromagnetic spectrum. The 0.1-2.0 THz band is unique in that the radiation is both highly absorbed by liquid water and has a relatively low coefficient of absorption in ice; less than 0.0001% of the radiation survives to a depth of 1.0 millimetre in liquid water, whereas 90% of the signal survives in ice at 0.45 THz. The liquid water absorption has limited the potential for deployment of THz radiation for imaging and therapeutics in human tissues to the level of the epidermis. By first freezing the skin in situ, THz penetration to a depth of 5.0 millimetres becomes viable. Computational modelling using tissue phantoms was used to explore the concept of in situ skin freezing. The modelling indicates that the border between frozen skin and underlying non-frozen tissue provides a reflective boundary, which is the main site for signal return to the surface. The non-frozen layer just under the frozen skin is also the site for most of the THz radiation absorption. The results show that the freezing method may be useful in estimating the depth of frozen skin tissue in cryotherapy, imaging skin lesions and as method of accurate, targeted thermal ablation of lesions within the dermis by delivering high energy THz pulses through a frozen “window”.

The aim of this study was to determine the optical absorption and scattering properties in a large Swedish cohort including 1765 subjects. The study was performed in the Linköping site within the national multicenter Swedish CArdioPulmonary bioImage Study (SCAPIS), a world unique study including detailed imaging and functional analysis of heart, vessels and lungs in 30 000 men and women in Sweden to predict and prevent cardiovascular disease and chronic obstructive pulmonary disease. The subjects, men and women between 50 and 64 years old, were randomly selected and recruited from the population registry in Sweden. Measurements on the volar forearm were performed at baseline and during a systolic occlusion provocation with an integrated system, including spatially resolved diffuse reflectance spectroscopy and laser Doppler flowmetry. Data were analyzed with an inverse Monte Carlo algorithm, accounting for both scattering, geometrical and absorbing properties of the tissue. The absorption coefficient was assumed to differ between the epidermis and the two dermis layers, while the reduced scattering coefficient was equal in all layers. The reduced scattering coefficient (@ 650 nm) was (M ± SD) = 1.68 ± 0.34 mm-1. Gender was found to significant change the fraction of small scattering particles and the reduced scattering coefficient. The absorption coefficient (@ 650 nm) for the dermis layers was 0.010 ± 0.005 mm-1. This large study on optical properties of skin can serve as reference values and provide new knowledge on how factors like gender, age, BMI etc. affect the optical properties.

UV Fluorescence Excitation Imaging (u-FEI) is able to visualize the re-epithelialization of skin wounds at 295 nm excitation wavelength. In this work, we investigated the feasibility of using u-FEI at 295 and 335 nm to visualize the formation of neo-epidermis and evaluate wound closure of partial and full-thickness skin wounds in an animal model. Partial and full-thickness skin wounds were created in the tail of rats. Wounds were imaged at different time points using u-FEI at 295/340 nm and 335/395 nm excitation/emission wavelengths, which correspond to the fluorescence ascribed to tryptophan moieties and pepsin-digestible collagen crosslinks. Because of their penetration depth, these wavelengths probe superficial and deeper fluorophores. Biopsies were collected at specific time points for histology and immunohistology analysis. Neo-epidermis had higher fluorescence intensity at 295 nm than normal skin and lasted one week in both partial and full-thickness skin wounds, then decreased to normal skin intensity values in partial-thickness wounds or decreased even further in full-thickness wounds. In contrast, the fluorescence from the 335 nm excitation band began to increase when the fluorescence at 295 nm was decreasing and show uniform fluorescence distribution when the wound was fully closed. H&E and immunohistology show that fluorescence intensity changes at 295 nm wavelength correlates with keratinocytes proliferation. The combined fluorescence at 295 and 335 nm excitation wavelengths may be useful in evaluating short and mid-term wound healing processes, in particular, formation of neo-epidermis and wound closure.

In this paper we will describe a non-intrusive, optically-based instrument that can quantitatively measure singlet molecular oxygen, a constituent of reactive oxygen species (ROS) produced by irradiation of human skin by the longer wavelength UV radiation known as UVA. UVA is causally associated with DNA damage and subsequent development of melanoma. We will present data from healthy human subjects that show formation of singlet molecular oxygen and concomitant production of thymine dimers, indicative of DNA damage. We will also discuss how this instrument may be a valuable tool for the development of more effective sunblock formulations for UVA.

Early diagnosis of pigmented lesions, specially melanoma, is an unmet clinical need that would help to improve patient prognosis. Apart from histopathological biopsy, the only gold standard non-invasive imaging technique during diagnosis is dermatoscopy (DD). Over the last years, new medical imaging techniques are being developed and Optical Coherence Tomography (OCT) has demonstrated to be very helpful on dermatology. OCT is non-invasive and provides in-depth structural microscopic information of the skin in real-time. In comparison with other novel techniques, as Reflectance Confocal Microscopy (RCM), the acquisition time is lower and the field-of-view higher. Hence, consolidated diagnosis techniques and novel imaging modalities can be combined to improve decision making during diagnosis and treatment.

With actual methods, the delineation of lesion margins directly on OCT images during early stages of the disease is still really challenging and, at the same time, relevant from a prognosis perspective. This work proposes combining DD and OCT images to take advantage of their complementary information. The goal is to guide lesions delineation on OCT images considering the clinical features on DD images. The developed method applies image processing techniques to DD image to automatically segment the lesion; later, and after a calibration procedure, DD and OCT images become coregistered. In a final step the DD segmentation is transferred into the OCT image. Applying advanced image processing techniques and the proposed strategy of lesion delimitation, histopathological characteristics of the segmented lesion can be studied on OCT images afterwards. This proposal can lead to early, real-time and non-invasive diagnosis of pigmented lesions.

An improved optical coherence tomography (OCT) technique called line-field confocal OCT (LC-OCT) has been developed for high-resolution skin imaging. Combining the principles of time-domain OCT and confocal microscopy with line illumination and detection, LC-OCT acquires multiple A-scans in parallel with dynamic focusing. With a quasi isotropic resolution of ∼ 1 μm, the LC-OCT images reveal a comprehensive structural mapping of skin, in vivo, at the cellular level down to a depth of ∼ 500 μm. LC-OCT images of various skin lesions, including carcinomas and melanomas, are found to well correlate with histopathological images. LC-OCT could significantly improve clinical diagnostic accuracy, while reducing the number of biopsies of benign lesions.

Spatial frequency domain imaging (SFDI) is a wide-field imaging technique that enables quantification of in vivo tissue optical properties. SFDI was employed to evaluate burn wounds in pigs where incomplete debridement resulted in skin graft failure. We observed increase in the magnitude of the reduced-scattering coefficient in the wound beds after debridement, prior to grafting in wounds that failed compared to the reduced scattering measured in the wound beds that did not fail. We anticipate that SFDI may be a useful means for determining appropriate debridement prior to grafting.

While most superficial (first degree) burns and full thickness (third degree) burns are easily diagnosed through standard clinical inspection, burns that fall between these extremes are challenging to accurately classify based on clinical appearance alone. Accurate early assessments have the potential to enable earlier debridement and grafting, thereby reducing complication rates, healing times, and chances for infection. To this end, several emerging technologies aim to objectively and non-invasively quantify burn severity, including Spatial Frequency Domain Imaging (SFDI), Laser Speckle Imaging (LSI), and infrared thermal imaging (IR). While these imaging modalities have some diagnostic ability for in-vivo assessment of burn severity, they have not been directly compared in a controlled experiment. Here we compare the ability of these techniques to assess the severity of graded burns in a porcine model (n=96 burns, 6 pigs). Biopsies were taken for histological analysis to verify burn severity. Clinical assessment, SFDI, LSI and thermal imaging were performed for all graded burns at 24 and 72 hours post-burn. In terms of accuracy of burn severity assessment, using histology as a reference, SFDI (85%) and clinical analysis (83%) performed significantly better that LSI (75%) and thermography (73%) at the 24 hour post-burn time point. There was no statistically significant improvement in assessment accuracy at the 72 hour post-burn time point, across the imaging modalities. These data indicate that SFDI may provide valuable information to clinicians in future clinical trials. This information can be obtained early in the process, which may hasten surgical intervention and reduce complications.

Spectroscopic imaging of human tissue analyzes backscattered light intensity separated by wavelength. We used a DLP-projector illuminating sinusoidal patterns with varying phase and varying spatial frequency on forearm skin. Detection was done with: 1) a snap-shot filter mosaic camera with 16 wide-band sensitive pixels; 2-3) a four cameras setup with narrow and wide bandwidth optical bandpass filters in the 450-700 nm range, respectively. The detected images were processed with a demodulation scheme, assessing tissue optical parameters, involving light absorption. Calibration was done using an optical phantom with known optical properties. From the absorption coefficient the concentration of skin blood and its oxygenation was determined. We will present results from forearm arterial occlusion and release experiments using the three setups above. Specifically, the effect of the filter bandwidth will be evaluated using data from the multi-camera setups. Furthermore, the snap-shot filter mosaic camera data may be explained by the calculation of modulation using an illumination and detector setup with a broad spectral transmission bandwidth, with considerable variation in μ_a of included chromophores. Approaches for either reducing the effective bandwidth of the filters or by including their characteristic in a light transport model for SFDI modulation, will be proposed.

Background: Serial analysis of cellular dynamics over time offers new insights into human skin responses to solar radiation. However, most of the previous studies are based on biopsy ex vivo analysis approaches that preclude the monitoring of the same cells and sites over time. Optical in vivo microscopy enables the possibility of real-time live cell imaging. Here we report a robust non-invasive method to achieve repeated access to the same micro-location over a long period with unprecedented precision. Methods: The technique is based on a temporary “surface marker” as landmark to help locate the same cells or microstructures between imaging sessions. At baseline, the region-of-interest (ROI) is determined and imaged. At follow up sessions, the ROI can be automatically located. Using this method, we precisely revisited the same cells in human skin after UVB radiation over two weeks. Skin microscopic responses was studied with a multimodality in vivo microscopy system capable of co-registered video rate reflectance confocal microscopy (RCM) imaging, two-photon fluorescence (TPF) imaging and second harmonic generation (SHG) imaging. Results: The quantitative analysis of TPF signal revealed that melanin distribution pattern changed with time after UVB exposure, suggesting that melanin migrates towards the skin surface. Blood flow was monitored in the same capillary over two weeks. Multimodal analyses enabled accurate calculation of viable epidermis, stratum corneum thickness and cell density variations over time, demonstrating the time points of tissue edema and cell proliferation.

Vitiligo is a skin condition in which pigment-producing cells are removed by the immune system, leading to patches of white skin on different parts of the body. Treatments, including UVB light therapy and skin micro-grafting, may lead to repigmentation of the skin; however, treatments are not uniformly successful, and it is currently unclear why some vitiligo areas repigment more rapidly than others. An optical imaging technique that allows non-invasive visualization of melanocytic activity in skin may advance the knowledge about this skin condition and help understand treatment impact. In this pilot study, we employ in-vivo multiphoton microscopy (MPM) to evaluate architectural and structural features of the melanocytes that repigment vitiligo skin. MPM is a nonlinear laser scanning microscopy technique that features sub-cellular resolution and label-free molecular contrast. MPM contrast in skin is derived from two-photon excited fluorescence of NADH/FAD+, keratin, melanin, and elastin, and second-harmonic generation of collagen. We employed a clinical MPM tomograph (MPTflex, JenLab, Germany) to image vitiligo and adjacent normal areas in 10 patients undergoing treatment. The treatment consisted of either UVB light therapy or skin micro-grafting treatment followed by UVB light therapy. We visualized pigment producing melanocytes near hair follicles, migrating melanocytes within the human epidermis, newly pigmented keratinocytes in the basal layer, and epidermal melanin granules. The overarching goal is to use this technology to better define the phenotypic characteristics of migrating melanocytes in the hope of improving transplantation therapies for vitiligo.

Confocal Raman spectroscopy (CRS) is a noninvasive optical method capable of providing endogenous molecule fingerprinting information as well as allowing depth-resolved measurements into biological tissue. For precise data acquisition in highly scattering tissue in vivo, reflectance confocal microscopy (RCM) has been integrated as imaging guidance with confocal Raman spectroscopy system. However, building a CRS system for point of interest (POI) Raman measurement with simultaneous full field of view (FOV) RCM imaging using a single laser is a challenge. In this work, we addressed the challenge using an optical Faraday isolator to separate the returning reflectance confocal signal from the incident laser beam. A single laser source was used for both RCM and CRS measurements by utilizing two polarized beam splitters (PBS): one for splitting the beam into a RCM illumination beam and a CRS excitation beam; the other for merging the two beam together before entering the objective lens. The confocal setting minimizes the Raman signal contribution from the scanning RCM beam to as small as 0.18%. Furthermore, this small portion of Raman signal will not contaminate the CRS Raman spectrum because they are excited by the same laser wavelength. The co-registration of the sectioning plane of the RCM and CRS were confirmed to be within 0.2 micron. This new integrated confocal Raman system allowed us to acquire confocal Raman signals at specific POI under real-time full FOV RCM guidance and monitoring. Application examples for both ex vivo sample and in vivo skin measurements will be presented.

Two-photon microscopy (TPM) was used on ex vivo human samples, including the normal skin and various skin cancers. Herein, specific characteristics of TPM images compatible with the histopathologic findings will be presented to evaluate its clinical availability.

Although both flashlamp-pumped pulsed dye laser and vascular-targeted photodynamic therapy have demonstrated safety and efficacy for port wine stains (PWS), the clinical results of these methods may be limited because the laser parameters used are virtually identical for all PWS patients despite their variations from site to site. A method that combines digital color-image processing with clustering segmentation based on color similarity and spatial proximity is proposed to refine the severity grading of PWS lesions. The evaluation in the color spaces of CIE-L*a*b*, value of a*, and erythema index are analyzed and compared, and the severity level grading is refined with the reference of a 10-level red color bar. The proposed clustering method can be used as a detailed objective assessment for PWS with a low-cost camera.

Low level light treatment using red and blue light is considered as a novel and non-invasive therapy in a variety of diseases, such as Acne, when the area of therapy is larger than the area that one light source covers. As a result, understanding of the light distribution is needed. On the other hand, dose is also of importance. At present, doses of therapy rely on rough estimation and experience. For this reason, it is of great significance to accurately calculate absorption doses of low-level light /laser therapy for people with various of skin. In this study, we used 3-D voxelized Monte Carlo simulation tool MCVM to accurately calculate the distribution of absorbed photon energy on face of a digital human head model VCH, which is a dataset of adult Chinese male corpse slice images. By simulating the light propagation on three different area on face, which are chain, cheek, and forehead, we demonstrated the typical energy and flux distribution for all these areas. And we found that 0.68cm away from the light source, the absorption intensity is only 0.001 times comparing to the position directly under light source. And the absorption distribution along the depth direction is also shown. The typical distribution in horizontal and depth direction may be a good guidance for the understanding of light therapy in the aspect of dose estimation and light source design.

Due to the topographical location and extensive size, skin encounters high dose of clastogen those cause cancer which can be cured, if diagnosed at the early stage. While visual inspection, histopathological study, bio-sensing, dermoscopy exhibit some limitations, noninvasive optical methods cater comfortable, early and precise diagnosis. In this research, we investigated a multispectral imaging method based on the diffuse reflectance spectroscopy (DRS) to estimate spatiotemporal changes in the light scattering and hemodynamic parameters in mice during cutaneous two-stage chemical carcinogenesis. In this method, Monte Carlo simulation-based empirical formulas assisted in the extraction of the light scattering power b, total hemoglobin concentration C_th, and tissue oxygen saturation StO₂ in the skin. In laboratory environment, we induced mice skin cancer by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-Otetradecanoylphorbol-13-acetate (TPA) and monitored the changes in the cutaneous tissue at a particular interval through capturing multispectral diffuse reflectance images and analyzing over the period of initiation, promotion and progression. The results displayed the decrease in b and increases in both C_th and StO₂ in tumor regions. Significantly, we found that the inception of rapid changes in the scattering parameter is about one to two week(s) earlier than the hemoglobin concentration. On the other hand, at the advanced stage, we also found the blackish discoloration of the skin in the tip of the papilloma when it experienced necrosis, which corresponds to the regional decrease in StO₂ of some large papilloma.