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Background:. Pigmented lesions such as melanosis have rarely been reported in patients with vulvar lichen sclerosus (VLS) that is typically characterized by hypopigmented lesions. Objective:. We aimed to analyze systematically anogenital melanosis in a large cohort of VLS patients. Methods:. We analyzed the clinical data of 198 female patients with VLS. The anogenital lesions of all patients were professionally photographed in a standardized position and illumination. Severity classification of architectural findings followed an easy-to-use clinical score. A modified Melasma Area and Severity Index and an image analysis software were used to evaluate the area and intensity of pigmentation. Results:. According to the clinical score, 79 (198/39.9%) patients showed grade 1 disease, 78 (198/39.4%) grade 2, 37 (198/18.7%) grade 3, and 4 (198/2%) grade 4 disease. About 111 (56.1%) of the 198 patients had anogenital melanosis with a median modified Melasma Area and Severity Index of 3.6 (0.4–14). Univariate analysis revealed that anogenital melanosis was positively correlated with the use of topical estrogens (P = .0018) and negatively correlated with the use of pulsed high-dose corticosteroids plus low-dose methotrexate (PHDC-LDM, P = .021). On multivariable analysis, the use of topical hormone therapy turned out to be a strong independent predictor for the presence of anogenital melanosis (odds ratio: 4.57, 95% confidence interval: 1.66–12.57, P = .0033), whereas PHDC-LDM use was an independent predictor for the absence of anogenital melanosis (odds ratio: 0.35, 95% confidence interval: 0.15–0.84, P = .018). Limitations:. The study includes the retrospective monocentric design. Conclusion:. Anogenital melanosis is a very frequent and so far, under-reported clinical finding in VLS patients. It is likely caused by the use of topical estrogens employed for VLS treatment. In contrast, patients with more severe disease and PHDC-LDM treatment appear to develop less likely anogenital melanosis.

Acrodermatitis chronica atrophicans (ACA) is not an infrequent condition in Europe. However, the characteristic skin lesions are often confused by non-dermatologists with other conditions. We report three unusual cases in which we made a definitive diagnosis of ACA complicated by cutaneous marginal zone lymphoma, juxta-articular fibrotic nodules, or bilateral sensory polyneuropathy. In all cases, correct diagnosis and adequate treatment was delayed over a period of at least 12 months. We initiated systemic antibiotics resulting in full recovery in these patients. The present case reports underscore that ACA may be associated with unusual clinical presentation which potentially result in delay of correct diagnosis and treatment. Hence, ACA diagnosis may be considerably delayed leading to inappropriate therapy exposure, prolonged patients’ suffering, and causing unnecessary cost. Thus, physicians who are not familiar with skin conditions should seek a timely dermatologist consultation.

Purpose Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with an increased risk of malignancy. The aim of this systematic review was to investigate the prevalence of different malignancies in HS.Methods This review meets the PRISMA criteria. A data-driven approach was used to conduct the research, which involved a detailed keyword search. The study considered meta-analyses, experimental studies, case-control studies, cross-sectional studies, cohort studies, and recently published cases, published in English or German. Excluded were reviews, summaries, and letters to the editor, as well as studies, which are not based on the human population.Results Out of the initial 443 publications found, 25 met the inclusion criteria for this systematic review. Patients with HS have a significantly increased risk of cancer, up to 50%. Additionally, the risk of oropharyngeal, central nervous system, colorectal, prostate, vulvar and non-melanocytic skin cancers increase with the severity of HS. The likelihood of comorbid lymphoma in patients with HS is significantly higher compared to healthy controls. In severe cases of HS, malignant degeneration of lesions in the groin, perianal, perineal, and gluteal region can occur in up to 4.6% of cases. This leads to the development of cSCC, which often have a complicated course, are more refractory to treatment and associated with a poorer outcome. The pathogenic mechanisms responsible for the malignant transformation of HS are currently unknown.Conclusions Patients with HS have a higher risk of cancer compared to the general population. Untreated, long-standing HS lesions can lead to complicated malignant degeneration resulting in cutaneous squamous cell carcinoma. The mechanisms underlying this malignant degeneration are not fully understood. HS patients also have an increased risk of developing other cancers, including prostate, oral, pharyngeal and colorectal cancers of the central nervous system and lymphomas.

BackgroundMycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL). Comprehensive analysis of MF cells in situ and ex vivo is complicated by the fact that is challenging to distinguish malignant from reactive T cells with certainty.MethodsTo overcome this limitation, we performed combined single-cell RNA (scRNAseq) and T-cell receptor TCR sequencing (scTCRseq) of skin lesions of cutaneous MF lesions from 12 patients. A sufficient quantity of living T cells was obtained from 9 patients, but 2 had to be excluded due to unclear diagnoses (coexisting CLL or revision to a fixed toxic drug eruption).ResultsFrom the remaining patients we established single-cell mRNA expression profiles and the corresponding TCR repertoire of 18,630 T cells. TCR clonality unequivocally identified 13,592 malignant T cells. Reactive T cells of all patients clustered together, while malignant cells of each patient formed a unique cluster expressing genes typical of naive/memory, such as CD27, CCR7 and IL7R, or cytotoxic T cells, e.g., GZMA, NKG7 and GNLY. Genes encoding classic CTCL markers were not detected in all clusters, consistent with the fact that mRNA expression does not correlate linearly with protein expression. Nevertheless, we successfully pinpointed distinctive gene signatures differentiating reactive malignant from malignant T cells: keratins (KRT81, KRT86), galectins (LGALS1, LGALS3) and S100 genes (S100A4, S100A6) being overexpressed in malignant cells.ConclusionsCombined scRNAseq and scTCRseq not only allows unambiguous identification of MF cells, but also revealed marked heterogeneity between and within patients with unexpected functional phenotypes. While the correlation between mRNA and protein abundance was limited with respect to established MF markers, we were able to identify a single-cell gene expression signature that distinguishes malignant from reactive T cells.

IntroductionMerkel cell carcinoma (MCC) is an aggressive skin cancer with a poor prognosis, which only improved with the introduction of immunotherapies. An MCC prediction model with high diagnostic accuracy is lacking. The aim was to develop an MCC prognostic score (MCC-PS) based on combinations of previously proposed risk factors.MethodsA multicentric, retrospective study was conducted to develop MCC-PS, which included age, neuron-specific enolase (NSE), C-reactive protein (CRP), creatinine, bilirubin, and international normalized ratio (INR). Creatinine, bilirubin, and INR were used to calculate the model of end-stage liver disease (MELD) score. A total of 98 patients were included in the study, including 36.7% with stage I according to American Joint Committee on Cancer 2018 (n = 36), 30.6% with stage II (n = 30), 25.5% with stage III (n = 25), and 7.1% with stage IV (n = 7). Survival data of MCC patients were correlated with selected laboratory parameters and risk factors. Primary endpoint was MCC-specific survival (MSS) and the secondary endpoint was progression-free survival. Several statistical methods were used to develop the prognostic score, including correlation analysis, Kaplan–Meier curves, Cox regression, and time-dependent receiver operating characteristic analysis.ResultsThe MCC-PS is based on the sum of the following baseline variables: elevated CRP (≥5.5 mg/l), elevated NSE (≥22.8 µg/l), MELD score ≥ 11, and age ≥ 75 years. An MELD score ≥ 11 was scored as 4 points, elevated NSE level as 3 points, elevated CRP level as 2 points, and age ≥ 75 years as 1 point. A high-risk group according to the MCC-PS was characterized by a score of 4 or more points. The high-risk group was associated with a worse prognosis than the low-risk group (1-year MSS 62%, 2-year 43.1%, 5-year 17.6% as compared to 1-year MSS 79.5%, 3-year 75%, 5-year 72%). Notably, the developed MCC-PS predicts MCC outcome measures with high accuracy (3-year MSS: area under the curve (AUC) 0.934, sensitivity 87.5% and specificity 82.2%; 5-year MSS: AUC 0.93, sensitivity 89% and specificity 82%).ConclusionMCC-PS is the first prognostic score predicting MCC outcome with a high accuracy based on five easily available laboratory parameters and patient’s age. An MCC-PS of 4 or more indicates a high-risk patient associated with a poor prognosis.

Dear Editor, In adults, bullous pemphigoid (BP) has been described in association with scabies. We here describe an infant with recalcitrant scabies who developed generalized BP as confirmed by serological and immunofluorescence studies. About four weeks after birth, an otherwise healthy non-vaccinated male infant was diagnosed with scabies. His parents and sister were diagnosed with scabies as well. [...]

The most frequent primary cutaneous lymphomas observed in childhood and adolescence are mycosis fungoides (MF) and CD30-positive lymphoproliferative diseases. We report a 22-year-old female who presented with a 6-year history of multiple well-demarcated large roundish-oval scaly and reddish-brownish patches and plaques on the trunk and extremities. Histopathology revealed the focal parakeratosis and prominent epidermotropism of atypical lymphocytes, which were positive for CD8, CD56, and TIA-1 and showed a loss of CD7 and CD5 expression. T-cell receptor (TCR) gene rearrangement analysis (multiplex-PCR, BIOMED-2) of the lesional skin demonstrated the rearrangement of the gamma chain (tube A: 162 nt). Based on clinicopathological findings and a complete work-up, she was diagnosed with juvenile non-poikilodermatous C8+/CD56+ MF in stage IA. Resolution of the skin lesions was achieved by 16-week narrowband UVB phototherapy and clobetasol propionate 0.05% ointment. Juvenile-onset non-poikilodermatous CD8+CD56+ MF represents a very rare MF subtype and is associated with an indolent course. In order to avoid too aggressive diagnostics and treatments, clinicians should be aware of this rare and indolent MF variant in childhood and adolescence.

Adenosquamous carcinoma of the skin (ASCS) or primary cutaneous adenosquamous carcinoma is a rare malignant neoplasm. It is characterized by the presence of both glandular and squamous cell components and a propensity for aggressive clinical behavior. Due to its rarity, it continues to pose diagnostic challenges. To date, only a few cases of this tumor have been reported, and even fewer have been thoroughly investigated via immunohistochemistry.

Immune responses of the epithelia of the upper respiratory tract are likely crucial in early inhibition of the viral replication and finally clearance of SARS-CoV-2. We aimed to compare the expression profiles of antimicrobial peptides/proteins (AMPs) and related cytokines observed in the nasopharynx of SARS-CoV-2-infected patients and non-infected controls and to assess the associations between these parameters and COVID-19 patients’ outcomes. We included 45 subjects who had tested positive for SARS-CoV-2 and 22 control subjects who had tested negative for SARS-CoV-2. Biomaterial for SARS-CoV-2 detection, as well as gene and protein expression studies, was obtained from all subjects using nasopharyngeal swabs which were performed a maximum of 7 days before inclusion in the study. Univariable and multivariable statistics were performed. When compared to the controls, the mRNA expression levels of human β-defensin 1 (hBD-1), LL-37, and trappin-2 were significantly higher in specimens of nasopharyngeal swabs from COVID-19 patients. Protein expression of hBD-1 was also increased in the COVID-19 group. mRNA expression levels of interferon-ɣ (IFN-ɣ), tumor necrosis factor- ɑ (TNF-ɑ), and interleukin-6 (IL-6) measured in SARS-CoV-2-infected patients were significantly higher than those observed in the controls, which could also be confirmed in the protein levels of IFN-ɣ and IL-6. A significant correlation between mRNA and protein levels could be observed only for IL-6. Univariable analysis revealed that low IFN-ɣ mRNA levels were associated with severe/fatal outcomes. The occurrence of COVID-19 pneumonia was significantly associated with lower expression levels of IL-6 mRNA, IFN-ɣ mRNA, and TNF-ɑ mRNA. Concerning the severe/fatal outcomes, the multivariable logistic regression model revealed that none of the aforementioned parameters remained significant in the model. However, the logistic regression model revealed that higher TNF-ɑ mRNA expression was a significant independent predictor of absence of pneumonia [odds ratio: 0.35 (95% CI 0.14 to 0.88, p = 0.024)]. In conclusion, nasopharyngeal expression of AMPs (hBD-1, LL-37, and trappin-2) and cytokines (IL-6, IFN-ɣ, and TNF-ɑ) is upregulated in response to early SARS-CoV-2 infection, indicating that these AMPs and cytokines play a role in the local host defense against the virus. Upregulated nasopharyngeal TNF-ɑ mRNA expression during the early phase of SARS-CoV-2 infection was a significant independent predictor of the absence of COVID-19 pneumonia. Hence, high TNF-ɑ mRNA expression in the nasopharynx appears to be a protective factor for lung complications in COVID-19 patients.

We are very happy that Dermato has now entered its fourth year, having published notable papers covering the wide field of dermatology and other closely related disciplines [...]

Abstract In most cases, clear cell acanthoma (CCA) is an uncommon solitary lesion with distinctive clinicopathological features. We report the case of an 80‐year‐old man with generalized asymptomatic skin lesions predominantly affecting his chest, abdomen and his legs. On dermoscopy, the lesions showed dotted vessels in a linear pearl‐like distribution (“pearl necklace”) surrounded by a slightly whitish halo. Histopathology clearly confirmed the diagnosis of CCA. In conclusion, CCA being an uncommon solitary skin lesion may also appear in very rare cases as a generalized eruptive skin condition.

Advanced cutaneous squamous cell carcinoma (cSCC) can be a life-threatening disease for which effective and safe treatment in advanced stages is very limited. GP-2250 has been recently proven to have—in vitro and in vivo—antineoplastic effects on cancer cells. This study aims to investigate the potential anti-neoplastic effects of GP-2250 on the cSCC cell lines SCC13 and A431 through dose finding assessments, MTT cytotoxicity assays, cell migration assays, BrdU proliferation assays and FCM analysis. Our preliminary results have shown for the first time evidence for anti-neoplastic effects of GP-2250 on cSCC cells, enhancing cytotoxicity, attenuating cancer cell proliferation, inducing apoptosis and reducing tumour cell migration. Further investigations evaluating the modes of action of GP-2250 on cSCC cell lines are warranted in order to justify the use in vivo studies.

Merkel cell carcinoma is a rare, aggressive skin cancer that mainly occurs in elderly and immunocompromised patients. Due to the success of immune checkpoint inhibition in MCC, the importance of immunotherapy and vaccines in MCC has increased in recent years. In this article, we aim to present the current progress and perspectives in the development of vaccines for this disease. Here, we summarize and discuss the current literature and ongoing clinical trials investigating vaccines against MCC. We identified 10 articles through a PubMed search investigating a vaccine against MCC. From the international clinical trial database Clinical.Trials.gov, we identified nine studies on vaccines for the management of MCC, of which seven are actively recruiting. Most of the identified studies investigating a vaccine against MCC are preclinical or phase 1/2 trials. The vaccine principles mainly included DNA- and (synthetic) peptide-based vaccines, but RNA-based vaccines, oncolytic viruses, and the combination of vaccines and immunotherapy are also under investigation for the treatment of MCC. Although the management of MCC is changing, when compared to times before the approval of immune checkpoint inhibitors, it will still take some time before the first MCC vaccine is ready for approval.

In patients with COVID-19, broad panels of immune checkpoint molecules (ICPMs) and the purinergic signaling have not been studied in parallel. We aimed to perform in-depth immunophenotyping of major cell subsets present in human peripheral blood of COVID-19 patients and controls using PD1, TIM3, LAG3, TIGIT, and CD200R, as well as CD39, as markers for the purinergic signaling pathway. We studied 76 COVID-19 patients and 12 healthy controls using peripheral blood mononuclear cells on flow cytometry. Univariable and multivariable statistics were performed. All ICPMs studied were significantly overexpressed on different cell subsets of COVID-19 patients when compared with healthy controls. Elevated lactate dehydrogenase; C-reactive protein; age; and high expression of CD45+, CD39+CD45+, TIM3+CD39+CD4+CD45+, and TIM3+CD39+CD8+CD3+CD4+ cells were significantly associated with severe COVID-19. On multivariable analysis, however, only high expression of CD39+CD45+ (OR 51.4, 95% CI 1.5 to 1763) and TIM3+CD39+CD4+CD3+CD45+ (OR 22.6, 95% CI 1.8 to 277) cells was an independent predictor for severe COVID-19. In conclusion, numerous ICPMs are overexpressed in COVID-19 patients when compared with healthy controls, suggesting a pathophysiological role of these molecules in SARS-CoV-2 infection. However, only TIM3 in co-expression with CD39 remained as a significant independent prognostic ICPM on multivariable analysis. The flow cytometric evaluation of TIM3+CD39+CD4+CD3+CD45+, as well as CD39+CD45+, is a powerful tool for the prognostication of COVID-19 patients on hospital admission.

Dear Editors: In 2016, Bessis and coworkers first reported Bier anemic spots, cyanosis, and urticaria-like eruption (BASCULE) syndrome [...]

A 63-year-old woman presented to the emergency department with acute dyspnea and progressive swelling of the face (Figure 1), neck, and upper trunk [...]

Dear Editors: Giant congenital melanocytic naevus (GCMN)-associated melanoma in adults is very rare [...]

Dear Editors: Pityriasis lichenoides-like mycosis fungoides (MF) is a rare variant of MF, presenting clinical findings of pityriasis lichenoides (PL) but histological features of MF [...]

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a life-threatening autoimmune disease associated with malignancies. Here, we present a patient initially misdiagnosed with “chronic” Stevens–Johnson syndrome. Over a year later, the patient was diagnosed with stage IV follicular lymphoma and treated with an anti-CD20 antibody. At this time, his skin condition had significantly worsened, with erythroderma and massive mucosal involvement, including in the mouth, nose, eyes, and genital region. Histopathology revealed lichenoid infiltrates with interface dermatitis, dyskeratoses, necrotic keratinocytes, and a dense CD8+ infiltrate with strong epidermotropism. Direct and indirect immunofluorescence tests for autoantibodies were negative. Remarkably, we retrospectively discovered a chronic increase in peripheral CD8+ lymphocytes, persisting for over a year. Consequently, the patient was diagnosed with antibody-negative PAMS. Three weeks later, he succumbed to respiratory failure. This dramatic case highlights the challenges in diagnosing PAMS, particularly in cases where immunofluorescence assays are negative. Importantly, we observed, for the first time, a chronic excess of CD8+ peripheral blood lymphocytes, associated with PAMS, consistent with the systemic, autoreactive T-cell-driven processes that characterize this condition.

Enhanced glycolysis (Warburg effect) driven by the BRAF oncogene, dysregulated GAPDH expression, and activation of the PI3K/AKT/mTOR signaling pathway may significantly contribute to the resistance-targeted therapy of BRAF-mutated melanomas. Therefore, we aimed to study for the first time the anti-tumor activity of the GAPDH inhibitor GP-2250 in BRAF-mutated melanoma cell lines and benign melanocytes. We employed three melanoma cell lines and one primary melanocyte cell line (Ma-Mel-61a, Ma-Mel-86a, SH-4 and ATCC-PCS-200-013, respectively), which were exposed to different GP-2250 doses. GP-2250’s effects on cell proliferation and viability were evaluated by means of the BrdU and MTT assays, respectively. The RealTime-Glo Annexin V Apoptosis and Necrosis Assay was performed for the evaluation of apoptosis and necrosis induction. RT-PCR and western blotting were implemented for the determination of AKT and STAT3 gene and protein expression analyses, respectively. The melanoma cell lines showed a dose-dependent response to GP-2250 during BrDU and MTT testing. The RealTime-Glo Annexin V assay revealed the heterogenous impact of GP-2250 on apoptosis as well as necrosis. With respect to the melanoma cell lines Ma-Mel-86a and SH-4, the responses and dosages were comparable to those used for the MTT viability assay. Using the same dose range of GP-2250 administered to melanoma cells, however, we observed neither the noteworthy apoptosis nor necrosis of GP-2250-treated benign melanocytes. The gene expression profiles in the melanoma cell lines for AKT and STAT3 were heterogenous, whereby AKT as well as STAT3 gene expression were most effectively downregulated using the highest GP-2250 doses. Immunoblotting revealed that there was a time-dependent decrease in protein expression at the highest GP-2250 dose used, whereas a time- as well as dose-dependent AKT decrease was predominantly observed in Ma-Mel-61a. The STAT3 protein expression of Ma-Mel-86a and SH-4 was reduced in a time-dependent pattern at lower and moderate doses. STAT3 expression in Ma-Me-61a was barely altered by GP-2250. In conclusion, GP-2250 has anti-neoplastic effects in BRAF-mutated melanoma cell lines regarding tumor cell viability, proliferation, and apoptosis/necrosis. GP-2250 is able to downregulate the gene and protein expression of aberrant tumorigenic pathways in melanoma cell lines. Since GP-2250 is a GAPDH inhibitor, the substance may be a promising combination therapy for tumors presenting the Warburg effect, such as melanoma.

With the end of the pandemic, COVID-19 has entered an endemic phase with expected seasonal spikes. Consequently, the implementation of easily accessible prognostic biomarkers for patients with COVID-19 remains an important area of research. In this monocentric study at a German tertiary care hospital, we determined the prognostic performance of different clinical and blood-based parameters in 412 COVID-19 patients. We evaluated the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), and absolute eosinopenia (AEP, 0/µL) of COVID-19 patients (n = 412). The Siddiqui and Mehra staging proposal, the WHO clinical progression scale, and COVID-19-associated death were used as COVID-19 outcome measures. With respect to Siddiqi and Mehra staging, patient age of older than 75 years, high C-reactive protein (CRP), absolute eosinopenia (AEP), cardiovascular comorbidities, and high ferritin were significant independent predictors for severe COVID-19. When outcome was determined according to the WHO clinical progression scale, patient age of older than 75 years, high CRP, high LDH, AEP, high neutrophil-to-lymphocyte ratio (NLR), and the presence of pulmonal comorbidities were significant independent predictors for severe COVID-19. Finally, COVID-19-associated death was predicted independently by patient age of older than 75 years, high LDH, high NLR, and AEP. Eosinopenia (< 40/µL) was observed in 74.5% of patients, and AEP in almost 45%. In conclusion, the present real-world data indicate that the NLR is superior to more complex systemic immune-inflammation biomarkers (e.g., SII and PIV) in COVID-19 prognostication. A decreased eosinophil count emerged as a potential hallmark of COVID-19 infection, whereas AEP turned out to be an accessible independent biomarker for COVID-19 severity and mortality.

BackgroundSézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma.ObjectiveTo compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS.MethodsWe utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq).ResultsWe scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as CCR7, IL7R and CD27. In the skin, we detected two major malignant T-cell populations: One subpopulation was closely related to the malignant T cells from the blood, while the other subpopulation expressed genes reminiscent of skin resident effector memory T cells including GZMB and NKG7. Pseudotime analysis indicated crucial transcriptomic changes in the transition of malignant T cells between blood and skin. These changes included the differential regulation of TXNIP, a putative tumor suppressor in CTCL, and the adaptation to the hypoxic conditions in the skin. Tumor cell proliferation in the skin was supported by stimulating interactions between myeloid cells and malignant T cells.ConclusionsUsing scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin.

There exist relatively sparse and conflicting data on high-level microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) in cutaneous malignancies. We aimed to determine the expression profiles of MMR proteins (MSH2, MSH6, MLH1, and PMS2) in different progression stages of cutaneous squamous cell carcinoma (cSCC, 102 patients in total) by immunohistochemistry, and search for MSI-H in patients with low-level MMR or dMMR using multiplex-PCR. Low-level MMR protein expression was observed in five patients: One patient with primary cSCC < 2 mm thickness and low-level MLH1, three patients with primary cSCC > 6 mm (including one with low-level MSH2, as well as MSH6 expression, and two with low-level PMS2), and one patient with a cSCC metastasis showing low-level MSH2 as well as MSH6. Intergroup protein expression analysis revealed that MLH1 and MSH2 expression in actinic keratosis was significantly decreased when compared to Bowen’s disease, cSCC < 2 mm, cSCC > 6 mm, and cSCC metastasis. In cases with low-level MMR, we performed MSI-H tests revealing three cases with MSI-H and one with low-level MSI-L. We found low-level MMR expression in a small subset of patients with invasive or metastatic cSCC. Hence, loss of MMR expression may be associated with tumour progression in a small subgroup of patients with non-melanoma skin cancer.

Growing evidence suggests that COVID-19 vaccines can induce hematological conditions. Here, we report a case of Evans’ syndrome, a combination of immune thrombocytopenic purpura and autoimmune hemolytic anemia following administration of the ChAdOx1 nCoV-19 vaccine. The present case further supports the notion that COVID-19 vaccines can trigger in rare cases severe persistent autoimmune-mediated hematological conditions which may predominantly occur in patients with underlying autoimmune conditions.

Hidradenitis suppurativa (HS) is a chronic skin disease that is often associated with metabolic disorders. Diabetes mellitus (DM) is a frequent comorbidity in HS. There is currently no established screening for DM in HS patients. The aim of our study was to identify high-risk groups of HS patients that develop DM and to assess the frequency of different types of DM present in HS patients. To do so, we conducted a monocentric study in 99 patients with HS. All patients underwent detailed clinical and laboratory assessments, including the determination of glycated hemoglobin. Among the 20.2% of patients that presented with DM, type 2 was by far the most prevalent (19 out of 20 patients). Moreover, male gender, age, BMI, Hurley stage, modified Hidradenitis Suppurativa Score (mHSS), DLQI and hypertension all correlated with the glycated hemoglobin levels in the HS patients. In the multivariable analysis, Hurley stage III, older age, and higher BMI were significantly associated with DM. Specifically, patients at Hurley stage III were at a 5.3-fold increased risk of having DM type II compared to patients at earlier Hurley stages. Since many of the HS patients had not been diagnosed, our study reveals shortcomings in the screening for DM and suggest that this should be routinely performed in HS patients at high risk to avoid secondary complications.

Spitzoid neoplasms are a challenging group of cutaneous melanocytic proliferations. They are characterized by epithelioid and/or spindle‐shaped melanocytes and classified as benign Spitz nevi (SN), atypical Spitz tumors (AST), or malignant Spitz tumors (MST). The intermediate AST category represents a diagnostically challenging group since on purely histopathological grounds, their benign or malignant character remains unpredictable. This results in uncertainties in patient treatment and prognosis. The molecular properties of Spitzoid lesions, especially their transcriptomic landscape, remain poorly understood, and genomic alterations in melanoma‐associated oncogenes are typically absent. The aim of this study was to characterize their transcriptome with digital mRNA expression profiling. Formalin‐fixed paraffin‐embedded samples (including 27 SN, 10 AST, and 14 MST) were analyzed using the NanoString nCounter PanCancer Pathways Panel. The number of significantly differentially expressed genes in SN vs. MST, SN vs. AST, and AST vs. MST was 68, 167, and 18, respectively. Gene set enrichment analysis revealed upregulation of pathways related to epithelial–mesenchymal transition and immunomodulatory‐, angiogenesis‐, hormonal‐, and myogenesis‐associated processes in AST and MST. A molecular signature of SN vs. MST was discovered based on the top‐ranked most informative genes: NRAS, NF1, BMP2, EIF2B4, IFNA17, and FZD9. The AST samples showed intermediate levels of the identified signature. This implies that the gene signature can potentially be used to distinguish high‐grade from low‐grade AST with a larger study cohort in the future. This combined histopathological and transcriptomic methodology is promising for prospective diagnostics of Spitzoid neoplasms and patient management in dermatological oncology.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting in inverse body regions. In a systematic review, the role of hormones in HS will be presented to better understand the pathomechanisms of HS. The review is based on the PRISMA criteria. Systematic research was carried out using keywords. Subsequently, the data were analyzed based on the clinical response and other relevant information. The main focus of our systematic review was on HS manifestation, exacerbation, sex hormones, antiandrogen therapy, thyroid function, polycystic ovary syndrome, insulin resistance, and adipokines. In HS, there appears to be a dysregulated adipokine release that is shifted towards pro-inflammatory adipokines. Insulin resistance is significantly more common in HS than in healthy patients regardless of BMI, age, and gender. Insulin resistance in HS patients leads to further cardiovascular disease. The mechanism of insulin resistance and role of adipokines should be investigated in future studies to better provide the pathomechanisms of HS. The role of androgens seems to be important in a certain subgroup of female patients. Anti-androgenic therapy can be useful and helpful in some patients. However, further studies are needed to better understand the hormonal relationship in HS.

Hypereosinophilic syndrome (HES) is a complex multisystem disease characterized by sustained overproduction of eosinophils. A 40-year-old woman presented with digital ischemia and gangrene on her distal fingers and toes. We diagnosed HES on the basis of marked eosinophilia, accumulation of eosinophils in organs, and cutaneous eosinophilic vasculitis after having excluded all differential diagnoses. On digital subtraction angiography, occlusion of several arteries of both lower legs was noted. HES may be associated with severe vascular damage including gangrene. The occurrence of digital gangrene is a differential diagnostic challenge that should also include investigations of blood parameters, such as eosinophils.

The present review summarizes up-to-date evidence addressing the frequently discussed clinical controversies regarding the use of immune checkpoint inhibitors (ICIs) in cancer patients with viral infections, including AIDS, hepatitis B and C, progressive multifocal leukoencephalopathy, influenza, and COVID-19. In detail, we provide available information on (1) safety regarding the risk of new infections, (2) effects on the outcome of pre-existing infections, (3) whether immunosuppressive drugs used to treat ICI-related adverse events affect the risk of infection or virulence of pre-existing infections, (4) whether the use of vaccines in ICI-treated patients is considered safe, and (5) whether there are beneficial effects of ICIs that even qualify them as a therapeutic approach for these viral infections.

Abstract Background Paraneoplastic hyperleucocytosis (PH) is sporadically seen in patients with advanced solid tumors. Case presentation We report a female patient with disseminated melanoma metastases. Two days after the first dosage of combined immunotherapy using the cytotoxic T lymphocyte antigen-4 (CTLA-4) blocker ipilimumab and the programmed death receptor-1 (PD-1) blocker nivolumab the patient developed asymptomatic hyperleucocytosis (over 120.000 leucocytes per μl) associated with elevated granulocyte colony-stimulating factor blood levels. Hematological and infectious disorders could be ruled out. Although paraneoplastic hyperleucocytosis spontaneously resolved she died from progressive disease about 60 days after start of treatment. Conclusions PH is extremely rare in malignant melanoma, however, most patients who developed this complication had preceding immunotherapies such as interleukin-2. The latter observation and the fact that our patient developed PH rapidly after initiation of ipilimumab and nivolumab immunotherapy indicate an immune-mediated mechanism which may trigger PH under unknown circumstances. The development of paraneoplastic hyperleucocytosis indicates a very poor prognosis.

Background: Melanoma of unknown primary (MUP) is an uncommon clinical subtype of melanoma of known primary (MKP). Objectives: We aimed to compare treatment outcomes of MUP and MKP patients who had undergone therapy with immune checkpoint inhibitors (ICPI). Methods: We studied 41 metastatic melanoma patients (32 with MKP and 9 with MUP) with an indication for ICPI. Results: Clinical characteristics such as age, gender, stage of disease, etc., did not significantly differ (P < .05) between MUP and MKP patients. 20/32 (62.5%) melanoma-specific deaths (MSD) were observed in the MKP group, whereas 2/9 (22.2%) were detected in the MUP group (P = .035). On logistic regression, the MUP status proved to be an independent predictor for a more favorable outcome under immunotherapy when compared to MKP (P = .030). Conclusion: Our preliminary results indicate that MUP patients show better clinical outcome under ICPI when compared to MKP.

Abstract Background Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested. Case presentation We report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla. Extirpation of a lymph node conglomerate revealed 5 melanoma lymph node metastases. Computed tomography showed a liver metastasis (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c). Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after the first combination therapy he developed progressive erythema, paraesthesia and pain on the fingertips of both hands. Both cold and warmth was not well tolerated by the patient. Complete work-up excluded associated conditions or factors such as haematological disorders, rheumatologic disorders, hypertension, diabetes or smoking. Treatment was initiated with prostacyclin 20 μg twice daily and oral prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after the first applications because the pain increased during infusion. The second course of nivolumab and ipilimumab was administered. About 2 weeks later, the patient presented with increased pain and small subungual necrosis. We treated the patient with oral analgetics and intravenous prednisolone 500 mg in tapering dosage. On digital substraction angiography occlusion of all arteries of the fingers was demonstrated. Further rheologic and anti-melanoma treatments were refused by the patient. About 2 months after the second course of nivolumab and ipilimumab combination therapy several fingers showed severe gangrene which finally led to amputations of end phalanges of several fingers. Histopathology did not reveal evidence for vasculitis or other primary vascular pathologies. During the following 2 months the patient experienced dramatic progress of his metastatic disease and finally died at multi-organ failure. Conclusion Presence of rapidly progressive digital ischemia in an elderly patient with cancer should always raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. In patients treated with immune checkpoint inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been reported so far. However, it is debatable whether immune checkpoint blockade may play a pathogenetic role in the development of PAVS in patients with malignancies.

In this article we describe efficacy and safety aspects of ultraviolet A1 (UV-A1) phototherapy in fibrosing conditions. UV-A1 is a specific phototherapeutic modality that is defined by a selective spectral range (340–400 nm). UV-A1 includes distinct modes of action qualifying this method for therapy of a variety of conditions, in particular fibrosing skin diseases. Concerning efficacy of UV-A1 phototherapy in fibrosing conditions, the best evidence obtained from randomized controlled trials exists for localized scleroderma. Moreover, fibrosing disorders such as lichen sclerosus and graft-vs.-host disease can be treated successfully by means of UV- A1. Regarding the optimal dosage regimen medium-dose UV-A1 seems to be linked to the best benefit/risk ratio. Possible acute adverse events of UV-A1 phototherapy include erythema and provocation of photodermatoses. Skin ageing and skin cancer formation belong to the chronic adverse events that may occur after long-term UV-A1 phototherapy.

We describe emergomycosis in a patient in Uganda with HIV infection. We tested a formalin-fixed, paraffin-embedded skin biopsy to identify Emergomyces pasteurianus or a closely related pathogen by sequencing broad-range fungal PCR amplicons. Results suggest that emergomycosis is more widespread and genetically diverse than previously documented. PCR on tissue blocks may help clarify emergomycosis epidemiology.