Robust Avoidance of Edge-Localized Modes alongside Gradient Formation in the Negative Triangularity Tokamak Edge.

In a series of high performance diverted discharges on DIII-D, we demonstrate that strong negative triangularity (NT) shaping robustly suppresses all edge-localized mode (ELM) activity over a wide range of plasma conditions: ⟨n⟩=0.1-1.5×10^{20} m^{-3}, P_{aux}=0-15 MW, and |B_{t}|=1-2.2 T, corresponding to P_{loss}/P_{LH08}∼8. The full dataset is consistent with the theoretical prediction that magnetic shear in the NT edge inhibits access to ELMing H-mode regimes; all experimental pressure profiles are found to be at or below the infinite-n ballooning stability limit. Our present dataset also features edge pressure gradients in strong NT that are closer to an H-mode than a typical L-mode plasma, supporting the consideration of NT for reactor design.

Turbulence characteristics and flow dynamics impacts on the H-mode transition in favourable magnetic geometry with lower power threshold.

The L-H transition power threshold (PLH) in favourable magnetic geometry (ion ∇B drift pointing towards X-point) is much lower than in the unfavourable magnetic geometry (ion ∇B drift pointing away from X-point) on multiple tokamaks. In a systematic experiment on DIII-D, the ion ∇B drift direction was changed continuously from the unfavourable to favourable configuration during plasma discharges. During such process, the input neutral beam power was kept constant at a value that was above PLH for favourable configuration, but lower than PLH for unfavourable configuration. Toroidal field and plasma current were also kept constant and there was little change in the edge electron density ne and electron temperature Te profiles. The density fluctuation amplitude was reduced approaching the transition, while a large increase of turbulence Reynolds stress and flow shear were simultaneously observed. The turbulence decorrelation rate was found to increase as the ion ∇B drift direction was moving towards the favourable configuration, but the flow shear also increased and exceeded the turbulence decorrelation rate. These measurements demonstrate an important correlation between turbulence and turbulence-driven flow and a lowering of PLH, provide insights into the underlyingphysics behind the hidden parameters and inform a more complete physics-based model of the L-H transition power threshold. This article is part of a discussion meeting issue 'H-mode transition and pedestal studies in fusion plasmas'.

Chemical peelings for the treatment of actinic keratosis: a systematic review and meta-analysis.

BACKGROUND: Actinic keratosis (AK) is a common precancerous lesion of the skin that may be treated with chemical peelings. Despite their long-standing usage and clinical experience, no evidence-based recommendation regarding the efficacy and safety of chemical peelings for AK exists. OBJECTIVES: To systematically review and synthesize the current knowledge on chemically exfoliative peelings as interventions for AK. METHODS: We performed a systematic literature research in Medline, Embase and CENTRAL and hand-searched pertinent trial registers for eligible records until 5 August 2019. Results from individual studies were pooled using a random-effects model or described in a qualitative synthesis. The risk of bias was estimated with the tools provided by the Cochrane Collaboration (randomized and non-randomized trials) and the Evidence Project (single-arm trials). RESULTS: Four randomized controlled trials, two non-randomized controlled trials and two single-arm studies with a total sample size of n = 170 patients were included. Trichloroacetic acid (TCA) plus Jessner's solution showed significantly lower participant complete clearance (RR 0.36, 95% CI: 0.14-0.90, two studies, I2  = 0%, P = 0.03) and lower lesion clearance (RR 0.92, 95% CI: 0.85-0.99, one study, P = 0.03) compared to 5-fluorouracil (5-FU) 5% cream. TCA as monotherapy showed lower lesion complete clearance (RR 0.75, 95% CI: 0.69-0.82, two studies, I2  = 7%, P < 0.001) and lower mean lesion reduction per patient compared to conventional photodynamic therapy (cPDT) (MD -20.48, 95% CI: -31.55 to -9.41, two studies, I2  = 43%, P = 0.0003). Pain was more pronounced in patients treated with cPDT in comparison with TCA (MD -1.71 95% CI: -3.02 to -0.41, two studies, I2  = 55%, P = 0.01). In the single-arm studies, 5-FU plus glycolic acid showed 92% lesion clearance and phenol peeling 90.6% participant complete clearance. All studies showed a high risk for bias. CONCLUSIONS: Future high-quality studies and a standardization of peeling protocols are warranted to determine the value of chemical peelings in the treatment of AK.

Cutaneous squamous cell carcinomas are associated with basal proliferating actinic keratoses.

BACKGROUND: In addition to the extent of atypical keratinocytes throughout the epidermis, actinic keratoses (AKs) are histologically characterized by downward-directed basal-layer expansion. It is not known whether this growth pattern correlates with the risk of developing invasive squamous cell carcinoma (iSCC). OBJECTIVES: To characterize the prevalence of downward-directed basal-layer expansion of AKs adjacent to iSCC. METHODS: The epidermis overlying and adjacent to iSCCs was assessed histologically. We determined the histological grade (AK I-III), basal growth pattern (PRO I-III) and accompanying parameters such as adnexal involvement. RESULTS: Among 307 lesions, 52·4% of AKs were histologically classified as AK grade I, 38·1% as AK II and 6·8% as AK III (χ2 -test, P < 0·001). Only 2·6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25·7%, PRO II in 31·9% and PROIII in 39·4% of cases. Only 2·9% of AKs showed no basal growth (χ2 -test, P < 0·001). In total 118 AKs (48·8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18·6% of cases, PRO II in 30·5% and PRO III in 50·8%. The epidermis above iSCCs could be assessed only for upwards-directed growth and showed no significant differences in the three AK grades (P = 0·42). CONCLUSIONS: Basal proliferative AKs, as well as atypical keratinocytes restricted to the lower third of the epidermis, are most commonly seen adjacent to iSCC, with less evidence for full-thickness epidermal dysplasia. Our study supports the important role of dysplastic keratinocytes in the epidermal basal layer and their potential association with iSCC.

Lysyl oxidase-like-2 mutations and reduced mRNA and protein expression in mid-dermal elastolysis.

BACKGROUND: Mid-dermal elastolysis (MDE) is a rare skin condition, characterized by selective loss of elastic fibres in the mid dermis. The pathogenesis of MDE is still unclear. AIM: To investigate expression of lysyl oxidase-like 2 (LOXL2) in a reasonable sample of patients with MDE and to search for mutations in LOXL2. METHODS: We investigated archived lesional tissue of 13 patients with MDE and skin tissue samples of 10 sex- and age-matched healthy controls (HCs). Gene and protein expression of LOXL2 was investigated using real-time reverse-transcription PCR and immunohistochemistry. Mutation analysis was performed using the Sanger method. RESULTS: We observed decreased LOXL2 mRNA expression in lesional skin of patients with MDE (0.48 ± 0.16) compared with healthy skin of the same patients (1.5 ± 0.51) and normal skin of HCs (1.9 ± 0.13). Compared with healthy patient skin (epidermis 2.38 ± 1.6, dermis 1.2 ± 1), LOXL2 protein expression in lesional patient skin (epidermis 1.1 ± 0.7, dermis 0.3 ± 0.45) was significantly decreased (P < 0.04 and P = 0.02, respectively). Mutation analysis of the entire LOXL2 gene could be performed for five patients, all of whom were found to have at least one mutation in the LOXL2 gene. Three of these had a mutation in the promoter region (c.967 G>C, c.1022 C>T, and c.1025 G>A, respectively), and one of them also had a mutation in the splice region of intron 11/exon 12 (IVS11-1 G>A). Of the remaining two patients, one had a mutation in exon 3 (T1391), and the other had a mutation in exon 11 (C663Y). CONCLUSIONS: Our present data suggest that decreased elastin renewal due to LOXL2 mutations and consecutive reduced LOXL2 expression contribute to the pathogenesis of MDE.

Histological classification of cutaneous squamous cell carcinomas with different severity.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer. Histology represents the gold standard to confirm the diagnosis of cSCC and is mandatory to determine important findings for tumour grading, such as tumour thickness, depth of invasion, degree of differentiation and histological subtype, perineural and vascular invasion, and assessing tumour margins. In daily clinical practice, the combination of clinical and histological features should be considered when grading the tumours and treating the patients, accordingly. This article aims to provide a structured overview of the most common histological findings of in situ and invasive cSCCs, namely those relevant to their severity, and should facilitate the understanding and evaluation of these results.

Evaluation of two histological classifications for actinic keratoses - PRO classification scored highest inter-rater reliability.

BACKGROUND: Actinic keratoses (AKs) can histologically be classified by the extent of atypical keratinocytes throughout the epidermis or their pattern of basal proliferation. Currently, no data on the inter-rater reliability of both scores is available. OBJECTIVE: To evaluate the inter-rater reliability of the two classification schemes; histological grade (AK I-III) and basal proliferation (PRO I-III). METHODS: Histological images of 54 AKs were classified by 21 independent dermatopathologists with regard to basal proliferation (PRO I-III), histological grade (AK I-III) and assumed risk of progression into invasive carcinoma. RESULTS: Overall, of the 54 AKs 16.7% (9/54) were classified as AK I, 66.7% (36/54) as AK II, and 16.7% (9/54) as AK III. With regards to basal growth pattern, 25.9% (14/54) were classified as PRO I, 42.6% (23/54) as PRO II, and 31.5% (17/54) as PRO III. We observed a highly significant inter-rater reliability for PRO-grading (P < 0.001) which was higher than for AK-grading (Kendall's W coefficient: AK = 0.488 vs. PRO = 0.793). We found substantial agreement for assumed progression risk for AKs with worsening basal proliferation (k = 0.759) compared to moderate agreement (k = 0.563) for different AK-gradings. CONCLUSIONS: Histological classification of basal growth pattern (PRO) showed higher inter-rater reliability compared to the established classification of atypical keratinocytes throughout epidermal layers. Moreover, experienced dermatopathologists considered basal proliferation to be more important in terms of progression risk than upwards directed growth patterns. It should be considered to classify AKs according to their basal proliferation pattern (PRO I-III).

Low Drosha protein expression in cutaneous T-cell lymphoma is associated with worse disease outcome.

BACKGROUND: Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types. OBJECTIVES: We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL). METHODS: We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed. RESULTS: On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P = 0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P = 0.017 and P = 0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P = 0.032) and DSD (P = 0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P = 0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P = 0.026) and elevated LDH (P = 0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively). CONCLUSIONS: Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.

Somatic mutations in kinetochore gene KNSTRN are associated with basal proliferating actinic keratoses and cutaneous squamous cell carcinoma.

BACKGROUND: Mutations in kinetochore gene KNSTRN accelerate the development of cutaneous squamous cell carcinoma (SCC) and may correlate with different histological classifications of actinic keratosis (AKs). OBJECTIVE: To determine KNSTRN gene mutation frequency in healthy skin (HS), actinically damaged skin (ADS), in AKs with different histomorphological gradings and invasive SCCs. METHODS: All samples were histologically evaluated. AK lesions were additionally classified according to their upwards (AK I-III) and downwards (PRO I-III) directed growth pattern. Mutation analyses of all samples were performed using the Sanger method. RESULTS: With one exception, all detected mutations in KNSTRN gene showed an alanine-to-glutamate substitution at codon 40 (p.Ala40Glu). p.Ala40Glu mutation was found in 6.9% (2/29) of HS, in 16.1% (5/31) of ADS, in 18.3% (20/109) of AKs and in 30.0% (9/30) of invasive SCCs. Further stratification of AKs using the common AK classification of Röwert-Huber revealed the p.Ala40Glu mutation in 14.7% (5/43), 13.3% (4/30) and 24.4% (11/45) (AK I, II and III). In contrast, the new PRO classification showed a distribution of 3.6% (1/28) in PRO I, 21.7% (13/60) in PRO II and 28.6% (6/21) in PRO III. Mutation frequency in HS showed significant differences compared to AKs classified as PRO III and invasive SCCs (P < 0.05). In contrast, there were no statistically significant differences between HS and AKs when classified according to Röwert-Huber. CONCLUSIONS: Recurrent somatic mutation p.Ala40Glu in KNSTRN gene is associated with basal proliferating AKs in accordance with invasive SCCs. This supports the impact of basal proliferative pattern in terms of progression.

Infrequent Occurrence of Peach Skin Streaking and the Role of Rainwater Attributes on Symptom Development.

Streaks lacking pigmentation have impacted red blush cultivars of peaches in many East Coast production areas, but the underlying cause is still unclear. Some evidence suggests that streaking may be caused by reactive agents in rainwater. Peach skin streaking was monitored over two consecutive years at a commercial farm with a history of streaking problems located near Ridge Spring, SC. Six cultivars (two early season, two midseason, and two late season) were evaluated, each in two locations (LocA and LocB). Among those 12 experimental block cultivars, streaking occurred only in 2017 in cv. Scarletprince of LocA with an incidence of 6%. That same year two nearby nonexperimental blocks with 'Scarletprince' revealed 11 and 25% streaking. Streaking was also monitored at the Musser Fruit Research Center (MFRC) in Seneca, SC. At that location, a high incidence of streaking was observed, with 50 and 64% in 'Julyprince' (2017) and 'Carored' (2018), respectively. Rainwater pH taken from each of the 12 experimental blocks ranged from 3.03 to 7.4, ozone (O3) levels ranged from <0.02 to 0.37 mg/liter, and chlorine (Cl2) and chlorine dioxide (ClO2) levels were either just above or under the detection limit of 0.01 mg/liter and 0.02 mg/liter, respectively. Although the electrical conductivity (EC) was below 100 µS/cm on average, we did measure EC values as high as 1,500 µS/cm. For all samples, the oxidation-reduction potential (ORP) ranged from 90 to 302 mV, indicating oxidizing conditions. Fruit harvested 1 or 2 weeks prior to commercial maturity and treated with solutions of high (10) or low (3) pH, ozone >0.37 mg/liter, and EC values of up to 3,000 µS/cm did not produce symptoms. However, streaking was reproduced with collected rainwater, but the remaining sample volume did not allow further analyses. Using 0.05% ClO2 to induce streaking, we show that fruit of different cultivars varied in susceptibility when treated 1 week prior to commercial maturity, with 'Juneflame' being the most susceptible and 'August Lady' being the least susceptible. Our study shows that multiple factors determine the occurrence of streaking in peach orchards, including cultivar susceptibility, ripening stage, and the presence of rainwater with sufficient amounts of a yet unknown reactive agent or agent combination.

Actinic keratosis area and severity index (AKASI) is associated with the incidence of squamous cell carcinoma.

BACKGROUND: Actinic keratoses (AKs) are commonly diagnosed clinically. Actinic keratosis area and severity index (AKASI) is a new easy-to-use tool to assess the severity of AKs on the head. OBJECTIVES: To determine the association between chronically UV-induced tumours such as basal cell carcinomas (BCC) or squamous cell carcinomas (SCC) and AKASI. METHODS: We performed a retrospective analysis of patients who had undergone oncological surgery due to UV-induced tumours and who were assessed for AKASI and Physician's global assessment (PGA) prior to surgery. Statistical analysis was performed to evaluate correlation between AKASI, PGA and invasive carcinomas. RESULTS: Of the 210 patients included, 26 patients had histologically diagnosed SCCs and presented with a median (range) AKASI of 6.9 (0-13.0) and PGA of 2 (0-4). In contrast, the 82 patients with BCCs showed a median (range) AKASI of 3.3 (0-15.2) and PGA of 1 (0-4). The Mann-Whitney U-test showed significant differences (P = 0.0018) between AKASI of patients with SCC and BCC. In addition, we found a significantly higher AKASI in patients with SCC compared to patients with non-invasive lesions like AK and Bowen disease (BD) (P = 0.0275). Spearman's coefficient of rank correlation between AKASI and PGA indicates that these measures of AK severity were strongly correlated (P < 0.0001; r = 0.90; 95% CI 0.865-0.920). CONCLUSIONS: Patients with SCC show significantly higher AKASI than patients with BCC or patients without invasive tumours. Hence, AKASI may be used to stratify risk for developing invasive SCC.

Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery.

BACKGROUND: Koebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event. OBJECTIVES: To study molecular pathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal. METHODS: We assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS and EGFR. RESULTS: All lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16 and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16 and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls. CONCLUSIONS: We observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of preneoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear.

Baseline laboratory parameters predicting clinical outcome in melanoma patients treated with ipilimumab: a single-centre analysis.

BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are only about 10%. Hence, it is important to explore biomarkers predicting ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict therapy outcome in melanoma patients who have undergone standard ipilimumab therapy in a real-world setting. METHODS: Databases of cutaneous melanoma patients (n = 52) who had received ipilimumab were reviewed and data collected on patient characteristics and diverse laboratory parameters. We performed univariate and multivariate statistics including logistic regression analysis and Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes, eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1 pretreatment as significant predictor for ORR following ipilimumab therapy. Low-LDH levels and more than two ipilimumab cycles turned out to be significant independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1 treatment before or after ipilimumab were significant independent predictors for improved MSS. All aforementioned parameters and faecal calprotectin did not turn out to be predictors for ipilimumab-induced autoimmune-related adverse events and autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab treatment is an independent predictor for improved PFS. Furthermore, low serum S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2) is significantly associated with prolonged PFS. Pretreatment calprotectin does not predict the occurrence of autoimmune colitis under ipilimumab therapy.

Actinic keratoses show variable histological basal growth patterns - a proposed classification adjustment.

BACKGROUND: Common histological classification schemes of actinic keratoses (AK) do not evaluate growth patterns at basal epidermal aspects of AK. Until now, the importance of basal epidermal growth patterns of AK has not been studied. OBJECTIVE: To investigate the extent of atypical keratinocytes throughout the epidermis and variation in basal growth patterns of AK. METHODS: AK lesions occurring on the head/face from patients seen in routine practice were assessed histologically. We determined histological grade (AK I-III), basal growth patterns of atypical keratinocytes (crowding, budding and papillary sprouting) and accompanying parameters. RESULTS: Of the 246 lesions included, 28.0% were histologically classified as AK I, 46.7% as AK II and 25.2% as AK III. Approximately 26.4% of the basal growth patterns were classified as crowding (pro I), 49.6% as budding (pro II), 17.9% as papillary sprouting (pro III) and 6.1% without basal directed growth. No significant correlation of the histological AK I-III grading and underlying growth patterns was observed (P = 0.4666). However, adnexal structure involvement (OR = 2.37; 95% CI 1.21-4.65), infiltration (OR = 2.53; 95% CI 1.31-4.90) and increased number of vessels (OR = 2.56; 95% CI 1.42-4.65) were independent positive predictive markers for pro II and pro III basal growth patterns. CONCLUSIONS: Basal growth patterns (pro I-III) in AK do not correlate with the established AK I-III histological grading system. Besides the degree of upward extension, varying degrees of downward extension exist. Histological classification should consider both, upwards and downward growth patterns when assessing AK.

A proposed scoring system for assessing the severity of actinic keratosis on the head: actinic keratosis area and severity index.

BACKGROUND: Actinic keratosis (AK) severity is currently evaluated by subjective assessment of patients. OBJECTIVES: To develop and perform an initial pilot validation of a new easy-to-use quantitative tool for assessing AK severity on the head. METHODS: The actinic keratosis area and severity index (AKASI) for the head was developed based on a review of other severity scoring systems in dermatology, in particular the psoriasis area and severity index (PASI). Initial validation was performed by 13 physicians assessing AK severity in 18 AK patients and two controls using a physician global assessment (PGA) and AKASI. To determine an AKASI score, the head was divided into four regions (scalp, forehead, left/right cheek ear, chin and nose). In each region, the percentage of the area affected by AKs was estimated, and the severities of three clinical signs of AK were assessed: distribution, erythema and thickness. RESULTS: There was a strong correlation between AKASI and PGA scores (Pearson correlation coefficient: 0.86). AKASI was able to discriminate between different PGA categories: mean (SD) AKASI increased from 2.88 (1.18) for 'light' to 5.33 (1.48) for 'moderate', 8.28 (1.89) for 'severe', and 8.73 (3.03) for 'very severe' PGA classification. The coefficient of variation for AKASI scores was low and relatively constant across all PGA categories. CONCLUSIONS: Actinic keratosis area and severity index is proposed as a new quantitative tool for assessing AK severity on the head. It may be useful in the future evaluation of new AK treatments in clinical studies and the management of AK in daily practice.

Actinic keratosis: correlation between clinical and histological classification systems.

BACKGROUND: There are several clinical and histological classification systems for grading actinic keratosis (AK) lesions. The Olsen clinical classification scheme grades AK lesions according to their thickness and degree of hyperkeratosis (grades 1-3). The Roewert-Huber histological classification system grades AK lesions based on the extent of epidermal atypical keratinocytes (AK I-III). OBJECTIVE: The aim of this study was to determine whether there is a correlation between these clinical and histological AK classification schemes. METHODS: One AK lesion from patients in three pivotal clinical studies and routine practice was assessed clinically and histologically. A match in grading was defined as Olsen grade 1 being classified histologically as AK I, Olsen grade 2 as AK II and Olsen grade 3 as AK III. RESULTS: Of the 892 lesions included, 29.0% were classified as Olsen grade 1, 59.6% as Olsen grade 2 and 11.3% as Olsen grade 3; 19.2% were histologically classified as AK I, 69.6% as AK II and 11.2% as AK III. Only 480 lesions (53.8%) had a matching clinical and histological classification. Of these matches, most were 'Olsen grade 2 = AK II' (83.1%). The Spearman's rank correlation coefficient for clinical and histological classification was r = 0.0499 (P = 0.137). CONCLUSIONS: Clinical classification of AK lesions using the system of Olsen does not accurately match histological classification of the same lesions using the system of Roewert-Huber. Consequently, it is not possible to draw conclusions about the histology of AK lesions from their clinical appearance. This finding reinforces the need to treat all AK lesions as well as field cancerization.

[Therapy of basal cell carcinoma]. / Therapie des Basalzellkarzinoms.

Basal cell carcinoma (BCC) represents the most common malignant skin tumour in fair-skinned people. Despite low metastatic potential, BCC can cause decisive tissue destruction and disfigurement by invasive growth. In addition to clinical and histologic diagnosis modern imaging techniques as optical coherence tomography and confocal laser microscopy have been introduced. BCCs with aggressive growth pattern and/or increased risk of relapse are preferentially treated surgically. For superficial BCCs various topical treatments and photodynamic therapy are available. Inhibitors of the sonic hedgehog pathway have been approved for symptomatic treatment of metastatic BCC and locally advanced BCC inappropriate for surgery or radiotherapy. Detailed knowledge of the clinical spectrum of BCC and an appropriate choice of therapy are mandatory for the successful treatment of BCC.

An unusually simple HP1 gene set in Hymenopteran insects.

The heterochromatin protein 1 (HP1) gene family includes a set of paralogs in higher eukaryotes that serve fundamental roles in heterochromatin structure and maintenance, and other chromatin-related functions. At least 10 full and 16 partial HP1 genes exist among Drosophila species, with multiple gene gains, losses, and sub-functionalizations within this insect group. An important question is whether this diverse set of HP1 genes and their dynamic evolution represent the standard rule in eukaryotic groups. Here we have begun to address this question by bio-informatically identifying the HP1 family genes in representative species of the insect order Hymenoptera, which includes all ants, bees, wasps, and sawflies. Compared to Drosophila species, Hymenopterans have a much simpler set of HP1 genes, including one full and two partial HP1s. All 3 genes appear to have been present in the common ancestor of the Hymenopterans and they derive from a Drosophila HP1B-like gene. In ants, a partial HP1 gene containing only a chromoshadow domain harbors amino acid changes at highly conserved sites within the PxVxL recognition region, suggesting that this gene has undergone sub-functionalization. In the jewel wasp Nasonia vitripennis, the full HP1 and partial chromoshadow-only HP1 are expressed in both germ line and somatic tissues. However, the partial chromodomain-only HP1 is expressed exclusively in the ovary and testis, suggesting that it may have a specialized chromatin role during gametogenesis. Our findings demonstrate that the HP1 gene family is much simpler and evolutionarily less dynamic within the Hymenopterans compared to the much younger Drosophila group, a pattern that may reflect major differences in the range of chromatin-related functions present in these and perhaps other insect groups.

FOXP3+ and CD39+ regulatory T cells in subtypes of cutaneous lupus erythematosus.

BACKGROUND: Lupus erythematosus (LE) is an autoimmune disease in which regulatory T cells play a pathogenetic role. OBJECTIVES: We aimed to assess and compare the quantities of lesional Tregs in subtypes of cutaneous LE (CLE) including chronic discoid LE (CDLE), LE tumidus (LET) and subacute CLE (SCLE). METHODS: Thirty-nine patients with CLE were enrolled in the study. Immunohistochemistry was performed for CD4, CD8, FOXP3 and CD39. RESULTS: We studied nine CDLE patients, 21 LET patients and nine patients with SCLE. SCLE lesions [37 (0-134)] showed a significantly (P = 0.024) decreased percentage of CD4+ cells when compared with CDLE [125 (0-146)] and LET [124 (0-240)] lesions. Moreover, the CD4/CD8 ratio in SCLE lesions [0.7 (0.5-1.8)] was significantly (P = 0.027) decreased when compared with CDLE [1.9 (1.5-2.8)] and LET [1.6 (0.8-2.9)] lesions. FOXP3 immunopositivity was significantly (P = 0.017) decreased in LET [0 (0-6)] and SCLE [1 (0-2)] lesions when compared with CDLE [6 (0-38)]. Moreover, in LET [2 (0-6)] and SCLE [2 (0-2)], we observed a significantly (P = 0.0049) diminished CD39-immunoreactivity when compared with CDLE [4 (2-12)]. CD4+ cell count is a significant (P = 0.0133) negative predictor for the diagnosis of SCLE (Odds ratio 0.978, 95% CI 0.960-0.99). CONCLUSIONS: Our data indicate that there are differences in quantities of lesional T helper cells, CD4/CD8 ratio and Tregs among subtypes of CLE. Interestingly, a more significant decrease in Tregs, which likely reflects greater loss of immune-tolerance, is observed in the more photosensitive subtypes of CLE such as SCLE and LET.