Sun protection in outdoor workers - Development and validation of standardized questionnaires for behavior and knowledge.

BACKGROUND AND OBJECTIVES: Outdoor workers are at increased risk of developing non-melanoma skin cancer. We aimed to address the lack of validated German-language measurement instruments for outdoor workers' sun safety behavior and knowledge by compiling and validating two questionnaires. PARTICIPANTS AND METHODS: By expert consensus, items for the assessment of protective behavior (OccuSun) were compiled based on existing instruments. For knowledge, a translation of the Skin Cancer and Sun Knowledge (SCSK) scale was selected. After a pre-test, a validation study including 68 outdoor workers (62% female) was conducted in 2020. RESULTS: The retest reliability was r = 0.93 (95% confidence interval: 0.86-0.96) for the protection score and rs = 0.78 (0.67-0.86) for the knowledge score. Protective behaviors were correlated with respective diary data (0.38 ≤ rs ≤ 0.74, p < 0.001) and skin pigmentation changes (-0.23 ≥ rs ≥ -0.42, 0.007 ≤ p ≤ 0.165) but not with self-reported sunburn frequency (0.21 ≥ rs ≥ -0.04). CONCLUSIONS: Among German outdoor workers, two questionnaires for the assessment of sun protection behavior (OccuSun) and knowledge (SCSK) demonstrated good reliability. The OccuSun had generally good validity. Both instruments are fit for subsequent validation to determine their sensitivity to change.

Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.

Myotonic dystrophy type 2 (DM2) is a tetranucleotide CCTG repeat expansion disease associated with an increased prevalence of autoimmunity. Here, we identified an elevated type I interferon (IFN) signature in peripheral blood mononuclear cells and primary fibroblasts of DM2 patients as a trigger of chronic immune stimulation. Although RNA-repeat accumulation was prevalent in the cytosol of DM2-patient fibroblasts, type-I IFN release did not depend on innate RNA immune sensors but rather the DNA sensor cGAS and the prevalence of mitochondrial DNA (mtDNA) in the cytoplasm. Sublethal mtDNA release was promoted by a chronic activation of the ATF6 branch of the unfolded protein response (UPR) in reaction to RNA-repeat accumulation and non-AUG translated tetrapeptide expansion proteins. ATF6-dependent mtDNA release and resulting cGAS/STING activation could also be recapitulated in human THP-1 monocytes exposed to chronic endoplasmic reticulum (ER) stress. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic endoplasmic reticulum stress and associated mtDNA leakage. This mtDNA is, in turn, sensed by the cGAS/STING pathway and induces a type-I IFN response predisposing to autoimmunity. Elucidating this pathway reveals new potential therapeutic targets for autoimmune disorders associated with repeat expansion diseases.

Psychosocial stress affects the change of mental distress under dermatological treatment-A prospective cohort study in patients with psoriasis.

Psoriasis is a chronic-inflammatory, immune-mediated disease leading to a state of increased systemic inflammation. Mental comorbidities often occur in the patients and may additionally affect the therapy outcome. Currently, it is unknown whether the disease severity, psychosocial stress or health-related quality of life determines the manifestation of anxiety/depression, or vice versa, in psoriasis. The interplay between these variables during the dermatological treatment of psoriasis remains to be elucidated in order to initiate appropriate psychological interventions and to identify patients at risk for comorbid anxiety/depression. In a prospective cohort study, the impact of disease severity, health-related quality of life and psychosocial stress on anxiety/depression were examined during the dermatological treatment in patients with moderate to severe psoriasis (patients with psoriasis = PSO). Patients were examined before (T1) and about 3 months after (T2) the beginning of a new treatment episode, in most cases by means of systemic therapy. Data were analysed, exploratory, using Bivariate Latent Change Score Models and mediator analyses. Assessments included patient-reported outcomes (Hospital Anxiety and Depression Scale/HADS, Perceived Stress Scale/PSS, Childhood Trauma Questionnaire/CTQ, Dermatology Life Quality Index-DLQI, Body Surface Area-BSA), at both T1 and T2. 83 PSO patients (37.3% women, median age 53.7, IQR 37.8-62.5, median BSA 18.0, IQR 9.0-40.0) with complete data of HADS and DLQI were included. In the total group, a higher anxiety/depression at T1 was associated with a lower improvement in psoriasis severity in the course of the dermatological treatment (γBSA  = 0.50, p < 0.001). In subgroups of PSO with low/high CTQ scores, anxiety/depression at T1 had no impact on the change in psoriasis severity. Only by tendency, in CTQ subgroups, a higher psoriasis severity at T1 was linked with a higher improvement in anxiety/depression at T2 (low/high CTQ, γHADS  = -0.16/-0.15, p = 0.08). An improvement in the health-related quality of life was positively associated with an improvement in anxiety/depression (Pearson's r = 0.49, p = 0.02). Here, the reduction of acute psychosocial stress seems to be a decisive factor, mediating this association (ß = 0.20, t [2,60] = 1.87; p = 0.07, 95% CI -0.01, 0.41). The results allude, that the initial severity of anxiety/depression may presumably have an impact on the treatment outcome in the total group. In contrast, analysing subgroups of patients with high/low childhood trauma, the impact of the initial disease severity on the course of anxiety/depression after a switch to a new dermatological treatment could not be conclusively ruled out. The latter results from the latent change score modelling should be treated cautiously because of the small sample size. A common aetiopathological mechanism for psoriasis and anxiety/depression might be assumed with impact of dermatological treatment on both. The change in perceived stress seems to play an important role in the manifestation of anxiety/depression, substantiating the need for adequate stress management in patients with increased psychosocial stress during their dermatological treatment.

Clinician's Ability to Identify Non-Melanoma Skin Cancer on 3D-Total Body Photography Sectors that Were Initially Identified during In-Person Skin Examination with Dermoscopy.

INTRODUCTION: Non-melanoma skin cancer (NMSC) is a cause of significant morbidity and mortality in high-risk individuals. Total body photography (TBP) is currently used to monitor melanocytic lesions in patients with high risk for melanoma. The authors examined if three-dimensional (3D)-TBP could be useful for diagnosis of NMSC. METHODS: Patients (n = 129; 52 female, 77 male) with lesions suspicious for NMSC who had not yet had a biopsy underwent clinical examination followed by examination of each lesion with 3D-TBP Vectra®WB360 (Canfield Scientific, Parsippany, NJ, USA) and dermoscopy. RESULTS: The 129 patients had a total of 182 lesions. Histological examination was performed for 158 lesions; the diagnoses included basal cell carcinoma (BCC; n = 107), squamous cell carcinoma (SCC; n = 27), in-situ SCC (n = 15). Lesions were located in the head/neck region (n = 138), trunk (n = 21), and limbs (n = 23). Of the 182 lesions examined, 12 were not visible on 3D-TBP; reasons for not being visible included location under hair and on septal of nose. Two lesions appeared only as erythema in 3D-TBP but were clearly identifiable on conventional photographs. Sensitivity of 3D-TBP was lower than that of dermoscopy for BCC (73% vs. 79%, p = 0.327), higher for SCC (81% vs. 74%, p = 0.727), and lower for in-situ SCC (0% vs. 33%, p = 125). Specificity of 3D-TBP was lower than that of dermoscopy for BCC (77% vs. 82%, 0.581), lower for SCC (75% vs. 84%, p = 0.063), and higher for in-situ SCC (97% vs. 94%, p = 0.344). Diagnostic accuracy of 3D-TBP was lower than that of dermoscopy for BCC (75% vs. 80%), lower for SCC (76% vs. 82%), and lower for in-situ SCC (88% vs. 89%). Lesion location was not associated with diagnostic confidence in dermoscopy (p = 0.152) or 3D-TBP (p = 0.353). If only lesions with high confidence were included in the calculation, diagnostic accuracy increased for BCC (n = 27; sensitivity 85%, specificity 85%, diagnostic accuracy 85%), SCC (n = 10; sensitivity 90%, specificity 80%, diagnostic accuracy 83%), and for in-situ SCC (n = 2; sensitivity 0%, specificity 100%, diagnostic accuracy 95%). CONCLUSION: Diagnostic accuracy appears to be slightly lower for 3D-TBP in comparison to dermoscopy. However, there is no statistically significant difference in the sensitivity and specificity of 3D-TBP and dermoscopy for NMSC. Diagnostic accuracy increases, if only lesions with high confidence are included in the calculation. Further studies are necessary to determine if 3D-TBP can improve management of NMSC.

BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells: Insights into mode of action and resistance mechanisms.

About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid antitumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS-mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate antitumor activity and also immunological effects in NRAS-mutant melanoma, providing an ideal backbone for combination treatments. In our study, the MEKi binimetinib, cobimetinib and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS-mutant melanoma cells using two- and three-dimensional cell culture models as well as RNA sequencing analyses. Furthermore, NRAS-mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS-mutant melanoma cells thereby significantly enhancing the antiproliferative and proapoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS-L, components of antigen-presenting machinery and the "don't eat me signal" molecule CD47 in the melanoma cells. The BRAFi/MEKi-resistant, NRAS-mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen-activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, our study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS-mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS-mutant melanoma.

Efficacy and safety of adjuvant immunoadsorption in pemphigus vulgaris and pemphigus foliaceus (IA-Pem Study): a multicentre randomized controlled trial.

BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially life-threatening autoimmune blistering diseases. Treatment is based on long-term immunosuppression with high doses of glucocorticosteroids in combination with potentially corticosteroid-sparing agents and/or rituximab. Immunoadsorption (IA) has emerged as a fast-acting adjuvant treatment option. OBJECTIVES: To assess the clinical efficacy of IA in addition to best medical treatment (BMT). METHODS: We conducted a multicentre (26 centres from Germany and Austria) randomized controlled trial in 72 patients with newly diagnosed, relapsed or chronic active PV or PF (34 female patients and 38 male patients, aged 42-72 years) comparing BMT (prednisolone 1.0 mg kg-1 per day plus azathioprine or mycophenolate) with adjuvant IA (BMT + IA). Central 1 : 1 randomization was done at the coordinating centre for clinical trials (KKS Marburg). The primary endpoint was analysed using Kaplan-Meier and Cox regression methods. RESULTS: The study was ended prematurely owing to safety concerns after random allocation of 72 patients to BMT + IA (n = 34) or BMT (n = 38). The primary endpoint, time to complete remission on therapy, was not significantly different for the two groups [hazard ratio (HR) 1.35, 95% confidence interval (CI) 0.68-2.69; P = 0.39]. The cumulative dose of prednisolone was significantly lower in the BMT + IA group compared with BMT alone (difference -1214, 95% CI -2225 to -70; P = 0.03). In a post hoc analysis, patients with more extensive PV/PF showed a tendency towards a shorter time to remission in the BMT + IA group compared with the BMT group (HR 1.87, P = 0.17 in patients with baseline Pemphigus Disease Area Index ≥ 15). While more adverse events were observed in patients in the BMT group (29 vs. 25), severe adverse events were more frequent in patients in the BMT + IA group (17 events in 10 patients vs. 11 events in 8 patients). CONCLUSIONS: In this study, adjuvant IA did not demonstrate a shorter time to clinical remission, but a corticosteroid-sparing effect was observed. In patients with extensive PV/PF, post hoc analysis suggests that adjuvant IA may lead to earlier remission, but potential adverse events must be carefully weighed against the expected benefits.

Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoantibody-driven blistering diseases, which present with erosions or blisters on skin and/or mucous membranes. Treatment is based on long-term immunosuppressive agents. Immunoadsorption (IA) is a procedure that removes autoantibodies from the blood and has emerged as a fast-acting treatment option for pemphigus.We conducted a trial comparing best medical treatment (BMT) (prednisolone 1.0 mg kg per day plus azathioprine or mycophenolate) with best medical treatment plus IA (BMT + IA). A total of 26 centres from Germany and Austria recruited 72 patients with active pemphigus (34 women and 38 men, aged 42­72 years) who were randomly allocated in a ratio of 1 : 1 to the treatment groups.Following inclusion of 72 patients in the BMT + IA (n = 34) or BMT (n = 38) groups, the study ended prematurely owing to safety concerns. The main outcome, time to complete remission (relief of all symptoms) while still receiving therapy, was not significantly different for the two groups. In contrast, the cumulative dose of prednisolone was significantly lower in the BMT + IA compared with BMT alone. In an additional analysis, patients with more extensive pemphigus showed a tendency towards a shorter time to remission in the BMT + IA group compared with the BMT group. While more adverse events were observed in the BMT group (29 vs. 25), severe adverse events were more frequent in the BMT + IA group (17 vs. 11). In this study, IA did not show a shorter time to clinical remission, but a prednisolone-sparing effect was observed. In patients with extensive pemphigus, adjuvant IA may possibly lead to earlier remission, but potential adverse events must be carefully weighed against the expected benefits.

[Optical coherence tomography for the diagnosis and differentiation of cutaneous cysts: a case series]. / Diagnose und Differenzierung von kutanen Zysten mit optischer Kohärenztomographie: eine Fallserie.

Cutaneous cystic lesions (n = 35) were examined with optical coherence tomography. Cysts were visible as a hyporeflective roundish area with a clear margin; in some cases, the epidermis was thinned. Epidermal cysts, trichilemmal cysts, and hidrocystomas had a linear margin representing the epithelium of the cyst, whereas mucoid pseudocysts showed no linear margin. Trichilemmal and epidermal cysts presented with hyperreflective content that corresponds to keratin. By visualizing the margin and the content of the cyst, it was possible to differentiate between different types of cysts.

A cytosolic mutp53(E285K) variant confers chemoresistance of malignant melanoma.

Malignant melanoma (MM) is known to be intrinsically chemoresistant, even though only ~20% of MM carry mutations of the tumor suppressor p53. Despite improvement of systemic therapy the mortality rate of patients suffering from metastatic MM is still ~70%, highlighting the need for alternative treatment options or for the re-establishment of conventional therapeutic approaches, including chemotherapy. Screening the p53 mutation status in a cohort of 19 patient-derived melanoma samples, we identified one rarely described missense mutation of p53 leading to E285K amino acid exchange (mutp53(E285K)). Employing structural and computational analysis we revealed a major role of E285 residue in maintaining stable conformation of wild-type p53 (wtp53). E285K mutation was predicted to cause interruption of a salt-bridge network affecting the conformation of the C-terminal helix of the DNA-binding domain (DBD) thereby preventing DNA interaction. In this context, a cluster of frequently mutated amino acid residues in cancer was identified to putatively lead to similar structural effects as E285K substitution (E285 cluster). Functional analysis, including knockdown of endogenous p53 and reconstitution with diverse p53 missense mutants confirmed mutp53(E285K) to have lost transcriptional activity, to be localized in the cytosol of cancer cells, by both means conferring chemoresistance. Re-sensitization to cisplatin-induced cell death was achieved using clinically approved compounds aiming to restore p53 wild-type function (PRIMA1-Met), or inhibition of AKT-driven MAPK survival pathways (afuresertib), in both cases being partially due to ferroptosis induction. Consequently, active ferroptosis induction using the GPX4 inhibitor RSL3 proved superior in tumorselectively fighting MM cells. Due to high prevalence of the E285-cluster mutations in MM as well as in a variety of other tumor types, we conclude this cluster to serve an important function in tumor development and therapy and suggest new implications for ferroptosis induction in therapeutic applications fighting MM in particular and cancer in general.

Case Report: Response of cutaneous lupus lesions in SLE to interferon receptor blockade parallels reduction of interferon score in blood.

Cutaneous lupus erythematosus (CLE), the main manifestation of systemic lupus erythematosus (SLE), is driven by type I interferons (IFNs) and often only partially responds to conventional therapies. Treatment of seven SLE patients with the monoclonal antibody anifrolumab induced fast and sustained remission of previously refractory CLE lesions, beginning within the first weeks of treatment. Decline in CLASI-A score was paralleled by a reduction in IFN score determined by mRNA expression of seven IFN-stimulated genes (ISGs) in blood. These data suggest that a subset of ISGs could be a valuable biomarker in CLE.

Determinants of Depressive Symptoms, Quality of Life, Subjective Health Status and Physical Limitation in Patients with Systemic Sclerosis.

Systemic sclerosis is a progressive connective tissue disease for which there is limited knowledge about physical limitations, quality of life and depression. The aim of this study was to assess these parameters during the disease process of systemic sclerosis, in a cross- sectional study of 79 patients and a longitudinal study of 33 patients over 10 years. Medical data were collected by physicians' questionnaires and sociodemographic data, pain, physical limitation, quality of life, subjective health status, risk of depressive symptoms by patients' questionnaires. Data analysis was descriptive and exploratory. Cross-tabulations, χ2 test and Student's t-test were used for calculations, Pearson's correlation to measure dependencies, and logistic regression analyses for categorized parameters. The cross-sectional analysis of 79 patients with systemic sclerosis (81% female, mean ± standard deviation age 61.5 ± 12.6 years) demonstrated a higher rate of patients with risk of depressive symptoms (42.3%) higher physical limitations, lower quality of life, and subjective health status than reference values for the general German population. Moderate to strong correlations between disease-related physical limitation, quality of life, subjective health status, risk of depressive symptoms and pain were detected (correlation according to Pearson -0.459 to -0.638, p < 0.001). Longitudinal analysis revealed a significant increase in disease activity, pain, physical limitation and risk of depressive symptoms (p < 0.001) during the disease process. This study demonstrates that nearly half of patients with systemic sclerosis probably experience depressive symptoms. The rate of patients with risk of depressive symptoms, pain and physical limitations increased during the systemic sclerosis disease process. Health-related quality of life and state of health declined, indicating the need for better interdisciplinary care for patients with systemic sclerosis.

Long-term safety and efficacy of risankizumab for the treatment of moderate-to-severe plaque psoriasis: Interim analysis of the LIMMitless open-label extension trial up to 5 years of follow-up.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease often requiring long-term therapy. OBJECTIVE: To evaluate the long-term safety and efficacy of risankizumab in patients with psoriasis. METHODS: LIMMitless is an ongoing phase 3, open-label extension study evaluating the long-term safety and efficacy of continuous risankizumab 150 mg every 12 weeks for adults with moderate-to-severe plaque psoriasis following multiple phase 2/3 base studies. This interim analysis assessed safety (ie, monitored treatment-emergent adverse events [TEAEs]) through 304 weeks. Efficacy assessments included determining the proportion of patients who achieved ≥90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90/100), static Physician's Global Assessment of clear/almost clear (sPGA 0/1), and Dermatology Life Quality Index of no effect on patient's life (DLQI 0/1) through 256 weeks. RESULTS: Among 897 patients randomized to risankizumab in the base studies, 706 were still ongoing at data cutoff. Rates of TEAEs, TEAEs leading to discontinuation, and TEAEs of safety interest were low. At week 256, 85.1%/52.3% of patients achieved PASI 90/100, respectively, 85.8% achieved sPGA 0/1, and 76.4% achieved DLQI 0/1. LIMITATIONS: Open-label study with no placebo or active-comparator group. CONCLUSIONS: Long-term continuous risankizumab treatment for up to 5 years was well tolerated and demonstrated high and durable efficacy.

The role of bacterial colonisation in severity, symptoms and aetiology of hand eczema: The importance of Staphylococcus aureus and presence of commensal skin flora.

BACKGROUND: The role and causality of the microbial ecosystem on the skin in relation to the development of hand eczema (HE) is still unknown. OBJECTIVES: To investigate the prevalence of different bacterial colonisations in HE patients and their association with the severity, symptoms and aetiology of the disease. METHODS: In a retrospective cohort study of 167 HE patients, bacterial swabs from lesional skin were collected for culturing. Patients were categorised according to bacterial colonisation, HE severity, HE symptoms and HE aetiology. RESULTS: The majority of the patients were tested positive for Staphylococcus aureus (S. aureus) (n = 131, 78.4%) and/or commensal skin flora (CSF; n = 130, 77.8%), while other bacteria species were found only sporadically. Severe HE was significantly more prevalent in skin with S. aureus (odds ratio [OR]: 5.13, 95% confidence interval [CI]: 2.21-11.94) and less common in skin with CSF (OR: 0.20, 95% CI: 0.05-0.88). S. aureus colonisation was also associated with atopic HE aetiology (p < 0.001) and acute HE symptoms such as blisters, erosions and crusts (p = 0.003). CONCLUSIONS: The main colonisation of HE patients is with S. aureus and is associated with disease severity, acute HE symptoms and atopic HE aetiology. CSF is associated with mild HE, which could result in new therapeutic approaches.

Leptomeningeal Metastases in Melanoma Patients: An Update on and Future Perspectives for Diagnosis and Treatment.

Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the highest rates of metastasis to the leptomeninges, with approximately 10-15% of patients with advanced disease developing LMD. Tumour cells that metastasise to the brain have unique properties that allow them to cross the blood-brain barrier, evade the immune system, and survive in the brain microenvironment. Metastatic colonisation is achieved through dynamic communication between metastatic cells and the tumour microenvironment, resulting in a tumour-permissive milieu. Despite advances in treatment options, the incidence of LMD appears to be increasing and current treatment modalities have a limited impact on survival. This review provides an overview of the biology of LMD, diagnosis and current treatment approaches for MM patients with LMD, and an overview of ongoing clinical trials. Despite the still limited efficacy of current therapies, there is hope that emerging treatments will improve the outcomes for patients with LMD.

Characteristics Associated With Refractory Course, Blindness, and Treatment Strategy-Related Outcomes in Patients With Mucous Membrane Pemphigoid.

Importance: Mucous membrane pemphigoid (MMP) is a rare and heterogeneous subepithelial autoimmune bullous disease with predominant mucosal involvement. Characteristics associated with the disease course and complications are yet to be delineated. Objectives: To evaluate characteristics associated with refractory disease course and blindness among patients with MMP and to estimate the association of different treatment strategies with the prognostic outcome. Design, Setting, and Participants: A retrospective cohort study of consecutive patients diagnosed with MMP and followed up for more than 1 year from 2007 to 2020 in 2 tertiary referral centers. Data were analyzed from January 1, 2009, to June 30, 2020. Main Outcomes and Measures: Characteristics associated with refractory disease course and blindness were evaluated using multivariable logistic regression model. Results: The study encompassed 121 patients with MMP (mean [SD] age, 66.0 [14.0] years; 78 (64.5%) were women), of whom 56 (46.3%) followed a refractory course and 13 (10.7%) developed blindness. Anti-LAD-1 IgA (odds ratio [OR], 3.42; 95% CI, 1.11-10.52; P = .03) and anti-dermal-epidermal/epithelial junction (DEJ) IgG (by indirect immunofluorescence on human salt-split skin; OR, 2.92; 95% CI, 1.26-6.78; P = .01) were significantly associated with refractory course. Development of blindness was associated with older age (≥68 years; OR, 6.38; 95% CI, 1.35-30.16; P = .009), initial presentation with bilateral ocular involvement (OR, 7.92; 95% CI, 2.04-30.68; P = .001), and scarring ocular lesions (OR, 5.11; 95% CI, 1.47-17.79; P = .006). However, 4 (30.8%) and 2 (15.4%) of those experiencing blindness had no ocular scarring lesions and unilateral ocular involvement at the onset of their disease, respectively. Patients progressing to blindness were more likely to be treated by 3 or more immunosuppressive/immunomodulatory drugs (OR, 4.07; 95% CI, 1.17-14.14; P = .02) and by cyclophosphamide (OR, 7.64; 95% CI, 2.24-26.09; P < .001). Patients developing blindness and refractory course were more frequently managed by intravenous immunoglobulin (OR, 7.64; 95% CI, 2.24-26.09; P < .001 and OR, 3.47; 95% CI, 1.42-8.45; P = .005, respectively). Conclusions and Relevance: Findings of this cohort study support that patients with MMP with anti-LAD-1 IgA and anti-DEJ IgG reactivity should be carefully monitored. While initial bilateral ocular disease and scarring ocular lesions were associated with blindness, patients initially presenting with unilateral and nonscarring ocular disease may still develop severe vision impairment.

Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases.

Despite remarkable advances in treating patients with metastatic melanoma, the management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an important mechanism for the adaptation of melanoma cells to the brain environment. In this study, the methylomes and transcriptomes of a cohort of matched melanoma metastases were evaluated by integrated omics data analysis. The identified 38 candidate genes displayed distinct promoter methylation and corresponding gene expression changes in intracranial compared with extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. In accordance with the underlying promoter methylation and gene expression changes, a significantly different protein expression was confirmed for STK10, PDXK, WDR24, CSSP1, NMB, RASL11B, phosphorylated PRKCZ, PRKCZ, and phosphorylated GRB10 in the intracranial metastases. The observed changes imply a distinct intracranial phenotype with increased protein kinase B phosphorylation and a higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of phosphorylated protein kinase B and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant alterations were identified that provide insights into the molecular mechanisms that discriminate brain metastases from other organ metastases, which could be exploited by targeting the affected signaling pathways.