Dynamic infrared imaging of cutaneous melanoma and normal skin in patients treated with BNCT.
Santa Cruz GA, Bertotti J, Marín J, González SJ, Gossio S, Alvarez D, Roth BM, Menéndez P, Pereira MD, Albero M, Cubau L, Orellano P, Liberman SJ.
Dpto. de Instrumentación y Control, Comisión Nacional de Energía Atómica, Av. del Libertador 8250 (1429), Buenos Aires, Argentina.
We recently initiated a program aimed to investigate the suitability of dynamic infrared imaging for following-up nodular melanoma patients treated with BNCT. The reason that makes infrared imaging attractive is the fact that it constitutes a functional and non-invasive imaging method, providing information on the normal and abnormal physiologic response of the nervous and vascular systems, as well as the local metabolic rate and inflammatory processes that ultimately appear as differences in the skin temperature. An infrared camera, with a focal plane array of 320 x 240 uncooled ferroelectric detectors is employed, which provides a video stream of the infrared emission in the 7-14 microns wavelength band. A double blackbody is used as reference for absolute temperature calibration. After following a protocol for patient preparation and acclimatization, a basal study is performed. Subsequently, the anatomic region of interest is subjected to a provocation test (a cold stimulus), which induces an autonomic vasoconstriction reflex in normal structures, thus enhancing the thermal contrast due to the differences in the vasculature of the different skin regions. Radiation erythema reactions and melanoma nodules possess typically a faster temperature recovery than healthy, non-irradiated skin. However, some other non-pathological structures are also detectable by infrared imaging, (e.g. scars, vessels, arteriovenous anastomoses and injuries), thus requiring a multi-study comparison in order to discriminate the tumor signal. Besides the superficial nodules, which are readily noticeable by infrared imaging, we have detected thermal signals that are coincident with the location of non-palpable nodules, which are observable by CT and ultrasound. Diffuse regions of fast temperature recovery after a cold stimulus were observed between the third and sixth weeks post-BNCT, concurrent with the clinical manifestation of radiation erythema. The location of the erythematous visible and infrared regions is consistent with the 3D dosimetry calculations.
Scanning for Skin Cancer: Infrared System Looks for Deadly Melanoma
Johns Hopkins University
Johns Hopkins researchers have developed a noninvasive infrared scanning system to help doctors determine whether pigmented skin growths are benign moles or melanoma, a lethal form of cancer. The prototype system works by looking for the tiny temperature difference between healthy tissue and a growing tumor. The researchers have begun a pilot study of 50 patients at Johns Hopkins to help determine how specific and sensitive the device is in evaluating melanomas and precancerous lesions. Further patient testing and refinement of the technology are needed, but if the system works as envisioned, it could help physicians address a serious health problem: The National Cancer Institute estimated that 68,720 new cases of melanoma were reported in the United States in 2009, and it attributed 8,650 deaths to the disease.
To avert such deaths, doctors need to identify a mole that may be melanoma at an early, treatable stage. To do this, doctors now look for subjective clues such as the size, shape and coloring of a mole, but the process is not perfect.
“The problem with diagnosing melanoma in the year 2010 is that we don’t have any objective way to diagnose this disease,” said Rhoda Alani, adjunct professor at the Johns Hopkins Kimmel Cancer Center and professor and chair of Dermatology at the Boston University School of Medicine. “Our goal is to give an objective measurement as to whether a lesion may be malignant. It could take much of the guesswork out of screening patients for skin cancer.”
With this goal in mind, Alani teamed with heat transfer expert Cila Herman, a professor of mechanical engineering in Johns Hopkins’ Whiting School of Engineering. Three years ago, Herman obtained a $300,000 National Science Foundation grant to develop new ways to detect subsurface changes in temperature. Working with Muge Pirtini, a mechanical engineering doctoral student, Herman aimed her research at measuring heat differences just below the surface of the skin.
Because cancer cells divide more rapidly than normal cells, they typically generate more metabolic activity and release more energy as heat. To detect this, Herman uses a highly sensitive infrared camera on loan from the Johns Hopkins Applied Physics Laboratory. Normally, the temperature difference between cancerous and healthy skins cells is extremely small, so Herman and Pirtini devised a way to make the difference stand out. First, they cool a patient’s skin with a harmless one-minute burst of compressed air. When the cooling is halted, they immediately record infrared images of the target skin area for two to three minutes. Cancer cells typically reheat more quickly than the surrounding healthy tissue, and this difference can be captured by the infrared camera and viewed through sophisticated image processing.
“The system is actually very simple,” Herman said. “An infrared image is similar to the images seen through night-vision goggles. In this medical application, the technology itself is noninvasive; the only inconvenience to the patient is the cooling.”
The current pilot study is designed to determine how well the technology can detect melanoma. To test it, dermatologist-identified lesions undergo thermal scanning with the new system, and then a biopsy is performed to determine whether melanoma is actually present.
“Obviously, there is a lot of work to do,” Herman said. “We need to fine-tune the instrument—the scanning system and the software—and develop diagnostic criteria for cancerous lesions. When the research and refinement are done, we hope to be able to show that our system can find melanoma at an early stage before it spreads and becomes dangerous to the patient.”
Alani, the skin cancer expert, is also cautiously optimistic. “We, at this point, are not able to say that this instrument is able to replace the clinical judgment of a dermatologist, but we envision that this will be useful as a tool in helping to diagnose early-stage melanoma,” Alani said. “We’re very encouraged about the promise of this technology for improving our ability to prevent people from actually dying of melanoma.”
The researchers envision a hand-held scanning system that dermatologists could use to evaluate suspicious moles. The technology also might be incorporated into a full-body-scanning system for patients with a large number of pigmented lesions, they said.
The skin cancer scanning system is protected under an international patent application submitted by the Johns Hopkins Technology Transfer office, with Herman, Alani and Pirtini listed as the inventors. No commercialization agreement has been reached, but the technology transfer staff has engaged in talks with investors and medical device firms concerning possible licensing deals. Any business arrangements involving the inventors would be managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
Johns Hopkins Kimmel Cancer Center: http://www.hopkinskimmelcancercenter.org/
Johns Hopkins Department of Mechanical Engineering: http://www.me.jhu.edu/
Johns Hopkins University news releases can be found on the World Wide Web at http://releases.jhu.edu/
Office of News and Information
Johns Hopkins University
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Quantitative visualization and detection of skin cancer using dynamic thermal imaging.
Herman C, Pirtini Cetingul M. Department of Mechanical Engineering, The Johns Hopkins University.
In 2010 approximately 68,720 melanomas will be diagnosed in the US alone, with around 8,650 resulting in death (1). To date, the only effective treatment for melanoma remains surgical excision, therefore, the key to extended survival is early detection (2,3). Considering the large numbers of patients diagnosed every year and the limitations in accessing specialized care quickly, the development of objective in vivo diagnostic instruments to aid the diagnosis is essential. New techniques to detect skin cancer, especially non-invasive diagnostic tools, are being explored in numerous laboratories. Along with the surgical methods, techniques such as digital photography, dermoscopy, multispectral imaging systems (MelaFind), laser-based systems (confocal scanning laser microscopy, laser doppler perfusion imaging, optical coherence tomography), ultrasound, magnetic resonance imaging, are being tested. Each technique offers unique advantages and disadvantages, many of which pose a compromise between effectiveness and accuracy versus ease of use and cost considerations. Details about these techniques and comparisons are available in the literature (4). Infrared (IR) imaging was shown to be a useful method to diagnose the signs of certain diseases by measuring the local skin temperature. There is a large body of evidence showing that disease or deviation from normal functioning are accompanied by changes of the temperature of the body, which again affect the temperature of the skin (5,6). Accurate data about the temperature of the human body and skin can provide a wealth of information on the processes responsible for heat generation and thermoregulation, in particular the deviation from normal conditions, often caused by disease.
However, IR imaging has not been widely recognized in medicine due to the premature use of the technology (7,8) several decades ago, when temperature measurement accuracy and the spatial resolution were inadequate and sophisticated image processing tools were unavailable. This situation changed dramatically in the late 1990s-2000s. Advances in IR instrumentation, implementation of digital image processing algorithms and dynamic IR imaging, which enables scientists to analyze not only the spatial, but also the temporal thermal behavior of the skin (9), allowed breakthroughs in the field. In our research, we explore the feasibility of IR imaging, combined with theoretical and experimental studies, as a cost effective, non-invasive, in vivo optical measurement technique for tumor detection, with emphasis on the screening and early detection of melanoma (10-13). In this study, we show data obtained in a patient study in which patients that possess a pigmented lesion with a clinical indication for biopsy are selected for imaging. We compared the difference in thermal responses between healthy and malignant tissue and compared our data with biopsy results. We concluded that the increased metabolic activity of the melanoma lesion can be detected by dynamic infrared imaging.
Infrared Thermography to Assess Proliferation and Involution of Infantile Hemangiomas
Javed Ayoub Mohammed, MD1
; Alexandra Balma-Mena, MD2
; Ajith Chakkittakandiyil, MD3
; Florentina Matea, MD4
; Elena Pope, MD5 JAMA Dermatol.
Importance Infantile hemangiomas (IHs) are common benign tumors of infancy that have the potential to interfere with vital organ function and cause permanent disfigurement. Currently, few objective and validated measures exist to assess IHs.
To determine the utility of infrared thermography in assessing and monitoring the growth of IHs.
Design, Setting, and Participants In a prospective cohort study conducted at an outpatient dermatology clinic of a tertiary care hospital between February 2011 and December 2012, a convenience sample of 42 infants aged 0 to 6 months with an IH were enrolled. The mean age of the study group was 3.7 months, with the majority of IHs being mixed type (57%) affecting the head and neck (81%). Of the infants, 36 (86%) were receiving active treatment during the study period, and patients were followed for a minimum of 3 clinical visits, at least 1 month apart.
Main Outcomes and Measures Ability of infrared thermography to assess the proliferation and involution of IHs compared with a visual analog scale. Secondary outcomes were reliability, ease of use, and parental acceptance of the instrument.
The mean temperature difference at baseline was 1.9°F (95% CI, 1.2°F to 2.7°F), which peaked at 3 months to 2.5°F (95% CI, 0.8°F to 4.2°F), and decreased progressively to 0.2°F (95% CI, −1.1°F to 1.4°F) at 18.5 months (P
< .001). This change in temperature was inversely correlated with mean visual analog scale (r
= −0.25). Mean temperature differences recorded at baseline and 30 minutes later were not significant (least squares mean baseline temperature, 87.9°F [95% CI, 87.4°F to 88.3°F], vs least squares mean temperature after 30 minutes, 88.1°F [95% CI, 87.7°F to 88.6°F] [P
= .14]). Multivariate analysis demonstrated facial location (F1,365
= 47.63, P
< .001), IH type (F2,365
= 3.26, P
= .04), age (F2,365
= 7.03, P
= .001), and surface area at baseline (F2,365
= 8.18, P
< .001) as factors significantly affecting temperature difference over time. Only IH type (Wald χ22
= 6.79, P
= .03) and treatment (Wald χ21
= 4.29, P
= .04) significantly affected time to reach a zero-temperature difference. All caregivers (100%) reported IRT to be easy to implement, quick to perform, and comfortable for their child.
CONCLUSIONS AND RELEVANCE
Infrared thermography is a reliable and valid measure of IH growth that is noninvasive, convenient, and well tolerated by infants, making it well suited to daily clinical practice. It has the potential to provide real-time objective results that can be used for routine monitoring and evaluating treatment efficacy.
Infantile hemangiomas (IHs) are the most common benign tumors of infancy, affecting nearly 10% of children.1,2
Their clinical presentation can vary significantly, from small superficial papules to large tumors that can interfere with vital organ function and/or cause permanent disfigurement. The natural history of IHs is characterized by proliferation and slow involution over several years.2
Accurate assessments of where on the proliferation-involution curve a particular IH lies, at any given time, is important in both making appropriate treatment recommendations, as well as evaluating treatment efficacy. Despite its importance, routine assessment of IHs has largely remained unchanged for decades, often relying solely on the physician’s subjective assessment of color, size, tenseness, and temperature.
Currently, few objective and validated measures exist to assess IHs. Visual analog scales (VAS) have been widely used in the literature to measure the change in the size and extent of IHs.3– 6
Several mathematical formulas using measured parameters have been proposed to be accurate estimates of IH volume, but none have proven ideal for all types.7– 9
Other modalities such as ultrasonography10,11
and various imaging techniques are not always practical for routine clinical assessments.
Both physicians and parents report that surface temperature tends to correlate with IH growth; the proliferative phase is characterized by increased tactile local temperature with normalization during involution. Its major limiting factor has been the lack of a quantifiable and convenient tool that can measure these temperature changes in the clinical setting. Recently, infrared thermography (IRT) has been shown to be an objective measure of local temperature differences and a safe and useful method to evaluate several thermal-related pathologic states.12
Infrared thermography has been used in the assessment of vascular malformations and burns, as well as digit reimplantation and prediction of diabetic foot ulcers.12– 14
However, its use in IHs has been limited to date, with only a few studies reporting its use.12,15,16
The purpose of the present study was to examine the clinical utility, reliability, and validity of IRT in monitoring the growth pattern of IHs.
The study protocol was approved by the Hospital for Sick Children Research Ethics Board, Toronto, Ontario, Canada. Written informed consent was obtained from the infants’ parents prior to inclusion in the study. This prospective cohort study was conducted between February 2011 and December 2012 at the Dermatology Department at the Hospital for Sick Children, Toronto, a tertiary academic referral center. Infants with an IH diagnosed between the ages of 0 and 6 months, with a minimum of 3 follow-up visits at least 1 month apart, were included. Exclusion criteria were mid-line lesions (due to inability to select a non-affected contralateral side) and ulcerated, secondarily infected, or actively bleeding IH. Age and sex were recorded for each patient, as well as the clinical characteristics of the IH including type (superficial, deep, or mixed), location, and surface area. Photographic documentation was performed for all IHs at each visit. The procedure for acquiring photographs was standardized through written guidelines. Data on the ease of administration of IRT, perception of invasiveness, and time to measure the temperature were collected using a structured questionnaire administered to parents.
The local temperature of each IH was independently measured by a research assistant using the TempTouch digital IRT device (Diabetica Solutions Inc). Several studies demonstrated its utility in reducing the incidence of diabetic foot ulcers by monitoring skin temperature.13,14
This thermographic device has a “gooseneck”-designed probe, allowing for easy access to nearly all anatomical locations. The probe is touched to the surface of the IH, and after a few seconds of contact it automatically displays the temperature on a digital screen. The device measures the temperature in Fahrenheit, and as a result these units were used for all subsequent analysis. For IHs with a width (measured across the lesion) of 3.99 cm or less, a single reading was taken from the center of the IH. For an IH with a width of 4 cm or greater, 2 readings were taken, one from the central region and one from the periphery of the IH. These values were chosen based on the IRT probe having a diameter of 1.5 cm. Infrared thermography was also used to measure the temperature from the contralateral nonaffected side to obtain a temperature difference, similarly to previous studies using this thermographic device.13,14
In addition, a temperature reading was performed 30 minutes from the first measurement to test reliability. This method was used at the first baseline visit and at all subsequent visits, which were typically within 2 months of each other. Patients were included in the final data analysis if they had a baseline visit and at least 2 follow-up visits.
The primary outcome of the study was to examine the ability of IRT to assess the proliferation and involution of IHs as evaluated using a VAS. The VAS uses a 100-mm scale, where −100 represents a doubling in the size and extent of the IH; 0, no change, and +100, complete resolution (therefore, 5 mm reflects a 10% change). One assessor (J.A.M.), blinded to the temperature readings, reviewed all pictures at the end of the study and provided a VAS score at each visit by comparing each follow-up visit photograph with baseline in terms of size and extent. The temperature difference (temperature of the IH minus temperature of the contralateral side) for each patient was compared with the changes in the VAS over time.
Descriptive statistics were used to summarize the data. For the primary outcome, the correlation (r
) between investigator VAS and temperature difference was calculated. Analysis of variance was used to compare initial and 30-minute temperature differences. To ascertain factors affecting temperature difference over time, a multivariate analysis using temperature as a continuous variable was used. Factors affecting time to zero-temperature difference were calculated using a multivariate log-logistic regression analysis. Statistical significance was set at P
< .05. All analyses were performed using SAS 9.2 (SAS Institute Inc).
Forty-two infants were enrolled, with the majority being female (n = 35 [83%]). The mean (SD) age at enrollment was 3.7 (1.36) months. The most common location was the head and neck area (n = 34 [81%]), followed by the trunk (n = 3 [7%]), extremities (n = 3 [7%]), and genital area (n = 2 [5%]). Mixed IHs (superficial and deep components) were the predominant type (n = 24 [57%]), with the least common being deep type (n = 4 [10%]). Most patients (n = 36 [86%]) were receiving treatment during the study, which included propranolol hydrochloride (n = 20 [56%]), nadolol (n = 6 [17%]), timolol maleate gel, 0.5% (n = 5 [14%]), and combination treatment (n = 5 [14%]).
The mean temperature difference at baseline was 1.9°F (95% CI, 1.2°F to 2.7°F), which peaked at 3 months to 2.5°F (95% CI, 0.8°F to 4.2°F). This was followed by a plateau between 8 to 12 months after which the temperature decreased progressively to 0.2°F (95% CI, −1.1°F to 1.4°F) at 18.5 months (P
< .001) (Figure
). The mean VAS score increased progressively over the same period and was inversely correlated with mean temperature difference (r
= −0.25) (Figure
). A multivariate analysis demonstrated facial location (F1,365
= 47.63, P
< .001), IH type (F2,365
= 3.26, P
= .04), age (F2,365
= 7.03, P
= .001), and surface area at baseline (F2,365
= 8.18, P
< .001) as factors affecting temperature difference over time. In an analysis of variables affecting time to reach a zero-temperature difference, between the affected and contralateral side, only IH type (Wald χ22
= 6.79, P
= .03) and treatment (Wald χ21
= 4.29, P
= .04) were significant (Table
). Receiving active treatment was associated with less time to reach a zero-temperature difference. At 18 months, 32 of 36 treated IHs (89%) reached a zero-temperature difference vs 3 of 6 untreated IHs (50%). For IH types, deep IHs required the least amount of time to reach a zero-temperature difference, followed by mixed and superficial IH. All deep (4 of 4) and superficial (14 of 14) IHs had zero-temperature difference at 18 months vs 17 of 24 mixed IHs (72%)
To assess reliability of the IRT, IH temperature assessments were repeated 30 minutes after the initial reading. The mean temperature difference between these 2 time points was not significant (least squares mean baseline temperature, 87.9°F (95% CI, 87.4°F to 88.3°F) vs least squares mean temperature after 30 minutes, 88.1°F (95% CI, 87.7°F to 88.6°F) (P
The results of the parent questionnaire revealed that of the 38 of 42 parents who completed the survey, 38 (100%) believed that IRT was an easy method to implement, with no parents disclosing any inconveniences of the tool. Similarly they reported that it took less than 30 seconds to measure the temperature and no parent expressed concerns about the child’s discomfort during the testing.
In this prospective study, IRT was demonstrated to be an objective and reliable method for assessing the proliferation and involution of IHs. It was also found to be a convenient and noninvasive technique that is well tolerated by patients and easily implemented into routine clinical practice.
Infantile hemangiomas are clinically heterogeneous, making it difficult to adequately quantify the size of one particular lesion and to monitor progression over time. At present, a standardized method for assessing the growth of IHs is lacking. Few modalities exist that are objective, reliable, and validated for every day clinical practice. Visual analog scale has been widely used as an objective measure,3– 6
but its validity is dependent on the quality of the picture and it is subject to intrapersonal and interpersonal variability. Several reports have proposed estimating the volume of IHs using mathematical formulas based on measured parameters. Both Tsang et al7
and Dixon et al8
described formulas for estimating the volume of IHs through assuming their shapes as perfect or half spheres. A third more versatile method has been developed that accurately measures the volume of ellipsoid IHs, not accounted for by the aforementioned formulas, and is as accurate in measuring spherical IHs.9
Although these methods can be performed at the bedside, no one formula is universally applicable to all IH shapes, and none measure the volume of IHs below the skin.7– 9
Furthermore, they all require taking precise measurements from an active infant and at times from difficult to access anatomical areas. Most recently, grading scales that attempt to standardize the severity of IHs and its complications have been developed for longitudinal use.17
These have been shown to have good reliability, but they were not designed to provide information with regard to IH volume and extent.17
Imaging such as ultrasonography and magnetic resonance imaging have also been used to objectively measure IH growth and involution. Several studies have used ultrasonography to measure IH thickness, as well as resistivity index, as a measure of blood flow to follow IH regression.11,18,19
However, the objectivity and reliability of the resistivity index has been questioned by some authors owing to high variability and dependency on the activity of the patient.11
Its everyday clinical use is further limited by interoperator variability11,20,21
and the need for an experienced ultrasonographer. In addition, painful ulcerated IHs and certain anatomical locations are not amenable to acquiring a sufficient ultrasound study, particularly in young, active children.11,19
In a study by Schiestl et al11
examining the efficacy of propranolol to treat IHs, only 11 of the 25 patients studied had technically sufficient ultrasound studies.11
Magnetic resonance imaging may provide an assessment of the volume and extent of IH,22,23
but its cost, need for sedation in young children, and limited availability precludes its routine use for monitoring of the progression of IHs. Magnetic resonance imaging use is largely limited to the diagnosis, evaluation, and progression of extracutaneous IHs.24
The use of IRT in the assessment of IH growth has been scarcely reported since it was first described in 1975 in a heterogeneous population of IHs and vascular malformations.15
Subsequently, Desmons et al,16
in a study of 25 IHs and IRT, reported a temperature difference of greater than 0.5°C between the IH center and the surrounding or contralateral skin in 92% of the IHs studied. Most recently, IRT was used to follow the clinical progression of 32 cutaneous IHs.12
Consistent with our findings, both studies reported a decrease in the temperature difference over the course of the studies, although the specific data, including patient ages and follow-up times, were not provided.12,16
In addition, the temperature change observed over time in the present study was closely correlated with previous studies describing IH growth characteristics.25
The peak temperature difference was achieved at 3 to 4 months of age, the period during which the most rapid proliferation of IHs is known to occur, while a steady decrease in temperature was noted starting at 12 months of age, when most IHs begin to involute.25
The changing temperature in IHs is thought to reflect changes in blood flow with ongoing proliferation characterized by increasing blood flow and involution characterized by a reduced blood flow secondary to endothelial cell apoptosis. The changes in blood flow lead to varying degrees of transmitted infrared radiation, which is detected by the IRT device.12,15,16
Interestingly, as some IHs neared almost complete involution, a negative temperature difference was detected (data not shown). These results suggest that the fibrofatty tissue that replaces tumoral tissue may be less well perfused than normal skin. Alternatively, this finding may reflect the fact that residual fibrofatty tissue, particularly from those resulting from mixed IH, may be farther from the body, leading to a reduced surface temperature.
Several factors were demonstrated to influence temperature change over time including facial location, IH type, age, and surface area at baseline. It has been well described that superficial IHs have a shorter growth phase than deep IHs,25
while clinically smaller IHs are often observed to involute more rapidly, potentially owing to their smaller volume. The influence of age at baseline may relate to its impact on the timing of the presentation before or after the peak temperature difference and as a result the overall temperature difference. We also examined variables affecting time to reach a zero-temperature difference because this was believed to be the best outcome measure correlating with significant clinical IH involution. In this analysis, only IH type and treatment were found to be significant. As expected, receiving active treatment was associated with a reduced time to zero-temperature difference. Of the IH types, deep IHs required the least amount of time to reach this outcome. This may have been secondary to the small sample size and thus needs to be interpreted with caution. Interestingly, the median time required to reach a zero-temperature difference for mixed IHs was less than for superficial IHs. However, a higher percentage of patients with superficial IHs (100%) vs mixed IHs (72%) achieved this end point at 18 months of age, reflecting the quicker overall involution of superficial IHs often observed in clinical practice.
As a tool to evaluate IH growth, IRT has several advantages. It is time efficient, safe, painless, and practical for monitoring IHs at virtually any cutaneous location. Most importantly, it was well accepted by parents as a noninvasive assessment tool and was well tolerated by infants. Saxena and Willital12
reported similar findings in a 10-year review of IRT in various pediatric conditions including IHs, vascular malformations, burns, wound infections, and digit amputations. These characteristics make IRT an ideal tool for making treatment related decisions at the bedside, in addition to providing an objective measure of IH involution in treatment intervention studies, an area currently lacking a readily available and noninvasive objective outcome tool. Infrared thermography in conjunction with clinical assessments may be able to better reassure parents that a particular IH is involuting, possibly avoiding unnecessary β-blocker treatment and parental anxiety. Likewise, IRT provides a temperature trend over time that has the potential to detect treatment failures, identify rebound growth earlier, and improve treatment related end points such as timing of β-blocker weaning and cessation. This is supported by a recent pilot study from our center that demonstrated IRT to be a useful tool to measure therapeutic response to a systemic β-blocker.26
Most promisingly, IRT has the advantage of potentially detecting all such changes before they are appreciated clinically; however, this requires further study. Its application to other vascular tumors such as congenital hemangiomas and hemangioendotheliomas also requires further investigation.
Several limitations of the study need to be considered. Imaging studies would have provided a more objective independent measure of IH growth; however, this was not feasible given the time needed and frequent follow-up required. For this reason, VAS was used because it is noninvasive, can be applied to all IH types, and is a well-accepted measure of growth in IH treatment trials. Although it was demonstrated that IRT can be used for monitoring all IH types at various locations, midline IHs were excluded because they do not have a corresponding contralateral area of normal skin from which to measure the temperature difference. Several studies have shown that the surrounding skin can be used, but this was not evaluated in the present study.15,16
Ulcerated, bleeding, and infected IHs were also excluded because these may have caused false temperature elevations that were not truly reflective of increased IH growth. In theory, these IHs could be followed with IRT, which may have the additional advantage of detecting ulcerations before they occur clinically and monitoring their resolution. This is supported by evidence from adult studies in which IRT has been proven to reduce diabetic ulcerations through detection of asymptomatic inflammation. The application to ulcerated IHs requires further evaluation.
With the emergence of newer and safer treatments for IHs, it has become increasingly important to have a standardized objective measure of growth. The present study demonstrates that IRT is a reliable and valid measure of IH growth that is well adapted to the clinical setting. It has the potential to provide the clinician with real-time results from which management decisions can be made and treatment efficacy evaluated. Future studies are required to evaluate IRT in relation to other objective measures of IH growth, as well as to assess its applicability in complicated IHs.
Accepted for Publication: January 27, 2014.
Corresponding Author: Javed Ayoub Mohammed, MD, Department of Pediatrics, Children’s Hospital at London Health Science Centre, University of Western Ontario, 769 Southdale Rd E, Unit 9D, London, ON N6E 3B9, Canada (firstname.lastname@example.org
Published Online: June 18, 2014. doi:10.1001/jamadermatol.2014.112.
Author Contributions: Drs Mohammed and Pope had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design:
Balma-Mena, Chakkittakandiyil, Pope.
Acquisition, analysis, or interpretation of data:
Mohammed, Matea, Pope.
Drafting of the manuscript:
Mohammed, Balma-Mena, Matea.
Critical revision of the manuscript for important intellectual content:
Mohammed, Chakkittakandiyil, Pope.
Administrative, technical, or material support:
Conflict of Interest Disclosures: None reported.
Additional Contributions: Ellen Maki, PhD, assisted with statistical analysis, Michelle V. Lee, RN, obtained photographic data, and Hanna Fadzeyeva assisted in data collection. Dr Maki and Ms Fadzeyeva received financial compensation for their contributions.
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Active and Passive Optical Imaging Modality for Unobtrusive Cardiorespiratory Monitoring and Facial Expression Assessment.
Blazek V, Blanik N, Blazek CR, Paul M, Pereira C, Koeny M, Venema B, Leonhardt S.
Because of their obvious advantages, active and passive optoelectronic sensor concepts are being investigated by biomedical research groups worldwide, particularly their camera-based variants. Such methods work noninvasively and contactless, and they provide spatially resolved parameter detection. We present 2 techniques: the active photoplethysmography imaging (PPGI) method for detecting dermal blood perfusion dynamics and the passive infrared thermography imaging (IRTI) method for detecting skin temperature distribution. PPGI is an enhancement of classical pulse oximetry. Approved algorithms from pulse oximetry for the detection of heart rate, heart rate variability, blood pressure-dependent pulse wave velocity, pulse waveform-related stress/pain indicators, respiration rate, respiratory variability, and vasomotional activity can easily be adapted to PPGI. Although the IRTI method primarily records temperature distribution of the observed object, information on respiration rate and respiratory variability can also be derived by analyzing temperature change over time, for example, in the nasal region, or through respiratory movement. Combined with current research areas and novel biomedical engineering applications (eg, telemedicine, tele-emergency, and telemedical diagnostics), PPGI and IRTI may offer new data for diagnostic purposes, including assessment of peripheral arterial and venous oxygen saturation (as well as their differences). Moreover, facial expressions and stress and/or pain-related variables can be derived, for example, during anesthesia, in the recovery room/intensive care unit and during daily activities. The main advantages of both monitoring methods are unobtrusive data acquisition and the possibility to assess vital variables for different body regions. These methods supplement each other to enable long-term monitoring of physiological effects and of effects with special local characteristics. They also offer diagnostic advantages for intensive care patients and for high-risk patients in a homecare/outdoor setting. Selected applications have been validated at our laboratory using optical PPGI and IRTI techniques in a stand-alone or hybrid configuration.
Infrared Imaging Tools for Diagnostic Applications in Dermatology.
Abhijit Achyut Gurjarpadhye, Mansi Bharat Parekh, Arita Dubnika, Jayakumar Rajadas, and Mohammed Inayathullah
Infrared (IR) imaging is a collection of non-invasive imaging techniques that utilize the IR domain of the electromagnetic spectrum for tissue assessment. A subset of these techniques construct images using back-reflected light, while other techniques rely on detection of IR radiation emitted by the tissue as a result of its temperature. Modern IR detectors sense thermal emissions and produce a heat map of surface temperature distribution in tissues. Thus, the IR spectrum offers a variety of imaging applications particularly useful in clinical diagnostic area, ranging from high-resolution, depth-resolved visualization of tissue to temperature variation assessment. These techniques have been helpful in the diagnosis of many medical conditions including skin/breast cancer, arthritis, allergy, burns, and others. In this review, we discuss current roles of IR-imaging techniques for diagnostic applications in dermatology with an emphasis on skin cancer, allergies, blisters, burns and wounds.
Skin is the largest organ of the human body and serves as a barrier between the surrounding environment and the body’s internal organs. With its multi-layered structure, skin protects the body from any potential attacks by pathogens in the surrounding atmosphere. Compromising integrity of this barrier or imbalance in the skin composition could lead to various skin injuries or conditions ranging from pruritus, rashes, scars to allergies and cancers. More importantly, several skin conditions are often symptoms of more serious systemic complications and must be examined promptly for early diagnosis [1–3].
The first step of diagnosis for such conditions usually involves visual inspection and non-invasive imaging. However, while there is normally a direct line-of-sight available for the stratum corneum of the skin, interrogating deeper layers requires more sophisticated techniques. Biopsy and microscopy may allow clinicians to examine the tissue and diagnose conditions, however, such techniques are invasive, time consuming and result in unnecessary scars. Ongoing advancements in photonics and in-depth understanding of light-tissue interactions have resulted in the development of several modern non-invasive imaging techniques. We discuss current trends and developments in infrared (IR) imaging techniques and their applications for diagnosis of dermal diseases and skin conditions.
Visible spectrum is a small portion of the electromagnetic radiation, to which the human eye is sensitive. However, longer wavelengths such as the IR spectrum are extremely useful in visualizing the structure as well as function of the deeper layers of the skin. While the IR spectrum covers wavelengths from 0.7 -1000 μm, only the initial narrow band of the spectrum is used for IR imaging. This spectrum is further divided into three sub-ranges such as near-IR (0.75 -2.5 μm), mid-IR (2.5 – 5 μm) and far-IR (5 -15 μm). The depth of penetration for imaging is largely dependent on the interaction of light with chromophores such as water and hemoglobin present in the skin. The light attenuation due to water in the near-IR range is minimal, thus offering greater depth of penetration; however, high absorption of light in the mid-IR range due to tissue water content results in significant light attenuation. Additionally, due to lack of tunable sources, fiber optic delivery systems and sensitive detectors, very few imaging techniques operate in the mid-IR range. Therefore, most of the biomedical IR imaging modalities utilize the near-IR spectrum for structural as well as functional imaging. Imaging in the far-IR range is predominantly emissive and focuses on recording thermal emissions of tissue.
Optical Coherence Tomography (OCT) is one of the imaging techniques that utilize near-IR radiation. The primary advantages of OCT are high speed, superior resolution and depth-resolved visualization. OCT is a modern imaging technique that uses non-ionizing near-IR radiation (800-1300 nm) for high-resolution (<15 μm), cross-sectional imaging of tissue. It is an optical analogue of ultrasound technology, which operates on the principle of low-coherence interferometry and depicts cross-sections of biological tissues based on the echo time delay of back-reflected light . OCT is a label-free, contactless, non-invasive modality, which has been found to be extremely useful in scientific research and in clinical applications. Due to scattering nature of tissue, the depth of penetration of OCT is typically in range of 1-2 mm, which makes it suitable for structural evaluation of the skin. Various sub-types of OCT have been used for evaluation of skin cancers [5–7], burns scars and wounds [8, 9]. Various techniques such as optical clearing  or mechanical compression [11, 12] have been implemented to improve the penetration depth.
In addition to OCT, near-IR imaging has been used for detection of cutaneous melanin in pigmented skin disorders . Melanin is one of the important endogenous chromophores, which plays a role in many benign and malignant skin disorders such as melanoma. Its autofluorescence under near-IR excitation has been utilized for detection of cutaneous melanin in the skin.
Far-IR imaging, also called thermal IR imaging, uses detectors such as bolometers to detect the infrared emissions from the objects under investigation. These detectors absorb the emissions from the object, which causes their temperature to change. This change in temperature causes change in electrical output as a result of some physical property of the sensor material such as temperature-dependent resistance. Thermal IR imaging has been used for non-contact evaluation of burn wound depths , sports-related injuries , or as an adjunctive screening method for breast cancer [16, 17].
APPLICATIONS OF INFRARED IMAGING FOR DIAGNOSIS IN VARIOUS SKIN CONDITIONS
A) SKIN CANCER
Due to its ability to metastasize, the most serious form of skin cancer is considered to be melanoma . Early detection is crucial to improve survival in patients with this disease. Non-invasive imaging systems that enable accurate quantitative detection of melanoma are important for reducing morbidity and mortality, as well as the cost of care associated with this disease .
Melanoma lesions have been observed to be warmer than the surrounding healthy tissue . By using heating or cooling stimulation, it has been demonstrated that the average thermal signature of melanomas is different than that for the healthy skin [21, 22]. For skin cancer, preliminary assessment thermal imaging can be used as non-invasive, non-contact and safe technique. IR instrumentation advancements, dynamic IR imaging and modern digital signal processing algorithms enabled scientists to analyze spatio-temporal thermal behavior of the skin – an important leap in the cancer diagnosis field .
In the recent years, use of thermal imaging techniques for the detection and differentiation of skin cancer stages have gained exceptional interest. Most studies follow the protocol of basal study for patient preparation and acclimatization. The anatomic region of interest is exposed to a provocation test (usually cold stimulation), which induces an autonomic vasoconstriction reflex in normal structures. Therefore the thermal contrast due to the differences in the vasculature of the different skin regions can be observed. Melanoma typically possesses a faster temperature recovery than healthy, non-irradiated skin. Nevertheless, some other non-pathological structures are also detectable by IR imaging, (e.g. scars, vessels, arteriovenous anastomoses and injuries), thus requiring a multi-study comparison in order to discriminate the tumor signal [18, 19,23–25].
Recent statistical analyses reveal that thermal conductivity and the variation in thickness, blood perfusion as well as specific heat of certain skin layers lead to significant changes in the skin surface temperature, which can influence the detectability of dynamic IR imaging and frequency modulated thermal wave imaging during diagnosis of small volume melanoma [26, 27].
OCT FOR SKIN CANCER DETECTION
Basal cell carcinoma (BCC) is the most common subtype of cancer in the United States . Suspicious lesions are normally biopsied for histopathological evaluation leaving behind unwanted scars and making the diagnosis lengthy and expensive. Recently, Polarization-Sensitive OCT (PS-OCT) – an extension of conventional OCT showed a strong potential for non-invasive assessment of skin lesions exhibiting possibility of BCC . Collagen matrix in the healthy skin is birefringent – an optical property of material that results in two different refractive indices that depend on polarization of the incident light. Skin cancer results in disruption of collagen distribution and alignment, thus destroying the birefringence of the collagen matrix [29–31]. PS-OCT can detect the loss of skin birefringence [32, 33] and could enable identification of BCC lesions .
Human skin color is produced by skin pigments that have spectral absorption properties in the visible range. The saturation levels of melanin and hemoglobin are the main contributors to the skin color and are important in dermatological diagnosis. Allergic dermatitis is characterized by allergic skin inflammation and can be induced by an allergic response to chemical substances brought on by environmental contamination . Spectrophotometric assessments of allergic dermatitis can be performed in the near-IR wavelength range for the evaluation of water content . Stamatas et al. proposed a visible and near-IR spectral imaging method for evaluating erythema and edema in which the values of apparent concentrations of oxyhemoglobin and water were calculated based on an algorithm that takes into account spectral contributions of deoxy-hemoglobin, melanin, and scattering . Nishino et al. proposed a long-wavelength near-IR spectral imaging technique for the assessment of allergic dermatitis to detect and visualize intracutaneous differences caused by the activation mechanisms of different types of allergic dermatitis . Recent studies show that IR thermography is a promising tool for screening the presence of digital dermatitis in dairy cows  suggesting that thermal and IR imaging is a multi-purpose method for all kinds of allergic mammal skin responses.
People with various bullous disorders exhibit blister formations. Autoimmune blistering diseases cause impaired adhesion among epidermal cells . Blisters and vesicles are easily diagnosed clinically, however, evaluating the exact pathology of the blister is where using optical imaging technologies may support clinical diagnosis . Liquid nitrogen- and mechanically induced subepidermal blisters appeared as dark areas under the elevated, hypereflective/backscattering epidermis [39–41]. Explorative studies show that OCT can visualize blisters, epidermis and epidermo-dermal junctions in vivo, thus representing a range of relevant morphologies that match histopathology [38, 42].
D) SKIN BURNS AND WOUNDS
THERMOGRAPHY FOR SKIN BURN ASSESSMENT
It is important to evaluate the surface and the depth of skin burn, especially in the case of a severe burn as the thorough evaluation enables the appropriate choice of treatment. Clinical assessment is currently the most frequently applied method in burn depth evaluation. Unfortunately, the use of this method results in a high number of false diagnoses. For most burn surgeons, burn depth is better defined by the time to heal, which can be linked to the risk of developing hypertrophic scarring. Digital IR thermal imaging, also known as thermography, detects IR radiation, which is used to determine the emitting surface’s temperature by producing a temperature-sensitive pattern on the imaged surface. Zhu et al, showed in 1990 that IR thermography was superior to subjective burn wound assessment . Recent works by Medina-Preciado et al., showed significant difference in the thermal pattern of superficial skin and deep skin burn wounds, which are especially difficult to assess clinically .
Other noninvasive techniques such as laser doppler imaging (LDI) have also been used in the prediction of burn wound severity and result in a higher sensitivity (97%) and specificity (100%) when performed within three days of the burn injury . However, even though LDI is accurate in assessing burn wounds, it is also more expensive and has a steeper learning curve than digital IR imaging . Another advantage of digital IR thermography is its ability to image large skin surface areas, which can aid in identifying regions with different burn depths and estimate the size of the grafts needed for deep skin burns.
OCT FOR BURN WOUNDS ASSESSMENT
Proliferation phase of wound healing involves formation of new blood vessels while the remodeling phase involves scar formation and collagen deposition at the wound site to increase the skin mechanical stability and strength. These stages could be monitored and assessed for quantitative evaluation of healing process using OCT in a non-contact manner. Gong et al  performed PS-OCT imaging of the burn scars and measured the attenuation coefficient of the scar tissue for its comparison with that of the surrounding healthy skin. The attenuation coefficient serves as a marker for the composition of scar or skin and therefore could be used for objective assessment of scars. Additionally, the same research group  also measured the magnitude of birefringence of scars using three-dimensional PS-OCT. Scar tissue typically lacks the birefringence a healthy skin tissue possesses owing to lack of alignment of the newly deposited collagen . Restoration of such birefringence is a marker for better alignment of collagen and could be monitored using PS-OCT.
LIMITATIONS OF THERMAL AND INFRARED IMAGING
Several biomedical imaging modalities operating in the IR spectrum have been developed in the recent years for diagnostic applications (). IR imaging techniques offer high scanning speeds, superior imaging resolution and pose no health hazards as they use non-ionizing radiations. While the IR spectrum has been found to be beneficial for dermatological diagnostic applications, the primary limitation of the IR imaging is the finite depth of penetration, usually confined to 2-3 mm. For skin affected by hypertrophic scarring, sclerosis, or scabs resulting from wounds, this shallow range poses a challenge. Also, native fluorophores such as oxygenated hemoglobin, which absorbs IR, further affect the imaging range adversely.
Additionally, while the IR imaging techniques provide insight into the structural details of the skin; lack of cellular and molecular-level specificity limits the use of these techniques to preliminary diagnosis of skin diseases. Further tests are still necessary for in-depth, comprehensive evaluation of disease symptoms. Novel approaches, such as multimodality imaging are being actively investigated to overcome such limitations .
Thermography, or thermal imaging has been used as a diagnostic tool in veterinary medicine [49–51]; however it is a relatively new technique for clinical application. The accuracy of detection of temperature variations, spatial resolution and reliability is still unclear, making the modality adjunctive instead of a primary diagnostic tool.
We highlighted most of the prominent imaging techniques and modalities operating in the IR region for examination of various skin conditions and for diagnosis of dermal diseases. Due to advantages such as depth-resolved, faster imaging at superior resolutions, IR-based diagnostic techniques are being increasingly preferred over invasive procedures for preliminary evaluation. In case of skin cancer diagnosis, techniques such as OCT have shown significant promise for better assessment of skin lesions and for preventing unneeded biopsies of benign lesions. Far-IR imaging techniques such as thermography or digital IR thermal imaging have the potential to become valuable tools for non-contact, biopsy-free burn wound assessment.
Research in IR imaging techniques has gained significant momentum in the recent years. Development of IR-based novel modalities may result in faster and more reliable diagnosis and could lead to decreased healthcare costs.
The authors thank Dr. Alfred T. Lane of the Stanford Department of Dermatology for his support in this review. The work described was supported by the National Center for Research Resources and the National Center for Advocacy Translational Sciences, National Institutes of Health, through UL1 TR000093 (formerly UL1 RR025744) and SPARK, Spectrum – the Stanford Center for Clinical and Translational Research and Education; the Stanford NIH/NCCR Clinical Translational Science Award grant number TL1 RR025742, and author AD was supported by the Baltic-American Freedom Foundation.
CONFLICT OF INTEREST: The authors declare no conflict of interest.
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Does the temperature gradient correlate with the photodynamic diagnosis parameter numerical colour value (NCV)?
Cholewka A, Stanek A, Kwiatek S, Sieroń A, Drzazga Z. Source Institute of Physics, Department of Medical Physics, University of Silesia, Uniwersytecka 4, 40-007 Katowice, Poland. email@example.com
Photodynamic diagnosis (PDD) as well as thermovision belong to the category of non-invasive optical diagnosis techniques. Among many different skin cancer diseases, basal cell carcinoma (BCC) is the most frequently occurring one (almost 95% of all skin tumours). In contrast, seborrhoeic keratosis represents almost 70% of benign skin tumours. In this paper we present infrared thermography as an additional method, combined with PDD, to show the differentiation between these two skin mutations.
The photodynamic diagnosis studies were performed by using the autofluorescence diagnosis system Xillix Onco. As an additional non-invasive diagnosis technique, thermovision studies were performed. Thermal imaging was done by using a Thermovision Camera A40M with a sensitivity of 0.07K. The thermograms of the chosen areas were performed in a special room with a temperature of 22.5±1°C. All patients were treated in the Chair and Clinic of Internal Diseases, Angiology and Physical Medicine in Bytom. Thirteen skin lesions were studied: 9 diagnosed as basal cell carcinoma and 4 as seborrhoeic keratosis. All skin lesions were confirmed in histopathological examinations.
RESULTS AND CONCLUSIONS
The results of the studies revealed significant differences in skin thermal mapping between patients suffering from basal cell carcinoma and seborrhoeic keratosis. It appears that benign skin lesions are characterised by a lower mean temperature than the surrounding healthy skin. To the contrary, cancerous skin mutations appeared on the thermal map at a higher mean temperature. Thermal images for the chosen skin lesions and temperature parameters derived from the thermograms are contiguous with the photodynamic diagnosis results and may give some additional diagnostic information.
Dynamic infrared imaging of cutaneous melanoma and normal skin in patients treated with BNCT.
Santa Cruz GA, Bertotti J, Marín J, González SJ, Gossio S, Alvarez D, Roth BM, Menéndez P, Pereira MD, Albero M, Cubau L, Orellano P, Liberman SJ.
Dpto. de Instrumentación y Control, Comisión Nacional de Energía Atómica, Av. del Libertador 8250 (1429), Buenos Aires, Argentina. firstname.lastname@example.org
We recently initiated a program aimed to investigate the suitability of dynamic infrared imaging for following-up nodular melanoma patients treated with BNCT. The reason that makes infrared imaging attractive is the fact that it constitutes a functional and non-invasive imaging method, providing information on the normal and abnormal physiologic response of the nervous and vascular systems, as well as the local metabolic rate and inflammatory processes that ultimately appear as differences in the skin temperature. An infrared camera, with a focal plane array of 320 x 240 uncooled ferroelectric detectors is employed, which provides a video stream of the infrared emission in the 7-14 microm wavelength band. A double blackbody is used as reference for absolute temperature calibration. After following a protocol for patient preparation and acclimatization, a basal study is performed. Subsequently, the anatomic region of interest is subjected to a provocation test (a cold stimulus), which induces an autonomic vasoconstriction reflex in normal structures, thus enhancing the thermal contrast due to the differences in the vasculature of the different skin regions. Radiation erythema reactions and melanoma nodules possess typically a faster temperature recovery than healthy, non-irradiated skin. However, some other non-pathological structures are also detectable by infrared imaging, (e.g. scars, vessels, arteriovenous anastomoses and injuries), thus requiring a multi-study comparison in order to discriminate the tumor signal. Besides the superficial nodules, which are readily noticeable by infrared imaging, we have detected thermal signals that are coincident with the location of non-palpable nodules, which are observable by CT and ultrasound. Diffuse regions of fast temperature recovery after a cold stimulus were observed between the third and sixth weeks post-BNCT, concurrent with the clinical manifestation of radiation erythema. The location of the erythematous visible and infrared regions is consistent with the 3D dosimetry calculations.