Skin cancer induction by the antimycotic drug voriconazole is caused by impaired DNA damage detection due to chromatin compaction.

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug Voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum (XP), caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase GCN5. Impairment of GCN5 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors (HDACi), rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair.

Retrospective Single-Center Case Study of Clinical Variables and the Degree of Actinic Elastosis Associated with Rare Skin Cancers.

(1) Background: Rare skin cancers include epithelial, neuroendocrine, and hematopoietic neoplasias as well as cutaneous sarcomas. Ultraviolet (UV) radiation and sunburns are important drivers for the incidence of certain cutaneous sarcomas; however, the pathogenetic role of UV light is less clear in rare skin cancers compared to keratinocyte cancer and melanoma. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure among selected rare skin cancers (atypical fibroxanthoma [AFX], pleomorphic dermal sarcoma [PDS], dermatofibrosarcoma protuberans [DFSP], Kaposi sarcoma [KS], Merkel cell carcinoma [MCC], and leiomyosarcoma [LMS]) while taking into account relevant clinical variables (age, sex, and body site). (2) Methods: We newly established a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 210 rare skin cancers from 210 patients with their clinical variables. (3) Results: TEG values were correlated with age and whether tumors arose on UV-exposed body sites. TEG values were significantly higher in AFX and PDS cases compared to all other analyzed rare skin cancer types. As expected, TEG values were low in DFSP and KS, while MCC cases exhibited intermediate TEG values. (4) Conclusions: High cumulative UV exposure is more strongly associated with AFX/PDS and MCC than with other rare skin cancers. These important results expand the available data associated with rare skin cancers while also offering insight into the value of differentiating among these tumor types based on their relationship with sun exposure, potentially informing preventative, diagnostic and/or therapeutic approaches.

Association of Global Ultraviolet Radiation With the Incidence of Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: Inflammation is a key pathomechanism for growth and rupture of intracranial aneurysms. Anti-inflammatory mechanisms may reduce rupture of intracranial aneurysms and the incidence of aneurysmal subarachnoid hemorrhage (SAH). Ultraviolet (UV) radiation from sunlight exposure induces systemic anti-inflammatory responses through immunosuppressive mechanisms. We studied whether SAH incidence is associated with UV radiation. METHODS: Global SAH incidence, time trends, and regional differences from 32 countries were linked to UV radiation data from the Tropospheric Emission Monitoring Internet Service. Odds between low vs high UV exposure and SAH incidence were calculated. Correlation analysis was performed using R (R 4.1.2). RESULTS: SAH incidences ranged from 1.3 to 27 per 100 000 patient-years (p-y) and UV index from 1.76 to 11.27. The correlation coefficient (rho) between SAH incidence and UV index was -0.48 (P = .012). SAH incidence was highest in Japan (13.7-27.9 p-y) with an UV index 6.28. UV index was highest in Chile 11.27 with a lower SAH incidence (3.8-4.8 p-y). The lowest UV index 1.76 was seen in Iceland with higher SAH incidence (9.8 p-y).Within Europe, regions with higher UV indices reported lower SAH incidences (Northwest Europe: SAH incidence p-y 8.61/UV index 2.85; Southeast Europe: SAH incidence p-y 7.37/UV index 4.65) with a significant inverse correlation (rho = -0.68, P = .004) and not a significant correlation between non-European countries (rho = -0.43, P = .19). Low exposure of UV radiation in global regions predicted higher than median incidences of SAH with an odds ratio 5.13 (95% CIs 1.02-31.5). CONCLUSION: The incidence of SAH is inversely associated with UV radiation. Further studies should assess the actual UV exposure in relation to SAH incidence and potential biological explanations for the relation we found.

Expression of the plasma membrane citrate carrier (pmCiC) in human cancerous tissues-correlation with tumour aggressiveness.

We have recently shown that cancer cells of various origins take up extracellular citrate through the plasma membrane citrate carrier (pmCiC), a specific plasma membrane citrate transporter. Extracellular citrate is required to support cancer cell metabolism, in particular fatty acid synthesis, mitochondrial activity, protein synthesis and histone acetylation. In addition, cancer cells tend to acquire a metastatic phenotype in the presence of extracellular citrate. Our recent study also showed that cancer-associated stromal cells synthesise and release citrate and that this process is controlled by cancer cells. In the present study, we evaluated the expression of pmCiC, fibroblast activation protein-α (FAP) and the angiogenesis marker cluster of differentiation 31 (CD31) in human cancer tissues of different origins. In the cohort studied, we found no correlation between disease stage and the expression of FAP or CD31. However, we have identified a clear correlation between pmCiC expression in cancer cells and cancer-associated stroma with tumour stage. It can be concluded that pmCiC is increased in cancer cells and in cancer-supporting cells in the tumour microenvironment at the later stages of cancer development, particularly at the metastatic sites. Therefore, pmCiC expression has the potential to serve as a prognostic marker, although further studies are needed.

[Ultraviolet radiation in the pathogenesis of lupus erythematosus]. / UV-induzierte Pathogenese des Lupus erythematodes.

Photosensitivity represents an increased inflammatory reaction to sunlight, which can be observed particularly in the autoimmune disease lupus erythematosus. Cutaneous lupus erythematosus (CLE) can be provoked by ultraviolet (UV) radiation and can cause both acute, nonscarring and chronic, scarring skin changes. In systemic lupus erythematosus, on the other hand, provocation by UV radiation can lead to flare or progression of systemic involvement. The etiology of lupus erythematosus is multifactorial and includes genetic, epigenetic and immunologic mechanisms. In this review, we address the effect of UV radiation on healthy skin and photosensitive skin using the example of lupus erythematosus. We describe possible mechanisms of UV-triggered immune responses that could offer therapeutic approaches. Currently, photosensitivity can only be prevented by avoiding UV exposure itself. Therefore, it is important to better understand the underlying mechanisms in order to develop strategies to counteract the deleterious effects of photosensitivity.

Hereditary epidermolytic palmoplantar keratosis due to a novel desmoglein-1 mutation: A case report.

Key Clinical Message: Keratosis palmoplantaris striata type I (SPPK-I) is a rare autosomal-dominant type of hereditary epidermolytic palmoplantar keratoderma, which can be caused by mutations in desmoglein-1 (DSG-1). Patients suffer from hyperkeratotic plaques and painful palmoplantar fissures. Unfortunately, treatment options including salicylic vaseline, topical corticosteroids, phototherapy, and retinoids are inefficient. Abstract: Hereditary palmoplantar keratodermas (PPKs) represent a heterogeneous group of rare skin disorders with epidermal palmoplantar hyperkeratosis. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate PPKs. We report a patient with keratosis palmoplantaris striata type I (SPPK-I) with a specific pathogenic variant [c.349C>T, p.(Arg117*)] in DSG1. Despite increased understanding, effective treatment options for PPK, including SPPK-I, remain limited.

Complete lymph node dissection in cutaneous melanoma patients with positive sentinel lymph node: Outcome and predictors in a retrospective cohort study over 16 years.

BACKGROUND: In melanoma treatment, complete lymph node dissection (CLND) has been considered the therapeutic gold standard in patients with positive sentinel lymph node biopsy (SLNB). This long-held approach was revised in 2017, with recent evidence questioning the therapeutic benefit of CLND in malignant melanoma (MM) therapy. In this study, we aimed to fill this knowledge gap by retrospectively analyzing the impact of CLND on MM patients' survival. METHODS: We retrospectively analyzed the multi-center population-based Clinical Cancer Registry at the Tumor Center Regensburg (TUDOK) database (2004-2020) to identify patients who had been diagnosed with SLN-positive MM and underwent (non)invasive management thereof. Patient cohorts were subdivided according to the treatment received (CLND and waiving CLND). Primary outcomes included overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rate. RESULTS: We identified 1143 MM patients, of whom 126 (11.0%) had positive SLN status. CLND was waived in the majority of SLN-positive MM cases (n = 71; 56.3%), with 55 (43.7%) patients undergoing CLND. Univariable and multivariable Cox regression revealed no significant advantage for CLND patients compared to non-CLND patients in OS (HR=0.970, p = 0.915 and HR=1.295, p = 0.479, respectively), RFS (HR=1.050, p = 0.849 and HR=1.220, p = 0.544, respectively), and cumulative recurrence rate (HR=1.234, p = 0.441 and HR=1.220, p = 0.544), respectively). CONCLUSION: We found that CLND had no significant impact on patient survival and MM recurrence rate, thus corroborating the validity of current clinical guidelines.

Phototherapy: Theory and practice.

Despite the development of highly effective biologics for skin diseases such as psoriasis or atopic dermatitis, UVA and UVB therapy, alone or in combination, are still essential components of various guidelines. Phototherapy is not only a first-line treatment and highly effective for a number of skin diseases, but is also economical and has few side effects. The targeted use of UVA and UVB, if necessary, in combination with the photosensitizer psoralen in the context of PUVA therapy, enables the dermatologist to effectively treat a wide variety of skin diseases. Indications for phototherapy include epidermal diseases such as atopic dermatitis, psoriasis and vitiligo, as well as photodermatoses, mycosis fungoides, graft-versus-host disease and deep dermal diseases such as scleroderma. This article reviews the physical principles, molecular mechanisms, current treatment regimens, and individual indications for phototherapy and photochemotherapy.

Investigation of Adverse Reactions in Tattooed Skin through Histological and Chemical Analysis.

BACKGROUND: Just as the number of tattooed people has increased in recent years, so has the number of adverse reactions in tattooed skin. Tattoo colourants contain numerous, partly unidentified substances, which have the potential to provoke adverse skin reactions like allergies or granulomatous reactions. Identification of the triggering substances is often difficult or even impossible. METHODS: Ten patients with typical adverse reactions in tattooed skin were enrolled in the study. Skin punch biopsies were taken and the paraffin-embedded specimens were analysed by standard haematoxylin and eosin and anti-CD3 stainings. Tattoo colourants provided by patients and punch biopsies of patients were analysed with different chromatography and mass spectrometry methods and X-ray fluorescence. Blood samples of 2 patients were screened for angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R). RESULTS: Histology showed variable skin reactions such as eosinophilic infiltrate, granulomatous reactions, or pseudolymphoma. CD3+ T lymphocytes dominated the dermal cellular infiltrate. Most patients had adverse skin reactions in red tattoos (n = 7), followed by white tattoos (n = 2). The red tattooed skin areas predominantly contained Pigment Red (P.R.) 170, but also P.R. 266, Pigment Orange (P.O.) 13, P.O. 16, and Pigment Blue (P.B.) 15. The white colourant of 1 patient contained rutile titanium dioxide but also other metals like nickel and chromium and methyl dehydroabietate - known as the main ingredient of colophonium. None of the 2 patients showed increased levels of ACE and sIL-2R related to sarcoidosis. Seven of the study participants showed partial or complete remission after treatment with topical steroids, intralesional steroids, or topical tacrolimus. CONCLUSIONS: The combination of the methods presented might be a rational approach to identify the substances that trigger adverse reactions in tattoos. Such an approach might help make tattoo colourants safer in the future if such trigger substances could be omitted.

Indurated erythema of abdominal skin: An unusual presentation of metastatic endometrial carcinoma-Case report with literature review.

Carcinoma erysipelatoides (CE) is a rare clinical manifestation of cutaneous metastasis, which mimics inflammatory conditions such as erysipelas. Depending on the site of the originating tumour, unusual manifestations involving different sites of the body may occur. We herein report a case of a 60-year-old female patient with metastatic endometrial carcinoma presenting as CE of the abdominal skin and the inguinal folds. Even though the diagnosis of advanced malignancy had been established before and she was currently receiving chemotherapy (carboplatin and paclitaxel), the clinical appearance closely resembled fungal (candidal intertrigo) and consecutively bacterial (erysipelas) infection, which resulted in treatment with antimycotics and antibiotics at first. Dermatohistopathological examination of skin biopsies revealed a diffuse and nodular infiltrate of pleomorphic atypical tumour cells with strong expression of cytokeratin 7 and PAX8, also detectable within lymphatic vessels. Therapy comprised antiseptic ointments to prevent superinfection, palliative electron beam radiation and supportive care. Since there were no targetable KRAS-, NRAS- and BRAF-gene mutations, systemic therapy was switched to checkpoint inhibition (pembrolizumab) in combination with lenvatinib. The overall prognosis of cutaneous metastasis of endometrial carcinoma is dismal with most patients succumbing to disease within few months. Similarly, our patient died after 3 months due to sepsis in the course of malignant pleural effusion. We aim to highlight the possibility of unusual sites of CE and the risk of respective clinical misdiagnoses.

Degree of Actinic Elastosis Is a Surrogate of Exposure to Chronic Ultraviolet Radiation and Correlates More Strongly with Cutaneous Squamous Cell Carcinoma than Basal Cell Carcinoma.

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Identification of high-risk patients with a seven-biomarker prognostic signature for adjuvant treatment trial recruitment in American Joint Committee on Cancer v8 stage I-IIA cutaneous melanoma.

PURPOSE: Many patients with resected American Joint Committee on Cancer (AJCC) early-stage cutaneous melanoma nonetheless die of melanoma; additional risk stratification approaches are needed. PATIENTS AND METHODS: Using prospectively-collected whole-tissue sections, we assessed in consecutive stage I-IIA patients (N = 439), a previously-validated, immunohistochemistry-based, 7-biomarker signature to prognosticate disease-free survival (DFS), melanoma-specific survival (MSS; primary end-point) and overall survival (OS), independent of AJCC classification. RESULTS: Seven-marker signature testing designated 25.1% of patients (110/439) as high-risk (stage IA, 13.3% [43/323], IB, 53.2% [42/79], and IIA, 67.6% [25/37]). A Kaplan-Meier analysis demonstrated high-risk patients to have significantly worse DFS, MSS and OS versus low-risk counterparts (P < 0.001). In multivariable Cox regression modelling also including key clinicopathological/demographic factors, 7-marker signature data independently prognosticated the studied end-points. Models with the 7-marker signature risk category plus clinicopathological/demographic covariates substantially outperformed models with clinicopathological/demographic variables alone in predicting all studied outcomes (areas under the receiver operator characteristic curve 74.1% versus 68.4% for DFS, 81.5% versus 71.2% for MSS, 80.9% versus 73.0% for OS; absolute differences 5.7%, 10.3% and 7.9%, respectively, favouring 7-marker signature risk category-containing models). CONCLUSION: In patients with AJCC early-stage disease, the 7-marker signature reliably prognosticates melanoma-related outcomes, independent of AJCC classification, and provides a valuable complement to clinicopathological/demographic factors.

GPR4 in the pH-dependent migration of melanoma cells in the tumor microenvironment.

Due to its high metastatic potential, malignant melanoma is one of the deadliest skin cancers. In melanoma as well as in other cancers, acidification of the tumor microenvironment (=TME, inverse pH-gradient) is a well-known driver of tumor progression and metastasis. Membrane-bound receptors, such as the proton-sensitive GPCR (pH-GPCR) GPR4, are considered as potential initiators of the signalling cascades relevant to malignant transformation. In this study, we investigated the pH-dependent migration of GPR4 wildtype/overexpressing SK-Mel-28 cells using an impedance-based electrical wounding and migration assay and classical Boyden chamber experiments. Migration of GPR4 overexpressing SK-Mel-28 cells was enhanced in a range of pH 6.5-7.5 as compared to controls in the impedance-based electrical wounding and migration assay. In Boyden chamber experiments, GPR4 overexpression only increased migration at pH 7.5 in a Matrigel-free setup, but not at pH 6.5. Results indicate that GPR4 is involved in the migration of melanoma cells, especially in the tumor periphery, and that this process is affected by pH in the TME.

Subtypes of Melanomas Associated with Different Degrees of Actinic Elastosis in Conventional Histology, Irrespective of Age and Body Site, Suggesting Chronic Ultraviolet Light Exposure as Driver for Lentigo Maligna Melanoma and Nodular Melanoma.

(1) Background: Ultraviolet (UV) radiation and sunburns are associated with an increased incidence of acquired nevi and melanomas. However, the data are controversial as to whether chronic UV exposure or high intermittent UV exposure is the major carcinogenic factor in melanocytic tumors. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure in nevi and different clinical melanoma subtypes (i.e., superficial spreading melanoma (SSM), nodular malignant melanoma (NMM), acral lentiginous melanoma (ALM), and lentigo maligna melanoma (LMM)) with respect to clinical variables (age, sex, and body site). (2) Methods: We defined a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 595 melanocytic lesions from 559 patients with their clinical variables. (3) Results: The TEG was correlated with age and UV-exposed body sites. Furthermore, the TEG was significantly higher in LMM than in all other types of melanomas and the TEG in NMM was higher than in SSM, irrespective of patient age and tumor site. (4) Conclusions: High cumulative UV exposure is more strongly associated with LMM and NMM than with other melanoma subtypes.

The Role of Citrate Homeostasis in Merkel Cell Carcinoma Pathogenesis.

Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor of the skin with a poor prognosis. The factors driving this cancer must be better understood in order to discover novel targets for more effective therapies. In the search for targets, we followed our interest in citrate as a central and critical metabolite linked to fatty acid synthesis in cancer development. A key to citrate uptake in cancer cells is the high expression of the plasma membrane citrate transporter (pmCiC), which is upregulated in the different adenocarcinoma types tested so far. In this study, we show that the pmCiC is also highly expressed in Merkel cell carcinoma cell lines by western blot and human tissues by immunohistochemistry staining. In the presence of extracellular citrate, MCC cells show an increased proliferation rate in vitro; a specific pmCiC inhibitor (Na+-gluconate) blocks this citrate-induced proliferation. Furthermore, the 3D in vivo Chick Chorioallantoic Membrane (CAM) model showed that the application of Na+-gluconate also decreases Merkel cell carcinoma growth. Based on our results, we conclude that pmCiC and extracellular citrate uptake should be considered further as a potential novel target for the treatment of Merkel cell carcinoma.

[Development of spindle cell squamous cell carcinoma within a longstanding pyoderma gangrenosum]. / Entwicklung eines spindelzelligen Plattenepithelkarzinoms auf dem Boden eines lang bestehenden Pyoderma gangraenosum.

Pyoderma gangrenosum (PG) is classified as a neutrophilic dermatosis and presents clinically as painful ulcerations with undermined livid erythema at the margin. Treatment with immunosuppressive drugs is often protracted. The development of malignant tumors in pyoderma gangrenosum has not been reported in the literature.

Bullous Pemphigoid in Patients Receiving Immune-Checkpoint Inhibitors and Psoriatic Patients-Focus on Clinical and Histopathological Variation.

BACKGROUND: The most common autoimmune blistering disease, bullous pemphigoid (BP), shows an increased prevalence in psoriatic patients and oncologic patients undergoing immune-checkpoint blockade (ICB). Even though the same autoantigens (BP180/BP230) are detectable, it remains obscure whether clinical or histopathological differences exist between these different groups of BP patients. In this study, we strived to analyze this matter based on own data and previously published reports. METHODS: We performed an institutional chart review from 2010-2020 to identify BP patients with psoriasis (n = 6) or underlying ICB (n = 4) and matched them with idiopathic cases of BP (n = 33). We compared clinical characteristics, subtypes, and dermatopathological determinants (e.g., tissue eosinophilia/neutrophilia, papillary edema, lymphocytic infiltration) among the groups. RESULTS: ICB-associated BP affects men more often and might show mucosal involvement more frequently. We found no statistically significant dermatopathological differences among the groups. CONCLUSIONS: Clinicians should be aware of an increased risk of BP in patients with psoriasis and oncologic patients receiving ICB; atypical pruritic skin lesions should prompt a workup including a skin biopsy for histopathology and direct immunofluorescence in these patients. Larger studies might be necessary to detect slight dermatopathological variation.

Incidence and Mortality of Malignant Melanoma in Relation to Dermatologist Density in Bavaria.

INTRODUCTION: Malignant melanoma is an aggressive skin tumor with a good prognosis when treated in an early tumor stage, but has a poor prognosis with distant metastases. The incidence of malignant melanoma has increased continuously over the last decades, with little change in mortality. One explanation for this is that melanomas are increasingly detected in early stages, especially after the establishment of statutory skin cancer screening in 2008, which allows a free skin examination every 2 years for people older than 35 years. METHODS: In this study incidence and mortality of malignant melanoma were correlated with the dermatologist density in Bavarian administrative regions. In addition, the incidence data were compared before and after the introduction of statutory skin cancer screening. RESULTS: There was a significant correlation between the incidence of malignant melanoma and dermatologist density (r = 0.258, p = 0.044), but no correlation between mortality and dermatologist density (r = 0.201, p = 0.121). Similarly, the increase of malignant melanoma incidence following the introduction of statutory skin cancer screening in 2008 was independent of dermatologist density (r = 0.021, p = 0.873). CONCLUSION: The dermatologist density in Bavaria correlates positively with the incidence of malignant melanoma. Despite an increased incidence, mortality was not elevated in the respective administrative regions.