Evaluation of the effects of Lake Hévíz sulfur thermal water on skin microbiome in plaque psoriasis: An open label, pilot study.

Psoriasis is a chronic inflammatory skin disease. It is associated with changes in skin microbiome. The aim of this study was to evaluate how Lake Hévíz sulfur thermal water influences the composition of microbial communities that colonizes skin in patients with psoriasis. Our secondary objective was to investigate the effects of balneotherapy on disease activity. In this open label study, participants with plaque psoriasis underwent 30-min therapy sessions in Lake Hévíz, at a temperature of 36 °C, five times a week for 3 weeks. The skin microbiome samples were collected by swabbing method from two different areas (lesional skin-psoriatic plaque and non-lesional skin). From 16 patients, 64 samples were processed for a 16S rRNA sequence-based microbiome analysis. Outcome measures were alpha-diversity (Shannon, Simpson, and Chao1 indexes), beta-diversity (Bray-Curtis metric), differences in genus level abundances, and Psoriasis Area and Severity Index (PASI). Skin microbiome samples were collected at baseline, and immediately after treatment. Based on the visual examination of the employed alpha- and beta-diversity measures, no systematic difference based on sampling timepoint or sample location could be revealed in these regards. Balneotherapy in the unaffected area significantly increased the level of Leptolyngbya genus, and significantly decreased the level of Flavobacterium genus. A similar trend was revealed by the results of the psoriasis samples, but the differences were not statistically significant. In patients with mild psoriasis, a significant improvement was observed in PASI scores.

Expression Patterns of Clock Gene mRNAs and Clock Proteins in Human Psoriatic Skin Samples.

Psoriasis is a systemic inflammatory skin disorder that can be associated with sleep disturbance and negatively influence the daily rhythm. The link between the pathomechanism of psoriasis and the circadian rhythm has been suggested by several previous studies. However, there are insufficient data on altered clock mechanisms in psoriasis to prove these theories. Therefore, we investigated the expression of the core clock genes in human psoriatic lesional and non-lesional skin and in human adult low calcium temperature (HaCaT) keratinocytes after stimulation with pro-inflammatory cytokines. Furthermore, we examined the clock proteins in skin biopsies from psoriatic patients by immunohistochemistry. We found that the clock gene transcripts were elevated in psoriatic lesions, especially in non-lesional psoriatic areas, except for rev-erbα, which was consistently downregulated in the psoriatic samples. In addition, the REV-ERBα protein showed a different epidermal distribution in non-lesional skin than in healthy skin. In cytokine-treated HaCaT cells, changes in the amplitude of the bmal1, cry1, rev-erbα and per1 mRNA oscillation were observed, especially after TNFα stimulation. In conclusion, in our study a perturbation of clock gene transcripts was observed in uninvolved and lesional psoriatic areas compared to healthy skin. These alterations may serve as therapeutic targets and facilitate the development of chronotherapeutic strategies in the future.

Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy.

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3+ cells and CD8+ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16+ and CD68+ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

Diagnosis of Skin Cancer: From the Researcher Bench to the Patient's Bedside.

The overall incidence and prevalence of skin cancer have shown a significant increase worldwide in the last several decades [...].

Altered expression patterns of clock gene mRNAs and clock proteins in human skin tumors.

The majority of our genes may be regulated in a daily rhythm, including the genes for cell cycle control. Epidemiological and genetic evidences suggest that disruption of circadian timing mechanisms makes our cells more vulnerable to cancer formation. The aim of this study was to investigate the relationship between expression patterns of circadian clock genes (period homolog (per)1, per2, clock, and cry1) and tumor development by analyzing human skin biopsies of malignant melanoma and nonmalignant naevus tumors. We found that mRNA levels and nuclear immunopositivity for the investigated clock genes were reduced by 30-60 % in both melanoma and in naevus biopsies if compared with adjacent nontumorous samples. The alterations in melanoma presented significant associations with clinicopathological characteristics (e.g., Breslow thickness). Contrary to previous reports, the moderate decrease of per1 expression seen in malignant tissues could not be linked to malignant transformation itself; rather, it reflects only the alterations in tissue composition. In turn, clock expression was upregulated in nontumorous cells of melanoma biopsies but not in melanoma cells or naevus cells. As this gene (clock) is closely related to cellular metabolism, our data suggest its role in the impaired regulation of metabolism in malignant tumors. Our results present the first clinical evidence for a possible link between circadian clock genes and human skin tumorigenesis.

Circadian clocks and tumor biology: what is to learn from human skin biopsies?

Some of the components of the circadian molecular clock have been shown to link directly to tumor suppression. Most studies on human tumorous biopsies with consistently down-regulated clock gene expression suggested a protective role for these genes against cancer formation. To highlight some limitations of this hypothesis we review these data in light of recent evidences from animal research, epidemiologic studies, and clinical data on skin tumors. We emphasize the role of circadian rhythmic orchestration in cellular metabolism with a potential in cancer development.

[Surgery for malignant melanoma - Expected standards]. / A melanoma malignum sebészeti ellátása ­ Elvárható standardok.

Melanoma surgery has changed significantly in recent years. The highly radical operations with many complications, in addition to which the complete and disease-free survival remained low, were gradually replaced by less radical operations. With the introduction of new systemic treatments (targeted and immuno-oncological) in adjuvant indications, certain surgeries, such as elective block dissections, have now been displaced from surgical treatments and the role of surgery has also been re-evaluated. The surgery for primary tumor removal, reexcision, sentinel lymph node biopsy and lymph region surgery, and surgical treatment of skin and distant metastases have changed. In this summary communication, the authors provide an overview of the currently accepted surgical therapy of melanoma malignum based on the international literature and their own practice.

[Dermoscopy of inflammatory skin diseases]. / Dermatoskopie entzündlicher Hauterkrankungen.

The dermoscope was initially used in dermatology to distinguish between pigmented and nonpigmented tumors, both benign and malignant. Over the last two decades, however, the spectrum of dermoscopy has broadened and its role in the diagnosis of nonneoplastic diseases, in particular inflammatory skin diseases, has become increasingly important. In the diagnosis of general and inflammatory skin diseases, it is recommended that dermoscopic evaluation should be performed after clinical examination. In the following summary, the dermoscopic features of the most common inflammatory skin diseases are described. Among the detailed parameters are the vascular structures, color, scaling, follicular findings, and specific signs associated with each disease.

Results of a Primary Skin-Cancer-Prevention Campaign in Early Childhood on Sun-Related Knowledge and Attitudes in Southern Hungary.

Avoidance of ultraviolet (UV) exposure in early childhood is important for reducing the lifetime risk of developing skin cancer. The goal of the present prospective, multicenter pilot study was to assess the sun-protection practices in kindergartens and daycare centers and to evaluate sun protection knowledge and behavior among caregivers employed in the surveyed facilities. The study consisted of two parts. A baseline questionnaire was completed by the caregivers in relation to knowledge regarding basic sun protection and sun protection practices of the participating facilities. Afterward, a thirty-minute presentation was hosted in reference to this topic. Six months following the presentation, a follow-up questionnaire was distributed among the caregivers, evaluating the attitude-related and behavioral changes towards children. A total of 153 caregivers from five daycare centers (children between 6 months and 3 years of age) and sixteen kindergartens (children between 3 and 7 years of age) willfully participated in our study. According to our results, the main source of information regarding sun protection originated from different types of media. We found that staying in shaded areas and the use of protective clothing were not frequent in the facilities. Following our presentation regarding skin types and sunscreen use, protective measures improved, but not significantly (p = 0.222). The majority (92.31%) of caregivers distributed the information throughout their environment and also to parents. Sun protection knowledge is necessary; however, motivation among caregivers and parents and involvement of children is also relevant. Hence, a continuous, repetitive educational program regarding sun-smart behavior is deemed essential.

The significance of imaging examinations during follow-up for malignant melanoma.

Currently, there is a general lack of consensus regarding optimal strategy and imaging during follow-up for patients suffering from melanoma. Our aim was to analyse the utility of various imaging procedures, in particular CT scans, during the follow-up of patients with different stages of melanoma. A retrospective analysis of the medical records of patients suffering from melanoma diagnosed between 2001 and 2011 was carried out at the Department of Dermatology, University of Pécs. Patients with in situ (Stage 0) and metastatic (Stage IV) melanoma were excluded from the analysis, as well as patients who succumbed during the first three years of follow-up. In total, 649 melanoma patients met the inclusion criteria. During the entire follow-up period, 90 recurrences were detected. The vast majority (n = 71; 79%) of the total metastatic cases (n = 90) were diagnosed within the first three years. In 35% of the cases, metastases were detected by CT. Although more than 66% of the CT scans were performed for Stage I patients, only three cases were positive (0.1%) within this population. On the basis of our results, intensive radiological work-up is not deemed necessary during the surveillance of patients in the early stages (IA-IIA) of melanoma. Initial and regular follow-up imaging examinations (preferably CT scans) may be recommended from Stage IIB of the disease.

Clinical, Laboratory and Histological Features of Dipeptidyl Peptidase-4 Inhibitor Related Noninflammatory Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering disease of elderly patients that has shown increasing incidence in the last decades. Higher prevalence of BP may be due to more frequent use of provoking agents, such as antidiabetic dipeptidyl peptidase-4 inhibitor (DPP4i) drugs. Our aim was to assess DPP4i-induced bullous pemphigoid among our BP patients and characterize the clinical, laboratory and histological features of this drug-induced disease form. In our patient cohort, out of 127 BP patients (79 females (62.2%), 48 males (37.7%)), 14 (9 females and 5 males) were treated with DPP4i at the time of BP diagnosis. The Bullous Pemphigoid Disease Area Index (BPDAI) urticaria/erythema score was significantly lower, and the BPDAI damage score was significantly higher in DPP4i-BP patients compared to the nonDPP4i group. Both the mean absolute eosinophil number and the mean periblister eosinophil number was significantly lower in DPP4i-BP patients than in nonDPP4i cases (317.7 ± 0.204 vs. 894.0 ± 1.171 cells/µL, p < 0.0001; 6.75 ± 1.72 vs. 19.09 ± 3.1, p = 0.0012, respectively). Our results provide further evidence that DPP4i-associated BP differs significantly from classical BP, and presents with less distributed skin symptoms, mild erythema, normal or slightly elevated peripheral eosinophil count, and lower titers of BP180 autoantibodies. To our knowledge, this is the first case series of DPP4i-related BP with a non-inflammatory phenotype in European patients.

Beneficial Effect of Lenalidomide-Dexamethason Treatment in Relapsed/Refractory Multiple Myeloma Patients: Results of Real-Life Data From 11 Hungarian Centers.

In Hungary, the cost of lenalidomide-based therapy is covered only for relapsed multiple myeloma (MM) patients, therefore lenalidomide is typically used in the second-line either as part of a triplet with proteasome inhibitors or as a doublet. Lenalidomide-dexamethasone is a standard treatment approach for relapsed/refractory MM, and according to recent large randomized clinical trials (RCT, the standard arm of POLLUX, ASPIRE, TOURMALINE), the progression-free survival (PFS) is expected to be approximately 18 months. We surveyed ten Hungarian centers treating MM and collected data of 278 patients treated predominantly after 2016. The median age was 65 years, and patients were distributed roughly equally over the 3 international staging system groups, but patients with high risk cytogenetics were underrepresented. 15.8% of the patients reached complete response, 21.6% very good partial response, 40.6% partial response, 10.8% stable disease, and 2.5% progressed on treatment. The median PFS was unexpectedly long, 24 months, however only 9 months in those with high risk cytogenetics. We found interesting differences between centers regarding corticosteroid type (prednisolone, methylprednisolone or dexamethasone) and dosing, and also regarding the choice of anticoagulation, but the outcome of the various centers were not different. Although the higher equivalent steroid dose resulted in more complete responses, the median PFS of those having lower corticosteroid dose and methylprednisolone were not inferior compared to the ones with higher dose dexamethasone. On multivariate analysis high risk cytogenetics and the number of prior lines remained significant independent prognostic factors regarding PFS (p < 0.001 and p = 0.005). Our results show that in well-selected patients Lenalidomide-dexamethasone can be a very effective treatment with real-world results that may even outperform those reported in the recent RCTs. This real world information may be more valuable than outdated RCT data when treatment options are discussed with patients.

[The complex dental and oral surgical management with 8-year follow up of a Gorlin‒Goltz syndrome patient]. / Gorlin­Goltz-szindrómás beteg komplex fogorvosi, szájsebészeti kezelése és 8 éves követése.

Gorlin-Goltz syndrome is an autosomal dominant hereditary disease. Its leading symptoms include keratocysts of the jaws, multiple basal cell carcinomas, skeletal abnormalities, intracranial calcifications and dyskeratosis of the soles and palms. One of the most common and often firstly discovered symptoms is the single or multiplex keratocysts of the jaws. The authors present a case of a child, diagnosed in their orthodontic department. Despite the rare occurrence of the disease, an early detection is important, especially in young patients. Regular follow-up and timely care for patients may avoid life-threatening malformations and radical surgical treatments. Orv Hetil. 2020; 161(2): 67-74.

Congenital ichthyosis associated with Trichophyton rubrum tinea, imitating drug hypersensitivity reaction.

Tinea corporis and congenital ichthyoses are common dermatological diseases. The association of the two disorders is plausible due to the immunological and barrier defects of ichthyoses; however, relatively limited literature is available in this field. Since superficial fungal infections possess atypical morphology in keratinization disorders, and could imitate other dermatological conditions, the correct diagnosis can be challenging. We present the case of a 54-year-old woman with ichthyosis, who was initially treated for drug-hypersensitivity reaction.

Role of the anatomic site in the association of HLA class I antigen expression level in metastases with clinical response to ipilimumab therapy in patients with melanoma.

BACKGROUND: The clinical response to immune checkpoint inhibitors (ICIs) in only part of the treated patients, in conjunction with the potentially serious side effects associated with this type of therapy, has emphasized the need to identify biomarkers to select patients who may benefit from ICI treatment. The aim of our study was to test human leukocyte antigen (HLA) class I and II expression in melanoma metastases as potential biomarkers of response to ipilimumab and survival in patients with metastatic melanoma, since these molecules play a crucial role in the interactions of malignant cells with host's immune system. MATERIALS AND METHODS: HLA class I and II antigen expression level in pretreatment surgical tissue samples (50 lymph node and 35 cutaneous or subcutaneous metastases) from 30 patients was analyzed by immunohistochemical staining with monoclonal antibodies. Expression levels were correlated to intratumoral density of lymphocytes expressing cluster of differentiation (CD)8, CD45RO, CD4, forkhead box P3 (FOXP3) and/or programmed cell death protein 1 (PD-1), to clinical response to treatment, and to patients' survival. RESULTS: HLA class I antigen expression level in lymph node metastases, but not in cutaneous or subcutaneous metastases was significantly correlated to density of CD8+ and CD45RO+ T cells and of lymphocytes expressing PD-1, as well as to clinical response and to patients' survival. CONCLUSIONS: Our results corroborate the role of HLA class I expression level (alone or in combination with T-cell density values) as a predictive biomarker of response to ipilimumab in patients with melanoma. In addition, our results show that this association is influenced by the anatomic site of the metastasis used to measure the HLA class I antigen expression level.

Poly(adenosine diphosphate-ribose) polymerase-1 expression in cutaneous malignant melanomas as a new molecular marker of aggressive tumor.

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes, which catalyses poly (ADP-ribosyl)ation of DNA-binding proteins and directly involved in genomic stability, DNA repair, and apoptosis. In this study, we evaluated the immunomorphology of PARP-1 in melanoma and its prognostic importance. We studied PARP-1 expression by immunohistochemistry in a selected series of 54 primary cutaneous malignant melanoma (CMM). The findings of the present study suggest that the neoplastic progression toward the invasive (both horizontal and vertical) growth phase of CMM cells is characterized by the loss of cleavage of PARP-1, probably signaling an imbalance of the apoptotic process in these cells and leading to further gain to aggression. Over-expression of full-length PARP-1 was correlated with recurrence and/or progression of the disease and so act as a promising new biological marker of CMM. Our study represents the evidence of a direct correlation between the PARP-1-mediated apoptotic process and the biologic behavior of CMM.

Possible immunotherapies of skin cancers / A bordaganatok immunterápiás kezelési lehetoségei

Skin cancers represent the most common type of malignancy. The incidence rate of melanoma and non-melanoma skin cancer depicts a continuous rise worldwide, which is attributed mainly (but not exclusively) to the growing incidence of non-melanoma skin cancer in the elderly population. Most skin cancer types are sensitive to immunotherapy. Melanoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma showed response rates of at least 40% for PD-1 inhibitor therapy as reported in recent articles. In this article we review the current and future immunotherapy agents and procedures for skin cancers.

Efficacy of weight loss intervention can be predicted based on early alterations of fMRI food cue reactivity in the striatum.

Increased fMRI food cue reactivity in obesity, i.e. higher responses to high- vs. low-calorie food images, is a promising marker of the dysregulated brain reward system underlying enhanced susceptibility to obesogenic environmental cues. Recently, it has also been shown that weight loss interventions might affect fMRI food cue reactivity and that there is a close association between the alteration of cue reactivity and the outcome of the intervention. Here we tested whether fMRI food cue reactivity could be used as a marker of diet-induced early changes of neural processing in the striatum that are predictive of the outcome of the weight loss intervention. To this end we investigated the relationship between food cue reactivity in the striatum measured one month after the onset of the weight loss program and weight changes obtained at the end of the six-month intervention. We observed a significant correlation between BMI change measured after six months and early alterations of fMRI food cue reactivity in the striatum, including the bilateral putamen, right pallidum, and left caudate. Our findings provide evidence for diet-induced early alterations of fMRI food cue reactivity in the striatum that can predict the outcome of the weight loss intervention.

Subchronic heavy metal and alcohol treatment in rats: changes in the somatosensory evoked cortical activity.

Young adult male Wistar rats were treated, by gavage, with 80 or 320 mg/kg Pb2+ (lead acetate), 0.4 or 1.6 mg/kg Hg2+ (mercuric chloride) or both by combining the lower doses. For combination with alcohol, ethanol was added to the rats' drinking water in 5 v/v %. After 12 weeks of treatment, electrophysiological recording was made from the somatosensory cortex in urethane anaesthesia. Evoked potentials obtained by stimulation of the whiskers were recorded. Both metals, and alcohol alone, increased significantly the latency of the evoked response. Alcohol seemed to abolish the effect of Pb, but not of Hg. Fatigue, calculated form the response amplitude, was increased by Pb and Hg treatment and this effect of Hg was reduced by ethanol. Evoked activity and its dynamic characteristics were sensitive to the complex neurotoxic effect induced in the rats and can provide a basis for developing functional markers.