Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro-inflammation cues.

Nonmelanoma skin cancers remain the most widely diagnosed types of cancers globally. Thus, for optimal patient management, it has become imperative that we focus our efforts on the detection and monitoring of cutaneous field carcinogenesis. The concept of field cancerization (or field carcinogenesis), introduced by Slaughter in 1953 in the context of oral cancer, suggests that invasive cancer may emerge from a molecularly and genetically altered field affecting a substantial area of underlying tissue including the skin. A carcinogenic field alteration, present in precancerous tissue over a relatively large area, is not easily detected by routine visualization. Conventional dermoscopy and microscopy imaging are often limited in assessing the entire carcinogenic landscape. Recent efforts have suggested the use of noninvasive mesoscopic (between microscopic and macroscopic) optical imaging methods that can detect chronic inflammatory features to identify pre-cancerous and cancerous angiogenic changes in tissue microenvironments. This concise review covers major types of mesoscopic optical imaging modalities capable of assessing pro-inflammatory cues by quantifying blood haemoglobin parameters and hemodynamics. Importantly, these imaging modalities demonstrate the ability to detect angiogenesis and inflammation associated with actinically damaged skin. Representative experimental preclinical and human clinical studies using these imaging methods provide biological and clinical relevance to cutaneous field carcinogenesis in altered tissue microenvironments in the apparently normal epidermis and dermis. Overall, mesoscopic optical imaging modalities assessing chronic inflammatory hyperemia can enhance the understanding of cutaneous field carcinogenesis, offer a window of intervention and monitoring for actinic keratoses and nonmelanoma skin cancers and maximise currently available treatment options.

Circulating Monocytes Are Predictive and Responsive in Moderate-to-Severe Plaque Psoriasis Subjects Treated with Apremilast.

Monocytes play a critical role in the inflammation associated with psoriasis, and their abnormalities have been reported as biomarkers of cardiovascular event risk, a psoriasis comorbidity. Monocytic cells in chronic inflammatory disorders express elevated levels of cAMP phosphodiesterase. Restoring cAMP levels using the oral cAMP phosphodiesterase-4 inhibitor, apremilast, improves clinical outcomes for a subset of patients with psoriasis. We asked whether aberrant monocyte subsets or transcriptomic pathways can function as biomarkers of psoriasis endotypes that can predict enhanced clinical responses to cAMP phosphodiesterase inhibition. A 16-week open-label study of 22 patients with monocyte flow cytometric and transcriptomic analysis was performed. Subjects with elevated hyperadhesive monocyte doublets at baseline were more likely to be responders to apremilast (P < .0001); 82% of subjects with elevated hyperadhesive monocyte doublets achieved 50% reduction in PASI compared with 46% in those without elevated doublets. We observed a significant reduction in hyperadhesive monocyte-containing doublets and monocyte-platelet aggregates, suggesting an effect of apremilast on the adhesiveness of blood monocytes during chronic inflammation. Monocyte differentially expressed gene transcripts predictive of clinical response uncovered pharmacoendotypes with distinct patterns of nucleotide metabolism, energetics, and differentiation. Further study to understand the basis of drug responsiveness and to develop an apremilast psoriasis treatment algorithm using monocyte-refined gene expression is required to validate and become practical in clinical use, offering patients a test that personalizes their likelihood of clinical response.

The role of sirtuins in dermal fibroblast function.

The sirtuins are a family of seven proteins that perform a variety of dermatological functions and help maintain both the structure and function of the skin. More specifically, the sirtuins have been shown to be altered in multiple dermal cell types including dermal fibroblasts. The functions of dermal fibroblasts are extensive, and include playing a significant role in wound healing as well as helping to maintain the integrity of the skin. As dermal fibroblasts age, they can undergo a state of permanent cell cycle arrest, known as cellular senescence. This senescent process can occur as a result of various stressors, including oxidative stress, ultraviolet radiation -induced stress, and replicative stress. In recent years, there has been a growing interest in both enhancing the cutaneous fibroblast's ability to facilitate wound healing and altering fibroblast cellular senescence. Thus, in this review, we examine the relationship between sirtuin signaling and dermal fibroblasts to understand how this family of proteins may modulate skin conditions ranging from the wound healing process to photocarcinogenesis associated with fibroblast senescence. Additionally, we offer supporting data from experiments examining the relationship between fibroblast senescence and sirtuin levels in an oxidative stress model indicating that senescent dermal fibroblasts exhibit diminished sirtuin levels. Furthermore, we survey the research on the role of sirtuins in specific dermatological disease states that where dermal fibroblast function has been implicated. Finally, we conclude with outlining potential clinical applications of sirtuins in dermatology. In sum, we find that the literature on the involvement of sirtuins in dermal fibroblasts is limited, with research still in its early stages. Nevertheless, intriguing preliminary findings merit additional investigation into the clinical implications of sirtuins in dermatology.

Topical Photodynamic Therapy Generates Bioactive Microvesicle Particles: Evidence for a Pathway Involved in Immunosuppressive Effects.

Although effective in treating actinic damage, topical photodynamic therapy (PDT) has been shown to be immunosuppressive through unknown mechanisms, which could potentially limit its effectiveness. Multiple types of environmental stressors, including PDT, can produce the immunosuppressive lipid mediator platelet-activating factor (PAF). Because PAF can produce subcellular microvesicle particles (MVPs), these studies tested whether PDT can generate PAF and MVP release and whether these are involved in PDT-induced immunosuppression. Previously, topical PDT using blue light and 5-aminolevulinic acid was found to be a potent stimulus for PAF production in mice and human skin explants and human patients, and we show that experimental PDT also generates high levels of MVP. PDT-generated MVPs were independent of the PAF receptor but were dependent on the MVP-generating enzyme acid sphingomyelinase. Patients undergoing topical PDT treatment to at least 10% of body surface area showed local and systemic immunosuppression as measured by inhibition of delayed-type hypersensitivity reactions. Finally, using a murine model of contact hypersensitivity, PDT immunosuppression was blocked by genetic and pharmacologic inhibition of acid sphingomyelinase and genetic inhibition of PAF receptor signaling. These studies describe a mechanism involving MVP through which PDT exerts immunomodulatory effects, providing a potential target to improve its effectiveness.

Inappropriate Testing of Streptococcal Pharyngitis in Children Aged Below 3 Years: Application of Statistical Process Control.

Group A strep tests in patients aged below 3 years are not recommended unless the patient has appropriate symptoms and a positive contact or signs of complications. The purpose of this quality improvement project was to increase the percentage of appropriately ordered strep tests among providers. Data were collected retrospectively and prospectively from 1163 patient visits. Providers were exposed to educational interventions, an electronic medical record order change, and provider feedback. Proportional control charts characterized the providers' behaviors and determined significant improvement among testing. The result was an increase in appropriate tests (13.7% to 37.8%), and the control charts showed sustainable results over time. This project demonstrates the efficacy of these methods to encourage antibiotic stewardship among providers. Furthermore, the interventions used here can be applied to other areas with low-value diagnostic testing. Future studies should investigate whether parental anxiety and educational programs influence testing and evaluate the efficacy of certain strategies.

Uncommon Petaloid Form of Seborrheic Dermatitis Seen in Fitzpatrick Skin Types V-VI.

Background: Seborrheic dermatitis (SD) is an inflammatory disease that has a papulosquamous morphology in areas rich in sebaceous glands such as the scalp, face, and body folds. Petaloid SD is an uncommon presentation found in patients with dark skin (Fitzpatrick Skin type V-VI). This form of SD can appear as pink or hypopigmented polycyclic coalescing rings or scaly macules and patches in the typical areas SD appears, which can mimic other conditions including lupus erythematosus. There is significant disproportion in the representation of darker skin types in dermatological textbooks and scarce literature on petaloid SD. This case demonstrates the presentation of the petaloid SD in an African American patient to contribute to the limited literature on dermatological conditions within this population. Case Report: A 25-year-old African American female with a history of mild hidradenitis suppurativa and asthma who presented with asymptomatic hypopigmented rashes throughout her face, scalp, and chest. She was diagnosed with the petaloid form SD and treated with ketoconazole shampoo once weekly, ketoconazole cream 1-2x daily, and hydrocortisone 2.5% ointment twice daily as needed. At six-week post-treatment follow-up, the patient's rashes significantly improved. Conclusions: The petaloid form of SD is commonly experienced in dark-skinned patients. While common treatments for SD are effective in this form of SD, special consideration of skin types, skincare habits, and haircare in the African American population should be explored. This case report demonstrates how this uncommon skin condition presents in patients of Fitzpatrick skin type V-VI and a successful treatment course.

Rosacea pathogenesis and therapeutics: current treatments and a look at future targets.

Rosacea is a chronic inflammatory skin condition associated with a significant health and economic burden from costs and loss of productivity due to seeking medical treatment. The disease encompasses multiple phenotypic manifestations involving a complex and multi-variate pathogenesis. Although the pathophysiology of rosacea is not completely understood, ongoing research is continually elucidating its mechanisms. In this review, current concepts of rosacea pathogenesis will be addressed which involve skin barrier and permeability dysfunction, the innate and adaptive immune systems, and the neurovascular system. More specifically, the cathelicidin pathway, transient potential receptor channels, mast cells, and the NLRP3 inflammasome pathway are various targets of current pharmacologic regimens. Future therapies may seek different mechanisms to act on current treatment targets, like the potential use of JAK/STAT inhibitors in ameliorating skin barrier dysfunction or TLR antagonists in alleviating cathelicidin mediated inflammation. Other potential treatments aim for entirely different molecular targets such as microvesicle particle mediated local and systemic inflammation. Ultimately rosacea is associated with a significant health and economic burden which warrants deeper research into its pathogenesis and resultant new treatment discovery.

Insights into Lichen Planus Pigmentosus Inversus using Minimally Invasive Dermal Patch and Whole Transcriptome Analysis.

Lichen Planus Pigmentosus inversus (LPPi) is a rare interface and lichenoid dermatitis (ILD) and supposed variant of lichen planus (LP) that presents as well-demarcated brown to grey macules in flexural and intertriginous areas. LPPi is deemed 'inversus' because its anatomical distribution in skin folds is opposite that seen in lichen planus pigmentosus (LPP) whose pigmented lesions arise on sun-exposed skin. Biopsy is required for the clinical diagnosis of all ILDs. Though multiple clinically-oriented studies have reported differences between LPP, LPPi, and LP, few molecular studies have been performed. In this case study, 3 patients, 2 with LPPi and one with LP, provided samples using minimally invasive whole transcriptome analysis using a dermal biomarker patch. This study confirms the involvement of interferon signaling and T-cell activation in LPPi and suggests an expression profile distinct from LP. Specific genes significantly upregulated in LPPi vs LP include an intergenic splice variant of the primary pigmentation determining receptor in humans and dysregulation of genes essential for ceramide synthesis and construction of the cornified envelope. This work expands upon our knowledge of the pathogenesis of LPPi vs LP, and supports the potential use of this technology in the diagnostic clinical setting to mitigate the need for invasive procedures.

Long-Term Efficacy of Dupilumab in Alopecia Areata.

BACKGROUND Dupilumab is a relatively new immune-modulating drug that has transformed the way clinicians treat common immunologic conditions, including atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. Blocking signaling molecules involved within the Th2 immune response, dupilumab is a proven effective treatment for moderate to severe atopic dermatitis - a condition whose disease pathogenesis is heavily linked to the dysregulation of this immunologic pathway. Interestingly, dupilumab has found broader clinical utility, showing efficacy in treating other distinct dermatologic diseases, including alopecia areata. CASE REPORT A 16-year-old White male with a past medical history of moderate atopic dermatitis presented to our clinic with complete scalp hair, eyebrow, and eyelash loss. At this time, the patient was given a clinical diagnosis of alopecia totalis. Understanding that dupilumab has been previously used for treatment in adults of this specific autoimmune condition, we started this adolescent patient on dupilumab to concomitantly treat his atopic dermatitis and alopecia areata. The patient gradually experienced complete regrowth of his hair and almost complete resolution of his atopic dermatitis. Three years after starting dupilumab, the patient remains without signs of alopecia totalis. CONCLUSIONS This case report demonstrates the long-term efficacy of dupilumab use in alopecia areata. More investigation is required to understand dupilumab's broadening clinical indications. Additionally, this case highlights the complex relationship between dysregulation of the Th2 response and autoimmunity. Crosstalk between immune pathways within the disease spectrum of alopecia areata may explain why dupilumab has been reported to both treat and exacerbate alopecia areata.

Stellate Hypopigmentation in a Pediatric Patient After Treatment with Intralesionally-Injected Corticosteroid.

BACKGROUND Several factors contribute to keloids in post-operative patients, including skin mechanics, genetics, and inflammatory processes. One of the most widely used treatment modalities for keloidal scars involves the intralesional injection of corticosteroids, such as triamcinolone acetonide (TAC). TAC is a first-line treatment option for keloids due to its proven efficacy and effectiveness in reducing collagen synthesis, glycosaminoglycan synthesis, inflammatory processes, and proliferation of fibroblasts. Some common adverse effects of intralesional corticosteroid injection include localized hypopigmentation, depigmentation, skin atrophy, and lipoatrophy. CASE REPORT In this report, we describe the case of a 3-year-old African American male patient who presented for dermatologic evaluation of a diffused stellate hypopigmentation attributed to intralesional corticosteroid injection following a keloid removal. Specifically, we summarize this case's clinical features, diagnosis, and outcomes. CONCLUSIONS The case illustrates self-limiting hypopigmentation that repigmented successfully without clinical intervention. Although previous reports of corticosteroid injections' adverse effects resulting in hypopigmentation have been published, this condition is uncommon or poorly reported in pediatric patients. This report aims to contribute to our understanding of the effects of administering corticosteroids in pediatric patients by virtue of diversifying the cases reported in the currently available literature.

UVB-Induced Microvesicle Particle Release and Its Effects on the Cutaneous Microenvironment.

Ultraviolet B radiation (UVB) has profound effects on human skin that results in a broad spectrum of immunological local and systemic responses and is the major cause of skin carcinogenesis. One important area of study in photobiology is how UVB is translated into effector signals. As the skin is exposed to UVB light, subcellular microvesicle particles (MVP), a subtype of bioactive extracellular vesicles, are released causing a variety of local and systemic immunological effects. In this review, we highlight keratinocyte MVP release in keratinocytes in response to UVB. Specifically, Platelet-activating factor receptor agonists generated by UVB result in MVP released from keratinocytes. The downstream effects of MVP release include the ability of these subcellular particles to transport agents including the glycerophosphocholine-derived lipid mediator Platelet-activating factor (PAF). Moreover, even though UVB is only absorbed in the epidermis, it appears that PAF release from MVPs also mediates systemic immunosuppression and enhances tumor growth and metastasis. Tumor cells expressing PAF receptors can use this mechanism to evade chemotherapy responses, leading to treatment resistance for advanced cancers such as melanoma. Furthermore, novel pharmacological agents provide greater insight into the UVB-induced immune response pathway and a potential target for pharmacological intervention. This review outlines the need to more clearly elucidate the mechanism linking UVB-irradiation with the cutaneous immune response and its pathological manifestations. An improved understanding of this process can result in new insights and treatment strategies for UVB-related disorders from carcinogenesis to photosensitivity.

Evidence for Systemic Reactive Oxygen Species in UVB-mediated Microvesicle Formation.

Recent studies have implicated subcellular microvesicle particles (MVP) in the ability of ultraviolet B radiation to exert both local and systemic effects. Indeed, UVB generates MVP (UVB-MVP) in human skin and systemically following phototherapy. The current studies were designed to test the hypothesis that the ability of UVB to generate MVP was dependent upon reactive oxygen species (ROS). To that end, we tested urine samples from subjects undergoing UVB phototherapy for the presence of isoprostanes as well as the oxidized guanosine derivative 8OHdG. We also conducted a clinical study in which volar forearms of subjects were treated with localized UVB and erythema/MVP measured. The same cohort was then treated with 7 days of vitamin C (2 g day-1 ) and vitamin E (1000 IU day-1 ), and UVB-induced MVPs tested on the contralateral forearm. Urine specimens from subjects undergoing phototherapy were found to have increased levels of isoprostanes and 8OHdG, with maximal levels noted 8-16 h post-treatment. Treatment with antioxidant vitamins resulted in diminished UVB-generated skin MVP to baseline levels. These studies suggest that whole-body UVB generates a systemic pro-oxidative response, and that antioxidants can attenuate localized skin UVB-MVPs.

Inhibition of photodynamic therapy induced-immunosuppression with aminolevulinic acid leads to enhanced outcomes of tumors and pre-cancerous lesions.

Photodynamic therapy (PDT) is a treatment option for tumors and pre-cancerous lesions, but it has immunosuppressive side effects that limit its effectiveness. Recent studies suggest that PDT-mediated immunosuppression occurs through a cyclooxygenase type 2 (COX-2) mediated pathway that leads to increases in regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which act as negative regulators of immune responses. Given this pathway, there are three main methods to block immunosuppression: i) Inhibiting the proliferation of Tregs, which can be achieved with the administration of cyclophosphamide or inhibitors of indoleamine 2,3-dioxygenase 1, an activator of Tregs; ii) inhibiting MDSCs by reducing hypoxia around the tumor to create an unfavorable environment or administering all-trans-retinoic acid, which converts MDSCs to a non-immunosuppressive state; and iii) inhibiting COX-2 through selective or non-selective COX-inhibitors. In the present review article, strategies that have shown increased efficacy of PDT in treating tumors and pre-cancerous lesions by blocking the immunosuppressive side effects are outlined and discussed.

Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia.

BACKGROUNDThe loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC.METHODSA human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion.RESULTSXenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs).CONCLUSIONThe elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.TRIAL REGISTRATIONClinicalTrials.gov (NCT03906253).FUNDINGNational Institutes of Health, Veterans Administration.

Vitamin D and Vitamin D Analogs as Adjuncts to Field Therapy Treatments for Actinic Keratoses: Current Research and Future Approaches.

Actinic keratoses (AK), also known as solar keratoses, are precancerous hyperkeratotic papules caused by long-term exposure to ultraviolet radiation. Management of AK prior to progression to cutaneous malignancy represents an important window of intervention. This is important on a population level, given the high incidence, morbidity, financial costs, and the low but measurable risk of mortality from cutaneous neoplasia. Treatments for AK have been refined for many years with significant progress over the past decade. Those recent advancements lead to questions about current treatment paradigms and the role of harnessing the immune system in field therapies. Recent studies suggest a key interplay between vitamin D and cancer immunity; in particular, the systemic and/or topical vitamin D analogs can augment field therapies used for severe actinic damage. In this review, we will examine the literature supporting the use of vitamin D-directed therapies to improve field therapy approaches. An enhanced understanding of these recent concepts with a focus on mechanisms is important in the optimized management of AK. These mechanisms will be critical in guiding whether selected populations, including those with immunosuppression, heritable cancer syndromes, and other risk factors for skin cancer, can benefit from these new concepts with vitamin D analogs and whether the approaches will be as effective in these populations as in immunocompetent patients.

Keratinocyte-derived microvesicle particles mediate ultraviolet B radiation-induced systemic immunosuppression.

A complete carcinogen, ultraviolet B (UVB) radiation (290-320 nm), is the major cause of skin cancer. UVB-induced systemic immunosuppression that contributes to photocarcinogenesis is due to the glycerophosphocholine-derived lipid mediator platelet-activating factor (PAF). A major question in photobiology is how UVB radiation, which only absorbs appreciably in the epidermal layers of skin, can generate systemic effects. UVB exposure and PAF receptor (PAFR) activation in keratinocytes induce the release of large numbers of microvesicle particles (MVPs; extracellular vesicles ranging from 100 to 1000 nm in size). MVPs released from skin keratinocytes in vitro in response to UVB (UVB-MVPs) are dependent on the keratinocyte PAFR. Here, we used both pharmacologic and genetic approaches in cells and mice to show that both the PAFR and enzyme acid sphingomyelinase (aSMase) were necessary for UVB-MVP generation. Our discovery that the calcium-sensing receptor is a keratinocyte-selective MVP marker allowed us to determine that UVB-MVPs leaving the keratinocyte can be found systemically in mice and humans following UVB exposure. Moreover, we found that UVB-MVPs contained bioactive contents including PAFR agonists that allowed them to serve as effectors for UVB downstream effects, in particular UVB-mediated systemic immunosuppression.

Wounding Therapies for Prevention of Photocarcinogenesis.

The occurrence of non-melanoma skin cancer (NMSC) is closely linked with advanced age and ultraviolet-B (UVB) exposure. More specifically, the development of NMSC is linked to diminished insulin-like growth factor-1 (IGF-1) signaling from senescent dermal fibroblasts in geriatric skin. Consequently, keratinocyte IGF-1 receptor (IGF-1R) remains inactive, resulting in failure to induce appropriate protective responses including DNA repair and cell cycle checkpoint signaling. This allows UVB-induced DNA damage to proliferate unchecked, which increases the likelihood of malignant transformation. NMSC is estimated to occur in 3.3 million individuals annually. The rising incidence results in increased morbidity and significant healthcare costs, which necessitate identification of effective treatment modalities. In this review, we highlight the pathogenesis of NMSC and discuss the potential of novel preventative therapies. In particular, wounding therapies such as dermabrasion, microneedling, chemical peeling, and fractionated laser resurfacing have been shown to restore IGF-1/IGF-1R signaling in geriatric skin and suppress the propagation of UVB-damaged keratinocytes. This wounding response effectively rejuvenates geriatric skin and decreases the incidence of age-associated NMSC.