Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

Ex Vivo Analysis of Cell Differentiation, Oxidative Stress, Inflammation, and DNA Damage on Cutaneous Field Cancerization.

Cutaneous field cancerization (CFC) refers to a skin region containing mutated cells' clones, predominantly arising from chronic exposure to ultraviolet radiation (UVR), which exhibits an elevated risk of developing precancerous and neoplastic lesions. Despite extensive research, many molecular aspects of CFC still need to be better understood. In this study, we conducted ex vivo assessment of cell differentiation, oxidative stress, inflammation, and DNA damage in CFC samples. We collected perilesional skin from 41 patients with skin cancer and non-photoexposed skin from 25 healthy control individuals. These biopsies were either paraffin-embedded for indirect immunofluorescence and immunohistochemistry stain or processed for proteins and mRNA extraction from the epidermidis. Our findings indicate a downregulation of p53 expression and an upregulation of Ki67 and p16 in CFC tissues. Additionally, there were alterations in keratinocyte differentiation markers, disrupted cell differentiation, increased expression of iNOS and proinflammatory cytokines IL-6 and IL-8, along with evidence of oxidative DNA damage. Collectively, our results suggest that despite its outwardly normal appearance, CFC tissue shows early signs of DNA damage, an active inflammatory state, oxidative stress, abnormal cell proliferation and differentiation.

Impact of artificial intelligence-based color constancy on dermoscopical assessment of skin lesions: A comparative study.

BACKGROUND: The quality of dermoscopic images is affected by lighting conditions, operator experience, and device calibration. Color constancy algorithms reduce this variability by making images appear as if they were acquired under the same conditions, allowing artificial intelligence (AI)-based methods to achieve better results. The impact of color constancy algorithms has not yet been evaluated from a clinical dermatologist's workflow point of view. Here we propose an in-depth investigation of the impact of an AI-based color constancy algorithm, called DermoCC-GAN, on the skin lesion diagnostic routine. METHODS: Three dermatologists, with different experience levels, carried out two assignments. The clinical experts evaluated key parameters such as perceived image quality, lesion diagnosis, and diagnosis confidence. RESULTS: When the DermoCC-GAN color constancy algorithm was applied, the dermoscopic images were perceived to be of better quality overall. An increase in classification performance was observed, reaching a maximum accuracy of 74.67% for a six-class classification task. Finally, the use of normalized images results in an increase in the level of self-confidence in the qualitative diagnostic routine. CONCLUSIONS: From the conducted analysis, it is evident that the impact of AI-based color constancy algorithms, such as DermoCC-GAN, is positive and brings qualitative benefits to the clinical practitioner.

Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors.

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.

Prevalence of Self-Reported Hand Eczema Signs among Healthcare Workers after the Third Wave of COVID-19 Pandemic: A Survey in a Northern Italy Hospital.

Background: Proper hand hygiene is one of the enhanced preventive measures immediately proposed to avoid the spreading of the severe acute respiratory syndrome coronavirus-2, also known as COVID-19. Objectives: The objective of this study was to estimate the prevalence of self-reported hand eczema signs and symptoms among healthcare workers in a Northern Italy University Hospital after the third wave of the COVID-19 pandemic. Materials and methods: A cross-sectional study was conducted in June 2021. The hospital workers were invited to complete an online questionnaire through a link sent via institutional e-mail to both health personnel and support staff. Results: Eight-hundred and sixty-three subjects completed the questionnaire; 51.1% of them self-reported suffering from at least one hand skin lesion. One-hundred thirty-seven responders declared that they changed their hand hygiene habits, and 88.9% of them carried out these modifications both in occupational and domestic environments. In detail, a change in terms of daily hand washing frequency is reported as follows: before the COVID-19 pandemic, only 27.8% and 10.1% of responders washed their hands 10-20 and 20+ times per day, respectively, while after the pandemic, the percentage increased to 37.8% and 45.8%, respectively. When comparing the health care workers with the administrative staff, we observed a statistically significative difference (p = 0.0001) in the daily hand washing frequency among the two groups, with a higher value in health care personnel. Accordingly, a higher prevalence of hand eczema signs (52.8% versus 45.6%) was detected in the healthcare group. Conclusions: We underline the potential role of the pandemic in the spread of hand eczema as an occupational disease and the need to implement its prevention.

Alpha-Tocopherol Protects Human Dermal Fibroblasts by Modulating Nitric Oxide Release, Mitochondrial Function, Redox Status, and Inflammation.

BACKGROUND: The altered balance between oxidants/antioxidants and inflammation, changes in nitric oxide (NO) release, and mitochondrial function have a role in skin aging through fibroblast modulation. Tocopherol is promising in counteracting the abovementioned events, but the effective mechanism of action needs to be clarified. OBJECTIVE: The aim of this study was to examine the effects of α-tocopherol on cell viability/proliferation, NO release, mitochondrial function, oxidants/antioxidants, and inflammation in human dermal fibroblasts (HDF) subjected to oxidative stress. METHODS: HDF were treated with H2O2 in the presence or absence of 1-10 µM α-tocopherol. Cell viability, reactive oxygen species (ROS), NO release, and mitochondrial membrane potential were measured; glutathione (GSH), superoxide dismutase (SOD)-1 and -2, glutathione peroxidase-1 (GPX-1), inducible NO synthase (iNOS), and Ki-67 were evaluated by RT-PCR and immunofluorescence; cell cycle was analyzed using FACS. Pro- and anti-inflammatory cytokine gene expression was analyzed through qRT-PCR. RESULTS: α-Tocopherol counteracts H2O2, although it remains unclear whether this effect is dose dependent. Improvement of cell viability, mitochondrial membrane potential, Ki-67 expression, and G0/G1 and G2/M phases of the cell cycle was observed. These effects were accompanied by the increase of GSH content and the reduction of SOD-1 and -2, GPX-1, and ROS release. Also, iNOS expression and NO release were inhibited, and pro-inflammatory cytokine gene expression was decreased, confirming the putative role of α-tocopherol against inflammation. CONCLUSION: α-Tocopherol exerts protective effects in HDF which underwent oxidative stress by modulating the redox status, inflammation, iNOS-dependent NO release, and mitochondrial function. These observations have a potential role in the prevention and treatment of photoaging-related skin cancers.

Rapid and exceptional response to Sonidegib in a patient with multiple locally advanced basal cell carcinomas.

Locally advanced basal cell carcinoma (laBCC) represents a rare but possible occurrence in the vast scenario of dermatological diseases. It is well known that most BCC has a pathological activation of the hedgehog pathway, making them susceptible to targeted therapy with selective inhibitors. Sonidegib, approved for the treatment of laBCC on the basis of the results of the basal cell carcinoma outcomes with LDE225 treatment study, demonstrated rapid efficacy and a manageable safety profile. Here, we describe the case of a patient affected by multiple laBCC treated with Sonidegib. The patient experienced an important regression of tumors after only 2 months of therapy, with few side effects. This result confirms the role of Sonidegib as a valid and well-tolerated therapeutic option for laBCC.

Purse-string suture versus full-thickness skin graft: An efficacy and safety comparison study.

Purse-string suture (PSS) and full-thickness skin graft (FTSG) are two different approaches to the closure of circular skin defects. In this study, we compare the feasibility and the aesthetic outcome of these two techniques in high operatory risk non-melanoma skin cancer (NMSC) patients. We performed a retrospective study on 65 patients, treated with PSS or FTSG, and evaluated after a minimum follow-up of 6 months. The post-surgery assessment was based on the Vancouver scar scale (VSS) and differences in terms of defect areas, operative and healing times were performed both with parametric and nonparametric tests. Operative times in PSS were significantly lower than those needed for FTSG, without perioperative adverse events; PSS required a waiting time before removing the suture greater than FTSG. After surgery, PSS resulted in a median defect area reduction of 73%. No significant differences were found in the median value for VSS in the two groups. Based on our clinical experience, the PSS advantages in terms of feasibility, rapidity of execution, and mean defect area reduction were confirmed. So, this technique seems to be appropriate for fragile patients affected by NMSC, that cannot hold long surgical sessions.

Tetracyclines in COVID-19 patients quarantined at home: Literature evidence supporting real-world data from a multicenter observational study targeting inflammatory and infectious dermatoses.

Tetracyclines (TetraC) are widely used in dermatology for both inflammatory and infectious dermatoses; recently both in vivo and in vitro studies started to suggest also a potential antiviral effect. During COVID-19 outbreak, several dermatological patients contracted SARS-CoV-2 experiencing only mild symptoms, but no protocol were approved. A multicenter prospective observational study that enrolled COVID-19 patients visited with teledermatology and undergoing TetraC was performed. About 38 adult outpatients (M/F: 20/18, age 42.6 years [21-67]) were enrolled. During the TetraC treatment, symptoms resolved in all patients within 10 days. Remarkably, ageusia and anosmia disappeared in the first week of TetraC treatment. TetraC seem a promising drug to treat COVID-19 outpatients with mild symptoms.

Angiotensin-converting enzyme gene insertion/deletion polymorphism and susceptibility to psoriasis: a systematic review and meta-analysis.

BACKGROUND: Psoriasis is a multifactorial disorder, impacted by both genetic and environmental factors. Herein, a meta-analysis assessed the association of angiotensin-converting enzyme gene insertion/deletion (ACE I/D) polymorphism and psoriasis susceptibility. METHODS: A systematic search was used in databases of PubMed/Medline, Scopus, Web of Science, and Cochrane Library up to January 2019 without language restriction. A dichotomous analysis was carried out by RevMan 5.3 using crude odds ratio (OR) and 95% confidence interval (CI) to investigate the association between ACE I/D polymorphisms and the risk of psoriasis. A funnel plot analysis was used by CMA 2.0 to estimate a significant existence of publication bias. RESULTS: Out of 61 studies retrieved from the databases, 16 studies were included in the meta-analysis. The pooled ORs for models of D vs. I, DD vs. II, ID vs. II, ID + DD vs. II, and DD vs. II + ID genotypes were 0.96 [95%CI: 0.82, 1.12; P = 0.58], 0.99 [95%CI, 0.73, 1.36; P = 0.96], 0.81 [95%CI, 0.72, 0.91; p: 0.0003], 0.91 [95%CI, 0.73, 1.13; P = 0.40], and 1.05 [95%CI, 0.85, 1.30; P = 0.68], respectively. A significant difference between ACE polymorphisms in patients with/without family history for the disease [OR = 1.44; 95%CI: 1.24, 1.67; P < 0.001] and also in patients mild/severe psoriasis [OR = 0.70; 95%CI: 0.55, 0.88; P = 0.002] was identified. CONCLUSION: The results of the meta-analysis showed that ACE I/D polymorphism may be associated with psoriasis susceptibility, while ID genotype seemed to have a protective role in Caucasian patients affected by psoriatic arthritis and in studies with hospital-based controls.

Non-Melanoma Skin Cancer: news from microbiota research.

Recently, research has been deeply focusing on the role of the microbiota in numerous diseases, either affecting the skin or other organs. What it is well established is that its dysregulation promotes several cutaneous disorders (i.e. psoriasis and atopic dermatitis). To date, little is known about its composition, mediators and role in the genesis, progression and response to therapy of Non-Melanoma Skin Cancer (NMSC). Starting from a bibliographic study, we classified the selected articles into four sections: i) normal skin microbiota; ii) in vitro study models; iii) microbiota and NMSC and iv) probiotics, antibiotics and NMSC. What has emerged is how skin microflora changes, mainly represented by increases of Staphylococcus aureus, Streptococcus pyogenes and Pseudomonas aeruginosa strains, modifications in the mutual quantity of ß-Human papillomavirus genotypes, of Epstein Barr Virus and Malassezia or candidiasis, may contribute to the induction of a state of chronic self-maintaining inflammation, leading to cancer. In this context, the role of S. aureus and that of specific antimicrobial peptides look to be prominent. Moreover, although antibiotics may contribute to carcinogenesis, due to their ability to influence the microbiota balance, specific probiotics, such as Lacticaseibacillus rhamnosus GG, Lactobacillus johnsonii NCC 533 and Bifidobacteria spp., may be protective.

Clinical Implications of Acquired BRAF Inhibitors Resistance in Melanoma.

Understanding the role of mitogen-activated protein kinase (MAPK) pathway-activating mutations in the development and progression of melanoma and their possible use as therapeutic targets has substantially changed the management of this neoplasm, which, until a few years ago, was burdened by severe mortality. However, the presence of numerous intrinsic and extrinsic mechanisms of resistance to BRAF inhibitors compromises the treatment responses' effectiveness and durability. The strategy of overcoming these resistances by combination therapy has proved successful, with the additional benefit of reducing side effects derived from paradoxical activation of the MAPK pathway. Furthermore, the use of other highly specific inhibitors, intermittent dosing schedules and the association of combination therapy with immune checkpoint inhibitors are promising new therapeutic strategies. However, numerous issues related to dose, tolerability and administration sequence still need to be clarified, as is to be expected from currently ongoing trials. In this review, we describe the clinical results of using BRAF inhibitors in advanced melanoma, with a keen interest in strategies aimed at overcoming resistance.

Non-Invasive Analysis of Actinic Keratosis before and after Topical Treatment Using a Cold Stimulation and Near-Infrared Spectroscopy.

Background and objectives: The possible evolution of actinic keratoses (AKs) into invasive squamous cell carcinomas (SCC) makes their treatment and monitoring essential. AKs are typically monitored before and after treatment only through a visual analysis, lacking a quantitative measure to determine treatment effectiveness. Near-infrared spectroscopy (NIRS) is a non-invasive measure of the relative change of oxy-hemoglobin and deoxy-hemoglobin (O2Hb and HHb) in tissues. The aim of our study is to determine if a time and frequency analysis of the NIRS signals acquired from the skin lesion before and after a topical treatment can highlight quantitative differences between the AK skin lesion area. Materials and Methods: The NIRS signals were acquired from the skin lesions of twenty-two patients, with the same acquisition protocol: baseline signals, application of an ice pack near the lesion, removal of ice pack and acquisition of vascular recovery. We calculated 18 features from the NIRS signals, and we applied multivariate analysis of variance (MANOVA) to compare differences between the NIRS signals acquired before and after the therapy. Results: The MANOVA showed that the features computed on the NIRS signals before and after treatment could be considered as two statistically separate groups, after the ice pack removal. Conclusions: Overall, the NIRS technique with the cold stimulation may be useful to support non-invasive and quantitative lesion analysis and regression after a treatment. The results provide a baseline from which to further study skin lesions and the effects of various treatments.

Primary trichodysplasia spinulosa polyomavirus infection in a kidney transplant child displaying virus-infected decoy cells in the urine.

We report a case of primary trichodysplasia spinulosa (TS) infection in a kidney transplant child and describe for the first time the presence of degenerated TS-associated polyomavirus (TSPyV)-infected cells in a TS patient's urine that are morphologically different from BK or JC polyomavirus-infected decoy cells.

Evaluation of the Salivary Level of Cortisol in Patients with Oral Lichen Planus: A Meta-Analysis.

Background and objective: Cortisol, as the main human glucocorticoid, is considered to be a biological marker of stress and anxiety. Since it is known that oral lichen planus (OLP) can appear and worsen during stressful events, cortisol levels have been previously studied in OLP patients. The present meta-analysis aims to assess the salivary concentration of cortisol in OLP patients compared to healthy controls. Materials and methods: Web of Science, PubMed, Cochrane Library, and Scopus databases were searched up to October 2018. The RevMan 5.3 software was used with the mean difference (MD) and 95% confidence intervals (CIs). The CMA 2.0 Software was used to evaluate the publication bias, sensitivity analysis, and meta-regression as possible sources of heterogeneity. Results: 10 studies were analyzed and a total of 269 OLP patients and 268 controls were included. The pooled MD of the salivary levels of cortisol in OLP patients compared with controls was 4.27 ng/mL (95% CI: 2.33, 6.21; P < 0.0001), thus, the salivary level of cortisol in OLP patients was significantly higher than in controls. In Indian-based population studies, a significant difference in the salivary cortisol levels in OLP patients compared with controls was detected (MD = 5.62 ng/mL; 95% CI: 2.67, 8.56; P = 0.0002). In addition, a significant difference in the salivary cortisol levels in the OLP patients compared with the controls was obtained in studies performed with enzyme-linked immunosorbent assay (ELISA) method (MD = 5.33 ng/mL; 95% CI: 2.72, 7.93; P < 0.0001). Conclusion: We suggest that supportive psychological treatment together with the conventional therapy could increase patients' capability to prevent stress, anxiety, and depression.

Identification of Risk Factors for Multiple Non-Melanoma Skin Cancers in Italian Kidney Transplant Recipients.

Background and objectives: Non-melanoma skin cancers (NMSCs) represent the most frequently encountered malignancy in organ transplant recipients and their incidence increases proportionally to the duration of immunosuppression. Furthermore, patients of this group often develop multiple and more aggressive cancers and, to date, risk factors for the development of multiple NMSCs have not been yet established. The present study aimed to identify risk factors for multiple NMSCs in a cohort of Italian kidney transplant recipients (KTRs). Materials and Methods: We consecutively included all KTRs referring to two post-transplant outpatient clinics of North-Western Italy between 2001 and 2017. In this cohort, we evaluated different clinical (endogenous and exogenous) risk factors in order to establish their correlation with NMSCs. Results: 518 KTRs were included, of which 148 (28.6%) developed keratinocyte cancers, with a single tumor in 77 subjects, two skin cancers in 31 patients, 3 in 21 patients, whereas at least 4 NMSCs developed in 19 KTRs. We observed an increased risk of the development of cutaneous neoplasms for the male gender, old age at transplantation (>50 years), light phototype, solar lentigo, history of sunburns, or chronic actinic damage. Considering patients affected by multiple keratinocyte neoplasms, we observed a significant association of actinic damage and solar lentigo with an increased risk of NMSCs; their significance was confirmed even at the multivariable model. Conclusions: Our results confirm the role played by chronic cutaneous actinic damage in carcinogenesis on KTRs and highlight the significance of individualized periodic dermatological screening.

Evaluation of serum lipid, lipoprotein, and apolipoprotein levels in psoriatic patients: a systematic review and meta-analysis of case-control studies.

INTRODUCTION: Psoriasis is a T cell-mediated inflammatory skin disease in which fatty acids may be a link between psoriasis and its comorbidity. AIM: The present meta-analysis aimed to evaluate lipid, lipoprotein, and apolipoprotein levels in the psoriatic patients compared with the control subjects. MATERIAL AND METHODS: Four databases, including Web of Science, Scopus, PubMed, and Cochrane Library were searched until July 2017. All records analysed were case-control studies. The quality of the questionnaires was evaluated using the Newcastle-Ottawa Scale (NOS). A random-effects meta-analysis was done by Rev Man 5.3 using mean difference (MD) and 95% confidence intervals (CIs). RESULTS: Out of 580 studies identified in four databases, 49 studies were included and analysed in this meta-analysis. The results showed that MD of total cholesterol, triglyceride, LDL, VLDL, HDL, Lp(a), Apo A1, and Apo B levels in the patients compared with the controls were (MD = 13.74 mg/dl; 95% CI: 7.72-19.75; p< 0.00001), (MD = 26.04 mg/dl; 95% CI: 20.77-31.31; p< 0.00001), (MD = 11.41 mg/dl; 95% CI: 6.26-16.57; p< 0.0001), (MD = 4.82 mg/dl; 95% CI: 3.63-6.00; p< 0.00001), (MD = -2.78 mg/dl; 95% CI: -4.53 - -1.03; p< 0.002), (MD = 8.51 mg/dl; 95% CI: 4.86-12.17; p< 0.0001), (MD = -6.60 mg/dl; 95% CI: -13.96 - 0.75; p< 0.08), and (MD = 9.70 mg/dl; 95% CI: 3.02-16.39; p< 0.004), respectively. CONCLUSIONS: This meta-analysis identified abnormality of serum lipid, lipoprotein, and apolipoproteinprofiles in psoriatic patients compared with the controls as well as possibly a greater risk of atherosclerosis and cardiovascular (CV) accidents in the patients.

Serum and Salivary IgA, IgG, and IgM Levels in Oral Lichen Planus: A Systematic Review and Meta-Analysis of Case-Control Studies.

Immunoglobulins (IgA, IgG, and IgM) are significant anti-inflammatory factors. The meta-analysis aimed to assess the serum and salivary levels of Igs as more important immunoglobulins in patients affected by oral lichen planus (OLP) compared to the healthy controls. Four databases, including PubMed/Medline, Scopus, Web of Science, and Cochrane Library as well as Iranian databases were checked up to January 2018 without language restriction. The quality of each involved study was done using the Newcastle⁻Ottawa Quality Assessment Scale (NOS) questionnaire. A random-effects model analysis was done by RevMan 5.3 software applying the mean difference (MD) plus 95% confidence intervals (CIs). The CMA 2.0 software was applied to calculate the publication bias among the studies. Out of 70 studies found in the databases, 8 studies were involved and analyzed in the meta-analysis. The meta-analysis included 282 OLP patients and 221 healthy controls. The pooled MDs of serum levels of IgA, IgG, and IgM were -0.13 g/L [95% CI: -0.24, -0.02; P = 0.02], 1.01 g/L [95% CI: -0.91, 2.93; P = 0.30], and -0.06 g/L [95% CI: -0.25, 0.14; P = 0.56], respectively; whereas, the salivary IgA and IgG levels were 71.54 mg/L [95% CI: 12.01, 131.07; P = 0.02] and 0.59 mg/L [95% CI: -0.20, 1.38; P = 0.14], respectively. Considering the few studies performed on saliva, the results suggested that the salivary levels, especially IgA level had higher values than the serum levels. Therefore, the salivary immunoglobulins can play a significant function in the OLP pathogenesis.