Redefine photoprotection: Sun protection beyond sunburn.

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.

Immune checkpoint inhibition and targeted therapy for melanoma: A patient-oriented cross-sectional comparative multicentre study.

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.

Low-dose total skin electron beam therapy plus oral bexarotene maintenance therapy for cutaneous T-cell lymphoma.

BACKGROUND: Total skin electron beam therapy (TSEBT) combined with systemic therapy or maintenance treatment is a reasonable approach to enhance the remission rate and duration in mycosis fungoides (MF) and Sézary syndrome (SS). This study assesses the efficacy of oral bexarotene therapy after low-dose TSEBT for patients with MF and SS. METHODS: In this prospective observational study, we recruited MF/SS patients for treatment with low-dose total skin electron beam therapy (TSEBT) with or without bexarotene therapy to describe outcomes and toxicities. RESULTS: Forty-six subjects with MF or SS underwent TSEBT between 2016 and 2021 at our institute. Following TSEBT, 27 patients (59 %) received oral bexarotene treatment. The median follow-up was 13 months. The overall response rate (ORR) for the cohort was 85 %. The response rate was significantly higher with combined modality (CM) than TSEBT alone (96 % vs. 68 %, p = 0.03). Median progression-free survival (PFS) for the CM was 17 months versus five months following TSEBT alone (p = 0.001). One patient (4 %) in the retinoid group discontinued the bexarotene therapy because of adverse events. The administration of bexarotene therapy did not increase radiation-related toxicities. CONCLUSIONS: Response rate and progression-free survival might be improved with TSEBT in combination with oral bexarotene compared to TSEBT alone.

Age as key factor for pattern, timing, and extent of distant metastasis in patients with cutaneous melanoma: A study of the German Central Malignant Melanoma Registry.

BACKGROUND: Melanoma incidence rates rise as people age, but the impact of aging on distant metastasis is unclear. OBJECTIVE: To investigate how timing, pattern, and extent of distant metastasis is influenced by age. METHODS: 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. RESULTS: 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. LIMITATIONS: The study was not population based. CONCLUSION: Pattern, timing, and extent of distant metastasis change as people age. These findings may be considered when treating patients with melanoma of different ages.

Primary cutaneous diffuse large B-cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences.

BACKGROUND AND OBJECTIVES: Primary cutaneous diffuse large B-cell lymphoma, NOS (PCLBCL/NOS) is a rare PCLBCL. Only few data are available for this tumor. The aim of this study was to identify clinical and/or immunohistochemical markers (in addition to Bcl-2) that characterize PCLBCL/NOS, assist in differentiating it from PCLBCL, leg type (PCLBCL/LT) and help to assess the clinical course/prognosis. PATIENTS AND METHODS: Bcl-2- PCLBCL/NOS) cases (n = 14 were compared with Bcl-2+ PCLBCL/LT cases (n = 29). RESULTS: PCLBCL/NOS patients were younger, predominantly male and had better survival rates than patients with PCLBCL/LT. Patients with PCLBCL/NOS presented more often with larger plaques limited to one or two contiguous body regions, whereas PCLBCL/LT cases often presented with disseminated lesions. Neoplastic cells had a higher proliferation rate (Ki67) in PCLBCL/LT patients. The tumor microenvironment of PCLBCL/NOS had a more prominent CD3+ infiltrate. Overall survival data for the whole cohort (n = 37) revealed that female gender and Bcl-2 expression correlated with a worse survival rate. Bcl-6 expression and centroblastic subtype correlated with better outcomes. None of the other markers studied (e.g. GCB/non-GCB subtype) correlated with survival rate. CONCLUSIONS: PCLBCL/NOS and PCLBCL/LT differ in their clinical behavior and outcomes. Bcl-2 still seems to be the best marker for discriminating between these two subgroups. Bcl-2, female gender and Bcl-6 represent prognostic markers for PCLBCL.

Aggressive primary cutaneous B-cell lymphomas show increased Angiopoietin-2-induced angiogenesis.

Primary cutaneous large B-cell lymphomas, leg type (PCLBCL/LT) are primary cutaneous B-cell lymphoma (PCBCL) with an intermediate prognosis. Therefore, antracycline-based polychemotherapy combined with rituximab has been recommended as first-line treatment. Yet, despite this regimen, the 5-year survival rate remains 50-66% only. Angiogenesis, the formation of a vascular network, is essential for the pathogenesis of nodal lymphomas. So far, no study has analysed angiogenesis and its key factors in PCLBCL/LT. The present study was aimed at characterizing angiogenesis in PCLBCL/LT to identify the angiogenic molecules as potential therapeutic targets. The intra-tumoral microvessel density (MVD) was assessed by immunohistochemical studies of CD20 and CD31. The MVD was higher in PCLBCL/LT compared with indolent PCBCL. Analyses of open-source microarray data showed correlation between the angiogenic molecule angiopoietin-2 (Ang-2) and pan-endothelial cell markers. ELISA studies determined a shift between Ang-2 and Ang-1 towards Ang-2 in the peripheral blood of PCLBCL/LT patients. Immunofluorescence costainings against the Ang receptor Tie2/angiogenic integrins/CD34 revealed that the vasculature in both aggressive and indolent PCBCL tumors harbours an endothelial cell subpopulation with reduced expression of Tie2. In contrast, the alternative Ang-2 binding partners, angiogenic integrins, are strongly expressed in PCBCL. In line with these findings, downstream targets of Ang-2-integrin signalling, that is phosphorylation of focal adhesion kinase at Tyr397, and sprouting angiogenesis are enhanced in PCLBCL/LT. Our data present Ang-2 as a promising therapeutic target and anti-angiogenic therapy as a new line in treatment of PCLBCL/LT as a hitherto intractable disease.

Allogeneic stem cell transplantation in patients with aggressive primary cutaneous T-cell lymphoma - a case series of the ADF working group "cutaneous lymphomas".

BACKGROUND: Allogeneic stem cell transplantation (alloSCT) is a treatment option for primary cutaneous T-cell lymphomas that may induce long-lasting complete remissions. Little information is available on safety and efficacy. PATIENTS AND METHODS: We retrospectively reviewed the data from patients with primary cutaneous T-cell lymphoma treated in the Departments of Dermatology of the Universities of Bochum, Mannheim and Cologne who received subsequent alloSCT between 2005 and 2012. RESULTS: Nine patients with aggressive primary cutaneous T-cell-lymphoma received alloSCT. With a follow-up of 14 to 36 months after transplantation, 4 patients are alive and in complete remission. Two patients had recurrent disease post-transplantation, which was successfully treated with donor lymphocyte infusions. Non-relapse mortality was observed in three patients in advanced disease stages within six months after alloSCT. One patient showed only partial remission and died of disease after 32 months and one patient died 26 months after alloSCT with cause of death unknown. CONCLUSIONS: This report documents the possible benefit of a graft-versus-lymphoma effect in primary cutaneous T-cell lymphoma, as has been observed for other T-cell malignancies and emphasizes that alloSCT warrants further studies in this setting.

Association of autoimmune diseases with lichen sclerosus in 532 male and female patients.

Lichen sclerosus is a relatively common chronic inflammatory skin disease that predominantly affects the anogenital area. Accumulating evidence indicates that lichen sclerosus in women may be associated with other autoimmune disease, whereas this association seems to lack in male patients. We retrospectively evaluated the prevalence of autoimmune diseases and serological parameters indicative for autoimmunity in male and female patients with lichen sclerosus. Of the 532 patients (396 women, 136 men; 500 adults, 32 children; mean age: 49 years; range 1-89 years; female:male ratio 3:1), 452 (85%) had genital and 80 (15%) had extragenital disease. In women, lichen sclerosus was significantly more often associated with at least one autoimmune disease as compared to men (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.9-9.6; p<0.0001). Moreover, female patients with lichen sclerosus had sinificantly more often associated autoimmune thyroid diseases (OR 4.7, 95% CI 1.8-11.9; p<0.0002), antithyroid-antibodies (OR 2.7, 95% CI 1.1-6.5; p=0.023), and elevated autoantibodies (OR 4.1, 95% CI 1.9-9.3; p<0.0001) as compared to male patients. This observation is suggestive for a different pathogenetic background in male and female patients.

Semantic modeling of cell damage prediction: a machine learning approach at human-level performance in dermatology.

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.