Radiation Dermatitis: Radiation-Induced Effects on the Structural and Immunological Barrier Function of the Epidermis.

An important hallmark of radiation dermatitis is the impairment of the mitotic ability of the stem/progenitor cells in the basal cell layers due to radiation-induced DNA damage, leading to suppressed cell renewal in the epidermis. However, this mechanism alone does not adequately explain the complex pathogenesis of radiation-induced skin injury. In this review, we summarize the latest findings on the complex pathogenesis of radiation dermatitis and correlate these with the clinical features of radiation-induced skin reactions. The current studies show that skin exposure to ionizing radiation induces cellular senescence in the epidermal keratinocytes. As part of their epithelial stress response, these senescent keratinocytes secrete pro-inflammatory mediators, thereby triggering skin inflammation. Keratinocyte-derived cytokines and chemokines modulate intercellular communication with the immune cells, activating skin-resident and recruiting skin-infiltrating immune cells within the epidermis and dermis, thereby orchestrating the inflammatory response to radiation-induced tissue damage. The increased expression of specific chemoattractant chemokines leads to increased recruitment of neutrophils into the irradiated skin, where they release cytotoxic granules that are responsible for the exacerbation of an inflammatory state. Moreover, the importance of IL-17-expressing γδ-T cells to the radiation-induced hyperproliferation of keratinocytes was demonstrated, leading to reactive hyperplasia of the epidermis. Radiation-induced, reactive hyperproliferation of the keratinocytes disturbs the fine-tuned keratinization and cornification processes, leading to structural dysfunction of the epidermal barrier. In summary, in response to ionizing radiation, epidermal keratinocytes have important structural and immunoregulatory barrier functions in the skin, coordinating interacting immune responses to eliminate radiation-induced damage and to initiate the healing process.

INFRARED THERMAL IMAGING CONTROL OF RADIATION DERMATITIS DYNAMICS.

BACKGROUND: Radiation-induced dermatitis impairs the quality of life of cancer patients and may lead to the need of interrupting radiotherapy. The grade of dermatitis is subjectively assessed by the visual examination. There is an urgent need for both objective and quantitative methods for assessing the current grade of dermatitis and predicting its severity at an early stage of radiotherapy. AIM: The aim of the study was to evaluate the advantages and limitations of infrared thermography for monitoring the current level of radiation-induced dermatitis and predicting its severity by quantitative analysis of the thermal field dynamics in the irradiated zone. MATERIALS AND METHODS: 30 adult patients were examined by infrared thermography during the course of 2D conventional radiotherapy for malignant tumors of various types and localizations. Our approach for quantifying the thermal field caused by dermatitis alone was applied. A statistical (correlation and ROC) analysis was performed. RESULTS: Dermatitis of varying severity was observed in 100% of the patients studied. The dynamics in the intensity of the anomalous thermal fields in the irradiated zone correlated with the dynamics of dermatitis grades, excluding the case of a radiosensitive tumor (correlation coefficient 0.74÷0.84). It was found that the maximum toxicity (dermatitis grade ≥ 3) develops in patients who how significant hyperthermia in the area of interest (≥ 0.7 °C) at an early stage of radiotherapy. The ROC analysis demonstrated the "good quality" of the prognosis method (AUC = 0.871). CONCLUSIONS: The non-invasive and cheap infrared thermography is a suitable tool for objective quantitative monitoring the current dermatitis grade during radiotherapy as well as predicting its severity for any tumor location.

Association of Staphylococcus aureus Colonization With Severity of Acute Radiation Dermatitis in Patients With Breast or Head and Neck Cancer.

Importance: Pathogenesis of acute radiation dermatitis (ARD) is not completely understood. Pro-inflammatory cutaneous bacteria may contribute to cutaneous inflammation after radiation therapy. Objective: To evaluate whether nasal colonization with Staphylococcus aureus (SA) before radiation therapy is associated with ARD severity in patients with breast or head and neck cancer. Design, Setting, and Participants: This prospective cohort study with observers blinded to colonization status was conducted from July 2017 to May 2018 at an urban academic cancer center. Patients aged 18 years or older with breast or head and neck cancer and plans for fractionated radiation therapy (≥15 fractions) with curative intent were enrolled via convenience sampling. Data were analyzed from September to October 2018. Exposures: Staphylococcus aureus colonization status before radiation therapy (baseline). Main Outcomes and Measures: The primary outcome was ARD grade using the Common Terminology Criteria for Adverse Event Reporting, version 4.03. Results: Among 76 patients analyzed, mean (SD) age was 58.5 (12.6) years and 56 (73.7%) were female. All 76 patients developed ARD: 47 (61.8%) with grade 1, 22 (28.9%) with grade 2, and 7 (9.2%) with grade 3. The prevalence of baseline nasal SA colonization was higher among patients who developed grade 2 or higher ARD compared with those who developed grade 1 ARD (10 of 29 [34.5%] vs 6 of 47 [12.8%]; P = .02, by χ2 test). Conclusions and Relevance: In this cohort study, baseline nasal SA colonization was associated with development of grade 2 or higher ARD in patients with breast or head and neck cancer. The findings suggest that SA colonization may play a role in the pathogenesis of ARD.

Radiation Recall Dermatitis Following Treatment With Pembrolizumab: A Case Report and Review of the Literature.

Radiation recall dermatitis is an inflammatory reaction of the skin that may infrequently occur in areas of the skin that have been previously treated with radiation therapy. This is thought to be due to a triggering agent administered after radiation therapy which leads to an acute inflammatory reaction, manifesting as a skin rash. We present the case of a 58-year-old male with recurrent invasive squamous cell carcinoma of the tongue, previously treated with chemotherapy and radiation therapy, who presented with progression of his disease. He was treated with pembrolizumab and subsequently developed a new-onset facial rash over the previously treated radiation field. The distribution of the rash was suggestive of radiation recall dermatitis. A biopsy showed dermal necrosis without evidence of dermatitis, vasculitis, or infectious process. This case highlights the incidence of a rare complication of immune checkpoint inhibitor therapy and emphasizes the need for careful monitoring for radiation recall dermatitis.

Chronic radiation dermatitis induced by cardiac catheterization: a case report and literature review.

Fluoroscopy-induced chronic radiation dermatitis (FICRD) is an uncommon but increasing complication that is challenging to diagnose due to its varied symptoms and delayed onset, usually from months to years after radiation exposure. For patients undergoing cardiac catheterization, high-risk factors for radiodermatitis include obesity, the presence of complex or chronic total occlusion lesions, the use of a fixed large beam angulation, and a procedure time of more than 2 hours. We present an individual with FICRD that had an indurated plaque on his back for 7 years to familiarize physicians with high-risk groups and early recognition of the disease.

Effects of topical timolol for the prevention of radiation-induced dermatitis in breast cancer: a pilot triple-blind, placebo-controlled trial.

INTRODUCTION: Radiation therapy is one of the standard methods in the treatment of breast cancer. Radiotherapy-induced dermatitis (RID) is a common complication of radiotherapy (RT) resulting in less tolerance in RT and even discontinuation of treatment. Timolol is a ß-adrenergic receptor antagonist that presents the best wound healing effects on both chronic and incurable wound healing. Topical forms of timolol could be effective in the prevention of RID due to the role of ß-adrenergic receptors in skin cells and keratinocyte migration, as well as the anti-inflammatory effect of timolol. However, no placebo-controlled randomized trial is available to confirm its role. The current trial aimed to evaluate the efficacy of topical timolol 0.5% (w/w) on the RID severity and patients' quality of life (QOL). METHOD: Patients aged older than 18 years with positive histology confirmed the diagnosis of invasive and localized breast cancer were included. Patients were randomized based on the random number table to receive each of the interventions of timolol 0.5% (w/w) or placebo topical gels from the first day of initiation of RT and for 6 weeks, a thin layer of gel twice daily. Patients were asked to use a thin layer of gel for at least two hours before and after radiation therapy. Primary outcomes were acute radiation dermatitis (ARD) grade using Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale and severity of desquamation based on Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Secondary outcomes were QOL based on Skindex16 (SD-16), maximum grade of ARD, and time of initial RD occurrence. RESULTS: A total of 64 female patients with an age range of 33 to 79 years were included. The means (SD) of age were 53.88 (11.02) and 54.88 (12.48) in the control and timolol groups, respectively. Considering the RTOG/EORTC and CTCAE scores the difference between groups was insignificant (P-Value = 0.182 and P-Value = 0.182, respectively). In addition, the mean (SD) of time of initial RID occurrence in placebo and timolol groups were 4.09 (0.588) and 4.53 (0.983) weeks, respectively (P-Value = 0.035). The maximum grade of RID over time was significantly lower in the timolol group. During the study period, 75.0% of patients in placebo groups had grade 2 of ARD while in the timolol group it was 31.3% (P-Value = 0.002). QoL was not significantly different between groups (P-Value = 0.148). CONCLUSION: Although the topical formulation of timolol, 0.5% (w/w), was found to reduce the average maximum grade of ARD and increase the mean (SD) time of initial RID occurrence, it showed no effect on ARD, severity, and QOL. However, future clinical trials should be performed to assess timolol gel formulation in larger study populations. TRIAL REGISTRATION: https://irct.ir/ IRCT20190810044500N11 (17/03/2021).

The Ability of the Nitric Oxide Synthases Inhibitor T1023 to Selectively Protect the Non-Malignant Tissues.

Previously, we showed that a nitric oxide synthase (NOS) inhibitor, compound T1023, induces transient hypoxia and prevents acute radiation syndrome (ARS) in mice. Significant efficacy (according to various tests, dose modifying factor (DMF)-1.6-1.9 against H-ARS/G-ARS) and safety in radioprotective doses (1/5-1/4 LD10) became the reason for testing its ability to prevent complications of tumor radiation therapy (RT). Research methods included studying T1023 effects on skin acute radiation reactions (RSR) in rats and mice without tumors and in tumor-bearing animals. The effects were evaluated using clinical, morphological and histological techniques as well as RTOG classification. T1023 administration prior to irradiation significantly limited the severity of acute RSR. This was due to a decrease in radiation alteration of the skin and underlying tissues, and the preservation of the functional activity of cell populations that are critical in the pathogenesis of radiation burn. The DMF values for T1023 for skin protection were 1.4-1.7. Moreover, its radioprotective effect was fully selective to normal tissues in RT models of solid tumors-T1023 reduced the severity of acute RSR and did not modify the antitumor effects of γ-radiation. The results indicate that T1023 can selectively protect the non-malignant tissues against γ-radiation due to hypoxic mechanism of action and potentiate opportunities of NOS inhibitors in RT complications prevention.

Predictive factors associated with radiation dermatitis in breast cancer.

PURPOSE: Radiation dermatitis (RD) is a side effect that frequently arises during radiotherapy (RT) in breast cancer patients. The present study investigates possible predictive factors of RD, as well as the use of skin treatments to manage symptoms. METHODS: Demographic and treatment characteristics were collected retrospectively, while skin symptoms and treatments were collected prospectively for patients who received adjuvant RT between December 2013 and November 2015. Patients were seen weekly by clinicians throughout treatment, during which a clinician-reported survey was completed on RD symptoms and skin treatments. Possible predictive factors were correlated with skin outcomes through a univariate ordinal logistic regression analysis. RESULTS: A total of 1093 patients were included in this analysis. Predictive factors for erythema included dose fractionation (p<0.0001), tissue volume irradiated by tangential fields (p = 0.01), and administration of a boost (p = 0.005). High BMI (≥30 kg/m2) (p = 0.0004) and boost (p = 0.02) were predictive of edema. A dose of 50 Gy/25 (p<0.0001) and a high irradiated tissue volume (p = 0.0001) were predictive of desquamation. A dose of 50 Gy/25 (p = 0.0005) and high BMI (p = 0.02) were predictors of pain. Bolus use was the only factor associated with bleeding (p = 0.02). Patients who developed desquamation were likely to receive corticosteroids/antihistamines (p<0.0001), topical antibiotics/antifungals (p<0.001), and dressings (p<0.0001). CONCLUSION: The findings of this study provide evidence of potential predictors of RD and methods of symptom management based on symptom severity. Prevention of RD is needed among high-risk groups, such as patients with a high BMI or receiving a standard fractionation, boost, or bolus.

Transplantation of the Stromal Vascular Fraction (SVF) Mitigates Severe Radiation-Induced Skin Injury.

Severe radiation-induced skin injury is a complication of tumor radiotherapy and nuclear accidents. Cell therapy is a potential treatment for radiation-induced skin injury. The stromal vascular fraction (SVF) is a newer material in stem cell therapy that is made up of stem cells harvested from adipose tissue, which has been shown to promote the healing of refractory wounds of different causes. In this study, SVF was isolated from patients with radiation-induced skin injury. Adipose-derived stem cells (ADSCs) accounted for approximately 10% of the SVF by flow cytometry. Compared with the control group of rats, administration with SVF attenuated the skin injury induced by electron beam radiation. The effect of SVF on the human skin fibroblast microenvironment was determined by proteomic profiling of secreted proteins in SVF-co-cultured human skin fibroblast WS1 cells. Results revealed 293 upregulated and 1,481 downregulated proteins in the supernatant of SVF-co-cultured WS1 cells. WS1 co-culture with SVF induced secretion of multiple proteins including collagen and MMP-1. In the clinic, five patients with radiation-induced skin injury were recruited to receive SVF transfer-based therapy, either alone or combined with flap transplantation. Autogenous SVF was isolated and introduced into a multi-needle precision electronic injection device, which automatically and aseptically distributed the SVF to the exact layer of the wound in an accurate amount. After SVF transfer, wound healing clearly improved and pain was significantly relieved. The patients' skin showed satisfactory texture and shape with no further wound recurrence. Our findings suggest that transplantation of SVF could be an effective countermeasure against severe radiation-induced skin injury.

Chronological Skin Changes Through Postmastectomy Radiotherapy Based on Radiotherapy Techniques: Using Quantitative Dermatological Measurements.

BACKGROUND: There has been few research on how to measure skin status quantitatively throughout the course of radiotherapy (RT). We evaluated the changes in the skin induced by 2 different RT techniques using objective measurements in breast cancer patients. METHODS: In this prospective study, between August 2015 and March 2019, serial measurements of the dermatological factors during and after postmastectomy radiotherapy (PMRT) were made in 40 breast cancer patients. PMRT was performed using the conventional photon tangential technique (PTT) or patient-tailored bolus technique (PTB). We analyzed these measurements using a mixed effect model and compared the clinically evaluated radiation dermatitis and patient-reported outcomes (PROs). RESULTS: The trend of changes in melanin and erythema was significantly different between the PTB and PTT groups (p = 0.045 and 0.016, respectively). At the 3-month follow-up erythema intensity and melanin were higher in the PTB group than in PTT group (both p < 0.001). Eight patients (40% in the PTB group) reported grade 2 radiation dermatitis and 1 patient (5% in the PTB group) reported grade 3 radiation dermatitis. No grade 2 or higher radiation dermatitis was found in the PTT group. Ten patients (50%) in the PTB group and 3 patients (15%) in the PTT group reported severe erythema likely due to questionable clinical evaluation, but hyperpigmentation was rarely reported at the follow-up visits. CONCLUSION: The PTB group showed higher intensity of erythema at the end of RT than the PTT group and the increase in melanin lasted until the 3-month follow-up visits in the PTB group. Moreover, patients subjectively appealed more severe symptoms following PTB in PROs.

Alterations in skin microbiome mediated by radiotherapy and their potential roles in the prognosis of radiotherapy-induced dermatitis: a pilot study.

Radiotherapy-induced dermatitis (RID) is an inflammatory cutaneous disorder that is acquired as an adverse effect of undergoing radiotherapy. Skin microbiome dysbiosis has been linked to the outcomes of several dermatological diseases. To explore the skin microbiota of RID and deduce their underlying impact on the outcome of RID, cutaneous microbiomes of 78 RID patients and 20 healthy subjects were characterized by sequencing V1-V3 regions of 16S rRNA gene. In total, a significantly apparent reduction in bacterial diversity was detected in microbiomes of RID in comparison to controls. Overall, the raised Proteobacteria/ Firmicutes ratio was significantly linked to delayed recovery or tendency toward the permanence of RID (Kruskal Wallis: P = 2.66 × 10-4). Moreover, applying enterotyping on our samples stratified microbiomes into A, B, and C dermotypes. Dermotype C included overrepresentation of Pseudomonas, Staphylococcus and Stenotrophomonas and was markedly associated with delayed healing of RID. Strikingly, coexistence of diabetes mellitus and RID was remarkably correlated with a significant overrepresentation of Klebsiella or Pseudomonas and Staphylococcus. Metabolic abilities of skin microbiome could support their potential roles in the pathogenesis of RID. Cutaneous microbiome profiling at the early stages of RID could be indicative of prospective clinical outcomes and maybe a helpful guide for personalized therapy.

Anti-inflammatory Effect of Red Macroalgae Bulung Sangu (Gracilaria sp.) Extract in UVB-Irradiated Mice.

BACKGROUND AND OBJECTIVE: Bulung Sangu, like many other macroalgae, is a source of beneficial phytochemical for health. This study was aimed to determine the anti-inflammatory effect of bulung sangu ethanol extract cream. MATERIALS AND METHODS: The compounds of bulung sangu ethanol extract were identified by using gas chromatography. The antioxidant activity of the extract was examined by the DPPH assay. The anti-inflammatory effect was analyzed in vivo against ultraviolet B (UVB) induction through variables of epidermal thickening and epidermal erosion scores. RESULTS: Our results showed that bulung sangu ethanol extract contained 18 compounds, in which, 11 compounds considered active as antioxidant and/or anti-inflammatory. Cream extract in both concentrations showed scavenging for more than 50%, with a concentration of 10% cream extract exhibited higher antioxidant activity compared to 5%. The in vivo assay showed a reduction of epidermal thickness and epidermal erosion in the application of both concentrations. The concentration of 10% cream extract showed higher reduction compared to 5% with results produced resembling normal. CONCLUSION: It can be concluded that bulung sangu displayed a potential source for being developed for the health and medicine aspect, especially for various activities supported by antioxidants and anti-inflammatory.

COVID-19 Vaccine-Induced Radiation Recall Phenomenon.

Radiation recall phenomenon (RRP) is an uncommon, late occurring, acute inflammatory skin reaction that emerges in localized areas coincident with previously irradiated radiation therapy (RT) treatment fields. RRP has been known to be triggered by a number of chemotherapy agents. To the best of our knowledge, this report is the first description of RRP after administration of the Pfizer-BioNTech vaccine for COVID-19, or any other currently available vaccine against COVID-19. Acute skin reactions were observed in 2 RT patients with differing timelines of RT and vaccinations. In both cases however, the RRP presented within days of the patient receiving the second dose of vaccine. For each RT course, the treatment planning dosimetry of the radiation fields was compared with the area of the observable RRP. RRP developed within the borders of treatment fields where prescription dose constraints were prioritized over skin sparing. Our observation is currently limited to 2 patients. The actual incidence of RRP in conjunction with Pfizer-BioNTech vaccine or any other vaccine against COVID-19 is unknown. For patients with cancer being treated with radiation with significant dose to skin, consideration should be given to the probability of RRP side effects from vaccinations against COVID-19.

A prospective feasibility study of a 1-mm bolus for postmastectomy radiotherapy.

BACKGROUND: The optimal chest wall bolus regimen for postmastectomy radiotherapy (PMRT) remains unknown. We aimed to prospectively evaluate the use of a 1-mm-thick daily tissue-equivalent bolus in patients who received PMRT using thermoluminescent dosimeters (TLDs) and skin toxicity assessment. METHODS: Patients with a 1-mm-thick daily bolus during PMRT were prospectively enrolled at The Juntendo University Hospital. The surface dose was measured in vivo under the 1-mm-thick bolus on the chest wall. We assessed the acute skin toxicity weekly during PMRT, and 1, 2, 4, and 12 weeks after the completion of PMRT. RESULTS: A total of 19 patients aged 32-79 years old received PMRT from July 2019 to January 2020. All patients completed the protocol treatment without interruptions, and the median follow-up was 32 weeks. In vivo dosimetry analysis revealed surface doses between 77 and 113% of the prescribed dose, with a mean of 92% of the prescribed radiation dose, and a standard deviation of 7% being delivered. Grade 2 dermatitis was found in 10 patients (53%), and Grade 3 dermatitis was found in one patient (5%). All cases of Grade 2 and 3 dermatitis were improved 4 weeks after PMRT. There were no cases of Grade 4 dermatitis and no chest wall recurrences during the treatment or follow-up period. CONCLUSIONS: Results confirmed the feasibility of using a 1-mm-thick daily bolus for PMRT, exhibiting an appropriate dose buildup and acceptable skin toxicity without treatment interruptions. TRIAL REGISTRATION: The University Hospital Medical Information Network Clinical Trials Registry, UMIN000035773 . Registered 1 July 2019.

Predictive Factors Increasing the Risk of Radiation Toxicity in Patients with Early Breast Cancer.

OBJECTIVES: Radiation induces adverse events on healthy tissues which may be augmented by certain factors. This study aimed to assess patients; tumor and treatment-related factors which increase the risk of radiation-induced toxicity in breast cancer patients. METHODS: This prospective study included postmenopausal early breast cancer patients treated at the clinical oncology department, Assiut University, Egypt between January 2015 and December 2018. Patients treated with mastectomy followed by conventional radiotherapy (25x 2 Gy) and either concurrent or sequential letrozole. Acute and late radiation toxicity was scored according to EORTC/RTOG and risk factors were analyzed. RESULTS: A total of 75 patients were included in the study. After a median follow-up of 24 months, 12 patients had > grade 2 acute dermatitis, 5 patients had > grade 2 cardiac toxicity and 3 patients had > grade 2 lung toxicity. Multivariate analysis revealed that trastuzumab use was associated with a decrease risk of acute dermatitis (p= 0.01) but boost irradiation was significantly associated with increased risk of acute dermatitis (p= 0.01). Late toxicity > grade 2 was observed in 6 patients, 14 patients, and 2 patients for skin, heart, and lung respectively. CONCLUSION: The use of boost irradiation was associated with increased risk of acute dermatitis, in the contrary; the use of trastuzumab seemed to be protective as observed in this study.

Effect of photobiomodulation therapy on radiodermatitis in a mouse model: an experimental animal study.

This study aimed to evaluate the effect of photobiomodulation (PBM) for prevention of radiodermatitis in an irradiated mouse model and compare the efficacy of PBM using 633- or 830-nm wavelengths. Irradiated mice were randomly distributed into three groups: A (633 nm), B (830 nm), and C (without PBM). On post-irradiation days 7 and 21, we compared acute damage and recovery in treated skin samples to non-irradiated skin using H&E, Masson's trichrome, anti-CD45 and PCNA immunohistochemistry, and a TUNEL assay. Grade 3 radiodermatitis was evident only in group C. Compared with that in group C, the skin in groups A and B had significantly less epidermal hyperplasia, inflammatory cell infiltration, and thinner dermis on day 7 and less inflammatory cell infiltration, fewer apoptotic cells, and thinner dermis on day 21. However, there was no significant difference between groups A and B. This study indicates PBM could prevent severe radiodermatitis by reducing epidermal and dermal damage, inflammation, and apoptosis. There was no difference in PBM efficacy between the 633- and 830-nm wavelengths.