Founder Mutations for Early Onset Melanoma as Revealed by Whole Exome Sequencing Suggests That This is Not Associated with the Increasing Incidence of Melanoma in Poland.

PURPOSE: Germline mutations within melanoma susceptibility genes are present only in minority of melanoma patients and it is expected that additional genes will be discovered with next generation sequence technology and whole-exome sequencing (WES). MATERIALS AND METHODS: Herein we performed WES on a cohort of 96 unrelated Polish patients with melanoma diagnosed under the age of 40 years who all screened negative for the presence of CDKN2Avariants. A replication study using a set of 1,200 melanoma patient DNA samples and similarly large series of healthy controls was undertaken. RESULTS: We selected 21 potentially deleterious variants in 20 genes (VRK1, MYCT1, DNAH14, CASC3, MS4A12, PRC1, WWOX, CARD6, EXO5, CASC3, CASP8AP2, STK33, SAMD11, CNDP2, CPNE1, EFCAB6, CABLES1, LEKR1, NUDT17, and RRP15), which were identified by WES and confirmed by Sanger sequencing for an association study. Evaluation of the allele distribution among carriers and their relatives in available family trios revealed that these variants were unlikely to account for many familial cases of melanoma. Replication study revealed no statistically significant differences between cases and controls. CONCLUSION: Although most of the changes seemed to be neutral we could not exclude an association between variants in VRK1, CREB3L3, EXO5, and STK33 with melanoma risk.

Effects of the soy isoflavones, genistein and daidzein, on male rats' skin.

INTRODUCTION: Genistein and daidzein are typical soy isoflavones with known estrogenic properties to provide protection against skin ageing in postmenopausal women and female rats. However their effect on male skin was very rarely studied. AIM: This study was designed to evaluate the effect of a mixture of genistein and daidzein on male rats' skin. MATERIAL AND METHODS: Male rats were administered this mixture in a dose of 2 or 20 mg/kg body weight (bw) per day for 5 days weekly mixed with regular rat chow, from prenatal life until sexual maturity. The female and male rats of the control group received regular rat chow. The skin epidermis thickness, number of fibroblasts in the dermis and diameter of collagen fibers in the dermis were measured using morphometric assay. The isoflavone effects on activities of antioxidant enzymes, lipid peroxides, and glutathione concentration in the skin were measured with commercially available kits. RESULTS: The thickness of the skin epidermis and collagen fibers in the dermis and amount of elastic fibers were significantly greater in the isoflavone-treated groups. Isoflavones significantly decreased catalase activity in the skin homogenates and at a higher dose inhibited lipid peroxides formation. CONCLUSIONS: Our results provide further support for the contribution of isoflavones to defence mechanisms against oxidative stress in the skin and suggest that genistein and daidzein supplementation may provide protection against skin ageing in males.

BRCA1/2 mutations are not a common cause of malignant melanoma in the Polish population.

The association of BRCA1/2 mutations with melanoma is not completely determined; the interpretation of variants of unknown significance is also problematic. To evaluate these issues we explored the molecular basis of melanoma risk by performing whole-exome sequencing on a cohort of 96 unrelated Polish early-onset melanoma patients and targeted sequencing of BRCA1/2 genes on additional 30 melanoma patients with familial aggregation of breast and other cancers. Sequencing was performed on peripheral blood. We evaluated MutationTaster, Polyphen2, SIFT, PROVEAN algorithms, analyzed segregation with cancer disease (in both families with identified BRCA2 variants) and in one family performed LOH (based on 2 primary tumors). We found neither pathogenic mutations nor variants of unknown significance within BRCA1. We identified two BRCA2 variants of unknown significance: c.9334G>A and c.4534 C>T. Disease allele frequency was evaluated by genotyping of 1230 consecutive melanoma cases, 5000 breast cancer patients, 3500 prostate cancers and 9900 controls. Both variants were found to be absent among unselected cancer patients and healthy controls. The MutationTaster, Polyphen2 and SIFT algorithms indicate that c.9334G>A is a damaging variant. Due to lack of tumour tissue LOH analysis could not be performed for this variant. The variant segregated with the disease. The c.4534 C>T variant did not segregate with disease, there was no LOH of the variant. The c.9334G>A variant, classified as a rare variant of unknown significance, on current evidence may predisposes to cancers of the breast, prostate and melanoma. Functional studies to describe how the DNA change affects the protein function and a large multi-center study to evaluate its penetrance are required.

Lesions on the back of hands and female gender predispose to stigmatization in patients with psoriasis.

BACKGROUND: Psoriasis vulgaris is characterized by disfiguring and stigmatizing skin lesions. The links among lesions distribution, severity, and stigmatization remain unclear. OBJECTIVE: We sought to investigate if the involvement of visible and sensitive areas is linked to stigmatization. METHODS: In all, 115 patients with psoriasis vulgaris were assessed for disease severity, skin lesions distribution, itch, and stigmatization using the Feelings of Stigmatization Questionnaire. Quality of life was assessed with the Dermatology Life Quality Index and the World Health Organization Quality of Life-BREF. RESULTS: The localization of psoriatic lesions on the back of hands was related to higher stigmatization levels (P = .011, total score of the Feelings of Stigmatization Questionnaire), but not the involvement of nails, the palms, the face, or the genital area nor overall disease severity. All patients reported some level of stigmatization, regardless of the localization of lesions and type of psoriasis. Higher levels of stigmatization characterized patients who claimed not to be able to hide their lesions by clothing (P = .025), women (P = .001), and the unemployed (P = .004). Stigmatization was the strongest predictor of quality of life impairment. LIMITATIONS: Only hospitalized patients were included. CONCLUSIONS: Psoriatic lesions on the back of hands are debilitating and warrant effective treatment. Special attention should be paid to female patients, who are more sensitive to stigmatization.

Structural and biophysical characteristics of human skin in maintaining proper epidermal barrier function.

The complex structure of human skin and its physicochemical properties turn it into an efficient outermost defence line against exogenous factors, and help maintain homeostasis of the human body. This role is played by the epidermal barrier with its major part - stratum corneum. The condition of the epidermal barrier depends on individual and environmental factors. The most important biophysical parameters characterizing the status of this barrier are the skin pH, epidermal hydration, transepidermal water loss and sebum excretion. The knowledge of biophysical skin processes may be useful for the implementation of prophylactic actions whose aim is to restore the barrier function.

Congenital candidiasis as a subject of research in medicine and human ecology.

Congenital candidiasis is a severe complication of candidal vulvovaginitis. It occurs in two forms,congenital mucocutaneous candidiasis and congenital systemic candidiasis. Also newborns are in age group the most vulnerable to invasive candidiasis. Congenital candidiasis should be considered as an interdisciplinary problem including maternal and fetal condition (including antibiotic therapy during pregnancy), birth age and rare genetic predispositions as severe combined immunodeficiency or neutrophil-specific granule deficiency. Environmental factors are no less important to investigate in diagnosing, treatment and prevention. External factors (e.g., food) and microenvironment of human organism (microflora of the mouth, intestine and genitalia) are important for solving clinical problems connected to congenital candidiasis. Physician knowledge about microorganisms in a specific compartments of the microenvironment of human organism and in the course of defined disorders of homeostasis makes it easier to predict the course of the disease and allows the development of procedures that can be extremely helpful in individualized diagnostic and therapeutic process.

Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study.

The E318K mutation in the MITF gene has been associated with a high risk of melanoma, renal cell carcinoma, and pancreatic cancer; the risk of other cancers has not been evaluated so far. Herein, we examined the possible association of E318K and a novel variant of the MITF gene, V320I, with the risk of cancers of different sites of origin in a Polish population. We assayed for the presence of the E318K and V320I missense mutations in 4,226 patients with one of six various cancers (melanoma or cancer of the kidney, lung, prostate, colon, or breast) and 2,114 controls from Poland. The E318K mutation was detected in 4 of 2,114 participants (0.19%) in the Polish control population, the V320I in 3 of 2,114 participants (0.14%) in the control group. We found no statistically significant differences in the prevalence of the E318K and V320I variants among cases and controls. We found two carriers of the E318K variant among melanoma patients (P = 0.95), one carrier among breast cancer patients (P = 0.77), one carrier among colorectal cancer patients (P = 0.82), and one carrier among kidney cancer patients (P = 0.64). Our study demonstrates a lack of strong association of E318K and V320I with increased risk of melanoma or cancers of the kidney, breast, prostate, lung, or colon.

Therapeutic effects of CO2 laser therapy of linear nevus sebaceous in the course of the Schimmelpenning-Feuerstein-Mims syndrome.

The Schimmelpenning-Feuerstein-Mims (SFM) syndrome is a rare phakomatosis which comprises a nevus sebaceous of Jadassohn, seizures and developmental delay associated with a wide spectrum of extracutaneous abnormalities including neurological, skeletal, ocular, cardiovascular and urogenital defects. We are presenting a case of an 18-year-old patient with systemic features of the SFM syndrome and an extensive linear nevus sebaceous partially removed with a carbon dioxide (CO2) laser. The treatment options of skin lesions in patients with SFM are discussed.

Psoriasis vulgaris and familial cancer risk- a population-based study.

BACKGROUND: Follow-up studies of psoriasis patients indicate an increased risk in the occurrence of malignancies at different sites of origin. Population stratification and/or complicated interpretation of evidence on the risk of cancer (due to the small number of patients included in most series) lead to inconsistent data. Herein we investigated the risk of occurrence of malignancies at different sites of origin in a series of 517 psoriasis patients and their 1st degree relatives. METHODS: We evaluated the tumour spectrum as well as the age of the patient at diagnosis of cancers in psoriasis families along with the observed and expected frequencies of malignancies. The distribution of 17 common mutations/polymorphisms in 10 known cancer susceptibility genes among psoriasis patients and 517 matched healthy controls were examined. No such study has been published to date. RESULTS: The statistical comparison of the observed and expected frequencies of cancers revealed a higher than expected occurrence of Hodgkin's lymphoma among males in psoriasis families when compared to the general population (OR=1.8, 95%CI 1.6-2.1, p=0.002). There was a non-significant tendency towards a younger age of onset and overrepresentation of laryngeal cancer and leukaemia in psoriasis families. We found no major differences in the distribution of cancer susceptibility mutations among our cases and the healthy controls. CONCLUSIONS: The results of our study suggest an increased risk of Hodgkin's lymphoma for male members of psoriasis families. Further studies are needed to confirm the findings and to evaluate whether or not the application of cancer surveillance protocols for Hodgkin's lymphoma, leukaemia and laryngeal cancer are justified in these families.

[Analysis of the chosen parameters of metabolic status in patients with psoriasis]. / Analiza wybranych parametrów stanu metabolicznego u pacjentów z luszczyca.

INTRODUCTION: Psoriasis is a chronic inflammatory dermatosis leading to the development of systemic inflammatory reaction. Previous data indicated the coexistence of psoriasis and the occurrence of metabolic disorders, with the common background of both processes determined by a chronic inflammation. The coexisting disorders, including type 2 diabetes, hypertension, heart ischemic disease, dislipidemia and obesity may have an important impact on intensity of psoriasis activity. MATERIAL AND METHODS: The analysis comprised of 82 randomly matched patients with various clinical forms of psoriasis, aged 17 to 81 years. In patients PASI and BSA indexes, BMI value and laboratory parameters of metabolic status (glucose and ureic acid levels, lipid fractions and CRP level in the serum) were evaluated. RESULTS: An average age in examined group was 54,3 years, an average time of presence of psoriasis symptoms was approximately 20 years. An average PASI value was 21,4; an average BSA value was 39.7%. The coexistence of type 2 diabetes was found in 14.6% of patients, hypertension in 42.7% and heart ischemic disease in 17%. Particularly large group of examined patients comprised persons with overweight (34.1%) and obesity (30.5%). Positive correlation between BSA and body weight, BSA and BMI value, BSA and abdominal circumference as well as positive correlation between PASI and body weight, PASI and BMI value, PASI and abdominal circumference were observed. Abnormal serum glucose levels were observed in 19.5% persons, ureic acid level in 2.9%, total cholesterol in 37.8% LDL cholesterol in 48.8%, and HDL cholesterol in 46.3%. CRP level was elevated in 43.9% patients. Positive correlation between BSA and ureic acid level, as well as PASI and ureic acid level was estimated. No correlation between PASI and the other laboratory parameters was found. CONCLUSIONS: The occurrence of metabolic syndrome is more common in patients with psoriasis in comparison to the general population. The extent and severity of psoriatic lesions correlate with high body weight, BMI and the level of ureic acid.

[Pemphigoid nodularis--diagnostic and therapeutic difficulties. A case report]. / Pemfigoid guzkowy--trudnosci diagnostyczne i terapeutyczne. Studium przypadku.

The case of a 62-year-old female patient diagnosed with an extremely rare clinical variant of pemphigoid--nodular pemphigoid, imitating prurigo nodularis, is presented in the paper. In connection with the existence of the typical prurigo nodularis-like appearance in the patient, the diagnosis was maintained for several months. However, because of no response to the treatment and the remarkably chronic course of the disease, the patient was admitted to the Department in order to extend the diagnostics and verify the previous diagnosis. The direct and indirect immunofluorescence examinations performed on the patient enabled the final diagnosis of a rare variant of pemphigoid without typical blisters, and effective treatment was carried out.

Association of MMP8 gene variation with an increased risk of malignant melanoma.

Matrix metalloproteinases (MMPs) are implicated in the development of cancers including malignant melanoma (MM) and breast cancer. We tested the possible association of MMP1 and MMP8 gene variation with these two types of cancer. We genotyped 300 unselected patients with MM, 300 consecutive breast cancer cases, 300 controls for melanoma, and 300 controls for breast cancer (age-matched and sex-matched healthy adults with negative cancer family histories). Our study showed that the MMP8 gene rs11225395 polymorphism was associated with the risk of developing MM (odds ratio: 1.69; 95% confidence interval: 1.02-2.80; P=0.040) for the A/A genotype and 1.49 (95% confidence interval: 1.03-2.17; P=0.035) for the A/G genotype compared with the G/G genotype. The A allele was over-represented among MM cases compared with controls (odds ratio=1.54; P=0.017). In-vitro assays showed that the A allele had a higher promoter activity than the G allele in melanoma cells. No association was detected between this variant and breast cancer susceptibility. We found no strong association between MMP1 variation and the risk of MM or breast cancer. The finding of this study indicates an influence of MMP8 gene variation on melanoma susceptibility.

Pulsed azithromycin treatment is as effective and safe as 2-week-longer daily doxycycline treatment of acne vulgaris: a randomized, double-blind, noninferiority study.

Efficacy and safety of azithromycin and doxycycline for the treatment of moderate acne vulgaris were evaluated (240 patients) in both intention-to-treat and per-protocol populations. The evaluation of clinical efficacy was based on the change in the number of facial inflammatory lesions from baseline to the end of treatment, and noninferiority was defined by the upper 95% confidence limit of the difference between two treatments being less than 9. Reduction in the number of lesions was similar with both azithromycin and doxycycline treatments (27 +/- 12 and 30 +/- 12, respectively) in both groups. Also, the upper 95% confidence limit of 5 inflammatory lesions has satisfied the noninferiority criterion. The incidence of adverse events did not differ between the two treatment groups. The shorter and simpler treatment schedule of azithromycin had similar efficacy and safety as doxycycline in the treatment of moderate acne vulgaris, confirming noninferiority of azithromycin as compared with doxycycline.

[Vitiligo as an aesthetic problem. Noninvasive therapeutic methods in vitiligo]. / Bielactwo nabyte jako problem estetyczny. Nieinwazyjne metody leczenia bielactwa.

Vitiligo is an idiopathic chronic skin disease that is notable for depigmented macules forming by destruction of melanocytes mediated by cells of the immune system. Vitiligo occurs in 1-2% of the population irrespective of race and without predilection to gender or age. The dynamics and extent of the disease vary widely, ranging from stable cases with isolated minor foci to states showing rapid progression and occupying large areas of the skin. For many patients, the disease represents a serious cosmetic defect which limits their activities in various spheres of life. There are many noninvasive methods of treatment but none of them offers a guarantee of complete therapeutic success. PUVA- and UVB-therapy are recognized as the most effective and most commonly used methods. The management of vitiligo should also include education, cosmetic correction options, and psychotherapy in some cases.

[Antimalarial drugs in contemporary dermatologic therapy]. / Miejsce leków przeciwmalarycznych we wspólczesnej terapii dermatologicznej.

Antimalarial drugs--chloroquine, hydroxychloroquine and quinacrine, initially devised for the treatment of malaria, have been used in the therapy of diverse skin diseases, including lupus erythematosus, dermatomyositis, porphyria cutanea tarda, and sarcoidosis. The mechanism of action of these drugs involves stabilization of lysosomal enzymes, inhibition of antigen-presenting cells and T lymphocyte stimulation, blocking of the pro-inflammatory cytokine cascade and endosomal toll-like receptor signaling. The understanding of potential mechanisms of action of antimalarials may extend their use to new areas in dermatology. This work describes the pharmacologic properties of antimalarial drugs and indications for their use in clinical practice. Moreover, the most important limitations of therapy with antimalarials and their adverse side effects are discussed.

[Nail diseases in cosmetology]. / Choroby paznokci w praktyce kosmetologicznej.

Clinical symptoms attributed to the nail apparatus and observed in cosmetology include atrophic or hypertrophic lesions, pathologic nail coloration, abnormalities of the nail surface, and disorders of the nail plate and bed junction. These symptoms may reflect pathologic processes limited to the nail apparatus or may be the consequence of a dermal or systemic disease. Even though the etiology of nail lesions is variegated, diseases of the nails are simply classified as infectious or non-infectious. The aim of this work was to present the most common diseases of the nail apparatus encountered in cosmetology. Often, nail diseases worsen the quality of life of the patient. In addition, the variegated symptomatology demonstrates that nail lesions should be viewed in a wider perspective because they often are important signs of pathologic processes taking place in the organism of the patient.