Myofibroblast stroma differentiation in infiltrative basal cell carcinoma is accompanied by regulatory T-cells.

INTRODUCTION: The implications of infiltrative compared to non-infiltrative growth of cutaneous basal cell carcinoma (BCC) on the tumor stroma and immune cell landscape are unknown. This is of clinical importance, because infiltrative BCCs, in contrast to other BCC subtypes, are more likely to relapse after surgery and radiotherapy. MATERIALS AND METHODS: This descriptive cross-sectional study analyzed 38 BCCs collected from 2018 to 2021. In the first cohort (n = 28), immune cells were characterized by immunohistochemistry and multiplex immunofluorescence staining for CD3, CD8, CD68, Foxp3, and α-SMA protein expression. In the second cohort (n = 10) with matched characteristics (age, sex, location, and BCC subtype), inflammatory parameters, including TGF-ß1, TGF-ß2, ACTA2, IL-10, IL-12A, and Foxp3, were quantified via RT-qPCR after isolating mRNA from BCC tissue samples and perilesional skin. RESULTS: Infiltrative BCCs showed significantly increased levels of α-SMA expression in fibroblasts (p = 0.0001) and higher levels of Foxp3+ (p = 0.0023) and CD3+ (p = 0.0443) T-cells compared to non-infiltrative BCCs. CD3+ (p = 0.0171) and regulatory T-cells (p = 0.0026) were significantly increased in α-SMA-positive tumor stroma, whereas CD8+ T-cells (p = 0.1329) and CD68+ myeloid cells (p = 0.2337) were not affected. TGF-ß1 and TGF-ß2 correlated significantly with ACTA2/α-SMA mRNA expression (p = 0.020, p = 0.005). CONCLUSION: Infiltrative growth of BCCs shows a myofibroblastic stroma differentiation and is accompanied by an immunosuppressive tumor microenvironment.

Diagnostic difficulties in pediatric annular dermatoses.

The polymorphic presentation of annular dermatoses in the pediatric population renders them a diagnostic challenge to the clinician. They include various distinct disease entities that can be vaguely categorized according to the age of onset. Herein, we report on a young girl with clinical characteristics of Wells' syndrome, while histological findings favored the diagnosis of annular erythema of infancy (AEI). Although morphological and histological similarities do exist, AEI and eosinophilic annular erythema (EAE) of childhood are considered as distinct entities in the literature. Wells' syndrome (WS) is an eosinophilic dermatosis and histologically characterized by eosinophilic dermal infiltration with the hallmark feature of "flame figures." Based on this case, we discuss and review the differential diagnoses of annular dermatoses in children.

BMP7 aberrantly induced in the psoriatic epidermis instructs inflammation-associated Langerhans cells.

BACKGROUND: Epidermal hyperplasia represents a morphologic hallmark of psoriatic skin lesions. Langerhans cells (LCs) in the psoriatic epidermis engage with keratinocytes (KCs) in tight physical interactions; moreover, they induce T-cell-mediated immune responses critical to psoriasis. OBJECTIVE: This study sought to improve the understanding of epidermal factors in psoriasis pathogenesis. METHODS: BMP7-LCs versus TGF-ß1-LCs were phenotypically characterized and their functional properties were analyzed using flow cytometry, cell kinetic studies, co-culture with CD4 T cells, and cytokine measurements. Furthermore, immunohistology of healthy and psoriatic skin was performed. Additionally, in vivo experiments with Junf/fJunBf/fK5cre-ERT mice were carried out to assess the role of bone morphogenetic protein (BMP) signaling in psoriatic skin inflammation. RESULTS: This study identified a KC-derived signal (ie, BMP signaling) to promote epidermal changes in psoriasis. Whereas BMP7 is strictly confined to the basal KC layer in the healthy skin, it is expressed at high levels throughout the lesional psoriatic epidermis. BMP7 instructs precursor cells to differentiate into LCs that phenotypically resemble psoriatic LCs. These BMP7-LCs exhibit proliferative activity and increased sensitivity to bacterial stimulation. Moreover, aberrant high BMP signaling in the lesional epidermis is mediated by a KC intrinsic mechanism, as suggested from murine data and clinical outcome after topical antipsoriatic treatment in human patients. CONCLUSIONS: These data indicate that available TGF-ß family members within the lesional psoriatic epidermis preferentially signal through the canonical BMP signaling cascade to instruct inflammatory-type LCs and to promote psoriatic epidermal changes. Targeting BMP signaling might allow to therapeutically interfere with cutaneous psoriatic manifestations.

[Eosinophilic annular erythema in a 20-month-old girl]. / Eosinophiles anuläres Erythem bei einem 20 Monate alten Mädchen.

We report on a 20-month-old girl with urticarial and partially annular skin lesions that were disseminated over the whole integument. The lesions persisted over 1 week and then gradually faded and reappeared on new body sites. The histological examination of a skin biopsy revealed an urticarial inflammation pattern with interstitial edema and a diffuse infiltration with many eosinophilic granulocytes without flame figures, neutrophils and lymphocytes. Laboratory investigations were inconspicuous and there was no eosinophilia. A diagnosis of eosinophilic annular erythema (EAE) of childhood was made which is a benign self-limiting skin disorder belonging to the group of eosinophilic dermatoses.

Mycosis fungoides and Sézary syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS) are primary cutaneous T-cell lymphomas (CTCL) with not yet fully understood etiology and pathogenesis. Conceptually, MF and SS are classified as distinct entities arising from different T helper cell subsets. MF is the most common CTCL entity, while SS is very rare. MF presents clinically with patch, plaque and/or tumor stages, but can also evolve as erythroderma, which in turn is pathognomonic for SS. SS is characterized by a detectable tumor-cell burden (Sézary cells) in the peripheral blood consistent with advanced-stage disease and a poor prognosis. In early-stage disease of MF, which is the predominant form, the prognosis is generally favorable. However, in up to 30 % of patients, there is progression of skin lesions, which can ultimately lead to visceral involvement. The histological manifestation of MF can be subtle in early-stage disease and therefore a careful clinicopathological correlation is paramount. The treatment of MF/SS is dependent on the disease stage. Therapeutic options include both skin-directed and systemic regimens. Apart from allogeneic stem cell transplantation (alloSCT), there is as yet no curative therapy for MF/SS. Accordingly, the treatment approach is symptom oriented and aims to reduce the tumor burden and improve health-related quality of life. However, the therapeutic landscape for CTCL is constantly being expanded by the discovery of novel therapeutic targets.

Regulation of the Immune Cell Repertoire in Psoriasis Patients Upon Blockade of IL-17A or TNFα.

INTRODUCTION: Targeting of the proinflammatory cytokine interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with the monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, is a successful therapy for chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown. METHODS: In this study, we compared the composition of cutaneous, lesional and non-lesional immune cells and blood immune cells in ixekizumab- or adalimumab-treated patients with psoriasis. RESULTS: Our data reveal that both treatments efficiently downregulate T cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to the skin of healthy subjects. Treatment with neither ixekizumab nor adalimumab reversed this DC imbalance in non-lesional skin of psoriatic patients. CONCLUSION: Our study shows that anti-IL-17A and anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients but fails to restore the disturbed immune cell repertoire in non-lesional skin.

Comparison of humans versus mobile phone-powered artificial intelligence for the diagnosis and management of pigmented skin cancer in secondary care: a multicentre, prospective, diagnostic, clinical trial.

BACKGROUND: Diagnosis of skin cancer requires medical expertise, which is scarce. Mobile phone-powered artificial intelligence (AI) could aid diagnosis, but it is unclear how this technology performs in a clinical scenario. Our primary aim was to test in the clinic whether there was equivalence between AI algorithms and clinicians for the diagnosis and management of pigmented skin lesions. METHODS: In this multicentre, prospective, diagnostic, clinical trial, we included specialist and novice clinicians and patients from two tertiary referral centres in Australia and Austria. Specialists had a specialist medical qualification related to diagnosing and managing pigmented skin lesions, whereas novices were dermatology junior doctors or registrars in trainee positions who had experience in examining and managing these lesions. Eligible patients were aged 18-99 years and had a modified Fitzpatrick I-III skin type; those in the diagnostic trial were undergoing routine excision or biopsy of one or more suspicious pigmented skin lesions bigger than 3 mm in the longest diameter, and those in the management trial had baseline total-body photographs taken within 1-4 years. We used two mobile phone-powered AI instruments incorporating a simple optical attachment: a new 7-class AI algorithm and the International Skin Imaging Collaboration (ISIC) AI algorithm, which was previously tested in a large online reader study. The reference standard for excised lesions in the diagnostic trial was histopathological examination; in the management trial, the reference standard was a descending hierarchy based on histopathological examination, comparison of baseline total-body photographs, digital monitoring, and telediagnosis. The main outcome of this study was to compare the accuracy of expert and novice diagnostic and management decisions with the two AI instruments. Possible decisions in the management trial were dismissal, biopsy, or 3-month monitoring. Decisions to monitor were considered equivalent to dismissal (scenario A) or biopsy of malignant lesions (scenario B). The trial was registered at the Australian New Zealand Clinical Trials Registry ACTRN12620000695909 (Universal trial number U1111-1251-8995). FINDINGS: The diagnostic study included 172 suspicious pigmented lesions (84 malignant) from 124 patients and the management study included 5696 pigmented lesions (18 malignant) from the whole body of 66 high-risk patients. The diagnoses of the 7-class AI algorithm were equivalent to the specialists' diagnoses (absolute accuracy difference 1·2% [95% CI -6·9 to 9·2]) and significantly superior to the novices' ones (21·5% [13·1 to 30·0]). The diagnoses of the ISIC AI algorithm were significantly inferior to the specialists' diagnoses (-11·6% [-20·3 to -3·0]) but significantly superior to the novices' ones (8·7% [-0·5 to 18·0]). The best 7-class management AI was significantly inferior to specialists' management (absolute accuracy difference in correct management decision -0·5% [95% CI -0·7 to -0·2] in scenario A and -0·4% [-0·8 to -0·05] in scenario B). Compared with the novices' management, the 7-class management AI was significantly inferior (-0·4% [-0·6 to -0·2]) in scenario A but significantly superior (0·4% [0·0 to 0·9]) in scenario B. INTERPRETATION: The mobile phone-powered AI technology is simple, practical, and accurate for the diagnosis of suspicious pigmented skin cancer in patients presenting to a specialist setting, although its usage for management decisions requires more careful execution. An AI algorithm that was superior in experimental studies was significantly inferior to specialists in a real-world scenario, suggesting that caution is needed when extrapolating results of experimental studies to clinical practice. FUNDING: MetaOptima Technology.

Prognostic value of indeterminate IFN-γ release assay results in HIV-1 infection.

In this prospective, longitudinal study on 948 HIV-1-infected patients, subjects with an indeterminate IFN-γ (gamma interferon) release assay (IGRA) result at baseline were at significantly higher risk of developing AIDS-defining manifestations other than tuberculosis (TB) irrespective of CD4(+) T cell count. Thus, in HIV-1-infected patients with advanced quantitative CD4(+) T cell depletion, an indeterminate IGRA might indicate an additional loss of global T cell function, warranting detailed clinical evaluation and careful follow-up.

Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma release assay in HIV-1-infected individuals.

BACKGROUND: The sensitivity of whole-blood interferon-gamma release assays to detect or predict active tuberculosis in individuals infected with human immunodeficiency virus type 1 (HIV-1) has as yet not been determined. Methods. In this prospective, longitudinal, single-center study, 830 HIV-1-infected patients underwent testing with the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay. Clinical screening for active tuberculosis was performed at least every 3 months for a median follow-up time of 19 months. RESULTS: At baseline, the QFT-GIT assay yielded positive or indeterminate results in 44 (5.3%) and 47 (5.7%) of the 830 patients, respectively. A positive QFT-GIT assay result occurred at significantly higher frequencies among black individuals than among white individuals (odds ratio, 4.84; 95% confidence interval, 2.25-9.97; P< .001), among patients from Africa than among patients from Austria (odds ratio, 6.57; 95% confidence interval, 2.99-14.25; P< .001), and among patients from high-prevalence countries than among patients from low-prevalence countries (odds ratio, 5.86; 95% confidence interval, 2.41-13.44; P< .001). In patients with indeterminate QFT-GIT assay results, both median actual and nadir CD4(+) T cell counts were significantly lower than in patients with interpretable QFT-GIT assay results (P< .001). At the time of baseline QFT-GIT screening, active tuberculosis was found in 7 (15.9%) of 44 individuals with a positive result and in 1 (0.1%) of 739 patients with a negative result. During the follow-up period, however, progression to active tuberculosis occurred exclusively in patients with a positive QFT-GIT assay result, at a rate of 8.1% (3 of 37 patients; P< .001). Collectively, the sensitivity of the QFT-GIT assay for active tuberculosis was 90.9% (95% confidence interval, 62.3%-98.4%). CONCLUSIONS: Our results suggest that the QFT-GIT assay may be a sensitive tool for the detection and prediction of active tuberculosis in HIV-1-infected individuals.

Enhanced therapy for primary and secondary syphilis: a longitudinal retrospective analysis of cure rates and associated factors.

For the treatment of early infectious syphilis, enhanced therapy with three dosages of benzathine penicillin G has been under consideration, particularly in the human immunodeficiency virus type 1 infected population (HIV-1). The serological outcome of 249 patients with primary and secondary syphilis treated with standard or enhanced therapy was analyzed retrospectively; 98% (139/142) achieved serological cure with a single dosage and 92% with enhanced therapy (P=0.033). In HIV-1 infected individuals, cure rates were 88% after a single dosage compared to 97% after three dosages (P=0.18). A fourfold decrease of Venereal Disease Research Laboratory (VDRL) titres was achieved within a median of 102 days after treatment initiation (SD=2; 95% CI=98-106). Patients aged over 40 years were 5.5 times (OR=5.52; 95% CI=1.43-21.32; P=0.013) and patients with low baseline VDRL titres (≤ 1:32) were 4 times (OR=4.25; 95% CI=1.21-14.87; P=0.024) more likely to experience serological failure.