Therapeutic modulation of KIT ligand in melanocytic disorders with implications for mast cell diseases.

KIT ligand and its associated receptor KIT serve as a master regulatory system for both melanocytes and mast cells controlling survival, migration, proliferation and activation. Blockade of this pathway results in cell depletion, while overactivation leads to mastocytosis or melanoma. Expression defects are associated with pigmentary and mast cell disorders. KIT ligand regulation is complex but efficient targeting of this system would be of significant benefit to those suffering from melanocytic or mast cell disorders. Herein, we review the known associations of this pathway with cutaneous diseases and the regulators of this system both in skin and in the more well-studied germ cell system. Exogenous agents modulating this pathway will also be presented. Ultimately, we will review potential therapeutic opportunities to help our patients with melanocytic and mast cell disease processes potentially including vitiligo, hair greying, melasma, urticaria, mastocytosis and melanoma.

The Gastrointestinal Microbiome and Immune Checkpoint Inhibitors: A Review of Human Interventional Studies Among Melanoma Patients.

Immune checkpoint inhibitors (ICI) are widely utilized for the treatment of malignant melanoma. Interestingly, gastrointestinal microbiome composition has emerged as a predictive biomarker of immunotherapy outcomes. This review seeks to assess the effect of microbiota-modulatory interventions on the clinical and immunological response of metastatic melanoma treated with ICIs. A systematic search was performed to retrieve studies and cases involving any microbiota-modulating intervention. Three studies assessed the effect of fecal microbiota transplantation (FMT) on ICI efficacy, and one case report assessed its effect on clearance of ICI-associated colitis. Overall, 37.5% of melanoma patients who had been previously refractory to ICI immunotherapy demonstrated complete or partial response following FMT and subsequent immunotherapy. 65% of immunotherapy-naïve melanoma patients demonstrated an objective response. No severe FMT-associated adverse events were reported, and FMT depicted efficacy in the remission of ICI-associated colitis. The results suggest that FMT may be a safe and moderately effective microbiota-modulating intervention to improve the efficacy of therapy in ICI-treated melanoma patients. Large, randomized, controlled trials are needed to determine optimal FMT donors and assess other microbiota-modulating interventions, such as pre- and probiotics, in melanoma patients.  J Drugs Dermatol. 2024;23(2):78-84.     doi:10.36849/JDD.7674.

Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers.

Hair graying holds psychosocial importance and serves as an excellent model for studying human pigmentation and aging in an accessible miniorgan. Current evidence suggests that graying results from an interindividually varying mixture of cumulative oxidative and DNA damage, excessive mTORC1 activity, melanocyte senescence, and inadequate production of pigmentation-promoting factors in the hair matrix. Various regulators modulate this process, including genetic factors (DNA repair defects and IRF4 sequence variation, peripheral clock genes, P-cadherin signaling, neuromediators, HGF, KIT ligand secretion, and autophagic flux. This leads to reduced MITF- and tyrosinase-controlled melanogenesis, defective melanosome transfer to precortical matrix keratinocytes, and eventual depletion of hair follicle (HF) pigmentary unit (HFPU) melanocytes and their local progenitors. Graying becomes irreversible only when bulge melanocyte stem cells are also depleted, occurring later in this process. Distinct pigmentary microenvironments are created as the HF cycles: early anagen is the most conducive phase for melanocytic reintegration and activation, and only during anagen can the phenotype of hair graying and repigmentation manifest, whereas the HFPU disassembles during catagen. The temporary reversibility of graying is highlighted by several drugs and hormones that induce repigmentation, indicating potential target pathways. We advise caution in directly applying mouse model concepts, define major open questions, and discuss future human antigraying strategies.

Treatment options and emotional well-being in patients with rosacea: An unsupervised machine learning analysis of over 200,000 posts.

Background: Many patients with rosacea join online support groups to gather and disseminate information about disease management and provide emotional support for others. Objective: To better understand rosacea patient's primary concerns for the disease as well as their disease search patterns online. Methods: Overall, 207,038 posts by 41,400 users were collected from June 1, 2017, to June 1, 2022, in a popular online forum. We applied Latent Dirichlet Allocation (LDA), an unsupervised machine learning model, to organize the posts into topics. Keywords for each topic supplied by LDA were used to manually assign topic and category labels. Results: Twenty-three significant topics of conversation were identified and organized into 4 major categories, including Management (50.33%), Clinical Presentation (24.14%), Emotion (21.97%), and Information Appraisal (3.57%). Limitations: Although we analyzed the largest forum on the internet for rosacea, generalizability is limited given the presence of other smaller forums and the skewed demographics of forum users. Conclusion: Social media forums play an important role for disease discussion and emotional venting. Although rosacea management was the most frequently discussed topic, emotional posting was a significantly prevalent occurrence.

Reflectance confocal microscopic visualization of melanocytic bodies in the stratum corneum overlying acral lentiginous melanoma.

BACKGROUND: We present a case of RCM evaluation of ALM surgical margins demonstrating intracorneal melanocytic bodies overlying subsequently confirmed melanoma in situ by histopathology. CASE PRESENTATION: A 73-year-old male with a history of acral lentiginous melanoma (ALM) of the right great toe presented to our clinic for evaluation of positive surgical margins. The positive margin was localized for examination and subsequent biopsy with reflectance confocal microscopy (RCM) which allowed targeted re-resection of the area of concern. Three punch biopsies were obtained in the area of concern, which confirmed residual melanoma in situ. Immunostains confirmed the cellular remnants in the stratum corneum were melanocytic. To correlate the intra stratum corneum findings seen with confocal to the histopathology, a 3D rendering of a stack of images was used to demonstrate the location. DISCUSSION: Typically, acral surfaces are challenging to examine with RCM due to the limited ability of light to penetrate thickened stratum corneum; however, we observed unique cellular features with confocal. Scattered hyper-reflective pleomorphic cells consistent with melanocytes were observed in the stratum corneum, although the visualized underlying epidermis appeared normal. Confocal microscopy may aid in diagnosis and management of ALM, especially in the context of positive surgical margins.

Efficacy and safety of topical treatments for seborrheic keratoses: a systematic review.

Seborrheic keratoses (SKs) are benign epidermal neoplasms presenting as waxy, brown to black papules and plaques. Patients often seek removal for cosmetic reasons or irritation. The objective of this systematic review is to assess the efficacy and safety of topical treatments for SKs. Studies involving any topical medication indicated for SK removal were retrieved from Embase, Scopus, PubMed, and Cochrane. The final search was conducted on November 9, 2021, and 26 reports met inclusion criteria. A quality rating scheme was utilized to assess evidence quality. Heterogeneity of treatments and outcome measures precluded meta-analysis. Topical treatments that yielded a good-to-excellent response include hydrogen peroxide, Maxacalcitol 25 µg/g, BID Tazarotene 0.1% cream, 5% potassium dobesilate cream, 1% diclofenac sodium solution, urea-based solution, and 65% and 80% trichloroacetic acid. Local skin reactions were often mild and transient. Topical hydrogen peroxide showed the greatest evidence for clinical clearance of SKs, although there are no studies to our knowledge that directly compared hydrogen peroxide to current first-line treatments (e.g. cryotherapy or shave excision). The results of this review suggest viable and safe treatment of SK with topical therapies; however, there remains demand for topical treatments that reliably equate or exceed the efficacy of current first-line therapies.Key PointsQuestion: Are safe and efficacious topical treatments for seborrheic keratoses available?Findings: Topical treatments for seborrheic keratoses yield different responses and may be associated with local skin reactions. Topical hydrogen peroxide shows the greatest evidence for clinical clearance of seborrheic keratoses and may be a viable option for patients requesting noninvasive removal. No studies to our knowledge directly compare hydrogen peroxide to current first-line treatments.Meaning: There remains demand for topical treatments that reliably equate or exceed the efficacy of current first-line therapies.

Dermoscopy and skin imaging light sources: a comparison and review of spectral power distribution and color consistency.

Significance: Dermoscopes incorporate light, polarizers, and optical magnification into a handheld tool that is commonly used by dermatologists to evaluate skin findings. Diagnostic accuracy is improved when dermoscopes are used, and some major artificial intelligence (AI) projects have been accomplished using dermocopic images. Color rendering consistency and fidelity are crucial for clinical diagnostics, AI, and image processing applications. Aim: With many devices available on the market, our objective was to measure the emission spectra of various dermoscopes, compare them with other light sources, and illustrate variations in reflected colors from images of a reference sample. Approach: A spectrometer measured the spectral power distribution (SPD) produced by four dermoscope models and three alternate light sources, illustrating differences in the emission spectra. Most dermoscopes use light-emitting diodes (LEDs), which are inconsistent when compared with one another. An LED was compared with halogen, xenon-arc, and daylight sources. Images of a micro ColorChecker were acquired from several sources, and three specific colors were selected to compare in CIELAB color space. Color consistency and color fidelity measured by color rendering index (CRI) and TM-30-18 graphical vectors show variation in saturation and chroma fidelity. Results: A marked degree of variation was observed in both the emission and reflected light coming from different dermoscopes and compared with other sources. The same chromophores appeared differently depending on the light source used. Conclusions: A lack of uniform illumination resulted in inconsistent image color and likely impacted metamerism and visibility of skin chromophores in real-world settings. Artificial light in skin examinations, especially LEDs, may present challenges for the visual separation of specific colors. Attention to LEDs SPD may be important, especially as the field increases dependency on machine/computer vision.

Improving dermal level images from reflectance confocal microscopy using wavelet-based transformations and adaptive histogram equalization.

OBJECTIVES: Reflectance confocal microscopy (RCM) generates scalar image data from serial depths in the skin, allowing in vivo examination of cellular features. The maximum imaging depth of RCM is approximately 250 µm, to the papillary dermis, or upper reticular dermis. Frequently, important diagnostic features are present in the dermis, hence improved visualization of deeper levels is advantageous. METHODS: Low contrast and noise in dermal images were improved by employing a combination of wavelet-based transformations and contrast-limited adaptive histogram equalization. RESULTS: Preserved details, noise reduction, increased contrast, and feature enhancement were observed in the resulting processed images. CONCLUSIONS: Complex and combined wavelet-based enhancement approaches for dermal level images yielded reconstructions of higher quality than less sophisticated histogram-based strategies. Image optimization may improve the diagnostic accuracy of RCM, especially for entities with dermal findings.

Diagnostic application of cyclin D1 fluorescent in situ hybridization for histologically undetermined early lesions of acral melanoma in situ: A case series.

Histologically undetermined early acral melanoma in situ (HUAMIS) is rare but a diagnostic challenge, being clinically and dermoscopically MIS (late onset, a large size (>7 mm), parallel ridges pattern) but microscopically without recognizable cytological atypia. Cyclin D1 (CCND1) gene amplification is a genetic aberration occurring in the early radial growth phase of AMs and could thus help determine malignancy for this disease. We determine the value of CCND1 amplification by FISH as a diagnostic marker for HUAMIS. CCND1 amplification was examined in paraffin-embedded skin biopsies and excisions using a dual-probes fluorescence in situ hybridization (FISH) (11q13 and CEP11). One FISH-negative case 6 was additionally examined by Mypath Melanoma (qRT-PCR). Seventeen cases (12 dysplastic nevi, 3 AMIS, and 2 invasive AM) were served as negative controls for FISH. All six patients (4 females and 2 males) were Hispanic. Pigment lesions were on the left plantar foot (4), right third finger palm (1), and right thumb subungual (1). All cases showed similar clinical and dermoscopical characteristics, including late onset (50 to 74 years old), long duration (from 2 to 15 years), large-sized pigments (from 16 to 40 mm), and a parallel ridge pattern. Junctional melanocytes with no or minimal atypia from five cases showed CCND1 amplifications. Four of 5 cases were received 1st or/and 2nd wide excisions, which demonstrated foci of histologically overt MIS. One FISH-negative case 6 demonstrated "likely malignancy" scores (>2) by Mypath Melanoma (qRT-PCR). None of negative controls showed the amplification. We propose here a simple CCND1 FISH is a practical diagnostic test to determine the malignancy of the very early progression phase of AM preceding histopathologically defined MIS. Cases presented here could be an indolent subtype of AMIS characterized by carrying a long latent radial growth phase without vertical growth, mimicking lentigo maligna.