Radiation-induced Skin Changes Research Articles

Friedrich Dessauer (1881-1963): the forgotten medical physicist, politician, and philosopher.

Today, the name Friedrich Dessauer is almost forgotten; however, his scientific, social, and political works should not be. Dessauer's professional career began at ayoung age as aprofessor of physics in Frankfurt am Main. It is said that he published 400 papers and 65book chapters and pamphlets. He was atechnical inventor who established laws that dealt with theories to explain the limited understanding of the effects of radiation on cells. He advocated for methods to improve the therapeutic ratio. As adevout Catholic politician, Dessauer was an early opponent of National Socialism. This led to him being thrown into prison for political reasons in 1933. He did not leave until 1934, and then for Istanbul, largely thanks to Turkish efforts and his appointment as director of alarge new institution. While he was already awell-known physicist in Germany, he had to start from scratch in order to build amodern institute. Arecent article in the journal Radiotherapy and Oncology celebrated his important contributions to radiology from Turkey. After his contract in Istanbul expired in 1937, he left for the small University of Fribourg in Switzerland, where he was unfortunately unable to continue his scientific productivity. Dessauer wrote textbooks as well as political and philosophical books, and attempted to bridge the gap between Catholicism and science. Additionally, after the war, he began to teach again in Frankfurt. In photos of Dessauer, radiation-induced skin changes on his face and hands were clearly visible. Towards the end of his life, he received many medals and honors for his achievements in Germany, some of them posthumously.

RISREAC Study: Assessment of Cutaneous Radiation Injury Through Clinical Documentation.

Radiation dermatitis (RD) occurs in 95% of patients receiving radiation therapy (RT) for cancer treatment, affecting 800 million patients annually. We aimed to demonstrate the feasibility of developing a historical RD cohort, Radiation Induced Skin Reactions (RISREAC) cohort. This retrospective study evaluated RD-related clinical documentation for 245 breast cancer patients who received RT at the University of Rochester Medical Center, to understand the RD progression, scoring, and management. All statistical analyses were performed at 0.05 level of significance. Clinician-documented RD severity was observed for 169 (69%) patients with a mean severity of 1.57 [1.46, 1.68]. The mean descriptor-based severity score of 2.31 [2.18, 2.45] moderately correlated (r = 0.532, P < 0.0001) with documented RD grade. Most patients (91.8%) received skin care treatment during RT, with 66.7% receiving more than 2 modalities. The RISREAC cohort is the first retrospective cohort established from clinical documentation of radiation-induced skin changes for the study of RD and cutaneous radiation injury (CRI). RD symptom descriptors were more reliably documented and suitable for all skin types compared to Radiation Therapy Oncology Group (RTOG) or Common Toxicity Criteria for Adverse Events (CTCAE) grades. A new descriptor-based scoring tool would be useful for RD and CRI.

A Quantitative Analysis of Inframammary Fold Position Changes With Radiation After Tissue Expander Placement and Exchange

BACKGROUND: Postmastectomy radiation therapy has well-defined ill effects on the character of the skin envelope of the breast, most directly causing contraction and elevation of the breast, especially at the inframammary fold (IMF). These effects negatively impact breast symmetry, overall aesthetic outcomes, and patient satisfaction. Though radiation-induced skin changes have been qualitatively described, quantitative changes to the position of the IMF due to radiation have not yet been described. Despite maneuvers to lower the fold when postmastectomy radiation therapy is expected, the reoperation rates have been reported as high as 28%. Delineating numerical values may allow more specific intraoperative adjustments to better approximate the IMF to the pretreatment level. Herein we discuss our analysis of the effect of radiation on IMF position in patients who underwent expander placement and subsequent radiation. METHODS: Patients who underwent breast reconstruction with tissue expanders from January 2015 to October 2019 at UCLA by four attending surgeons were reviewed. Operative reports were reviewed and indicated disruption of the IMF in all patients during mastectomies, requiring resetting of the IMF with suture. Patient inclusion criteria required that patients have corresponding sets of pictures at three timepoints: (1) preoperative (before mastectomy), (2) postoperative (after tissue expander placement and before radiation), and (3) postradiation (before exchange to permanent implant). Photographs were retrospectively analyzed by a single surgeon. In the lateral view, the distance from the acromion to IMF was measured, compared with acromion to elbow, and recorded as a ratio to allow for variation of photographic focal length differences. Changes in IMF from pre- to postradiation were measured as a percentage change. RESULTS: Fifteen patients with appropriate photos over the past year were analyzed of which 10 had pictures at all three timepoints, and 5 had only the last 2 timepoints and were excluded. All operative reports were reviewed verifying that the IMF was disrupted after mastectomy in all group. Fourteen had unilateral radiation and 1 had bilateral radiation, thus 16 breasts were reviewed separately. For the 10 patients with preoperative photos, the IMF ratio from timepoints 1–3 (preoperative to postradiation) was −12.5% + 5.2%, indicating a significant elevation of the IMF following radiation. CONCLUSIONS: Inframammary position after tissue expander placement and radiation reliably elevates approximately 12% above the position of the preoperative fold. This study is the first of its kind to quantitatively measure radiation change elevation on the IMF in tissue expander reconstructions. This finding may be a useful guide for setting the IMF at the time of tissue expander placement and avoid need for the second stage fold lowering at the time of implant exchange.

Nasal Colonization with Staphylococcus Aureus Before Radiation Therapy Predicts Radiation Dermatitis: A Prospective Study

Acute radiation dermatitis (RD) is a common side effect of radiation therapy (RT). Radiation-induced skin changes are thought to increase the risk of secondary skin infection. However, little is known regarding the baseline incidence of microbial colonization prior to RT and whether it is associated with development of RD. The goals of our prospective study are to 1) characterize the incidence of baseline bacterial colonization in patients undergoing RT, and 2) examine the association between radiation dermatitis severity and baseline bacterial colonization. We hypothesize that microbial colonization prior to initiation of RT is associated with development of RD. We are presenting preliminary results from a prospective trial in which patients with cancers of the head and neck, breast, or anus undergo bacterial culture from the nares and the area of skin subject to radiation, prior to RT initiation. Patients are evaluated weekly during RT, and dermatitis is graded using CTCAE version 4.0. Descriptive statistics and odds ratios are utilized to present associations between culture results and skin toxicity. Forty-eight subjects with cancers of the breast (48%), head and neck (44%), and anus (8%) have completed RT to date. Baseline bacterial culture for Staphylococcus aureus was positive in the nares for 10 subjects (21%) and positive on the skin in 3 subjects (6%). All 3 subjects with positive skin cultures also had a positive nares culture. Twenty-eight patients (58%) developed grade 1 dermatitis, 15 (31%) developed grade 2 dermatitis, and 5 (10%) developed grade 3 dermatitis. 18 subjects (38%) received silver sulfadiazine for RD. Positive culture for S. aureus at baseline was associated with increased risk of grade 2-3 dermatitis (80% v. 32%, OR=8.7, p=0.012) and with receipt of silver sulfadiazine (70% v. 29%, OR=5.7, p=0.025). Bacterial colonization with S. aureus prior to RT initiation is a risk factor for developing high-grade RD. Because a positive nares culture was able to predict skin toxicity, even in the absence of a positive skin culture, antimicrobial therapy in the nares prior to RT initiation ought to be explored as a strategy to lessen the severity of RD. Further studies are needed to understand the association between microbial colonization and development of RD.

Radiation-Induced Skin Changes after Postmastectomy Radiation Therapy: A Pilot Study on Indicators for Timing of Delayed Breast Reconstruction.

Delayed autologous breast reconstruction is commonly recommended in patients requiring postmastectomy radiation. This study examines gross and histologic changes in the breast skin of patients who have undergone postmastectomy radiation to help determine when radiation-induced skin changes begin to stabilize. A prospective pilot study was conducted on eight patients with invasive breast cancer who required mastectomy and radiotherapy. At the time of mastectomy and 2, 4, 6, 8, and 12 months after completion of radiotherapy, a punch biopsy was taken from the radiated mastectomy skin of each patient. Serial standardized photographs were taken before and after radiotherapy to evaluate the degree of hyperpigmentation and graded by three blinded plastic surgeons. Skin biopsies were processed for histologic assessment of inflammation, elastin organization, and vascularity. Grading of patient photographs revealed an increase in hyperpigmentation after radiotherapy compared with baseline with a gradual improvement over time. SMAD3 immunostaining demonstrated a trend toward an increase in inflammation over 12 months. The elastin distribution within samples showed an increase in fiber disorganization, thickening, and clumping, with no improvement throughout the study period. The average number of vessels per high powered field decreased steadily through the duration of the study. Histologic changes in dermal inflammation, elastin organization, and vascularity do not appear to correspond with the gradual improvement of hyperpigmentation, resulting from postmastectomy radiation. These histologic changes persist beyond the 12 month observation period and will require clinical correlation to determine the potential impact on postoperative outcomes.

Intensity-modulated radiotherapy for paranasal sinuses and base of skull tumors

Paranasal sinus and skull base tumors are rare aggressive head and neck cancers, and typically present in the locally advanced stages. As a result, achieving wide surgical resection with clear margins is a challenge for these tumors, and radiotherapy is thus usually indicated as an adjuvant modality following surgery to optimize local control. Given the integral role of radiotherapy in the management of this subgroup of head and neck tumors, the advent of intensity-modulated radiotherapy (IMRT) has led to substantial improvement of clinical outcomes for these patients. This is primarily driven by the improvement in radiation dosimetry with IMRT compared to conventional two dimensional (2D)- and 3D-techniques, in terms of ensuring dose intensity to the tumor target coupled with minimizing dose exposure to critical organs. Consequently, the evident clinical benefits of IMRT have been in reduction of normal tissue toxicities, ranging from critical neurological symptoms to less debilitating but bothersome symptoms of eye infections and radiation-induced skin changes. Another domain where IMRT has potential clinical utility is in the management of a subset of non-resectable T4 paranasal sinus and skull base tumors. For these inoperable lesions, the steep dose-gradient between tumor and normal tissue is even more advantageous, given the crucial need to maintain dose intensity to the tumor. Innovative strategies in this space also include the use of induction chemotherapy for patient selection. In this review, we summarized the data for the aforementioned topics, including specific discussions on the different histologic subtypes of paranasal sinus and skull base tumors.

Localized acneiform eruption induced by radiation therapy

Radiation-induced skin changes and dermatoses occur in the majority of patients receiving radiotherapy and may produce significant adverse effects. Radiation-induced acneiform eruption is a rare but likely an underreported cutaneous adverse effect. This is a case of a localized comedonal eruption induced by radiation therapy exposure in a 47-year-old male treated for a malignant tumor. Recognition and proper management of this presentation are important for the optimization of patient health, reassurance of the patient and the treating team, and avoidance of any unnecessary delays in surgical reconstruction planning.

Temporal and Spatial Quantification of Tissue Oxygen Saturation and Melanin Deposition During Whole Breast Radiation Using Noninvasive Spatial Frequency Domain Imaging

Radiotherapy is a critical component in the treatment of breast cancer. During radiation therapy (RT), patients develop varying degrees of erythema with some developing dry or moist desquamation. Additionally, patients can develop permanent discoloration of the skin and thickening of underlying breast tissue. Quantifying radiation-induced skin changes during and after radiation is challenging, since standardized scoring systems (RTOG Radiation Morbidity Scoring Scheme and CTCAE v.4) are subjective. Development of a non-invasive technique to reproducibly and objectively measure acute and late radiation-induced skin changes is needed. Spatial frequency domain imaging (SFDI) is a non-invasive and rapid functional imaging technique. It uses spatially-structured light at 8 different wavelengths (470 - 850 nm) to quantitatively map superficial tissue absorption and scattering in a wide-field, noncontact imaging geometry. Tissue oxygen saturation, oxyhemoglobin, deoxyhemoglobin, and melanin content can be calculated from the SFDI absorption data. Ten female patients undergoing RT for breast cancer were given written informed consent and enrolled in an IRB-approved, prospective pilot trial for SFDI of skin changes during and after RT. Dose to the whole breast was 50 Gy, followed by 10 Gy electron boost to the lumpectomy cavity or chest wall scar. Patients were measured before initiation of RT, weekly during their RT, 2 weeks after RT, and every 3 months using SFDI. Photographs were taken at the time of SFDI measurement to document cosmesis. The contralateral, untreated breast was also measured and used as an internal control. Melanin content steadily increased in the treated breast and correlated with hyperpigmentation noted by the physician. The onset of melanin increase is observable as early as 10 Gy. Throughout the treatment course, total hemoglobin steadily increased and correlated with area of erythema. There was a sudden reduction in tissue oxygen saturation after 40 Gy, suggesting radiation-induced damage of the microvasculature. Tissue oxygen saturation and oxyhemoglobin returned to baseline 2 weeks after completion of radiation. Melanin concentration peaked at the end of radiation, but was persistently elevated even after 3 months on followup examination. Our preliminary data from ten patients have validated the feasibility and reproducibility of SFDI to measure spatial and temporal changes in the skin during and after breast RT. We plan to recruit more females of different skin types and backgrounds, to identify different patterns of melanin and hemoglobin changes in radiated breast tissue. In the future, SFDI can be used to measure efficacy of different creams used to reduce acute and late effects of radiation-induced dermatitis and hyperpigmentation, and potentially predict patient’s skin response to breast RT from pre-treatment SFDI measurements.

An Innovative Risk-Reducing Approach to Postmastectomy Radiation Delivery after Autologous Breast Reconstruction.

Introduction:Postmastectomy radiation therapy (PMRT) has known deleterious side effects in immediate autologous breast reconstruction. However, plastic surgeons are rarely involved in PMRT planning. Our institution has adopted a custom bolus approach for all patients receiving PMRT. This offers uniform distribution of standard radiation doses, thereby minimizing radiation-induced changes while maintaining oncologic safety. We present our 8-year experience with the custom bolus approach for PMRT delivery in immediate autologous breast reconstruction.Methods:All immediate autologous breast reconstruction patients requiring PMRT after 2006 were treated with the custom bolus approach. Retrospective chart review was performed to compare the postirradiation complications, reconstruction outcomes, and oncologic outcomes of these patients with those of previous patients at our institution who underwent standard bolus, and to historical controls from peer-reviewed literature.Results:Over the past 10 years, of the 29 patients who received PMRT, 10 were treated with custom bolus. Custom bolus resulted in fewer radiation-induced skin changes and less skin tethering/fibrosis than standard bolus (0% vs 10% and 20% vs 35%, respectively), and less volume loss and contour deformities compared with historical controls (10% vs 22.8% and 10% vs 30.7%, respectively).Conclusions:Custom bolus PMRT minimizes radiation delivery to the internal mammary vessels, anastomoses, and skin; uniformly doses the surgical incision; and provides the necessary radiation dose to prevent recurrence. Because custom bolus PMRT may reduce the deleterious effects of radiation on reconstructive outcomes while maintaining safe oncologic results, we encourage all plastic surgeons to collaborate with radiation oncologists to consider this technique.

Changes in skin microcirculation during radiation therapy for breast cancer

Background: The majority of breast cancer patients who receive radiation treatment are affected by acute radiation-induced skin changes. The assessment of these changes is usually done by subjective methods, which complicates the comparison between different treatments or patient groups. This study investigates the feasibility of new robust methods for monitoring skin microcirculation to objectively assess and quantify acute skin reactions during radiation treatment.Material and methods: Laser Doppler flowmetry, laser speckle contrast imaging, and polarized light spectroscopy imaging were used to measure radiation-induced changes in microvascular perfusion and red blood cell concentration (RBC) in the skin of 15 patients undergoing adjuvant radiation therapy for breast cancer. Measurements were made before treatment, once a week during treatment, and directly after the last fraction.Results: In the treated breast, perfusion and RBC concentration were increased after 1–5 fractions (2.66–13.3 Gy) compared to baseline. The largest effects were seen in the areola and the medial area. No changes in perfusion and RBC concentration were seen in the untreated breast. In contrast, Radiation Therapy Oncology Group (RTOG) scores were increased only after 2 weeks of treatment, which demonstrates the potential of the proposed methods for early assessment of skin changes. Also, there was a moderate to good correlation between the perfusion (r = 0.52) and RBC concentration (r = 0.59) and the RTOG score given a week later.Conclusion: We conclude that radiation-induced microvascular changes in the skin can be objectively measured using novel camera-based techniques before visual changes in the skin are apparent. Objective measurement of microvascular changes in the skin may be valuable in the comparison of skin reactions between different radiation treatments and possibly in predicting acute skin effects at an earlier stage.

Radiation dermatitis: an overview.

Radiation therapy has been a commonly employed modality for a variety of ailments, including cancer. Patients undergoing radiation often experience acute and/or chronic skin changes that can be detrimental to their quality of life. Many topical agents and specialized wound dressings are being used for the prevention and management of radiation-induced skin changes. However, no single therapeutic option has been found to be consistently effective.

Acute and Chronic Cutaneous Reactions to Ionizing Radiation Therapy.

Ionizing radiation is an important treatment modality for a variety of malignant conditions. However, development of radiation-induced skin changes is a significant adverse effect of radiation therapy (RT). Cutaneous repercussions of RT vary considerably in severity, course, and prognosis. When they do occur, cutaneous changes to RT are commonly graded as acute, consequential-late, or chronic. Acute reactions can have severe sequelae that impact quality of life as well as cancer treatment. Thus, dermatologists should be informed about these adverse reactions, know how to assess their severity and be able to determine course of management. The majority of measures currently available to prevent these acute reactions are proper skin hygiene and topical steroids, which limit the severity and decrease symptoms. Once acute cutaneous reactions develop, they are treated according to their severity. Treatments are similar to those used in prevention, but incorporate wound care management that maintains a moist environment to hasten recovery. Chronic changes are a unique subset of adverse reactions to RT that may develop months to years following treatment. Chronic radiation dermatitis is often permanent, progressive, and potentially irreversible with substantial impact on quality of life. Here, we also review the etiology, clinical manifestations, pathogenesis, prevention, and management of late-stage cutaneous reactions to radiotherapy, including chronic radiation dermatitis and radiation-induced fibrosis.

Abstract P2-13-01: An innovative risk-reducing approach to post-mastectomy radiation delivery following autologous breast reconstruction

Abstract Introduction: There is no consensus among radiation oncologists regarding delivery of post-mastectomy radiation therapy (PMRT) after immediate autologous breast reconstruction, and plastic surgeons rarely participate in this decision-making process. However, radiation-induced changes markedly influence flap outcomes and affect the flap permanently. We present an innovative approach for PMRT delivery, through the use of custom bolus. This technique provides individualized, targeted PMRT to the reconstructed breast to minimize flap-related complications. Methods: All patients who underwent mastectomy with immediate autologous reconstruction between 2005 and 2014 at our institution were identified. Radiation was delivered to the reconstructed autologous breast in 29 patients. Post-irradiation complications and reconstruction outcomes were compared for patients treated with custom bolus, standard PMRT, and historical controls. Results: Over the past 10 years, 157 patients (226 breasts) underwent immediate autologous tissue breast reconstruction following mastectomy. Of the 29 patients who received PMRT, 10 were treated with custom bolus. The custom bolus uses perforated Aquaplast and a nearly tissue-equivalent wax to form a cast which conforms to the irregular contours of the chest wall, allowing for easy application through the duration of treatment. Pre-irradiation computed tomography was used to optimize dose distribution, evaluate the internal mammary vessels, and target the deeper tissues adjacent to the chest wall (minimizing dose inhomogeneity to the skin). Custom bolus resulted in fewer radiation-induced skin changes and less skin tethering/fibrosis than standard bolus (0% vs 10% and 20% vs 35%, respectively), and less volume loss and contour deformities compared with historical controls (10% vs 22.8% and 10% vs 30.7%, respectively). Conclusion: The use of custom bolus tailors radiation delivery to the internal mammary vessels, anastomoses, and skin; uniformly doses the surgical incision; and provides the necessary radiation dose to prevent recurrence, thus not compromising oncologic safety. It is easily fabricated, cost-effective and placement is straightforward and reproducible. Because radiation has negative effects on autologous breast reconstruction and often results in vascular intimal fibrosis and fat necrosis, plastic surgeons should participate in radiation planning. Our custom bolus PMRT technique reduces the incidence of these radiation effects. Citation Format: Piper ML, Evangelista M, Amara D, Daar DA, Foster RD, Fowble B, Sbitany H. An innovative risk-reducing approach to post-mastectomy radiation delivery following autologous breast reconstruction. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-13-01.

Cell-Assisted Lipotransfer Improves Volume Retention in Irradiated Recipient Sites and Rescues Radiation-Induced Skin Changes.

Radiation therapy is not only a mainstay in the treatment of many malignancies but also results in collateral obliteration of microvasculature and dermal/subcutaneous fibrosis. Soft tissue reconstruction of hypovascular, irradiated recipient sites through fat grafting remains challenging; however, a coincident improvement in surrounding skin quality has been noted. Cell-assisted lipotransfer (CAL), the enrichment of fat with additional adipose-derived stem cells (ASCs) from the stromal vascular fraction, has been shown to improve fat volume retention, and enhanced outcomes may also be achieved with CAL at irradiated sites. Supplementing fat grafts with additional ASCs may also augment the regenerative effect on radiation-damaged skin. In this study, we demonstrate the ability for CAL to enhance fat graft volume retention when placed beneath the irradiated scalps of immunocompromised mice. Histologic metrics of fat graft survival were also appreciated, with improved structural qualities and vascularity. Finally, rehabilitation of radiation-induced soft tissue changes were also noted, as enhanced amelioration of dermal thickness, collagen content, skin vascularity, and biomechanical measures were all observed with CAL compared to unsupplemented fat grafts. Supplementation of fat grafts with ASCs therefore shows promise for reconstruction of complex soft tissue defects following adjuvant radiotherapy.

Posterior Thoracic Echocardiography for Assessment of Native and Prosthetic Aortic Valves in the Presence of Pleural Effusion

Many patients with aortic stenosis have difficult imaging windows due to advanced age, kyphosis, prior chest surgeries, radiation-induced skin changes, or hyperinflated lungs from pulmonary disease. Here we describe 4 cases to illustrate that in a subset of patients with pleural effusion, a posterior imaging approach can be used to obtain diagnostic images for native and prosthetic aortic valves. In these cases, nondiagnostic transthoracic echocardiographic images were obtained from conventional imaging windows, leading to inaccurate or incomplete assessment of the aortic valve. In all cases, images obtained from a posterior thoracic approach provided important additional diagnostic information.

Radiation induced angiosarcoma a sequela of radiotherapy for breast cancer following conservative surgery.

Radiation induced angiosarcomas (RIA) can affect breast cancer patients who had radiotherapy following conservative breast surgery. They are very rare tumors and often their diagnosis is delayed due to their benign appearance and difficulty in differentiation from radiation induced skin changes. Therefore it is very important that clinicians are aware of their existence. We report here a case of RIA followed by discussion and review of literature.

Radiation dermatitis: Clinical presentation, pathophysiology, and treatment 2006

I onizing radiation is used to treat a variety of primary tumors, as well as to palliate metastatic disease. Dermatologists are no strangers to this modality of therapy and, since the discovery of x-rays by Roentgen in 1895, have incorporated radiation into their practice to treat malignant skin tumors, as well as benign skin diseases such as acne, eczema, and cutaneous fungal infections. In the past 30 years, other therapeutic modalities have largely supplanted radiation in the treatment of these benign disorders. Dermatologists today are more commonly called on to treat the cutaneous repercussions of radiation therapy (RT), which are a function of technique, target, total dose, volume, as well as individual variations. RT, either as monotherapy or in combination with other treatment modalities, is a powerful tool in tumor control, limited primarily by injury adjacent to normal tissue. Radiation-induced skin changes were recognized soon after the discovery of x-rays and were scientifically reported as early as 1902. Even when the skin is not the primary target, it may be injured as an ‘‘innocent bystander’’ and develop profound alterations on functional, gross, and molecular levels. This is not only true after therapeutic radiation, but also after interventional procedures. Serious radiationinduced skin injuries have been reported after unexpectedly high doses of kilovoltage irradiation exposure during fluoroscopic imaging, including cardiac catheterization. Increasingly sophisticated therapeutic regimens and modern equipment have improved the delivery and ameliorated, but not

Effect of therapeutic radiation on wound healing

Nonhealing wounds present a significant clinical problem. Therapeutic radiation, when applied to the treatment of malignancy, may result in acute and chronic effects on the skin.1 Healing impairment as well as other functional losses is often observed in irradiated skin. This chapter explores the biology of radiation-induced skin changes, describes models for studying wound healing in chronically irradiated skin, and reviews clinical aspects of radiation-damaged skin.