Survival Outcomes of Mohs Surgery versus Wide Local Excision for Less Common Nonmelanoma Skin Cancers: A Stabilized Inverse Probability of Treatment Weighting Analysis.

BACKGROUND: Compared with wide local excision (WLE), Mohs micrographic surgery (MMS) can not only remove the tumor tissue but also ensure a negative margin. However, there is limited evidence on whether there is a difference in prognosis between the two techniques for less common nonmelanoma skin cancers (NMSCs). OBJECTIVES: The aim of our study was to compare the survival outcomes of MMS and WLE for less common NMSCs. METHODS: This study retrospectively analyzed data from the Surveillance, Epidemiology, and End Results dataset between 2003 and 2018. The less common NMSCs include Merkel cell carcinoma, skin appendage neoplasm, fibromatous malignancy, and other rare NMSCs. The stabilized inverse probability of treatment weighting (SIPTW) and the Kaplan-Meier methods were adopted to assess the overall survival (OS) and cancer-specific survival (CSS). Furthermore, the Cox proportional hazards, Fine-and-Gray regression analysis, and subgroup analysis models were applied to examine the effects of MMS versus WLE based on all-cause and cancer-specific mortality. RESULTS: We identified 6,582 individuals with less common NMSCs for survival analysis, among which 1,946 patients (29.5%) had undergone MMS and 4,636 (70.5%) had received WLE. Diseases diagnosed in the most recent year, older age, the White race, married status, eyelid/face site, small tumor size, and localized disease were factors significantly associated with MMS treatment. Compared with the WLE group, the MMS group had comparable OS before and after the SIPTW analysis. Additionally, after adjusting for other confounding covariates, the surgery type (WLE vs. MMS) did not show significant associations with all-cause mortality (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 0.94-1.14, p = 0.517) and disease-specific mortality (HR: 1.16, 95% CI: 0.95-1.42, p = 0.134). Moreover, the subgroup analysis validated these findings. CONCLUSION: MMS and WLE have comparable OS and CSS for less common NMSCs.

"Your Skin Tells You" Campaign for Keratinocyte Cancers: When Individuals' Selection Makes the Difference.

BACKGROUND: Prevention campaigns for skin cancers have focused primarily on melanoma, and over time there has been increasing awareness of the need to select the population to be screened to maximize program effectiveness. OBJECTIVES: The objective of the study was to report the results of a free dermatological initiative, as part of an awareness campaign dedicated to keratinocyte cancers, targeting individuals pre-selected through a short questionnaire. METHODS: One day of dermatological consultations was held at 15 dermato-oncology referral centers during May 22-June 30, 2021. For selection, individuals answered a telephone interview consisting of 7 yes/no questions on risk factors. Demographics, clinical characteristics of suspicious tumors, and histopathologic diagnosis of excised lesions were collected. Suspicion rate, detection rate, and positive predictive values (PPVs) for any skin cancer, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma were calculated. RESULTS: A total of 320 individuals (56.9% males; 43.1% females) with a median age of 69.6 (range 21-91) years qualified for the screening initiative. Overall, skin cancers and precancerous lesions were diagnosed in 65.9% of the patients. Suspicion rate was 28.7% for any skin cancer (92/320), 22.8% for BCC (73/320), 4.7% for cSCC (15/320), and 1.2% for melanoma (4/320). Detection rate was 23.4% for any skin cancer (PPV 93.7%), 18.1% for BCC (PPV 95.1%), 4.4% for cSCC (PPV 93.3%), and 0.9% for melanoma (PPV 75%). CONCLUSIONS: Selection of individuals at high risk is a cost-effective approach for early detection campaigns for keratinocyte cancers.

Mammalian target of rapamycin inhibitors for prolonged secondary prevention of nonmelanoma skin cancer in solid organ transplant recipients.

Immunosuppressive agents are essential for graft survival in solid-organ transplant recipients (SOTRs), but they have substantial durable side effects, including a higher incidence of aggressive nonmelanoma skin cancers (NMSCs). Hitherto, only one class of immunosuppressants, mammalian target of rapamycin inhibitors (mTORi), may inhibit skin tumor formation, however their durable effectiveness is controversial. To evaluate the sustained effectiveness of mTORi in reducing NMSCs' incidence in SOTRs, a retrospective study was conducted in a specialized dermatology clinic for SOTRs of a tertiary university-affiliated medical center. SOTRs with a history of at least one histologically proven NMSC were followed for 6 years: 3 years after transplantation, before initiation of mTORi, and 3 years under mTORi treatment. The cohort consisted of 44 SOTRs. Treatment with mTORi was initiated on average 6.27 (3.34-6.34) years following transplantation. In the 3 years before mTORi treatment initiation, the mean number of new NMSCs per patient was 2.11 (1-14). This value decreased to 1.2 (0-19) in the 3 years under mTORi treatment (p = 0.0007). Analysis by NMSC type yielded a significant decrease in both SCCs and BCCs. This study found that mTORi are effective for prolonged secondary prevention of NMSCs in SOTRs.

Immunotherapy for the Treatment of Squamous Cell Carcinoma: Potential Benefits and Challenges.

Melanoma and nonmelanoma skin cancers (NMSCs) are recognized as among the most common neoplasms, mostly in white people, with an increasing incidence rate. Among the NMSCs, squamous cell carcinoma (SCC) is the most prevalent malignancy known to affect people with a fair complexion who are exposed to extreme ultraviolet radiation (UVR), have a hereditary predisposition, or are immunosuppressed. There are several extrinsic and intrinsic determinants that contribute to the pathophysiology of the SCC. The therapeutic modalities depend on the SCC stages, from actinic keratosis to late-stage multiple metastases. Standard treatments include surgical excision, radiotherapy, and chemotherapy. As SCC represents a favorable tumor microenvironment with high tumor mutational burden, infiltration of immune cells, and expression of immune checkpoints, the SCC tumors are highly responsive to immunotherapies. Until now, there are three checkpoint inhibitors, cemiplimab, pembrolizumab, and nivolumab, that are approved for the treatment of advanced, recurrent, or metastatic SCC patients in the United States. Immunotherapy possesses significant therapeutic benefits for patients with metastatic or locally advanced tumors not eligible for surgery or radiotherapy to avoid the potential toxicity caused by the chemotherapies. Despite the high tolerability and efficiency, the existence of some challenges has been revealed such as, resistance to immunotherapy, less availability of the biomarkers, and difficulty in appropriate patient selection. This review aims to accumulate evidence regarding the genetic alterations related to SCC, the factors that contribute to the potential benefits of immunotherapy, and the challenges to follow this treatment regime.

Preferentially expressed antigen in melanoma expression in nonmelanoma skin cancers and melanocytes in surrounding skin.

BACKGROUND: Immunohistochemistry for preferentially expressed antigen in melanoma (PRAME) has been studied in melanocytic lesions but not nonmelanoma skin cancers (NMSCs). This study evaluated PRAME expression in NMSCs and dermoepidermal junction (DEJ) melanocytes in the surrounding skin. METHODS: Ninety-nine NMSCs were studied: 23 Merkel cell carcinomas (MCCs), 25 well to poorly differentiated squamous cell carcinomas (SCCs), 14 basal cell carcinomas (BCCs), five basosquamous carcinomas, four sebaceous carcinomas, ten atypical fibroxanthomas, 11 dermatofibrosarcoma protuberans, and seven leiomyosarcomas. Staining quality was considered low or high intensity. Staining quantity was reported as negative 0%, 1% to 24%, 25% to 50%, and >50%. DEJ melanocyte PRAME expression was recorded. RESULTS: Forty-eight percent of NMSCs showed PRAME expression, mostly low intensity in fewer than 25% of cells. High-intensity expression was noted in one poorly differentiated SCC, six BCCs, and seven MCCs. Only MCCs showed expression in greater than 25% of tumor cells. Focal DEJ melanocytes expressed high-intensity PRAME in 18% of cases, most commonly SCCs (11/23). CONCLUSIONS: PRAME is negative or expressed with low intensity in a small percentage of NMSCs, with the exception of some MCC showing high-intensity and diffuse staining. Focal DEJ melanocytes showed high-intensity PRAME reactivity in the skin surrounding some NMSCs.

The value of preoperative high-resolution MRI with microscopy coil for facial nonmelanoma skin cancers.

BACKGROUND: The extent and depth of facial nonmelanoma skin cancers and the involvement of adjacent structures are critical features for surgical planning, but they are difficult to assess clinically. High-resolution MRI (HR-MRI) with microscopy coil may facilitate detailed evaluation of skin lesions. The authors performed this prospective study to determine the value of high-resolution microscopy coil MRI in the preoperative evaluation of nonmelanoma skin cancer. MATERIALS AND METHODS: Between October 2018 and August 2019, 16 lesions from fifteen consecutive patients with facial nonmelanoma skin cancer were evaluated using high-resolution microscopy coil MRI about tumor extent, depth, margins, characteristic, and their spatial relationship with adjacent structures. The preoperative HR-MRI results were compared with the intraoperative findings and with the histopathology, with special note to the depth of invasion. RESULTS: Among the 16 lesions, HR-MRI imaging was found to provide accurate evaluation of tumor extent, depth, and margins and determine whether there was involvement of adjacent structures. The tumor depth measured on HR-MRI showed good correlation with histopathologic results (CCC: 0.973), and Bland-Altman analysis finding no significant bias existed between the two measurements. All lesions except one were completely resected with primary excision. Only one lesion required further excision. During follow-up for 3-15 months, no tumor recurrence was observed in any case. CONCLUSIONS: HR-MRI is an accurate, noninvasive imaging technique that can be used as preoperative evaluation tool for facial nonmelanoma skin cancer. It can accurate predict tumor depth, margins, and involvement of structure. The valuable information it provided facilitates surgeons optimize surgical planning.

Programmed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review.

BACKGROUND: Immunotherapy using programmed cell death 1 protein (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors has been increasingly reported in a variety of nonmelanoma skin cancers (NMSCs). OBJECTIVE: To analyze the evidence of PD-1 and PD-L1 inhibitors in the treatment of NMSC. METHODS: A primary literature search was conducted with the PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases through October 28, 2018, to include studies on the use of PD-1 or PD-L1 inhibitors in patients for NMSC. Two reviewers independently performed study selection, data extraction, and critical appraisal. RESULTS: This systematic review included 51 articles. The most robust evidence was in the treatment of Merkel cell carcinoma and cutaneous squamous cell carcinomas, as supported by phase 1 and 2 clinical trials. Treatment of basal cell carcinoma, cutaneous sarcoma, sebaceous carcinoma, and malignant peripheral nerve sheath tumor also showed benefit with PD-1/PD-L1 inhibitors, but data are limited. There does not appear to be efficacy for PD-1/PD-L1 inhibitors in cutaneous lymphomas. LIMITATIONS: More investigation is needed to determine the efficacy, tumor responsiveness, and the safety profile of PD-1 and PD-L1 inhibitors in NMSC. CONCLUSION: PD-1 and PD-L1 inhibitors exhibit treatment efficacy in a variety of NMSCs.

The use of cisplatin electrochemotherapy in nonmelanoma skin cancers: A single-center study.

Electrochemotherapy (ECT) is a well-known nonconventional skin cancer ablative method that was shown to be safe and effective for treating both locoregional disease spreading and disseminated cutaneous and subcutaneous lesions from different types of cancer. The most common medications used are bleomycin and cisplatin. In the last years many studies were performed on ECT, lead it to be a valid therapeutic option in many international guidelines. Nevertheless, there are still no clear indications regarding timing of its use. The main aim of this study was first to assess the safety and effectiveness of intralesional cisplatin ECT for treating different types of nonmelanoma skin cancer in a group of eligible patients. The second endpoint was to assess patients' tolerability and symptoms improvement through the treatment. A single-center prospective study was performed. Patients with squamous cell carcinoma, basal cell carcinoma, or skin metastases were selected during 1 month. The ideal setting was the presence of two or three lesions with a maximum diameter of 2 cm. Both primary, recurrent, and metastatic lesions were included. Before and 8 weeks after treatment, all patients were evaluated to assess the number, measurement, and anatomical site of skin lesions using photography and metric notation. The medical device for membrane electroporation was the CLINIPORATOR EPS02 model. The cisplatin concentration was at least 1 mg/mL. The dose for each single lesion was calculated based on its volume, as is the standard procedure for ECT. Local or systemic adverse events and changes in symptoms were evaluated with a questionnaire based on a visual analog scale that was administrated before and after ECT. Eight patients with a total of 18 lesions underwent the procedure (six men and two women). Four out of eight (50%) patients had a complete response to the treatment. However, all eight patients had an overall tumor response (100%), experiencing an improvement in symptoms including less pain and bleeding from the tumor. Our study clearly show that ECT with intralesional cisplatin is a valuable and safety procedure for nonmelanoma skin cancer and cutaneous tumor metastasis. ECT with cisplatin was able to achieve a good local disease control leading to complete response in an half of cases. The results were stable after 1 year of follow-up. The outer ear area displayed a really good response, due to both ear's anatomical configuration and intralesional cisplatin pharmacological characteristics.

Identification of Molecular Targets of Dietary Grape-Mediated Chemoprevention of Ultraviolet B Skin Carcinogenesis: A Comparative Quantitative Proteomics Analysis.

We recently showed that dietary grape powder (GP) imparts considerable protection against ultraviolet B (UVB)-mediated skin carcinogenesis in SKH-1 mice. To determine molecular mechanisms of this response, we employed tandem mass tag (TMT) quantitative global proteomics approach on skin tumors from mice exposed to 180 mJ/cm2 UVB twice per week and fed control or 5% GP diet. We found 2629 proteins modulated by GP feeding, with 34 identified using stringent cutoffs (false discovery rate (FDR) q-value ≤ 0.1, fold change ≥ 1.2, p-value ≤ 0.05, ≥ 3 unique peptides). Ingenuity Pathway Analysis helped identify seven proteins involved in protein ubiquitination, including the deubiquitinase UCHL5 and 6 subunits of the 20S proteasome (PSMA1,3,4,6 and PSMB4,7). A second data set without the FDR q-value identified 239 modulated proteins, seven of which are involved in protein ubiquitination. Further, 14 proteins involved in acute phase response signaling were modulated >1.5-fold, including acute phase proteins APCS, FGA, FGB, HP, HPX, and RBP1. Evaluation of upstream regulators found inhibition of ERK1/2 phosphorylation and NF-κB p65, and an increase in IκBα in GP-treated tumors. Overall, our data suggested that GP consumption may mitigate tumorigenesis by enhancing protein ubiquitination and degradation caused by oxidative stress, and manipulates an otherwise tumor-promoting anti-inflammatory environment.

In vivo reflectance confocal microscopy image interpretation for the dermatopathologist.

Reflectance confocal microscopy (RCM) is a technology utilized for bedside diagnosis of cutaneous pathology by non-invasive, in vivo, cellular-level imaging. With the recent establishment of reimbursement codes by the US Centers for Medicaid and Medicare Services, RCM is now likely to be employed by clinical dermatologists and impact decision making on skin cancer management. Dermatopathologists, therefore, would benefit from learning how to interpret RCM images and how RCM findings correlate with histopathological criteria of diagnosis. This review briefly explains the principles behind RCM image acquisition, describes the key RCM features of normal skin, and delineates the RCM characteristics of frequently observed benign and malignant neoplasms.

Neoplastic Multifocal Skin Lesions: Biology, Etiology, and Targeted Therapies for Nonmelanoma Skin Cancers.

Neoplastic skin lesions are multifocal, diffuse skin infiltrations of particular relevance in the differential diagnosis of ulcerative, nodular, or crusting skin lesions. Nonmelanoma skin cancers (NMSCs), namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and also actinic keratosis (AK), are the most common malignant tumors in humans. BCCs do not proliferate rapidly and most of the times do not metastasize, while SCCs are more infiltrative, metastatic, and destructive. AKs are precursor lesions of cutaneous SCCs. The classical therapy of NMSCs makes use of photodynamic therapy associated with chemotherapeutics. With improved understanding of the pathological mechanisms of tumor initiation, progression, and differentiation, a case is made towards the use of targeted chemotherapy with the intent to reduce the cytotoxicity of classical treatments. The present review aims to describe the current state of the art on the knowledge of NMSC, including its risks factors, oncogenes, and skin carcinogenesis, discussing the classical therapy against new therapeutic options.

Pigmented nonmelanoma skin cancers of the genital area: a diagnostic and therapeutic challenge - monocentric experience and review of the literature.

Nonmelanoma skin cancers (NMSC), comprising basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are typically encountered on photo-exposed skin. Nevertheless, several cases of NMSC have been described in covered areas such as the genital region; furthermore, some of these lesions may express a variable degree of pigmentation. Due to the existence of mucosal melanoma, an accurate diagnosis is paramount. In this narrative review, we focused our attention on management and - in particular- diagnosis of pigmented NMSC (pNMSC) located in the genital region, emphasizing the features assessed by dermoscopy and reflectance confocal microscopy. As an implementation, we included data on pNMSC from the Dermatology Unit of the University of Campania Vanvitelli. BCC in the genital region represents only 1% of all BCC cases. It has been supposed that the mutation of patched 1 may lead to the development of BCC even without concomitant UV exposure. Pigmented variants on genitals have seldom been described. More prominent dermoscopic features seem to be blue-gray ovoid nests and arborizing vessels associated with whitish structureless areas. SCC and Bowen's disease (BD) - a variant of in situ SCC - may be encountered in the genital area and are sometimes associated with human papillomavirus (HPV) infection. Pigmented SCC is very rare, and most of the literature is focused on pigmented BD (pBD), which is mainly characterized by gray-brown dots in a linear fashion and glomerular vessels without evident scales. In conclusion, pNMSC is rarely encountered on genitals; evaluation with dermoscopy or other ancillary devices like RCM is important both to exclude benign lesions like seborrheic keratosis and lentigo and to rule out melanoma.

[Skin cancer from solar ultraviolet radiation exposure at work]. / Hautkrebs durch solare Ultraviolettstrahlung am Arbeitsplatz.

Due to their professional activities, outdoor workers are exposed to an increased risk of developing occupational skin cancer caused by solar ultraviolet (UV) radiation as defined by occupational disease (OD) number 5103. Since the amendment to the Occupational Diseases Ordinance ("Berufskrankheitenverordnung", BKV) in 2015, squamous cell carcinomas or multiple actinic keratoses of the skin caused by natural UV radiation in outdoor workers in Germany can be recognized as occupational disease in the sense of OD number 5103. The main cause of nonmelanoma skin cancer (NMSC) is solar UV radiation; it is the most relevant occupational carcinogen in terms of the number of exposed workers (i.e., outdoor workers). Circumstances associated with climate change include increased terrestrial UV radiation, an increase in the number of cloudless days and therefore the number of hours of direct sunshine, adverse meteorological effects to the stratospheric ozone layer, and so-called low ozone events and associated more intense UV radiation. In the future, comprehensive considerations will have to be made as to how prevention concepts can be effectively designed to avoid the development of occupational skin cancer in outdoor workers. The treatment of future cases of skin cancer will be a particular challenge due to their high number and only a limited number of dermatologists available. Hopefully, prevention of skin cancer will become even more important in the future.

Skin cancers arising within tattoos: A systematic review.

Background: Tattooing is a widespread practice and has increased in popularity over time. Many lesions have been described in relation to tattoos, including malignant tumors. Objectives: The primary goal of this review is to determine whether the frequency of published cases of skin cancers within tattoos has been increasing over time. Methods: Our review is in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and reporting criteria. The databases MEDLINE via PubMed, Embase via Elsevier, and Scopus via Elsevier were searched from inception to February 23, 2023. No data or publication date limits were imposed. Results: Our review identified 160 cases of cutaneous tumors arising within tattoos. An increase in published cases over time was observed. Most reported tumors developed within red tattoo pigment (36.9%), with the largest contribution by squamous cell carcinoma and keratoacanthoma lesions. Limitations: There was a lack of consistency of information in published case reports which limited the scope of our analysis. Small sample size was also a limitation of this review. Conclusions: With the increased popularity of tattoos, it is helpful to continue reporting cases of cutaneous malignancies within tattoos. Awareness of the frequency and severity of tumors within tattoos may be communicated to the public.

Radiation Therapy in Non-Melanoma Skin Cancers: An Italian Survey on Behalf of the Italian Association of Radiotherapy and Clinical Oncology.

AIMS: The National Palliative Care and Interventional Radiotherapy Study Groups of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) carried out a survey whose aim was to obtain a "snapshot" of the real-world practice of nonmelanoma skin cancer (NMSC) treatments in Italy. MATERIALS AND METHODS: The survey was conducted on SurveyMonkey's online interface and was sent via e-mail to our society Radiation Oncologists. RESULTS: Fifty-eight Italian radiation oncologists (ROs), representing 54 centers, answered the survey. Thirteen percent of the ROs declared they treat fewer than 10 NMSC lesions annually, 36% treat between 11 and 20, and 51% treat more than 20 lesions annually. Interventional radiotherapy (IRT) was offered by 25% of the ROs, and every case was reportedly discussed by a multidisciplinary team (71%). Electrons (74%), volumetric modulated arc therapy (V-MAT) (57%), three-dimensional conformal radiotherapy (3D-CRT) (43%), and IRT (26%) were the main treatment options. With external beam radiotherapy (EBRT), 46 and 53 different RT schedules were treated for curative and palliative intent, respectively; whereas for IRT, there were 21 and 7 for curative and palliative intent, respectively. The most popular EBRT curative options were 50-70.95/22-35 fractions (fx) and 50-70 Gy/16-20fx and for EBRT palliative settings, 30Gy/10fx, and 20-35Gy/5fx. For IRT, the most popular curative options were 32-50Gy/8-10fx and 30-54Gy/3-5fx, whereas 30Gy/6fz was the palliative option. Less than 10 re-RT cases were reported in one year in 42.5%, 11-20 cases in 42.5%, and >20 cases annually in 15%. Electrons (61%), VMAT (49%), and BRT (25%) were the most widely used approaches: 20-40Gy in 10fx and 20-25Gy in 5fx were the recommended fractionations. CONCLUSION: The survey shows a variegated reality. A national registry with more detailed data could help in undercover its causes.

High-resolution full-field optical coherence tomography microscope for the evaluation of freshly excised skin specimens during Mohs surgery: A feasibility study.

Histopathology for tumor margin assessment is time-consuming and expensive. High-resolution full-field optical coherence tomography (FF-OCT) images fresh tissues rapidly at cellular resolution and potentially facilitates evaluation. Here, we define FF-OCT features of normal and neoplastic skin lesions in fresh ex vivo tissues and assess its diagnostic accuracy for malignancies. For this, normal and neoplastic tissues were obtained from Mohs surgery, imaged using FF-OCT, and their features were described. Two expert OCT readers conducted a blinded analysis to evaluate their diagnostic accuracies, using histopathology as the ground truth. A convolutional neural network was built to distinguish and outline normal structures and tumors. Of the 113 tissues imaged, 95 (84%) had a tumor (75 basal cell carcinomas [BCCs] and 17 squamous cell carcinomas [SCCs]). The average reader diagnostic accuracy was 88.1%, with a sensitivity of 93.7%, and a specificity of 58.3%. The artificial intelligence (AI) model achieved a diagnostic accuracy of 87.6 ± 5.9%, sensitivity of 93.2 ± 2.1%, and specificity of 81.2 ± 9.2%. A mean intersection-over-union of 60.3 ± 10.1% was achieved when delineating the nodular BCC from normal structures. Limitation of the study was the small sample size for all tumors, especially SCCs. However, based on our preliminary results, we envision FF-OCT to rapidly image fresh tissues, facilitating surgical margin assessment. AI algorithms can aid in automated tumor detection, enabling widespread adoption of this technique.

The Roles of Skin Langerhans Cells in Immune Tolerance and Cancer Immunity.

Langerhans cells (LC) are a unique population of tissue-resident macrophages with dendritic cell (DC) functionality that form a network of cells across the epidermis of the skin. Their location at the skin barrier suggests an important role for LC as immune sentinels at the skin surface. The classification of LC as DC over the past few decades has driven the scientific community to extensively study how LC function as DC-like cells that prime T cell immunity. However, LC are a unique type of tissue-resident macrophages, and recent evidence also supports an immunoregulatory role of LC at steady state and during specific inflammatory conditions, highlighting the impact of cutaneous environment in shaping LC functionality. In this mini review, we discuss the recent literature on the immune tolerance function of LC in homeostasis and disease conditions, including malignant transformation and progression; as well as LC functional plasticity for adaption to microenvironmental cues and the potential connection between LC population heterogeneity and functional diversity. Future investigation into the molecular mechanisms that LC use to integrate different microenvironment cues and adapt immunological responses for controlling LC functional plasticity is needed for future breakthroughs in tumor immunology, vaccine development, and treatments for inflammatory skin diseases.

Design, Physicochemical Characterization, and In Vitro Permeation of Innovative Resatorvid Topical Formulations for Targeted Skin Drug Delivery.

Nonmelanoma skin cancers (NMSCs) are the most common malignancies worldwide and affect more than 5 million people in the United States every year. NMSC is directly linked to the excessive exposure of the skin to solar ultraviolet (UV) rays. The toll-like receptor 4 (TLR4) antagonist, resatorvid (TAK-242), is a novel prototype chemo preventive agent that suppresses the production of inflammation mediators induced by UV exposure. This study aimed to design and develop TAK-242 into topical formulations using FDA-approved excipients, including DermaBaseTM, PENcreamTM, polyethylene glycol (PEG)-400, propylene glycol (PG), carbomer gel, hyaluronic acid (HA) gel, and Pluronic® F-127 poloxamer triblock copolymer gel for the prevention of skin cancer. The physicochemical properties of raw TAK-242, which influence the compatibility and solubility in the selected base materials, were confirmed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Raman spectroscopy, and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopic analysis. The permeation behavior of TAK-242 from the prepared formulations was determined using Strat-M® transdermal diffusion membranes, and 3D cultured primary human-derived epidermal keratinocytes (EpiDermTM). Despite TAK-242's high molecular weight and hydrophobicity, it can permeate through reconstructed human epidermis from all formulations. The findings, reported for the first time in this study, emphasize the capabilities of the topical application of TAK-242 via these multiple innovative topical drug delivery formulation platforms.