Eosinophilic granulocytes as a potential prognostic marker for cancer progression and therapeutic response in malignant melanoma.

The importance of eosinophilic granulocytes in cancer has been widely discussed in recent years. The current study reviews the evidence on the role of eosinophilic granulocytes in melanoma as a prognostic marker for cancer progression and the efficacy of treatment with modern immune checkpoint inhibitors. A total of 33 human clinical studies were included in the review, with heterogeneous data due to differences in patients populations, study design and inclusion of small study groups. However, 28 of the 33 studies suggested that eosinophilic granulocytes could be used as a prognostic biomarker for outcome and/or potential response to systemic treatment and/or occurrence of adverse events in melanoma patients. Nevertheless, the exact role of eosinophils remains to be elucidated. Further prospective, larger and better controlled studies are warranted to clarify the significance of eosinophilic granulocytes in patients with melanoma, in more details.

Dimethyl Fumarate Used as an Effective Treatment for Granuloma Annulare Disseminatum: An Immunohistochemical Case Study.

This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin disease. In this case, progressive GAD was treated with DMF, resulting in significant improvement of skin lesions within 5 weeks and complete healing within 7 months. Clinical response was associated with a reduction in inflammatory cells, including both T cell subsets (CD4+ > CD8+), CD183+/CXCR3+ cells, Langerhans cells (CD1a+), myeloid DCs, M1- and M2-like macrophages and the activation marker HLA-DR in immunohistochemical analysis. These findings support the use of DMF as a promising treatment option for this rare skin condition.

HPV Vaccination in Immunosuppressed Patients with Established Skin Warts and Non-Melanoma Skin Cancer: A Single-Institutional Cohort Study.

cSCC (cutaneous squamous cell carcinoma) and its precursors are a major cause of morbidity, especially in immunosuppressed patients, and are frequently associated with human papillomavirus (HPV) infections. The purpose of this study is to investigate the therapeutic potential of alpha-HPV vaccination for immunosuppressed patients with established cSCC and its precursors. In this retrospective study, all patients who received Gardasil-9®, a nonavalent HPV vaccine, as secondary prophylaxis were examined. Dermatologic interventions in both the pre- and post-vaccination periods were analyzed with zero-inflated Poisson regression and a proportional intensity model for repeated events with consideration of the clinically relevant cofactors. The hazard ratio for major dermatologic interventions was 0.27 (CI 0.14-0.51, p < 0.001) between pre- and post-Gardasil-9® intervention. Gardasil-9® vaccination showed good efficacy in reducing major dermatologic interventions even after correction of relevant cofactors and national COVID-19 caseloads during the observational period. Alpha-HPV vaccination may potentially cause a significant decrease in dermatologic interventions and overall mortality as well as healthcare costs in immunosuppressed patients with high skin tumor burden.

Melanoma Prognosis and Associated Risk Factors: A Retrospective Cohort Study Using Semantic Map Analysis.

The overall patterns of correlations among various melanoma risk factors have not yet been examined. The aim of this study was to assess the impact of different parameters on disease-free and melanoma-related overall survival. A retrospective cohort study was conducted encompassing all patients with a primary cutaneous melanoma diagnosed in a university referral centre. Associations were explored using semantic map analysis, which uses graph theory to find the strongest path of connections between variables. A total of 1,110 melanoma patients (median follow-up 10.6 years) were included. The analysis revealed a clustering of variables around 2 main hubs: Breslow thickness < 1 mm and ≥ 4 mm. Factors connected with high melanoma thickness were: older age, positive sentinel lymph node biopsy findings, presence of ulceration, nodular melanoma type, and light skin phototype. Both disease-free and melanoma-related overall survival were in this cluster and connected with positive sentinel lymph node biopsy and Breslow ≥ 4 mm. Patients with Breslow between 1 and 3.9 mm were also in this cluster and linked with negative sentinel lymph node biopsy, nodular melanoma and safety distance > 10 mm. This semantic analysis confirmed the close link between Breslow thickness, age, sentinel lymph node biopsy findings, skin type, melanoma subtype and prognosis, and provides prognostic information useful for the further stratification and management of patients with melanoma.

Randomized Open-Label Trial Comparing Teledermatology vs. Face-to-Face Consultation in the Follow-Up of Patients with Mild-to-Moderate Acne.

Background: Acne vulgaris is one of the most common dermatological diseases, especially in adolescents and young adults. Objective: The current study aimed to compare teledermatology versus face-to-face consultation in the follow-up of patients with mild-to-moderate acne. Methods: In this investigator-initiated, parallel arms, open-label, randomized clinical trial, after screening, participants were randomly assigned in a 1:1 ratio to be followed up through teledermatology or standard face-to-face consultations for a period of 6 months. The primary endpoint was the cumulative time spent by physician for consultations or online assessments. Results: Out of 24 patients (21 females and 3 males; mean age 23.0 ± 3.3 years) underwent randomization in the two study groups. In intention-to-treat analysis, the cumulative time spent by physician was higher in the teledermatology group compared to face-to-face consultations with an average difference of 8:24 mm:ss (95% CI: 1:17-15:31). However, the cumulative time spent by the patient was significantly lower in the teledermatology group (mean difference 1:21:39 hh:mm:ss; 95% CI: 41:51-2:01:27). An optimal reduction of acne-severity was observed in both groups, without significant differences between them. The patient's satisfaction did not change significantly over time and between groups, and was generally quite high. AEs were reported by one patient in the teledermatology group and four patients in the consultation group. Conclusion: Acne might be an optimal disease to be followed up using a teledermatology platform, to relieve the burden on patients and medical staff. However, it is necessary to implement more user-friendly platforms in order to achieve the best possible results in the treatment and follow-up of acne patients.

Long-Term Follow-Up of Lentigo Maligna Patients Treated with Imiquimod 5% Cream.

BACKGROUND: The study investigated the long-term efficacy of imiquimod 5% cream for LM, with a focus on disease recurrence and the possible prognostic factors of disease-free survival (DFS) in a cohort, with long-term follow-up. METHODS: Consecutive patients with histologically confirmed LM were included. Imiquimod 5% cream was applied until weeping erosion appeared on the LM-affected skin. The evaluation was performed through clinical examination and dermoscopy. RESULTS: We analyzed 111 patients with LM (median age: 72 years, 61.3% women) with tumor clearance after imiquimod therapy, with a median follow-up of 8 years. The overall patient survival rates were 85.5% (95% confidence interval (CI): 78.5-92.6) and 70.4% (95% CI: 60.3-80.5) at 5 and 10 years, respectively. Among the 23 patients (20.1%) with relapse at follow-up, 17 (73.9%) were treated with surgery, five (21.7%) continued imiquimod therapy, and one (4.3%) underwent both surgery and radiotherapy. After adjustment for age and LM area in multivariable models, localization of LM in the nasal region was identified as a prognostic factor for DFS (HR = 2.66; 95% CI: 1.06-6.64). CONCLUSION: If surgical excision is not possible due to the patients' age/comorbidities or critical cosmetic localization, imiquimod could provide optimal outcomes with an optimal risk of relapse for the management of LM.

Skin hyperpigmentation after sclerotherapy with polidocanol: A systematic review.

Skin hyperpigmentation after sclerotherapy with polidocanol-containing sclerosants is a common local side effect. Sclerotherapists should be familiar with factors that trigger hyperpigmentation after sclerotherapy with polidocanol-containing sclerosants. A systematic literature review of works reporting hyperpigmentation after sclerotherapy for telangiectasias, reticular veins, side branches and truncal varices with polidocanol-containing sclerosants was performed. Reported incidence rates, follow-up periods and potentially triggering factors were assessed and analysed. The search yielded 1687 results; of these, 27 reports met the inclusion criteria. The incidence of hyperpigmentation seemed to increase with higher concentrations of polidocanol and was more evident after sclerotherapy for epifascial veins than for intrafascial truncal veins when the polidocanol concentration was more than 0.25%. Regarding sclerotherapy for telangiectasias and reticular veins, the incidence of hyperpigmentation ranged between 2% and 25% for polidocanol 0.25% (liquid and foam), between 12.5% and 67.9% for polidocanol 0.5% (liquid and foam) and between 13% and 73% for polidocanol 1% (liquid and foam). Regarding truncal veins, the incidence ranged from 7% to 45.8% for polidocanol 1% (liquid and foam), from 16% to 17% for polidocanol 2% (foam) and from 7.4% to 32.5% for polidocanol 3% (liquid and foam). Regarding the treatment of side branches, the incidence of hyperpigmentation ranged from 5.6% to 53% for both foam and liquid sclerotherapy. Regarding the duration of hyperpigmentation, there are few data describing reticular veins and telangiectasias. Hyperpigmentation persisting for more than 6 months has been reported to have an incidence of up to 7.5%. Hyperpigmentation persisting for more than 1 year after foam polidocanol 1%-3% treatment for truncal veins has an incidence ranging from 8.1% to 17.5%. Other factors such as higher volumes and compression therapy after treatment seem to have a minor influence. Data regarding hyperpigmentation after polidocanol-related sclerotherapy are poor and should be improved by higher-quality research.

Swiss Recommendations for Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer in Switzerland and worldwide. Most BCCs can be treated in a curative setting. However, patients can develop locally destructive and, rarely, metastatic tumors that require a different treatment approach. The clinical subtype of individual lesions provides prognostic information and influences management decisions. Surgical excision, topical therapies, and radiotherapy are highly effective in the majority of subtypes as well as in low- and high-risk diseases. For patients with low-risk diseases and superficial tumors not amenable to surgery, several nonsurgical alternatives are available. Systemic therapy is indicated for high-risk BCCs, which are not amenable to either surgery or radiotherapy. Hedgehog pathway inhibitors (HHI) are currently approved. Other therapeutic options such as immune checkpoint inhibitors show promising results in clinical trials. This first version of Swiss recommendations for diagnosis and management of BCC was prepared through extensive literature review and an advisory board consensus of expert dermatologists and oncologists in Switzerland. The present guidelines recommend therapies based on a multidisciplinary team approach and rate of recurrence for individual lesions. Based on the risk of recurrence, two distinct groups have been identified: low-risk (easy-to-treat) and high-risk (difficult-to-treat) tumors. Based on these classifications, evidence-based recommendations of available therapies are presented herein.

Subcapsular Sinus Macrophages Promote Melanoma Metastasis to the Sentinel Lymph Nodes via an IL1α-STAT3 Axis.

During melanoma metastasis, tumor cells originating in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN). This process facilitates tumor cell spread across the body. Here, we characterized the innate inflammatory response to melanoma in the metastatic microenvironment of the sLN. We found that macrophages located in the subcapsular sinus (SS) produced protumoral IL1α after recognition of tumoral antigens. Moreover, we confirmed that the elimination of LN macrophages or the administration of an IL1α-specific blocking antibody reduced metastatic spread. To understand the mechanism of action of IL1α in the context of the sLN microenvironment, we applied single-cell RNA sequencing to microdissected metastases obtained from animals treated with the IL1α-specific blocking antibody. Among the different pathways affected, we identified STAT3 as one of the main targets of IL1α signaling in metastatic tumor cells. Moreover, we found that the antitumoral effect of the anti-IL1α was not mediated by lymphocytes because Il1r1 knockout mice did not show significant differences in metastasis growth. Finally, we found a synergistic antimetastatic effect of the combination of IL1α blockade and STAT3 inhibition with stattic, highlighting a new immunotherapy approach to preventing melanoma metastasis.

Transcutaneous sentinel lymph node detection in cutaneous melanoma with indocyanine green and near-infrared fluorescence: A diagnostic sensitivity study.

Sentinel lymph node (SLN) biopsy with preoperative radiocolloid-based lymphoscintigraphy and blue dye injection is considered the standard procedure for staging nodal metastases in early-stage cutaneous melanoma patients with clinically uninvolved lymph nodes. While this combination renders good accuracy in SLN detection, radiation exposure and the frequent allergic reactions to the blue dye are considered drawbacks of this technique. Indocyanine green (ICG) is a water-soluble fluorescent dye that can be identified through near-infrared fluorescence imaging (NIRFI). The aim of this prospective diagnostic sensitivity study was to assess the feasibility of ICG and NIRFI to identify SLNs in melanoma transcutaneously ("before skin incision") and to analyze the various factors influencing detection rate, in comparison to lymphoscintigraphy. This study included 93 patients undergoing SLN biopsy for cutaneous melanoma. The region and the number of the SLNs identified with lymphoscintigraphy and with ICG were recorded. Patients' characteristics, as well as tumor details were also recorded preoperatively. One hundred and ninety-four SLNs were identified through lymphoscintigraphy. The sensitivity of ICG for transcutaneous identification of the location of the SLNs was 96.1% overall, while the sensitivity rate for the number of SLNs was 79.4%. Gender and age did not seem to influence detection rate, but a body mass index >30 kg/m2 was associated with a lower identification rate of the number of SLNs (P = .045). Transcutaneous identification of SLNs through ICG and NIRFI technology is a feasible technique that could potentially replace in selected patients the standard SLN detection methodology in cutaneous melanoma.

The Immunohistochemical Assessment of Neoangiogenesis Factors in Squamous Cell Carcinomas and Their Precursors in the Skin.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer. Well-limited forms can be easily treated with excision, but locally advanced cancers can, unfortunately, progress to metastasis. However, it is difficult to establish the prognosis for cutaneous squamous cell carcinoma and its potential to metastasize. Therefore, this study aimed to evaluate neoangiogenesis in cSCC, as it plays a major role in the dissemination of neoplasia. A literature review was performed on selected neoangiogenic factors (VEGF, ANG1/2, Notch1, CD31/34/105, EGF, etc.). Most of them, including VEGF, EGFR, and CD105, had more elevated levels in the advanced stages of the lesion. The same is true for Notch1, p53, and TGFß, which are the most frequently mutated tumor suppressors in this type of skin cancer. In addition, the inhibition of some of these markers, using Ang1 analogs, inhibitors of EGFR, TRAF6, or combined inhibitors of EGFR and IGF-IR, may lead to a decrease in tumor size. In conclusion, this literature review identified diagnostic and prognostic markers, as well as possible factors that can be used for the targeted therapy of spinaliomas.

Noncontrast-enhanced 3-Tesla MRI using surface coil as a complementary test for assessment of distribution and depth of locoregional cutaneous metastases of malignant melanoma.

Locoregional and distant metastases account for most cases of morbidity and mortality associated with melanoma. In addition, local recurrences of melanoma might be the onset of disseminated disease. Therefore, precise diagnosis and therapy are warranted to minimize morbidity and increase survival in a subset of patients. However, the correct distribution of the metastatic lesions on the skin is often difficult to estimate. We present the application of noncontrast-enhanced 3-Tesla MRI using surface coil to detect locoregional cutaneous metastases of malignant melanoma on the basis of the topographic assessment of skin lesions. Furthermore, in a systematic review, we summarize the current knowledge about application of MRI in assessment of location, distribution, and depth of cutaneous primary malignant melanoma. MRI might be applied to evaluate the location, distribution, size, and depth of the locoregional cutaneous metastasis of malignant melanoma to identify the optimal cost-effective treatment strategies and monitor their effects.

Reliability Assessment and Validation of the Skin Hyperpigmentation Index Compared to the Physician Global Assessment Score.

BACKGROUND: The skin hyperpigmentation index (SHI), a new objective method for measuring skin hyperpigmentation, needs validation. OBJECTIVE: To gain evidence of the reliability and validity of the SHI. METHODS: Fifteen raters were divided into 3 groups (5 dermatologists, 5 nondermatologist physicians, and 5 nonphysician clinicians). Each rated 5 pigmented mole lesions with mild-to-severe hyperpigmentation to determine intra- and interrater reliability. All raters photographed the lesions and rated them using the subjective Physician Global Assessment (PGA) score. The same photographs were then assessed based on automatic computer measurement software using the online SHI tool (https://shi.skinimageanalysis.com). RESULTS: The SHI reliability was excellent for all intra- and interrater assessments, while most PGA assessments showed good intra- and interrater agreement. Between-group reliability was excellent for SHI, while moderate-to-good for PGA evaluations. Concordance between the SHI and PGA assessments was strong across all groups of assessors. CONCLUSION: There is evidence that the SHI is a reliable instrument for measuring skin hyperpigmentation, and can be used by nonexperienced clinicians.

Melanoma of the Nail Apparatus: An Analysis of Patients' Survival and Associated Factors.

BACKGROUND: There are no proper management guidelines for nail apparatus melanoma (NAM). OBJECTIVE: This study aimed to describe the clinical features, the presence of locoregional and distant metastases and disease-free and overall survival of NAM treated at our institution. METHODS: A retrospective cohort review of patients with single, primary localized histopathologically confirmed NAM was performed. Collected data consisted of patients' characteristics and tumor features. In addition, local recurrence, locoregional metastases, distant metastases, disease-free survival (DFS) and overall survival (OS) were used as the main outcomes in our analysis. RESULTS: Thirty patients with NAM were included. The overall survival (OS) in our patients at 5 and 10 years was 85.6 and 73.4%, respectively. DFS was significantly higher in patients with primary tumor location in the hand and without tumor-infiltrating lymphocytes (p value = 0.01 and 0.04, respectively). The patients with in situ melanoma or Breslow thickness <1 mm had a significantly higher chance of DFS and OS (90.0 and 94.1% at 5 years, respectively) than those with thicker NAM (58.3 and 55.6% at 5 years, respectively). A total of 53.3% of 30 patients underwent primary excision and covering with a full-thickness skin graft, while 13.3% of our 30 patients underwent digit amputation. The patients who underwent excision and covering with a full-thickness skin graft showed a complete overall survival (100% at 5 years). CONCLUSION: Primary tumor location in the hand and lower tumor thickness might be correlated with better patients' survival. The study results suggest that total amputation might not be necessary in all NAM cases.

Comparison of teledermatological examinations with conventional office visits in management of acne vulgaris: A review of current literature.

Acne vulgaris is the most common skin disease in the world, particularly affecting adolescents and young adults. Telemedicine has grown rapidly in the past few years and represents a new simplification in modern medicine. The aim of this literature review is to provide an overview of acne vulgaris in teledermatology and to identify the differences between teledermatological examinations and face-to-face consultations. For this purpose, a systematic literature search of the PubMed database was performed, up to the end of 2019. The content of 109 studies matching the keywords acne, acne vulgaris, teledermatology, telehealth, or telemedicine was screened, and 13 studies were systematically reviewed and compared. The analysis of the studies shows that patients living in remote areas benefit greatly from online visits since it is less time consuming and financially favorable, which is also associated with higher patient satisfaction. In addition, the satisfaction of doctors, the main safety concerns of patients, and a brief insight into telemedicine in other specialties are discussed. Taking the results of the different studies into account, the conclusion is that telemedicine is well accepted and often even desired by most patients and will likely become a very important part of modern medicine in the future.

Efficacy Assessment of the High-Frequency High-Intensity Focused Ultrasound as a New Treatment for Actinic Keratosis.

BACKGROUND: Actinic keratosis (AK) is the most common precancerous cutaneous lesion, with risk of progression to cutaneous squamous cell carcinoma. In the current study, we evaluated the efficacy of 20-MHz high-intensity focused ultrasound (HIFU), as a new treatment modality for AK. MATERIALS AND METHODS: Patients with AK lesions (grades I-III) treated with HIFU were included in the study. The clinical assessment was performed 3 months after therapy. RESULTS: Twenty-one patients (14 men, 7 women) with 108 AK lesions (grades I-III) were included in the current study. Ages ranged from 62 to 85 years (mean 72.6 years). Clinically complete resolution of the actinic damage in the treated area was detected in 72.2% of lesions. Furthermore, 28 lesions (26%) showed a reduction of the AK grade, or partial response, after the therapy. Most of the patients experienced annoying but short pain during the procedure. However, late adverse effects of the therapy, such as hypopigmentation, hyperpigmentation and erythema were reported only in a small portion of the lesions. CONCLUSIONS: 20-MHz HIFU could be an effective and safe alternative treatment for AK.

ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1.

Autophagy is a highly conserved cellular process in which intracellular proteins and organelles are sequestered and degraded after the fusion of double-membrane vesicles known as autophagosomes with lysosomes. The process of autophagy is dependent on autophagy-related (ATG) proteins. The role of autophagy in cancer is very complex and still elusive. We investigated the expression of ATG proteins in benign nevi, primary and metastatic melanoma tissues using customized tissue microarrays (TMA). Results from immunohistochemistry show that the expression of ATG5 and ATG7 is significantly reduced in melanoma tissues compared to benign nevi. This reduction correlated with changes in the expression of autophagic activity markers, suggesting decreased basal levels of autophagy in primary and metastatic melanomas. Furthermore, the analysis of survival data of melanoma patients revealed an association between reduced ATG5 and ATG7 levels with an unfavourable clinical outcome. Currently, the mechanisms regulating ATG expression levels in human melanoma remains unknown. Using bioinformatic predictions of transcription factor (TF) binding motifs in accessible chromatin of primary melanocytes, we identified new TFs involved in the regulation of core ATGs. We then show that nuclear respiratory factor 1 (NRF1) stimulates the production of mRNA and protein as well as the promoter activity of ATG5 and ATG7. Moreover, NRF1 deficiency increased in vitro migration of melanoma cells. Our results support the concept that reduced autophagic activity contributes to melanoma development and progression, and identifies NRF1 as a novel TF involved in the regulation of both ATG5 and ATG7 genes.

Isolate Virulence and Cultivar Response in the Winter Wheat: Pyrenophora tritici-repentis (Tan Spot) Pathosystem in Oklahoma.

Prevalence of tan spot of wheat caused by the fungus Pyrenophora tritici-repentis has become more prevalent in Oklahoma as no-till cultivation in wheat has increased. Hence, developing wheat varieties resistant to tan spot has been emphasized, and selecting pathogen isolates to screen for resistance to this disease is critical. Twelve isolates of P. tritici-repentis were used to inoculate 11 wheat cultivars in a greenhouse study in splitplot experiments. Virulence of isolates and cultivar resistance were measured in percent leaf area infection for all possible isolate x cultivar interactions. Isolates differed significantly (P < 0.01) in virulence on wheat cultivars, and cultivars differed significantly in disease reaction to isolates. Increased virulence of isolates detected increased variability in cultivar response (percent leaf area infection) (r = 0.56, P < 0.05) while increased susceptibility in cultivars detected increased variance in virulence of the isolates (r = 0.76, P < 0.01). A significant isolate × cultivar interaction indicated specificity between isolates and cultivars, however, cluster analysis indicated low to moderate physiological specialization. Similarity in wheat cultivars in response to pathogen isolates also was determined by cluster analysis. The use of diverse isolates of the fungus would facilitate evaluation of resistance in wheat cultivars to tan spot.

Efficacy of Combined in-vivo Electroporation-Mediated Gene Transfer of VEGF, HGF, and IL-10 on Skin Flap Survival, Monitored by Label-Free Optical Imaging: A Feasibility Study.

Preventing surgical flaps necrosis remains challenging. Laser Doppler imaging and ultrasound can monitor blood flow in flap regions, but they do not directly measure the cellular response to ischemia. The study aimed to investigate the efficacy of synergistic in-vivo electroporation-mediated gene transfer of interleukin 10 (IL-10) with either hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) on the survival of a modified McFarlane flap, and to evaluate the effect of the treatment on cell metabolism, using label-free fluorescence lifetime imaging. Fifteen male Wistar rats (290-320 g) were randomly divided in three groups: group-A (control group) underwent surgery and received no gene transfer. Group-B received electroporation mediated hIL-10 gene delivery 24 h before and VEGF gene delivery 24 h after surgery. Group-C received electroporation mediated hIL-10 gene delivery 24 h before and hHGF gene delivery 24 h after surgery. The animals were assessed clinically and histologically. In addition, label-free fluorescence lifetime imaging was performed on the flap. Synergistic electroporation mediated gene delivery significantly decreased flap necrosis (P = 0.0079) and increased mean vessel density (P = 0.0079) in treatment groups B and C compared to control group-A. NADH fluorescence lifetime analysis indicated an increase in oxidative phosphorylation in the epidermis of the group-B (P = 0.039) relative to controls. These findings suggested synergistic in-vivo electroporation-mediated gene transfer as a promising therapeutic approach to enhance viability and vascularity of skin flap. Furthermore, the study showed that combinational gene therapy promoted an increase in tissue perfusion and a relative increase in oxidative metabolism within the epithelium.