Functionally distinct cancer-associated fibroblast subpopulations establish a tumor promoting environment in squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis (AK), a precancerous lesion, or the in situ carcinoma, Bowen's disease (BD). During this progression, malignant keratinocytes activate dermal fibroblasts into tumor promoting cancer-associated fibroblasts (CAFs), whose origin and emergence remain largely unknown. Here, we generate and analyze >115,000 single-cell transcriptomes from healthy skin, BD and cSCC of male donors. Our results reveal immunoregulatory and matrix-remodeling CAF subtypes that may derive from pro-inflammatory and mesenchymal fibroblasts, respectively. These CAF subtypes are largely absent in AK and interact with different cell types to establish a pro-tumorigenic microenvironment. These findings are cSCC-specific and could not be recapitulated in basal cell carcinomas. Our study provides important insights into the potential origin and functionalities of dermal CAFs that will be highly beneficial for the specific targeting of the cSCC microenvironment.

Subcutaneous panniculitis-like T-cell lymphoma: brief review and report of successful treatment with mycophenolate mofetil.

Subcutaneous panniculitis-like T-cell lymphoma is a rare, indolent cutaneous cytotoxic alpha-beta T-cell lymphoma, where no specific therapy regimen is defined. We present a case with a diagnostically challenging association with anti-double stranded DNA and provides one of the first reports of a successful treatment with mycophenolate mofetil and glucocorticosteroids.

[Cutaneous pseudolymphoma after hirudotherapy : Case report and review]. / Kutane Pseudolymphome nach Hirudotherapie : Fallbericht und Literaturübersicht.

The term cutaneous pseudolymphoma (C-PSL) is defined in the literature as a benign, reactive lymphoproliferation that clinically and/or histopathologically imitates cutaneous lymphoma. The exact etiopathogenesis has not been fully elucidated to date. A distinction is made between primary, idiopathic PSL without an identifiable cause and secondary PSL with a known stimulus. We report the occurrence of pseudolymphoma after treatment with medicinal leeches (hirudotherapy). To the best of our knowledge, a total of only nine cases of cutaneous PSL after hirudotherapy have been reported in the literature to date.

Detailed Long-term Dynamics of Neutrophil-to-Lymphocyte Ratio under Biologic Treatment Reveals Differential Effects of Tumour Necrosis Factor-alpha and Interleukin 12/23 Antagonists.

Psoriasis is thought to be associated with a reduced life expectancy through systemic inflammation. A comparative, retrospective analysis of neutrophil-to-lympho-cyte ratio, a biomarker of systemic inflammation and cardiovascular risk, under 196 treatments with tumour necrosis factor-α and interleukin-12/23 antagonists was performed. Neutrophil-to-lympho-cyte ratio decreased significantly within 3 months of initiation of treatment and remained stable at reduced levels for at least 33 months. Dynamics were more pronounced and neutrophil-to-lympho-cyte ratio under treatment was lower in patients treated with tumour necrosis factor-α compared with interleukin-12/23 antagonists (geometric mean (95% confidence interval): 2.03 (1.9, 2.1) vs 2.63 (2.2, 3.2), respectively, p = 0.014). tumour necrosis factor-α antagonist treatment and baseline neutrophil-to-lympho-cyte ratio were independent predictors of a median low cardiovascular risk neutrophil-to-lympho-cyte ratio (< 2.15) during treatment (odds ratio (95% confidence interval): 0.53 (0.4-0.8) and 4.68 (1.0-19.1), p = 0.001 and p = 0.032, respectively). These results demonstrate a rapid and sustained reduction in biomarkers of systemic inflammation under biologic treatment. Furthermore, these data suggest class-specific effects on systemic inflammation, which may be relevant for the prevention of psoriasis co-morbidity by systemic treatment.

Real-Time Detection of Tumor Cells during Capture on a Filter Element Significantly Enhancing Detection Rate.

Circulating tumor cells (CTCs) that enter the bloodstream play an important role in the formation of metastases. The prognostic significance of CTCs as biomarkers obtained from liquid biopsies is intensively investigated and requires accurate methods for quantification. The purpose of this study was the capture of CTCs on an optically accessible surface for real-time quantification. A filtration device was fabricated from a transparent material so that capturing of cells could be observed microscopically. Blood samples were spiked with stained tumor cells and the sample was filtrated using a porous structure with pore sizes of 7.4 µm. The possible removal of lysed erythrocytes and the retention of CTCs were assessed. The filtration process was observed in real-time using fluorescence microscopy, whereby arriving cells were counted in order to determine the number of CTCs present in the blood. Through optimization of the microfluidic channel design, the cell retention rate could be increased by 13% (from 76% ± 7% to 89% ± 5%). Providing the possibility for real-time detection significantly improved quantification efficiency even for the smallest cells evaluated. While end-point evaluation resulted in a detection rate of 63% ± 3% of the spiked cells, real-time evaluation led to an increase of 21% to 84% ± 4%. The established protocol provides an advantageous and efficient method for integration of fully automated sample preparation and CTC quantification into a lab-on-a-chip system.

Evaluation of Psoriasis Area and Severity Index as a Proxy for Bio-markers of Systemic Disease under Treatment with Tumour Necrosis Factor-alpha and Interleukin 12/23 Antagonists in Patients with Psoriasis: A Retrospective Cohort Study of 186 Treatment Cycles.

The efficacy of psoriasis treatments is usually evaluated using the Psoriasis Area and Severity Index (PASI). However, there is a lack of systematic statistical assessments of PASI as a proxy for systemic disease in individual patients. Therefore, a retrospective study of 186 treat-ments with adalimumab, etanercept, and ustekinumab for psoriasis (341 patient-years) was performed. While PASI significantly and independently correlated with biomarkers of systemic inflammation (especially neutrophil-to-lymphocyte ratio, C-reactive protein), the strengths were only weak-to-moderate and varied considerably inter-individually. A decrease in PASI indicated a neutrophil-to-lymphocyte ratio decrease and a C-reactive protein decrease or stable low margin C-reactive protein in ≥ 80%. Sensitivity, specificity, and positive predictive value of PASI 0 and PASI 2.75 (optimal Youden Index) for low cardiovascular risk C-reactive protein were 24%, 92%, 85%, and 62%, 61%, 76%, respectively. Performance was similar using absolute thresholds and PASI 100 or PASI 75, and overall worse for low cardiovascular risk neutrophil-to-lympho-cyte ratio and if psoriasis arthritis was present. In conclusion, PASI allows robust low-order estimates of systemic inflammation, but cannot substitute for laboratory biomarkers for more precise assessments.

Long-term safety of combination treatment with methotrexate and tumor necrosis factor (TNF)-α antagonists versus TNF-α antagonists alone in psoriatic patients.

Methotrexate, a folic acid analog, is the conventional systemic anti-psoriatic agent most commonly chosen for combination with biologics in the treatment of psoriasis. Real-world long-term safety data of this combination versus biologic treatment alone in dermatological practice are sparse. Here, we present results of a comparative retrospective study of laboratory dynamics and adverse events in psoriatic patients receiving a tumor necrosis factor (TNF)-α antagonist (adalimumab or etanercept) with and without concomitant methotrexate (176 treatment courses, mean duration of 629 days). Co-treatment with methotrexate significantly (P < 0.05) correlated with a decrease of leukocyte, neutrophil and erythrocyte counts and an increase of glutamate pyruvate transaminase (GPT) (Pearson correlation, n > 148). The relative risk for a Common Terminology Criteria for Adverse Events (CTCAE) grade 1-2 laboratory adverse event was significantly elevated to 1.11 for anemia and 1.16 for a GPT increase if the patients received concomitant methotrexate at the time the laboratory test was performed. Combination treatment was given for equal or more than 30% of the time (MTX≥30% ) during 12% of the treatment courses. During these treatment courses, dynamics of leukocyte (-8.1%), neutrophil (-8.1%), erythrocyte (-3.2%) counts and GPT (+16.9%) from baseline to average under treatment were significantly more pronounced. CTCAE grade 3-4 laboratory adverse events occurred in 9.5% and 5.2% of treatment courses with and without MTX≥30% , respectively (p = 0.70), and affected transaminases in 90% of the cases. Methotrexate was discontinued due to CTCAE grade 3-4 laboratory adverse events in 4.25% of the treatment courses with MTX of 30% or more. Elevated baseline γ-glutamyl transferase levels significantly predicted the occurrence of CTCAE grade 3-4 laboratory adverse events and should trigger investigations for pre-existing liver disease or alcohol abuse. In conclusion, our comparative data supplement previous short-term studies and support a tolerable long-term safety profile of the combination treatment. However, given the additional toxicities and low evidence for benefits, alternative options such as biologic monotherapy or switching to a different biologic should be considered in a dermatological setting.

Scleromyxedema.

Scleromyxedema is a rare, cutaneous deposition disorder from the group of mucinoses, which can affect multiple organs and is virtually always associated with a monoclonal gammopathy. Cutaneous manifestations are usually generalized, 2 to 3 mm sized, dome-shaped or flat-topped, waxy, slightly red to skin-colored papules and sclerodermoid indurations. Neurological, rheumatological, cardiovascular, gastrointestinal, respiratory tract, renal and ophthalmologic manifestations can occur, with decreasing frequency. A serious and potentially lethal complication is the dermato-neuro syndrome which manifests with flu-like prodromes followed by fever, convulsions and coma. Untreated, scleromyxedema usually takes an unpredictable and potentially lethal progressive disease course over several years. According to a widely acknowledged classification by Rongioletti a diagnosis of scleromyxedema can be rendered when (1) generalized, papular and sclerodermoid eruption, (2) a histological triad of mucin deposition, fibroblast proliferation and fibrosis, and (3) monoclonal gammopathy are present, and (4) thyroid disease is absent. Apart from the classic microscopic triad, an interstitial granuloma annulare like pattern was also described. The pathogenesis of scleromyxedema is unknown. A potential role for various, as yet unknown serum factors has been discussed. An unequivocal causal relationship between paraproteinemia and disease manifestations could not be established to date. High dose intravenous immunoglobulins (IVIg) are the first-line treatment of choice according to the most recent European guidelines.

High-Dose Intravenous Immunoglobulin in Skin Autoimmune Disease.

The immunomodulatory potential and low incidence of severe side effects of high-dose intravenous immunoglobulin (IVIg) treatment led to its successful application in a variety of dermatological autoimmune diseases over the last two decades. IVIg is usually administered at a dose of 2 g per kg body weight distributed over 2-5 days every 4 weeks. They are most commonly used as a second- or third-line treatment in dermatological autoimmune disease (pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatomyositis, systemic vasculitis, and systemic lupus erythematosus). However, first-line treatment may be warranted in special circumstances like concomitant malignancy, a foudroyant clinical course, and contraindications against alternative treatments. Furthermore, IVIg can be considered first line in scleromyxedema. Production of IVIg for medical use is strictly regulated to ensure a low risk of pathogen transmission and comparable quality of individual batches. More common side effects include nausea, headache, fatigue, and febrile infusion reactions. Serious side effects are rare and include thrombosis and embolism, pulmonary edema, renal failure, aseptic meningitis, and severe anaphylactic reactions. Regarding the mechanism of action, one can discriminate between functions of the Fcγ region and the F(ab)2 region and their effects on a cellular level. These functions are not mutually exclusive, and more than one pathway may contribute to the beneficial effects. Here, we present a historical background, details on manufacturing, hypotheses on the mechanisms of action, information on the clinical application in the abovementioned conditions, and a brief outlook on future directions of IVIg treatment in dermatology.

[Diffuse plane xanthomas associated with mycosis fungoides]. / Diffuse plane Xanthome bei Mycosis fungoides.

Cutaneous xanthomas may develop in patients with lipid abnormalities, chronic inflammatory diseases or cancer. Especially myeloproliferative diseases may be accompanied by dystrophic xanthomas. We report on a normolipemic patient with cutaneous xanthomas who was subsequently diagnosed with mycosis fungoides. In addition to illustrative clinical and histopathological images, we present an overview of reports on dystrophic xanthomas in mycosis fungoides, the most frequent cutaneous T­cell lymphoma.

Routine Laboratory Parameter Dynamics and Laboratory Adverse Events in Psoriasis Patients on Long-term Treatment with Adalimumab, Etanercept, and Ustekinumab.

Only limited data on laboratory parameter dynamics and safety under prolonged biologic treatment in a "real-world" scenario are available for recommendations on screening and monitoring. This study is a retrospective analysis of routine parameter dynamics and laboratory adverse events (LAE) in psoriasis patients on long-term treatment (n = 199) with tumour necrosis factor (TNF)-α-antagonists (adalimumab, etanercept), and the interleukin (IL)12/23-antagonist ustekinumab. Overall, neutrophil (PMN) counts (-11%) and triglycerides (+9%) changed considerably. TNF-α-antagonists and ustekinumab differentially affected lymphocyte counts (+13% and ±0%, respectively). Dynamics were pronounced during the first 180 days of treatment. In 340 treatment-years, 15 Common Terminology Criteria for Adverse Events (CTCAE) III-IV° LAE were recorded (11 involved liver enzymes). They prompted alteration of the biologic regime in only 2 cases. Age, sex, previous systemic treatments, and psoriatic arthritis did not significantly predict LAE. Liver enzyme and triglyceride screening may be warranted in some instances. Our data suggest that unguided monitoring of other routine laboratory parameters is unnecessary under long-term biologic treatment.

Evaluating blood levels of neuron specific enolase, chromogranin A, and circulating tumor cells as Merkel cell carcinoma biomarkers.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Although used to monitor MCC patients, the clinical utility of neuron-specific enolase (NSE) and chromogranin A (ChrA) blood levels is untested. EpCAM-positive circulating tumor cells (CTC) reflect disease status in several epithelial tumors. Here we investigate the use of NSE and ChrA blood levels and CTC counts as biomarkers for MCC disease behavior. METHODS: NSE and ChrA blood levels from 60 patients with MCC were retrospectively analyzed; 30 patients were additionally screened for CTC. Biomarker values were correlated to clinical parameters. RESULTS: Despite routine use by some physicians, NSE and ChrA blood levels did not correlate with progression free survival, disease specific survival, or MCC recurrence. We found CTC in 97% of tested MCC patients. CTC counts were elevated in patients with active disease, suggesting their potential use in monitoring MCC. CONCLUSIONS: NSE and ChrA levels were not effective in predicting outcomes or detecting recurrences of MCC. In contrast, CTC counts have potential utility as a biomarker for MCC disease behavior.

Linear IgA Bullous Dermatosis Secondary to Infliximab Therapy in a Patient with Ulcerative Colitis.

Linear IgA bullous disease (LABD) is a rare vesiculobullous autoimmune skin disorder whose etiology and pathogenesis are not completely understood. Its occurrence has been related to malignancies, inflammatory diseases and several drugs. This report describes a 49-year-old Caucasian male with a 14-year history of ulcerative colitis who received infliximab to treat the refractory course of his bowel disease. During induction therapy with infliximab, he developed LABD. Treatment with infliximab was discontinued, and the skin lesions were successfully treated with oral steroids and dapsone. Considering the close chronological relation between administration of the tumor necrosis factor-α inhibitor and onset of the skin disease, we hypothesize that this is the first reported case of infliximab-induced LABD. Similar to psoriasis, it may represent a 'paradoxical' autoimmune reaction triggered by anti-tumor necrosis factor-α therapy.

Baseline anti-dsDNA concentrations and previous treatments predict response to Adalimumab and Etanercept: a retrospective investigation of 146 psoriasis patients.

BACKGROUND: Adalimumab and Etanercept are TNF-α antagonists commonly used for treatment of moderate-to-severe psoriasis and psoriatic-arthritis. Reliable instruments to assist the selection of patients for a specific treatment in a real-world scenario are unavailable. OBJECTIVE: To identify patient characteristics and baseline laboratory parameters predicting response to Adalimumab- and Etanercept-treatment. METHODS: We report a retrospective observational study including 116 and 64 psoriasis-patients treated with Adalimumab and Etanercept, respectively, at a dermatological outpatient clinic of a university hospital. Thirty four patients contributed data to both biologics. First occurrence of either loss-of-response or serious-side-effects (LOR/SSE) was chosen as clinical endpoint and predictors were identified using Cox-regression. RESULTS: Baseline anti-double-stranded DNA (anti-dsDNA) concentrations, number of previous treatments with TNF-α antagonists in general and previous treatment with Etanercept in particular significantly predicted LOR/SSE to Adalimumab. The predictive effect of baseline anti-dsDNA was conserved in TNF-α antagonist naïve patients. Number of previous systemic treatments other than TNF-α antagonists significantly predicted LOR/SSE to Etanercept. Age and baseline psoriasis area and severity index (PASI) did not predict response to either biologic in a clinically significant manner. CONCLUSION: Our data suggests that treatment with Adalimumab may promise best results in psoriasis-patients with (A) low baseline anti-dsDNA concentrations, and (B) no previous TNF-α antagonist treatment. A clinically significant predictive effect of age and baseline PASI on response to Adalimumab and Etanercept is unlikely.