Polysensitization in the Spanish Contact Dermatitis Registry (REIDAC): A 2019-2022 prospective study with cluster and network analysis.

BACKGROUND: There is still limited clinical-practice data on specific clinical and patch test features, as well as on allergen clusters in polysensitization (PS). OBJECTIVES: To determine the frequency, relevance, symptoms duration and risk factors in polysensitized patients and to assess possible allergen aggregation. METHODS: Prospective multicentric study (January 2019-December 2022) conducted in setting of the Spanish Contact Dermatitis Register (REIDAC). Clinical and patch test data of polysensitized and oligosensitized patients were compared, and risk factors of PS were investigated with logistic multivariate regression. Unsupervised hierarchical clustering and network analysis were used to study allergen aggregation in PS. RESULTS: A total of 10,176 patients were analysed. PS was found in 844 (8.3%). Current relevance was significantly higher in polysensitized patients (p < 0.01). Risk factors for PS were atopic dermatitis (OR: 1.58, 95% CI: 1.24-2.02), age (≥60 years vs. ≤24 years, OR: 1.75, 95% CI: 1.25-2.44) and some special locations (legs vs. face OR: 1.54, 95% CI: 1.05-2.25, hands vs. face OR: 1.46, 95% CI:1.15-1.85, arms vs. face OR: 1.49, 95% CI:1.01-2.20, trunk vs. face OR: 1.40, 95% CI:1.06-1.85). Cluster and network analyses revealed specific-allergen clusters and significant associations, including allergens belonging to metals group, fragrances and botanicals group, topical drugs group, rubber allergens and biocides. CONCLUSIONS: This study confirms that PS is structured by discernible patterns of specific-allergen clusters and reinforces significant allergen associations in PS. Cross-reactivity and/or concomitant sensitization could explain the formation of allergen clusters in PS.

Interplay between Humoral and CLA+ T Cell Response against Candida albicans in Psoriasis.

Candida albicans (CA) infections have been associated with psoriasis onset or disease flares. However, the integrated immune response against this fungus is still poorly characterized in psoriasis. We studied specific immunoglobulins in plasma and the CA response in cocultures of circulating memory CD45RA- cutaneous lymphocyte antigen (CLA)+/- T cell with autologous epidermal cells from plaque and guttate psoriasis patients (cohort 1, n = 52), and also healthy individuals (n = 17). A complete proteomic profile was also evaluated in plaque psoriasis patients (cohort 2, n = 114) regarding their anti-CA IgA levels. Increased anti-CA IgA and IgG levels are present in the plasma from plaque but not guttate psoriasis compared to healthy controls. CA cellular response is confined to CLA+ T cells and is primarily Th17. The levels of anti-CA IgA are directly associated with CLA+ Th17 response in plaque psoriasis. Proteomic analysis revealed distinct profiles in psoriasis patients with high anti-CA IgA. C-C motif chemokine ligand 18, chitinase-3-like protein 1 and azurocidin were significantly elevated in the plasma from plaque psoriasis patients with high anti-CA levels and severe disease. Our results indicate a mechanism by which Candida albicans exposure can trigger a clinically relevant IL-17 response in psoriasis. Assessing anti-CA IgA levels may be useful in order to evaluate chronic psoriasis patients.

PCM1::JAK2 fusion associates with an atypical form of mycosis fungoides.

Deregulation of JAK-STAT pathway seems to be relevant in mycosis fungoides (MFs). We report the case of a 23-year-old woman diagnosed of atypical MF carrying isolated PCM1::JAK2 fusion and eosinophilia. The disease was refractory to common treatments and progressed increasing the number of large CD30 positive T-cells. After progression, treatment with brentuximab vedotin was decided and decreased the proportion of large cells, but the low-grade component persisted, and the skin lesions worsened. Immunohistochemical expression of p-STAT3 detected in most tumor cells demonstrated the abnormal activation of JAK-STAT pathway. Very few cases of mature T-cell lymphomas carrying PCM1::JAK2 gene fusion have been reported to date, and we review previous cases described with this alteration. Described cases shared similar clinicopathological features and low genetic complexity, and the presence of PCM1::JAK2 fusion associates with a distinctive form of the disease.

Study of Excipients in Delayed Skin Reactions to mRNA Vaccines: Positive Delayed Intradermal Reactions to Polyethylene Glycol Provide New Insights for COVID-19 Arm.

BACKGROUND: Skin local reactions to mRNA COVID-19 vaccines have been linked to the use of vaccine excipients. The aim of the study is to evaluate the role of skin testing excipients in delayed skin reactions due to mRNA COVID-19 vaccines. METHODS: Skin testing among a group of healthcare workers with skin reactions due to mRNA vaccines was performed. Patch testing and intradermal testing (IDT) with polyethylene glycol (PEG)-400, PEG-2000, trometamol, and 1,2-dimyristoyl-sn-glycero-3-phosphocholine were performed. Healthcare workers without skin reactions to vaccines were used for skin testing as controls. RESULTS: Thirty-one healthcare workers (from a total of 4315 vaccinated healthcare workers) experienced cutaneous adverse vaccine reactions. Skin testing was performed in sixteen of the healthcare workers (11 delayed large local reactions (DLLR) and 5 widespread reactions). Positive IDT for PEG-2000 1% in DLLR was seen in 10 (90.9%) patients, in comparison with one (16.6%) individual with a delayed widespread reaction. Delayed positive IDT reactions for PEG-2000 1% on day 2 were observed in three (27.3%) patients with DLLR. Patch testing of the excipients was negative. Among 10 controls, only one exhibited a transient positive IDT reaction to PEG-2000 1%. CONCLUSIONS: Immediate and delayed reactions to IDT are frequently detected in patients with DLLR. The observation of positive delayed intradermal reactions to PEG disclosed only in patients with DLLR reinforces a possible role of PEG in the development of these reactions. Skin testing of other excipients is of little importance in clinical practice.

Epidermal growth factor receptor gene numerical aberrations are frequent events in actinic keratoses and invasive cutaneous squamous cell carcinomas.

Epidermal growth factor receptor (EGFR) gene amplification and protein overexpression are common in several cancers. EGFR status has seldom been studied in cutaneous squamous carcinomas (SCCs), or their precursors, actinic keratoses (AKs). We evaluated the presence of EGFR genomic aberrations and EGFR protein overexpression in 25 AKs and 35 invasive SCCs by means of fluorescence in situ hybridization (FISH) and immunohistochemistry. EGFR numerical aberrations were detected in 52% of AKs and 77.1% of SCCs (P = 0.042). EGFR amplification was identified in 12% of AKs and 20% of SCCs. No differences regarding EGFR numerical aberrations were observed when AKs with high-grade dysplasia were compared with SCCs. A good correlation was observed between EGFR numerical aberrations and EGFR overexpression. Our results suggest that EGFR numerical aberrations occur in the early stages of epithelial carcinogenesis in skin, not playing a role in the progression from low-grade SCCs into more aggressive phenotypes.

Heinz-Lippmann disease as an underrecognized cause of chronic venous insufficiency-associated cutaneous ulcers: Clinical and imaging findings.

Venous insufficiency is a frequent cause of consultation in primary care settings. Heterotopic ossification, consisting of an abnormal formation of true bone in extraskeletal soft tissues, is an underrecognized complication of chronic venous insufficiency that may cause torpid ulcers. We report a case of 78-year-old woman, with a long-standing history of venous insufficiency and tibial fracture, showing a non-healing ulcer associated with subcutaneous calcifications of the left lower extremity. Gold standard of imaging diagnosis are both plain radiographs and computed tomography but also magnetic resonance imaging could be useful for assessing the characteristics of the pathology. We describe a case of Heinz-Lippmann disease, diagnosed by using both computed tomography and magnetic resonance imaging.

Epigenetic Silencing of Tumor Suppressor miR-124 Directly Supports STAT3 Activation in Cutaneous T-Cell Lymphoma.

Increasing evidence supports a potential role for STAT3 as a tumor driver in cutaneous T-cell lymphomas (CTCL). The mechanisms leading to STAT3 activation are not fully understood; however, we recently found that miR-124, a known STAT3 regulator, is robustly silenced in MF tumor-stage and CTCL cells. OBJECTIVE: We studied here whether deregulation of miR-124 contributes to STAT3 pathway activation in CTCL. METHODS: We measured the effect of ectopic mir-124 expression in active phosphorylated STAT3 (p-STAT3) levels and evaluated the transcriptional impact of miR-124-dependent STAT3 pathway regulation by expression microarray analysis. RESULTS: We found that ectopic expression of miR-124 results in massive downregulation of activated STAT3 in different CTCL lines, which resulted in a significant alteration of genetic signatures related with gene transcription and proliferation such as MYC and E2F. CONCLUSIONS: Our study highlights the importance of the miR-124/STAT3 axis in CTCL and demonstrates that the STAT3 pathway is regulated through epigenetic mechanisms in these cells. Since deregulated STAT3 signaling has a major impact on CTCL initiation and progression, a better understanding of the molecular basis of the miR-124/STAT3 axis may provide useful information for future personalized therapies.

Extranodal natural killer/T-cell lymphoma, nasal type: a Spanish multicentric retrospective survey.

BACKGROUND: Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is an aggressive lymphoma with a very low incidence in western populations. OBJECTIVE: To review the clinicopathological features and outcome of a multicentre series of ENKTL in Spain. MATERIALS & METHODS: A multicentre retrospective study was performed based on cases of ENKTL, collected from 1995 to 2004, from 12 dermatology departments included in the Spanish Lymphoma Study Group. The clinical, histopathological, and evolutive features of all these cases were reviewed. RESULTS: Eighteen patients (three male, 15 female) with median age of 67 years were included in the study. The onset of lesions occurred in the nasal region in 11 patients and on the skin outside this region in the remaining cases. The observed lesions were clinically heterogeneous, corresponding to papules, plaques, and nodules, with or without ulceration. All patients except four received different polychemotherapy regimens, either alone (n = 11) or in combination with radiotherapy (n = 4). After a variable follow-up period (1-36 months), only two patients remained alive. One patient was recently diagnosed (four months ago) with ENKTL in the nasal region and the other presented with skin-limited disease. The median overall survival was 9.5 months. CONCLUSIONS: The results of this retrospective survey confirm that ENKTL is a rare subtype of lymphoma in the Spanish population. All patients showed an aggressive clinical course and poor prognosis, regardless of the initial clinical presentation. Prospective data on larger series of patients treated homogenously are needed to establish the best treatment modality.

Epithelial antigenic specificities of circulating autoantibodies in mucosal lichen planus.

BACKGROUND: Mucosal lichen planus (LP) is an inflammatory disease of the mucous membranes of unknown origin. The antigen-specific autoantibodies or T cells responsible for this disease have not yet been established. OBJECTIVES: This study was designed to study the antigenic specificities of circulating antibodies in patients with mucosal LP and to review previous findings on this topic. METHODS: We tested a series of consecutive cases of mucosal LP in our clinic by enzyme-linked immunosorbent assay using desmoglein 3 (Dsg3) and BP180 fusion proteins. RESULTS: Three of 22 patients were positive for anti-NC16A antibodies. Interestingly, we found a middle-aged woman with severe disease with circulating anti-Dsg3 antibodies at high levels, typical of pemphigus vulgaris. Levels of these antibodies positively correlated with the severity of clinical manifestations. We failed to detect anti-desmoglein antibodies in any other patient in our series and in the literature review. CONCLUSIONS: Some patients with mucosal LP may present with circulating anti-BP180 antibodies at low levels. We also report the first case with positive anti-Dsg3 antibodies. The pathogenic relevance of these autoantibodies remains unknown.

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma.

About 5% of all cutaneous squamous cell carcinomas (cSCCs) metastasize, which is the principal cause of death by this type of cancer. However, to date there are no reliable biomarkers that categorize those SCC patients that will progress to metastasis. Nuclear active IKKα diminishes Maspin levels in prostate cancer facilitating its metastatic potential. In this paper, we describe the immunohistochemical analysis of active IKK and Maspin in 56 metastasizing and 51 non-metastasizing primary cSCC to measure their association with cancer behaviour. We also determined the effect of inhibiting IKK activity in SCC cell growth and migration in vitro. We found that high levels of nuclear active IKK in the primary tumour are predictive of cSCC metastatic capacity, in particular when combined with poor tumour differentiation and a history of tumour recurrence. Active IKK inversely correlated with Maspin levels in cSCC tumours, and samples negative for Maspin are exclusively found in the metastatic group. Mechanistically, IKK activity regulates cellular motility and SCC cell survival. Our results indicate that nuclear active IKK is a robust biomarker to predict cSCC outcome, and suggest the possibility of targeting IKK activity as a future therapy for treating metastatic cSCC.

Notch1 Pathway Activation Results from the Epigenetic Abrogation of Notch-Related MicroRNAs in Mycosis Fungoides.

Notch is a family of transmembrane receptors that participate in the regulation of cell differentiation, proliferation, and stemness. Notch pathway activation has also been found associated with different human cancers including primary cutaneous T-cell lymphomas (CTCL). The elucidation of the mechanisms driving Notch activation in these particular diseases has remained elusive. Here we studied the possibility that DNA methylation at Notch pathway gene promoters and/or deregulation of Notch-associated microRNAs contribute to activate Notch in mycosis fungoides (MF). By genome-wide DNA methylation analysis, we failed to detect any consistent methylation at the Notch1, the Notch-ligand Jagged1, or the Notch-target Hes1 gene promoters, but found a significant methylation of the Notch-related microRNAs, in particular miR-200c and miR-124. Downregulation of miR-200c is associated with overexpression of Jagged1, concomitant to Notch1 activation. CTCL cell lines were infected with lentiviral vector encoding for miR-200c and ectopic expression of miR-200c in CTCL lines resulted in Jagged1 protein downregulation associated with a reduction in the levels of active Notch1. Our study deciphers an epigenetic mechanism regulating the Notch pathway in (MF) that might contribute to the future design of more specific therapeutic strategies.

Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance.

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.