Machine learning is transforming the field of histopathology. Especially in classification related tasks, there have been many successful applications of deep learning already. Yet, in tasks that ...rely on regression and many niche applications, the domain lacks cohesive procedures that are adapted to the learning processes of neural networks. In this work, we investigate cell damage in whole slide images of the epidermis. A common way for pathologists to annotate a score, characterizing the degree of damage for these samples, is the ratio between healthy and unhealthy nuclei. The annotation procedure of these scores, however, is expensive and prone to be noisy among pathologists. We propose a new measure of damage, that is the total area of damage, relative to the total area of the epidermis. In this work, we present results of regression and segmentation models, predicting both scores on a curated and public dataset. We have acquired the dataset in collaborative efforts with medical professionals. Our study resulted in a comprehensive evaluation of the proposed damage metrics in the epidermis, with recommendations, emphasizing practical relevance for real world applications.
Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, promoting tumor initiation, growth, progression, metastasis, and immune evasion. Recently it was ...shown that cancer cell-derived exosomes induce a tumor-promoting phenotype in TAMs. Exosome-loaded proteins, DNA, and RNAs may contribute to the macrophage reprogramming. However, the exact mediators and mechanisms, particularly in melanoma, are not known. In this study we examined the effects of cutaneous melanoma-derived exosomes on macrophage function and the underlying mechanisms. First, we showed that exposure to melanoma exosomes induces a tumor-promoting TAM phenotype in macrophages. Sequencing revealed enrichment for several miRNAs including miR-125b-5p in cutaneous melanoma exosomes. We showed that miR-125b-5p is delivered to macrophages by melanoma exosomes and partially induces the observed tumor-promoting TAM phenotype. Finally, we showed that miR-125b-5p targets the lysosomal acid lipase A (LIPA) in macrophages, which in turn contributes to their phenotype switch and promotes macrophage survival. Thus, our data show for the first time that miR-125b-5p transferred by cutaneous melanoma-derived exosomes induces a tumor-promoting TAM phenotype in macrophages.
Topical corticosteroids are the current first-line therapy for vulvar lichen sclerosus (VLS). UV-A1 phototherapy may be a promising alternative treatment option, but controlled studies are lacking.
...To compare the efficacy of high-potent topical corticosteroids with UV-A1 phototherapy in the treatment of VLS.
A 2-arm randomized clinical trial was conducted at a university hospital dermatology department according to the intention-to-treat principle with last observation carried forward. The study population comprised 30 female patients with VLS.
Treatment of VLS with clobetasol propionate, 0.05%, ointment applied once daily for 3 months or medium-dose UV-A1 (50 J/cm²) home-based phototherapy, performed 4 times weekly for 3 months.
Mean relative reduction of the total clinician's score (TCS) was considered the primary outcome measure. Secondary outcome measures included the reduction of pruritus and burning and/or pain according to a visual analog scale (VAS), a health-related quality of life score (Skindex-29), 20-MHz ultrasonography, and histopathological analysis before and after 3 months of therapy.
Fifteen patients were randomized in each treatment arm, and 2 patients dropped out in both treatment arms. After therapy, both therapies resulted in a significant decrease in mean TCS (51.4% 95% CI, 39.7% to 63.0% for clobetasol ointment P < .001 and 35.6% 95% CI, 18.2% to 53.1% for UV-A1 phototherapy P = .006). No significant difference was found between both treatments (P > .05). The Skindex-29 (mean difference MD, 29.6 95% CI, 7.9 to 51.2 P = .009) and the VAS score for pruritus (MD, 4.6 95% CI, 1.5 to 7.7 P = .005) and burning and/or pain (MD, 4.2 95% CI, 1.9 to 6.6 P = .001) significantly decreased after clobetasol treatment. After UV-A1 phototherapy, the VAS score for burning and/or pain (MD, 3.2 95% CI, 0.7 to 5.7 P = .01) was also significantly reduced; however, there was no significant reduction in pruritus (MD, 2.1 95% CI, 0.5 to 3.7 P = .16) and in the Skindex-29 score (MD, 4.9 95% CI, -12.6 to 22.4 P > .99). A significant reduction of the corium thickness and a significant increase in dermal density in 20-MHz ultrasonography as well as significant histopathological reduction of the inflammatory infiltrate was observed after clobetasol treatment but not after UV-A1 phototherapy.
Although resulting in a significant clinical improvement, UV-A1 phototherapy was inferior to the current gold standard treatment with topical high-potent corticosteroids with respect to practicability, relief of itch, and improvement in quality of life. UV-A1 phototherapy may be considered a potential second-line treatment for VLS.
clinicaltrials.gov Identifier: NCT01400022.
Background
Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences.
Objective
Evaluation of the impact of disease and treatment on the daily ...life of patients receiving systemic therapy for melanoma.
Methods
A German‐wide, cross‐sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient‐reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list.
Results
Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients.
Conclusions
Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient‐reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment.
Melanoma incidence rates rise as people age, but the impact of aging on distant metastasis is unclear.
To investigate how timing, pattern, and extent of distant metastasis is influenced by age.
...Analysis of a single-center cohort of 1457 patients of the German Central Malignant Melanoma Registry with prospectively documented follow-up. Findings were compared with those for 1682 patients from 5 different institutions. All patients presented initially with stage IA to IIC and developed distant metastasis in their further disease course.
The number of metastatic sites decreased with increasing age at melanoma diagnosis (P < .001). The rate of stage M1d disease decreased from 50.2% in patients aged 50 years or younger to 30.1% in patients older than 70 years, and the rate of stage M1b disease increased from 5.8% to 21.5%. The rate of lung metastases remained stable in all investigated age groups (P = .54). Distant metastases occurred earlier and were more synchronized in patients older than 70 years than in patients aged 50 years or younger. An age-dependent decrease in metastatic sites and stable rate of lung metastasis were found and confirmed by data on the multi-institutional cohort.
The study was not population based.
Pattern, timing, and extent of distant metastasis change as people age. These findings may be considered when treating patients with melanoma of different ages.
Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The ...mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma.
Redefine photoprotection: Sun protection beyond sunburn van Bodegraven, Mirja; Kröger, Marius; Zamudio Díaz, Daniela F. ...
Experimental dermatology,
January 2024, 2024-Jan, 2024-01-00, 20240101, Letnik:
33, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Excessive exposure to ultraviolet (UV) light leads to acute and chronic UV damage and is the main risk factor for the development of skin cancer. In most countries with western lifestyle, the topical ...application of sunscreens on UV‐exposed skin areas is by far the most frequently used preventive measure against sunburn. Further than preventing sunburns, increasing numbers of consumers are appreciating sunscreens with a medium‐ to high‐level sun protective factor (SPF) as basis for sustainable‐skin ageing or skin cancer prevention programs. However, recent investigations indicate that clinically significant DNA damages as well as a lasting impairment of cutaneous immunosurveillance already occur far below the standard of one minimal erythema dose (MED) sunburn level, which contributes to the current discussion of the clinical value of high‐protective SPF values. Ex vivo investigations on human skin showed that the application of SPF30 reduces DNA damage for a day long sun exposure (24 MED) drastically by about 53% but is significantly surpassed by SPF100 reducing DNA damage by approx. 73%. Further analysis on different SPF protection levels in UV‐exposed cell culture assays focusing on IL‐18, cell vitality and cis/trans‐urocanic acid support these findings. Whereas SPF30 and SPF50+ sunscreens already offer a solid UVB cover for most indications, our results indicate that SPF100 provides significant additional protection against mutagenic (non‐apoptotic‐) DNA damage and functional impairment of the cutaneous immunosurveillance and therefore qualifies as an optimized sunscreen for specifically vulnerable patient groups such as immunosuppressed patients, or skin cancer patients.
The application of a sunscreen with SPF100 protects the skin significantly better against skin damage by altering the inflammation marker IL‐18, cell vitality, cis‐UCA levels and DNA damage compared to SPF30 and SPF50+ by up to 40%.
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