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BackgroundDue to a large variety in treatment outcomes reported in therapeutic trials and lacking patient-relevant outcomes, it is hard to adequately compare and improve current therapies for patients with capillary malformations (CMs). The Core Outcome Set for Capillary Malformations (COSCAM) project aims to develop a core outcome set (COS) for use in future CM trials, in which we will first develop a core outcome (sub)domain set (CDS). Here, we describe the methods for the development of a CDS and present the results of the first development stage.MethodsThe COSCAM project is carried out according to the recommendations of the Cochrane Skin Core OUtcomes Set INitiative (CS-COUSIN) and the Core Outcome Measures in Effectiveness Trials (COMET) initiative. During the first stage, we identified all potentially relevant outcome subdomains based on a systematic review, two focus group sessions and input from patient representatives of Dutch patient organizations and the COSCAM-founding group. In stage two, we will present the subdomains in a three-round e-Delphi study and online consensus meeting, in which CM patients, parents/caregivers and CM experts worldwide rate the importance of the proposed subdomains, hereby finalizing the core outcome (sub)domains of the CDS.ResultsA total of 67 potential outcome subdomains were included; sixteen were previously used in the literature, 20 were proposed by Dutch patients and their parents/caregivers (n = 13) in focus group sessions and 38 were suggested by the experts of the COSCAM-founding group. Seven were excluded because of overlap.ConclusionThe final CDS may serve as a minimum standard in future CM trials, thereby facilitating adequate comparison of treatment outcomes. After this CDS development, we will select appropriate outcome measurement instruments to measure the core outcome subdomains.

This presentation will discuss recent advances in multiphoton microscopy (MPM) as a tool for in-vivo imaging of human skin to evaluate MPM's potential to enhance the diagnostic accuracy of skin diseases and guide effective treatment.

Here we present a handheld, implementation of Spatial Frequency Domain Spectroscopy (SFDS) that employs line imaging. The new instrument can measure 1088 spatial locations that span a 3 cm line as opposed to our benchtop system that only collects a single 1 mm diameter spot. This imager, however, retains the spectral resolution (∼ 1 nm) and range (450 to 1000 nm) of our benchtop system. The device also has tremendously improved mobility and portability, allowing for greater ease of use in clinical setting. A smaller size also enables access to different tissue locations, which increases the flexibility of the device. The design of this portable system not only enables SFDS to be used in clinical settings, but also enables visualization of properties of layered tissues such as skin.

We have developed a multimode dermoscope (SkinSpect™) capable of illuminating human skin samples in-vivo with spectrally-programmable linearly-polarized light at 33 wavelengths between 468nm and 857 nm. Diffusely reflected photons are separated into collinear and cross-polarized image paths and images captured for each illumination wavelength. In vivo human skin nevi (N = 20) were evaluated with the multimode dermoscope and melanin and hemoglobin concentrations were compared with Spatially Modulated Quantitative Spectroscopy (SMoQS) measurements. Both systems show low correlation between their melanin and hemoglobin concentrations, demonstrating the ability of the SkinSpectTM to separate these molecular signatures and thus act as a biologically plausible device capable of early onset melanoma detection.

Background and objectivePulsed dye laser (PDL) is a commonly used treatment for Port Wine Stain birthmarks (PWS). However, deeper components of PWS are often resistant to PDL. Deeper penetrating lasers, including the long pulsed Neodymium:Yttrium Aluminum Garnet (Nd:YAG) laser have been used, but carry greater risk. This study evaluates the distinct blood vessel thermal responses to visible (595 nm) and near infrared (1,064 nm) lasers using animal and numerical models.Study design/materials and methodsBlood vessels in the rodent dorsal skin chamber (DSC) were irradiated by a 595 nm PDL and a long-pulsed 1,064 nm Nd:YAG laser. Laser-induced immediate and 1-hour post-structural and functional changes in the vessels were documented. Numerical simulations were conducted using a 1,000 µm depth SD mouse skin fold to simulate experimental conditions.ResultsPDL irradiation produced immediate blood vessel hemorrhage. Modeling indicated this occurs due to preferential heating of the superior parts of large blood vessels. Nd:YAG irradiation resulted in blood vessel constriction; modeling indicated more uniform heating of vessel walls.ConclusionPDL and Nd:YAG lasers result in distinct tissue responses. This supports different observable clinical treatment end points when using these devices. Vessel constriction associated with the Nd:YAG may be more difficult to observe and is one reason this device may carry greater risk.

Selective photothermolysis is the basic principle for laser treatment of vascular malformations such as port wine stain birthmarks (PWS). During cutaneous laser surgery, blood inside blood vessels is heated due to selective absorption of laser energy, while the surrounding normal tissue is spared. As a result, the blood and the surrounding tissue experience a local thermodynamic non-equilibrium condition. Traditionally, the PWS laser treatment process was simulated by a discrete-blood-vessel model that simplifies blood vessels into parallel cylinders buried in a multi-layer skin model. In this paper, PWS skin is treated as a porous medium made of tissue matrix and blood in the dermis. A two-temperature model is constructed following the local thermal non-equilibrium theory of porous media. Both transient and steady heat conduction problems are solved in a unit cell for the interfacial heat transfer between blood vessels and the surrounding tissue to close the present two-temperature model. The present two-temperature model is validated by good agreement with those from the discrete-blood-vessel model. The characteristics of the present two-temperature model are further illustrated through a comparison with the previously-used homogenous model, in which a local thermodynamic equilibrium assumption between the blood and the surrounding tissue is employed.

In vivo imaging of pigmented lesions in human skin was performed with a clinical multiphoton microscopy (MPM)- based tomograph (MPTflex, JenLab, Germany). Two-photon excited fluorescence was used for visualizing endogenous fluorophores such as NADH/FAD, keratin, melanin in the epidermal cells and elastin fibers in the dermis. Collagen fibers were imaged by second harmonic generation. Our study involved in vivo imaging of benign melanocytic nevi, atypical nevi and melanoma. The goal of this preliminary study was to identify in vivo the characteristic features and their frequency in pigmented lesions at different stages (benign, atypical and malignant) and to evaluate the ability of in vivo MPM to distinguish atypical nevi from melanoma. Comparison with histopathology was performed for the biopsied lesions. Benign melanocytic nevi were characterized by the presence of nevus cell nests at the epidermal-dermal junction. In atypical nevi, features such as lentiginous hyperplasia, acanthosis and architectural disorder were imaged. Cytological atypia was present in all the melanoma lesions imaged, showing the strongest correlation with malignancy. The MPM images demonstrated very good correlation with corresponding histological images, suggesting that MPM could be a promising tool for in vivo non-invasive pigmented lesion diagnosis, particularly distinguishing atypical nevi from melanoma. © 2013 SPIE.

BackgroundPhotodynamic therapy (PDT) offers the potential for enhanced treatment of nonmelanoma skin cancer (NMSC) with minimal scarring. Yet, PDT has not achieved consistent long term effectiveness to gain widespread clinical acceptance for treatment of skin cancer. Therapeutic response varies between practitioners, patients and lesions. One important contributing factor is the absence of quantitative tools to perform in vivo dosimetry. To this end, we have developed a new quantitative imaging device that can be used to investigate parameters related to optimizing dosimetry.MethodsWe present a spatial frequency domain imaging (SFDI) based device designed to: (1) determine the optical properties at the therapeutic wavelength, which can inform variations in light penetration depth and (2) measure the spatially resolved oxygen saturation of the skin cancer lesions and surrounding tissue. We have applied this system to a preliminary clinical study of nine skin cancer lesions.ResultsOptical properties vary greatly both spatially [101%, 48% for absorption and reduced scattering, respectively] and across patients [102%, 57%]. Blood volume maps determined using visible wavelengths (460, 525, and 630 nm) represent tissue volumes within ∼1 mm in tissue (1.17 ± 0.3 mm). Here the average total hemoglobin concentration is approximately three times greater in the lesion than that detected in normal tissue, reflecting increased vasculature typically associated with tumors. Data acquired at near infrared wavelengths (730 and 850 nm) reports tissue blood concentrations and oxygenations from the underlying dermal microvasculature (volumes reaching 4.36 ± 1.32 mm into tissue).ConclusionsSFDI can be used to quantitatively characterize in vivo tissue optical properties that could be useful for better informing PDT treatment parameters. Specifically, this information provides spatially resolved insight into light delivery into tissue and local tissue oxygenation, thereby providing more quantitative and controlled dosimetry specific to the lesion. Ultimately, by optimizing the execution of PDT, this instrument has the potential to positively improve treatment outcomes.

Port-wine stain (PWS) birthmarks are one class of benign congenital vascular malformation. Laser therapy is the most successful treatment modality of PWS. Unfortunately, this approach has limited efficacy, with only 10% of patients experiencing complete blanching of the PWS. To address this problem, several research groups have developed technologies and methods designed to study treatment outcome and improve treatment efficacy. This article reviews seven optical imaging techniques currently in use or under development to assess treatment efficacy, focusing on: reflectance spectrophotometers/tristimulus colorimeters; laser Doppler flowmetry and laser Doppler imaging; cross-polarized diffuse reflectance colour imaging system; reflectance confocal microscopy; optical coherence tomography; spatial frequency domain imaging; and laser speckle imaging.

Cryosurgery is a surgical technique that employs freezing to destroy target tumor tissue. While the main objective during a cryosurgical procedure is to ensure tissue destruction within the cryolesion, the greatest challenge is how to spare the surrounding healthy tissues from cryoablation. In this work, a historical review of the field of cryosurgery is presented followed by a theoretical study where a mathematical model is developed for cryosurgery on a basal cell carcinoma (BCC) using liquid nitrogen (LN2) spray. The model takes into consideration the anatomic structure of skin tissue and the irregular geometry of BCC. In particular, a methodology for quantitatively determining the extent of the intracellular ice formation (IIF) zone based on the tissue temperature and cooling rate (CR) is proposed, which can directly relate to the necrosis of the cancer cells after cryosurgery. The model is then used to analyze formation of the IIF zone during cryosurgery on a BCC and quantification is provided for the volume of the final IIF zone. A parametric study is also carried out to investigate the effect of various protocol parameters on the final IIF zone. The results should be useful for dermatologists for pre-treatment surgery planning.

Background and Objective: Spatial Frequency Domain Imaging (SFDI) is a non-contact wide-field optical imaging technology currently being used to study the optical properties and chromophore concentrations of in-vivo malignant melanomas and benign pigmented lesions. Our objective is to develop a motion correction procedure in order to assess the concerns of subject-motion related variables during clinical measurements. Study Design/Materials and Methods: SFDI motion-correction is a two-part procedure which utilizes a fiduciary marker and canny-edge detection in order to reposition and align the frame-to-frame regions-of-interest (ROI). Motioninduced phase-shifts are subsequently sampled before the entire image-set is processed by a modified demodulation formula. By comparing the results of the adjusted processing method with data gathered from the current non-corrected method, we were able to systematically characterize the impact of motion variables on SFDI measurements. Results: Motion-corrected SFDI data from moving phantom measurements and clinical patient measurements showed up to 84.58% decrease in absorption (μa) variance and up to 92.63% decrease in reduced-scattering (μs') variance. Stationary phantom test-measurements showed almost no difference between motion corrected and standard processing. Conclusion: SFDI motion correction is necessary for obtaining high-fidelity in-vivo optical property measurements of pigmented lesions in a clinical setting. © 2011 Copyright SPIE - The International Society for Optical Engineering.

A LED based spatial frequency domain imaging (SFDI) system has been developed to provide personalized photodynamic therapy for BCC. We present the instrument design, validation of performance and initial characterization of wide-field properties of BCC. © 2010 Optical Society of America.

Currently the only method for positively identifying malignant melanoma involves invasive and often undesirable biopsy procedures. Available ex-vivo data indicates increased vascularization in the lower regions of excised melanoma, as compared to dysplastic nevi. The ability to interrogate this region of tissue in-vivo could lead to useful diagnostic information. Using a newly developed fiber based superficial probe in conjunction with a steady-state frequency-domain photon migration (SSFDPM) system, we can probe the upper 1-2 mm of tissue, extracting functional information in the near infrared (650-1000 nm) range. To test the resolution and detection range of the superficial probe in this context,deformable silicone phantoms have been fabricated that simulate normal skin with melanocytic lesions. These phantoms consist of a two-layered matrix with the optical properties of normal light skin, containing several cylindrical inclusions that simulate highly absorbing pigmented lesions such as melanoma. The e inclusions are varied in depth, diameter, and optical properties in order to fully test the probe's detection capabilities. It was found that, depending on absorption, we can typically probe to a depth of 1.0-1.5 mm in an inclusion, likely reaching the site of angiogenesis in an early-stage melanoma. Additionally, we can successfully interrogate normal tissue below lesions 1.5mm deep when absorption is about 0.4/mm or less. This data indicates that the superficial probe shows great promise for non-invasive diagnosis of pigmented lesions.© 2009 SPIE.

We employ speckle imaging and window chamber models to study vascular remodeling processes after light-based therapies. Our data demonstrate that the response involves substantial remodeling over a monitoring period of up to 30 days post-intervention. © 2007 Optical Society of America.

Basel cell carcinoma (BCC) is the most common human skin malignancy. Its incidence has increased significantly in Australia, Europe and North America over the past decade. A number of modalities are currently used for treatment of BCC, including cryosurgery which offers a potential for high cure rate, low cost, minimal bleeding and good cosmetic effect. However, cryosurgery is not used frequently for BCC because no current method exists to design adequate treatment parameters. We present a numerical analysis on the thermal history of the target tissue during cryosurgery of a nodular BCC using liquid nitrogen (LN2) spray. The model uses Pennes equation to describe the heat transfer within the target tissue. A convective thermal boundary is used to describe the heat interaction between the tissue and LN2, and the apparent heat capacity method is applied to address the tissue phase change process. A parametric study is conducted on the convective heat transfer coefficient (hs: 104-106 W/m 2·K), cooling site area (rs/R0: 0.5-1.0) and spray time (t: 0-30 sec.), with the objective to understand the thermal history during tissue freezing, including lethal temperature (-50°C) and cooling rate (CR). Results demonstrate that propagation of the lethal isotherm is sensitive to the convective heat transfer coefficient, hs, with a range of 104-5×104 W/m2·K. Increasing the cooling site area can significantly enhance cooling efficiency, producing dramatic increase in the amount of tissue encompassed by the lethal isotherm. The cooling rate (CR) shows a highly dynamic distribution during the cooling process: the highest CR drops quickly from 140°C/sec. (t=0.5 sec.) to 20°C/sec. (t=5 sec.). The highest CR is initially located close to the cooling site but moves toward the inside of the tissue as treatment proceeds. The model presented herein provides a simulation tool for treatment planning of cryosurgery using LN2 spray, in which the protocol parameters, e.g. cooling site area and spray time, can be determined for an optimal outcome. The quantitative predictions on the propagation of lethal isotherm and the distribution of CR should help to optimize cryosurgery efficacy. Copyright © 2006 by ASME.

It is common in some cryosurgical procedures to rely on freeze-thaw cycle(s) to destroy undesirable tissues. Most research in cryosurgery focuses on the freezing process and much less attention has been paid to thawing or re-warming. However, as ice melts during thawing, the extracellular solution can become locally hypotonic, driving water into cells, resulting in cell expansion and ultimately, membrane rupture. Therefore, the thermal history of the target tissue during both the freezing and thawing processes is critical for cell viability. To better understand and predict the thermal history during cryosurgery, we developed a two-dimensional numerical model to describe the complete freeze-thaw cycle during liquid nitrogen cutaneous cryosurgery. A stratified anatomical structure of human skin is considered in the model. The numerical simulation applies temperature-dependent thermal and physical properties for human skin tissue and considers the typical thermal boundary conditions for clinical practice. Parametric studies are performed to explore the influence of spray cooling, spray duration and surface heating. Results are discussed concentrating on iceball front propagation, lethal temperature isotherm evolution, tissue temperature variation and cooling rates. These results are expected to provide both quantitative and graphical support to cutaneous cryosurgery and suggest approaches to optimize current cryosurgical protocols. Copyright © 2005 by ASME.

Background and Objectives: Pulsed dye laser (PDL) irradiation is the standard clinical treatment for vascular lesions. However, PDL treatment of port wine stain birthmarks (PWS) is variable and unpredictable. Photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A (BPD) and yellow light may induce substantial vascular effects and potentially offer a more effective treatment. In this study, we utilize a rodent dorsal skinfold model to evaluate the vascular effects of BPD-PDT at 576 nm as compared to PDL. Study Design/Materials and Methods: A dorsal skinfold window was created on the backs of female Sprague-Dawley rats, allowing epidermal and subdermal irradiation and subdermal imaging. One mg/kg BPD was administered intravenously via a jugular venous catheter. Study groups were: control (no BPD, no light), PDL (585 nm, τ p 1.5 ms, 10 J/cm 2), and PDT (BPD + continuous wave irradiation (CW) at 576nm, τ p 16 min, 96 J/cm 2). Vessels were imaged and assessed for damage using laser speckle imaging (LSI) before, immediately after, and 18 hours post-intervention. Results: Epidermal irradiation was accomplished without blistering, scabbing or ulceration. PDL and PDT resulted in similar reductions in vascular perfusion 18 hours post-intervention (34.6% and 33.4%, respectively). Conclusions: BPD-PDT can achieve safe and selective vascular effects and may offer an alternative therapeutic option for treatment of hypervascular skin lesions including PWS birthmarks.

It is common in some cryosurgical procedures to rely on freeze-thaw cycle(s) to destroy undesirable tissues. Most research in cryosurgery focuses on the freezing process and much less attention has been paid to thawing or re-warming. However, as ice melts during thawing, the extracellular solution can become locally hypotonic, driving water into cells, resulting in cell expansion and ultimately, membrane rupture. Therefore, the thermal history of the target tissue during both the freezing and thawing processes is critical for cell viability. To better understand and predict the thermal history during cryosurgery, we developed a two-dimensional numerical model to describe the complete freeze-thaw cycle during liquid nitrogen cutaneous cryosurgery. A stratified anatomical structure of human skin is considered in the model. The numerical simulation applies temperature-dependent thermal and physical properties for human skin tissue and considers the typical thermal boundary conditions for clinical practice. Parametric studies are performed to explore the influence of spray cooling, spray duration and surface heating. Results are discussed concentrating on iceball front propagation, lethal temperature isotherm evolution, tissue temperature variation and cooling rates. These results are expected to provide both quantitative and graphical support to cutaneous cryosurgery and suggest approaches to optimize current cryosurgical protocols. Copyright © 2005 by ASME.

Cryogen spray cooling (CSC) is used to minimize the risk of epidermal damage during various laser dermatologic surgeries. However, as the application of single or multiple cryogen spurts becomes available on some commercial lasers devices, it is necessary to determine the optimal CSC parameters for different laser surgeries. The objective of this study was to measure the time the sprayed surface of a human skin phantom (HSP) remains below water freezing temperature 0°C, referred to as subzero time (ts), and below the cryogen boiling temperature -26°C, referred to as residence time (tr), as well as the minimum surface temperature (Tmin) and the time at which Tmin occurs (tTmin,) for two HSP-initial temperatures (20 °C and 70°C) during and after the application of single (SCS) and multiple cryogen spurts (MCS). For this propose, a HSP was used to measure ts, tr, Tmin, and tTminn for nine sequences: one SCS of ΔtT = TCT = 40 ms; four MCS sequences, all adding to a ΔtT of 40 ms but with different TCT up to 110 ms and, finally; four SCS that matched the TCT of the four MCS sequences, but lead to different ΔtT. Our results show that the differences between SCS and MCS sequences with the same TCT are negligible for all variables measured (ts, tr, Tmin, tTmin). Moreover, in this interval (40 ms≤ TCT ≤ 110 ms), this variables show a remarkable linear dependence with the TCT. Copyright © 2004 by ASME.

We report a novel application of optical coherence tomography (OCT), to monitor post-laser irradiation collagen injury in skin model. An artificial skin model (RAFT) which closely approximates human skin, was irradiated with a Perovskite laser (λ = 1341 nm). We investigated dynamic changes in a RAFT after laser irradiation through OCT and compared the results to those of histology. OCT images clearly delineated areas of post-irradiation collagen injury and allowed non-invasive monitoring of the wound healing process. Histology was correlated well with OCT images. OCT has advantages because it is non-invasive and allows serial monitoring at the same site over time. Our study showed that OCT may be a useful tool for determination of optimal parameters for non-ablative laser skin rejuvenation (NALSR) using different devices.

Previous studies suggest that optimal port wine stain (PWS) laser treatment parameters require knowledge of skin characteristics such as blood vessel size, depth, and distribution. Effective and rapid imaging modalities are not widely available. In the present study, photothermal tomography (PTT) images of an in vivo hamster window model and human PWS skin were obtained and analyzed. Subtherapeutic laser light pulses at 585 and 600 nm were applied to skin surface and image sequences acquired with an infrared camera. A nonnegatively constrained conjugate gradient algorithm was used to reconstruct a PTT image of the initial temperature distribution immediately following pulsed laser irradiation. Vessel dimensions determined from PTT images of hamster window model skin compared well with those measured directly using video microscopy. PTT images of human PWS skin contained vessels with estimated diameters of 200-250 μm over a 250-320 μm depth range. Use of dual wavelength excitation (DWE) analysis allowed for imaging of shallow vessels.

We demonstrate a novel application of optical coherence tomography (OCT) to monitor post-laser irradiation collagen injury in model skin. An artificial skin model (RAFT), which closely approximates human skin, was irradiated with a Perovskite laser (λ = 1341 nm), which is under investigation for potential use as a nonablative laser skin rejuvenation device (NALSR). OCT was used to determine the extent of laser injury immediately post irradiation and, subsequently, to monitor tissue recovery over a seven-day period. OCT images clearly delineated areas of post-irradiation collagen injury and allowed noninvasive monitoring of the wound healing process. Histology was used for comparison and correlated well with OCT images. OCT offers advantages over standard histology as it is noninvasive and allows serial monitoring at the same site over time. Our results indicate that OCT has potential as a method for characterization of collagen injury post-laser irradiation and may be a useful tool for determination of optimal parameters for NALSR using different devices under investigation for this indication.