NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis.

Natural killer (NK) cells are innate lymphoid cells, and their presence within human tumors correlates with better prognosis. However, the mechanisms by which NK cells control tumors in vivo are unclear. Here, we used reflectance confocal microscopy (RCM) imaging in humans and in mice to visualize tumor architecture in vivo. We demonstrated that signaling via the NK cell receptor NKp46 (human) and Ncr1 (mouse) induced interferon-γ (IFN-γ) secretion from intratumoral NK cells. NKp46- and Ncr1-mediated IFN-γ production led to the increased expression of the extracellular matrix protein fibronectin 1 (FN1) in the tumors, which altered primary tumor architecture and resulted in decreased metastases formation. Injection of IFN-γ into tumor-bearing mice or transgenic overexpression of Ncr1 in NK cells in mice resulted in decreased metastasis formation. Thus, we have defined a mechanism of NK cell-mediated control of metastases in vivo that may help develop NK cell-dependent cancer therapies.

Isolated solar angioedema: A systematic review of the literature.

Solar urticaria is a well-recognized photodermatosis, sometimes accompanied by angioedema. However, isolated solar angioedema (ISA) is a rare and unrecognized entity. The purpose of our work was to systematically review the available data on ISA. Therefore, a systematic review of studies evaluating ISA was performed. Additionally, a case of a 21-years-old patient from our photodermatosis service is presented. The search yielded 421 publications, with 3 eligible for review. Together with our case, 5 cases were included overall. All patients were female. Four out of 5 patients first experienced ISA at childhood or early adulthood (age range 6-22 years). UVA photoprovocation was positive in the 3 out of the 4 patients who were tested. Improvement was noted following NB-UVB hardening (2 out of 5 patients) or a short course of oral prednisone (3 out of 5 patients) combined with regular sunscreen application. To conclude, ISA is an extremely rare entity, although it may be underdiagnosed due to lack of awareness. The clinician must consider ISA in the differential diagnosis of angioedema since it can have a detrimental effect on quality of life. Besides sun avoidance, there is no consensus regarding treatment.

Self-administered daylight-activated photodynamic therapy for the treatment of hand eczema: A prospective proof-of-concept study.

Photodynamic therapy (PDT), traditionally used in patients with nonmelanoma skin cancer, has been found to be effective for various inflammatory skin conditions. Daylight-activated PDT (DL-PDT), in which the sun serves as the light source, is substantially less painful than conventional PDT. This study aimed to determine the safety and efficacy of DL-PDT in a series of patients with chronic hand eczema (CHE). A proof-of-concept prospective design was used. Eight patients diagnosed with CHE at a tertiary dermatology clinic underwent DL-PDT. The first treatment was administered at the clinic and subsequent treatments (up to four total) were self-administered at home at 2-week intervals. Outcome was evaluated with the Investigator Global Assessment (IGA; score 0-4), Dermatology Life Quality Index (DLQI; score 0-24), and blinded review of clinical photographs (graded on a quartile scale by percent improvement). There were six male and two female patients of mean age 35 years. All underwent at least three treatments. The IGA score improved by 2.5 points at 1 month, 2.7 at 3 months, and 2.2 at 6 months post-treatment, and the DLQI score improved by 7.9, 6.6, and 6.1 points, respectively. Clinical photograph grades improved by 2.9 points at 3 months. Side effects were mild and transient. All patients had some degree of recurrence after 6 months of treatment. The self-administered DL-PDT is easy to perform, moderately effective, and safe to use in patients with CHE. Repeated treatments might be required to maintain remission.

Daylight photodynamic therapy for the treatment of actinic cheilitis.

BACKGROUND: Actinic cheilitis (AC) is a common, chronic premalignant condition resulting from protracted sun exposure affecting the vermilion border of the lower lip. Treatment of AC aims at terminating the progression to squamous cell carcinoma by obliterating the primary lesion, and includes ablative methods; nonablative modalities such as cryotherapy, electrodessication, chemical peeling, topical imiquimod and 5-fluorouracil; and photodynamic therapy (PDT). Daylight-activated PDT, in which natural daylight serves as the light source, showed promising results in the treatment of actinic keratoses with substantially less pain than conventional PDT. PURPOSE: To determine the safety and efficacy of daylight PDT in a series of patients with AC. METHODS: Eleven patients with AC were treated with daylight PDT. All patients underwent repeated treatment sessions until clinical and histological remission were achieved. RESULTS: Cure rate was 91% (10 of 11 patients, three females/eight males; mean age 59.2 ± 14.4 years). Mean number of treatments to attain cure was 2.7. Patients experienced mild erythema and minimal to no pain during treatment. CONCLUSIONS: Daylight PDT is a promising modality for the treatment of AC, with impressive cosmetic results and few side effects.

Palmar Telangiectasias: A Cutaneous Sign for Smoking.

BACKGROUND: Telangiectasias are permanent dilations of blood capillaries which appear in a variety of medical conditions. Cutaneous palmar telangiectasias have been postulated to be associated with smoking. OBJECTIVE: To determine whether a significant correlation exists between palmar telangiectasias and smoking habits. PATIENTS AND METHODS: A total of 124 volunteers participated in this observational study by allowing physical evaluation of their palms and by completing a questionnaire. RESULTS: Palmar telangiectasias were found to be associated with current or past smoking. Neither age nor gender was found to be a co-contributor. DISCUSSION: Palmar telangiectasias were found to constitute highly specific and sensitive markers for prolonged smoking.

Combined pulsed dye and CO2 lasers in the treatment of angiolymphoid hyperplasia with eosinophilia.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon dermatosis of unknown etiology that manifests as characteristic red nodules and papules with a predilection for the scalp and periauricular region. Treatment is required for both esthetic and functional reasons, as lesions may ulcerate and bleed. Many treatment approaches have been reported, including excision, systemic medical approaches, topical or intralesional therapies, and non-invasive modalities including cryotherapy, electrosurgery, and laser. Treatments have exhibited variable efficacy, and the recurrence rate is 100 %. We report the combination of pulsed dye laser and CO2 laser in the treatment of ALHE in 14 patients. All patients exhibited clinical response after a mean of 2.4 ± 0.4 treatment sessions. The clinical efficacy of the combined treatment, together with its well-tolerated nature, render the use of pulsed dye laser in combination with CO2 laser, a viable treatment for debulking ALHE lesions. Ongoing maintenance treatments are needed to due to the high degree of relapse.

Vector and reservoir control for preventing leishmaniasis.

BACKGROUND: Leishmaniasis is caused by the Leishmania parasite, and transmitted by infected phlebotomine sandflies. Of the two distinct clinical syndromes, cutaneous leishmaniasis (CL) affects the skin and mucous membranes, and visceral leishmaniasis (VL) affects internal organs. Approaches to prevent transmission include vector control by reducing human contact with infected sandflies, and reservoir control, by reducing the number of infected animals. OBJECTIVES: To assess the effects of vector and reservoir control interventions for cutaneous and for visceral leishmaniasis. SEARCH METHODS: We searched the following databases to 13 January 2015: Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS and WHOLIS, Web of Science, and RePORTER. We also searched trials registers for ongoing trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating the effects of vector and reservoir control interventions in leishmaniasis-endemic regions. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for trials and extracted data from included RCTs. We resolved any disagreements by discussion with a third review author. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included 14 RCTs that evaluated a range of interventions across different settings. The study methods were generally poorly described, and consequently all included trials were judged to be at high or unclear risk of selection and reporting bias. Only seven trials reported clinical outcome data which limits our ability to make broad generalizations to different epidemiological settings and cultures. Cutaneous leishmaniasisOne four-arm RCT from Afghanistan compared indoor residual spraying (IRS), insecticide-treated bednets (ITNs), and insecticide-treated bedsheets, with no intervention. Over 15 months follow-up, all three insecticide-based interventions had a lower incidence of CL than the control area (IRS: risk ratio (RR) 0.61, 95% confidence interval (CI) 0.38 to 0.97, 2892 participants, moderate quality evidence; ITNs: RR 0.32, 95% CI 0.18 to 0.56, 2954 participants, low quality evidence; ITS: RR 0.34, 95% CI 0.20 to 0.57, 2784 participants, low quality evidence). No difference was detected between the three interventions (low quality evidence). One additional trial of ITNs from Iran was underpowered to show a difference.Insecticide treated curtains were compared with no intervention in one RCT from Venezuela, where there were no CL episodes in the intervention areas over 12 months follow-up compared to 142 in control areas (RR 0.00, 95% CI 0.00 to 0.49, one trial, 2938 participants, low quality evidence).Personal protection using insecticide treated clothing was evaluated by two RCTs in soldiers, but the trials were underpowered to reliably detect effects on the incidence of CL (RR 0.40, 95% CI 0.13 to 1.20, two trials, 558 participants, low quality evidence). Visceral leishmaniasisIn a single RCT of ITNs versus no intervention from India and Nepal, the incidence of VL was low in both groups and no difference was detected (RR 0.99, 95% CI 0.46 to 2.15, one trial, 19,810 participants, moderate quality evidence).Two trials from Brazil evaluated the effects of culling infected dogs compared to no intervention or IRS. Although they report a reduction in seroconversion over 18 months follow-up, they did not measure or report effects on clinical disease. AUTHORS' CONCLUSIONS: Using insecticides to reduce phlebotomine sandfly numbers may be effective at reducing the incidence of CL, but there is insufficient evidence from trials to know whether it is better to spray the internal walls of houses or to treat bednets, curtains, bedsheets or clothing.

Treatment of solar urticaria using antihistamine and leukotriene receptor antagonist combinations tailored to disease severity.

BACKGROUND: Solar urticarial (SU) is characterized by erythema, whealing, and/or pruritus occurring minutes after sun exposure. Treatment is difficult and often unsatisfactory. OBJECTIVES: To determine the action spectra and minimal urticaria dose (MUD) and to tailor a treatment regimen graded according to disease severity in a series of patients with SU. PATIENTS AND METHODS: Eleven patients (seven females, four males, age range: 5-60 years) with a clinical history suggestive of SU, verified by photo-provocation tests to ultraviolet A (UVA), visible light, and/or UVB, were treated with various combinations of antihistamines and leukotriene receptor antagonist. RESULTS: All patients were sensitive to visible light (median MUD 50 J/cm(2)). Three patients were sensitive to UVA (median MUD 3.75 J/cm(2)), and one patient was sensitive to UVB (MUD of 0.03 J/cm(2)). Two patients experienced a spontaneous remission without treatment. One patient declined treatment. The remaining eight patients were managed by a combination of antihistamines (desloratidine, fexofenadine, cetirizine HCl) and a leukotriene receptor antagonist (montelukast). Seven of the 8 patients experienced a sustained remission of symptoms and signs following treatment. CONCLUSIONS: Photoprovocation for SU with determination of action spectra and MUD enables specifically tailored treatment regimens consisting of combinations of antihistamines and leukotriene receptor antagonist.

Diagnosis and management of oral leishmaniasis--case series and literature review.

The worldwide prevalence of leishmaniasis is increasing because of ecologic changes and increased medical profession awareness. Furthermore, solitary cases have been recently reported in Western countries. The authors describe the epidemiology, mode of transmission, and diagnosis of leishmaniasis and present 4 oral cases treated with systemic, localized, or combined therapy. The authors suggest that clinicians should maintain a high index of suspicion for atypical, resistant, oral and perioral lesions in individuals with a history of traveling in certain geographic regions. After diagnosis, treatment should be determined jointly by experts from the fields of oral and maxillofacial surgery, oral medicine, and dermatology based on leishmaniasis species and clinical presentation.

Synthesis and evaluation of thiazolidinedione and dioxazaborocane analogues as inhibitors of AI-2 quorum sensing in Vibrio harveyi.

Two focused libraries based on two types of compounds, that is, thiazolidinediones and dioxazaborocanes were designed. Structural resemblances can be found between thiazolidinediones and well-known furanone type quorum sensing (QS) inhibitors such as N-acylaminofuranones, and/or acyl-homoserine lactone signaling molecules, while dioxazaborocanes structurally resemble previously reported oxazaborolidine derivatives which antagonized autoinducer 2 (AI-2) binding to its receptor. Because of this, we hypothesized that these compounds could affect AI-2 QS in Vibrio harveyi. Although all compounds blocked QS, the thiazolidinediones were the most active AI-2 QS inhibitors, with EC(50) values in the low micromolar range. Their mechanism of inhibition was elucidated by measuring the effect on bioluminescence in a series of V. harveyi QS mutants and by DNA-binding assays with purified LuxR protein. The active compounds neither affected bioluminescence as such nor the production of AI-2. Instead, our results indicate that the thiazolidinediones blocked AI-2 QS in V. harveyi by decreasing the DNA-binding ability of LuxR. In addition, several dioxazaborocanes were found to block AI-2 QS by targeting LuxPQ.

RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.

Inherited disorders of elastic tissue represent a complex and heterogeneous group of diseases, characterized often by sagging skin and occasionally by life-threatening visceral complications. In the present study, we report on an autosomal-recessive disorder that we have termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis). The disorder was mapped to chromosome 20p11.21-p11.23, and a homozygous frameshift mutation in RIN2 was found to segregate with the disease phenotype in a large consanguineous kindred. The mutation identified results in decreased expression of RIN2, a ubiquitously expressed protein that interacts with Rab5 and is involved in the regulation of endocytic trafficking. RIN2 deficiency was found to be associated with paucity of dermal microfibrils and deficiency of fibulin-5, which may underlie the abnormal skin phenotype displayed by the patients.

Low-irradiance red LED traffic lamps as light source in PDT for actinic keratoses.

LED light sources for photodynamic therapy have become increasingly popular due to their narrow emission spectra that accurately match the absorption spectrum of porphyrins. Photodynamic therapy at low fluence rates has been shown to be as effective as high output irradiation for treatment of non-melanoma skin cancers. Fifteen patients with multiple non-hypertrophic actinic keratoses covering the scalp and the face were treated with aminolaevulinic acid photodynamic therapy using ordinary red LED traffic lamps as light source. All 15 patients improved clinically after one photodynamic therapy session. Only two patients required a second session to obtain satisfactory remission. Pain was minimal during these sessions. Red LED traffic lights constitute a simple alternative to far more complicated and expensive PDT light sources.

Single-cell transcriptomics reveals a senescence-associated IL-6/CCR6 axis driving radiodermatitis.

Irradiation-induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By combining scRNA-seq analysis of whole skin-derived irradiated cells with genetic ablation and molecular inhibition studies, we show that senescence-associated IL-6 and IL-1 signaling, together with IL-17 upregulation and CCR6+ -mediated immune cell migration, are crucial drivers of IRIAD. Bioinformatics analysis colocalized irradiation-induced IL-6 signaling with senescence pathway upregulation largely within epidermal hair follicles, basal keratinocytes, and dermal fibroblasts. Loss of cytokine signaling by genetic ablation in IL-6-/- or IL-1R-/- mice, or by molecular blockade, strongly ameliorated IRIAD, as did deficiency of CCL20/CCR6-mediated immune cell migration in CCR6-/- mice. Moreover, IL-6 deficiency strongly reduced IL-17, IL-22, CCL20, and CCR6 upregulation, whereas CCR6 deficiency reciprocally diminished IL-6, IL-17, CCL3, and MHC upregulation, suggesting that proximity-dependent cellular cross talk promotes IRIAD. Therapeutically, topical application of Janus kinase blockers or inhibition of T-cell activation by cyclosporine effectively reduced IRIAD, suggesting the potential of targeted approaches for the treatment of dermal side effects in radiotherapy patients.

Fluorescence imaging for the demarcation of basal cell carcinoma tumor borders.

BACKGROUND: Basal cell carcinoma (BCC) is a common malignancy accounting for 80% of all nonmelanoma skin cancers. Mohs micrographic surgery (MMS) is considered superior to alternative treatments, but the procedure is time consuming and costly. Alternative simpler techniques to facilitate accurate tumor demarcation are therefore in demand. Fluorescence imaging following application of 5-aminolevulinic acid is a noninvasive diagnostic technique that gives rapid information about the superficial extent of the skin tumor. OBJECTIVE: To ascertain whether fluorescence imaging improves the clinical tumor border assessment by investigating the consistency between tumor size determination by MMS, clinical assessment, and fluorescence imaging. METHODS: Eighteen patients with histologically verified nodular BCCs on the face scheduled for MMS were included in the study. The night before the surgical procedure, 5-aminolevulinic methyl ester cream was applied to the lesion. The following morning, tumor borders were determined clinically (clinical size), after illumination with Wood's light (fluorescence size), and by the tumor defect left on the skin surface following removal of the MMS specimen (Mohs size). RESULTS: The median tumor sizes were 93.05 mm2 (Mohs size), 61.05 mm2 (clinical size), and 72.75 mm2 (fluorescence size). The interclass correlation coefficients between Mohs size and fluorescence size was 0.984 and Mohs size and clinical size was 0.752. CONCLUSION: Tumor border estimation by fluorescence imaging and clinical assessment underestimate the genuine tumor size determined by MMS; however, the fluorescence size showed a higher degree of consistency with the Mohs size than did the clinical size.

Omalizumab for the Treatment of Solar Urticaria: Case Series and Systematic Review of the Literature.

BACKGROUND: Solar urticaria (SU) is a rare photodermatosis causing a significant impact on patients' quality of life. Although the condition can be controlled with phototherapy and/or a combination therapy of antihistamines and leukotriene antagonist in most patients, a subset of patients require additional therapy with omalizumab; however, efficacy data are sparse. OBJECTIVE: The objective of this study was to determine the efficacy and safety of omalizumab for treating SU. METHODS: A case series of 5 patients with SU refractory to antihistamine and leukotriene antagonist combination who were treated with omalizumab is described. In addition, a systematic review of studies evaluating patients with SU treated with omalizumab was conducted. The primary outcome was partial/complete clinical response. Secondary outcomes were 10-fold decreases in the baseline minimal urticarial dose and adverse events. RESULTS: Our case series included 5 patients with SU. Monthly omalizumab doses of 150 to 600 mg resulted in clinical improvement in all patients and complete remission in 4. No adverse effects were reported. The systematic review included 22 studies (48 patients). All patients failed to control disease with antihistamines before omalizumab treatment. Patients received omalizumab at monthly doses of 150 to 750 mg over a follow-up period of 4 to 200 weeks. Thirty-eight patients (79%) experienced clinical improvement. Four patients (11%) had mild adverse effects. CONCLUSIONS: Omalizumab provided clinical benefits in approximately 80% of patients with SU. Patients failing to improve on standard omalizumab doses may benefit from higher monthly dosages.