Tumour regression predicts better response to interferon therapy in melanoma patients: a retrospective single centre study.

We hypothesise that regression may have an impact on the effectiveness of adjuvant IFN therapy, based on its role in the host immune response. Our purpose is to investigate regression and ulceration as prognostic factors in case of interferon-alpha (IFN)-treated melanoma patients. We followed 357 IFN-treated melanoma patients retrospectively, investigating progression-free survival (PFS) and overall survival (OS) depending on the presence of ulceration and regression. A Kaplan-Meier analysis was performed, and we used a Cox regression analysis to relate risk factors. The survival function of the Cox regression was used to measure the effect of regression and ulceration on PFS and OS depending on the Breslow thickness (T1-T4) of the primary tumour. Regression was significantly positively related to PFS ( P  = 0.0018, HR = 0.352) and OS ( P  = 0.0112, HR = 0.380), while ulceration showed a negative effect (PFS: P  = 0.0001, HR = 2.629; OS: P  = 0.0003, HR = 2.388). They influence survival independently. The most favourable outcome was measured in the regressed/non-ulcerated group, whereas the worse was in the non-regressed/ulcerated one. Of risk factors, Breslow thickness is the most significant predictor. The efficacy of regression is regardless of Breslow thickness, though the more favourable the impact of regression was in the thicker primary lesions. Our results indicate that regression is associated with a more favourable outcome for IFN-treated melanoma patients, whereas ulceration shows an inverse relation. Further studies are needed to analyse the survival benefit of regression in relation to innovative immune checkpoint inhibitors.

[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.

Significant improvement in melanoma survival over the last decade: A Hungarian nationwide study between 2011 and 2019.

BACKGROUND: Recent real-world studies have reported significant improvements in the survival of malignant melanoma in the past few years, mainly as a result of modern therapies. However, long-term survival data from Central Eastern European countries such as Hungary are currently lacking. METHODS: This nationwide, retrospective study examined melanoma survival in Hungary between 2011-2019 using the databases of the National Health Insurance Fund (NHIF) and Central Statistical Office (CSO) of Hungary. Crude overall survival and age-standardized 5-year net survival as well as the association between age, sex and survival were calculated. RESULTS: Between 2011 and 2019, 22,948 newly diagnosed malignant melanoma cases were recorded in the NHIF database (47.89% male, mean age: 60.75 years (SD: ±16.39)). Five-year overall survival was 75.40% (women: 80.78%; men: 69.52%). Patients diagnosed between 2017-2019 had a 20% lower risk of mortality compared to patients diagnosed between 2011-2012 (HR 0.80, 95% CI 0.73-0.89; p < 0.0001). Age-standardized 5-year net survival rates in 2011-2014 and 2015-2019 were 90.6% and 95.8%, respectively (women: 93.1% and 98.4%, men: 87.8% and 92.7%, respectively). The highest age-standardized 5-year net survival rates were found in the 0-39 age cohort (94.6% in the 2015-2019 period). CONCLUSION: Hungary has similar melanoma survival rates to Western European countries. Based on net survival, the risk of dying of melanoma within 5 years was cut by more than half (55%) during the study period, which coincides with the successful implementation of awareness campaigns and the wide availability of modern therapies.

Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts.

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

Improving Quality Indicator of Melanoma Management - Change of Melanoma Mortality-to-Incidence Rate Ratio Based on a Hungarian Nationwide Retrospective Study.

INTRODUCTION: The incidence of melanoma has been increasing in the last decades. A retrospective Hungarian epidemiological study provided real-world data on incidence and mortality rates. There have been changing trends in incidence in Hungary in the last decade and mortality decreased, shifting mortality-to-incidence rate ratios (MIR). MIR is an indicator of cancer management quality. OBJECTIVES: Our aim is to show the changes of melanoma MIR in Hungary between 2011 and 2018 and to compare the real-world evidence-based results of our Hungarian nationwide retrospective study with other European countries. METHODS: MIR is calculated from the age-specific standardized incidence and mortality rates from our study. Annual MIR values are presented for the total population and for both sexes between 2011 and 2018, along with 95% confidence intervals. Comparison with European countries are shown for 2012 and 2018 based on the GLOBOCAN database and Eurostat health care expenditure per capita data. RESULTS: MIR decreased by 0.035 during the study years. The decrease was same in both sexes (0.031). Male had higher MIRs in all study years. In both 2012 and 2018, Hungarian MIR in both sexes was lower than the European Union average (males: 0.192 vs. 0.212 and 0.148 vs. 0.174 respectively, women: 0.107 vs. 0.129 and 0.083 vs. 0.107 respectively). DISCUSSION: Hungarian mortality-to-incidence ratio is the lowest in Central and Eastern Europe and is close to the level of Western and Northern European countries. The results are driven by the high number of new diagnosed melanoma cases.

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.

Efficacy of Biologics Targeting Tumour Necrosis Factor-alpha, Interleukin-17 -12/23, -23 and Small Molecules Targeting JAK and PDE4 in the Treatment of Nail Psoriasis: A Network Meta-analysis.

The comparative efficacy of registered anti-psoriatic biologics and small molecules in treating nail symptoms has not been systematically evaluated. The aim of this study was to perform a network meta-analysis to determine the efficacy of biologics and small mole-cules in nail psoriasis. A Bayesian network meta- analysis of 17 randomized clinical trials (a total of 6,053 nail psoriatic patients) was performed, comparing the short-term (week 10-16) efficacy of biologics and small molecules in the treatment of nail psoriasis. All active treatments were found to be superior to place-bo. Ixekizumab 80 mg every 4 weeks (Nail Psoriasis Severity Index (NAPSI) % improvement, Surface Under the Cumulative Ranking (SUCRA)=0.92) and etanercept 50 mg twice weekly (probability of achiev-ing NAPSI 50, SUCRA=0.82) proved the best short-term treatment options. However, efficacy end-points in psoriasis trials were not optimized for nail assessment, and outcome parameters were highly heterogeneous, limiting comparability. In conclusion, outcome parameters and efficacy endpoints of nail psoriasis trials should be standardized.

Periodontitis: a newly identified comorbidity in psoriasis and psoriatic arthritis.

Introduction: Psoriasis is a chronic autoimmune skin disease with strong genetic background and environmental triggers. Patients with psoriasis and psoriatic arthritis are at greater risk of developing other chronic and potentially severe comorbidities, such as psoriatic arthritis, hyperlipidemia, type 2 diabetes mellitus, obesity, metabolic syndrome, cardiovascular diseases or depression. Recently, accumulating epidemiologic, genetic and pathogenetic evidence indicates that psoriasis is also associated with periodontitis, a chronic progressive inflammatory disease, which may result in tooth loss without early and adequate therapy.Areas covered: In this review article we summarize and discuss in detail the available epidemiologic, genetic, microbiological and immunological links between psoriasis and periodontitis.Expertopinion: Periodontitis, via the immunomodulatory effect of the oral microbiota, may play both a direct and indirect role in the development or exacerbation of psoriasis, and may influence the efficacy of antipsoriatic therapy. These new findings indicate a need for increased awareness, early recognition and focus on prevention of periodontitis for patients with psoriasis.

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.

Long-term drug survival and predictor analysis of the whole psoriatic patient population on biological therapy in Hungary.

Persistence is an important component of therapeutic success, which depends on a variety of factors. Persistence measured under optimal conditions during clinical trials does not necessarily coincide with persistence observed in the real-world settings. The aim of the present study was to compare persistence rate of TNF-alpha inhibitors and interleukin 12/23 inhibitor in all psoriasis patients in Hungary, as well as to analyze the predictors of persistence. Data collected from 1263 patients over a period of 46 months were subjected to a retrospective analysis. Drug survival rate has been calculated according to Kaplan-Meier analysis and Cox regression was used to study the predictors. The overall persistence rate for the four biologicals exceeded 60% after 3 years. The persistence rate of ustekinumab at 3 years was 67.83%, which was superior compared to that of the TNF-alpha inhibitors, where the mean persistence rate was shown to be 50.76% (p < .05). Male patients showed significantly higher persistence than females (HR = .76, p < .05 CI: 0.63, 0.92). Age, therapy-naïve status and use of concomitant MTX did not have significant effect on drug survival. Persistence rate of ustekinumab was significantly higher than that of TNF-alpha inhibitors, and among predictors, only male gender influenced persistence significantly.

[How to choose the optimal therapy? New issues in the treatment of metastatic melanoma]. / Hogyan válasszunk megfelelõ szert? Új kérdések az áttétes melanoma kezelésében.

The last few years brought about a complete paradigm-shift in the field of melanoma therapy: eight new drugs, including three immunooncologic, four targeted and one oncolytic virus, became available in the daily practice. These new treatments provide a significantly increased overall survival potential for patients with metastatic melanoma. Choosing the optimal treatment for the individual patient, however, requires the careful evaluation of several patient- and drug-related factors, and poses a great challenge for the oncologists. This review summarizes the practical aspects of the selection of the optimal melanoma treatment.

Presence of antidrug antibodies correlates inversely with the plasma tumor necrosis factor (TNF)-α level and the efficacy of TNF-inhibitor therapy in psoriasis.

Antidrug antibodies have been shown to be associated with a loss of response during biologic therapy. Despite the potential association, there has been no report on the simultaneous monitoring of the following parameters in psoriasis: presence of neutralizing antibodies, plasma tumor necrosis factor (TNF)-α concentration, TNFi concentration and disease activity. Plasma concentrations of adalimumab, infliximab, etanercept and their respective antidrug antibodies, as well as plasma concentrations of TNF-α were measured in 77 psoriasis patients receiving biologic therapy, and the values were correlated with the clinical activity of the skin disease. Antidrug antibodies were identified in the plasma of 25% of infliximab-treated patients and 29.6% of adalimumab-treated patients, but not in the etanercept group. Clinical severity scores were significantly higher in the antibody-positive patients. In patients receiving infliximab or adalimumab therapy, the presence of antidrug antibodies was directly associated with reduced plasma TNF-inhibitor concentration and elevated plasma TNF-α level.

Utility of serum TNF-α, infliximab trough level, and antibody titers in inflammatory bowel disease.

AIM: To assess tumor necrosis factor-α (TNF-α), infliximab (IFX) concentrations, and antibodies against IFX molecules in patients with inflammatory bowel disease (IBD) who develop loss of response, side effects, or allergic reaction during anti TNF-α therapy. METHODS: Blood samples of 36 patients with response loss, side effects, or hypersensitivity to IFX therapy (Group I) and 31 patients in complete clinical remission (Group II) selected as a control group were collected to measure trough serum TNF-α level, IFX, and anti-IFX antibody (ATI) concentration. We examined the correlation between loss of response, the development of side effects or hypersensitivity, and serum TNF-α, IFX trough levels, and ATI concentrations. RESULTS: The serum TNF-α level was shown to be correlated with the presence of ATI; ATI positivity was significantly correlated with low trough levels of IFX. ATIs were detected in 25% of IBD patients with loss of response, side effects, or hypersensitivity, however no association was revealed between these patients and antibody positivity or lower serum IFX levels. Previous use of IFX correlated with the development of ATI, although concomitant immunosuppression did not have any impact on them. CONCLUSION: On the basis of the present study, we suggest that the simultaneous measurement of serum TNF-α level, serum anti TNF-α concentration, and antibodies against anti TNF-α may further help to optimize the therapy in critical situations.

Smoking as a permissive factor of periodontal disease in psoriasis.

BACKGROUND: Population-based studies have identified smoking as a pathogenetic factor in chronic periodontitis. At the same time, chronic periodontal disease has also been found to occur more often in persons suffering from psoriasis than in controls with no psoriasis. It is known that smoking aggravates both periodontal disease and psoriasis, but so far it has not been investigated how smoking influences the occurrence and severity of periodontal disease in psoriasis. METHODS: A hospital-based study was conducted to investigate this question. The study population consisted of 82 psoriasis patients and 89 controls. All patients received a full-mouth periodontal examination, and a published classification based on bleeding on probing, clinical attachment level and probing depth was utilized for staging. Both patients and controls were divided into smoker and non-smoker groups, and the resulting groups were compared in terms of periodontal status. Beyond the descriptive statistics, odds ratios were computed. RESULTS: Psoriasis in itself increased the likelihood of severe periodontal disease to 4.373 (OR, as compared to non-smoker controls, p<0.05), while smoking increased it to 24.278 (OR, as compared to non-smoker controls, p<0.001) in the studied population. In other words, the risk of severe periodontal disease in psoriasis turned out to be six times higher in smokers than in non-smokers. CONCLUSIONS: The results of this study corroborate those of other studies regarding the link between psoriasis and periodontal disease, but they also seem to reveal a powerful detrimental effect of smoking on the periodontal health of psoriasis patients, whereby the authors propose that smoking may have a permissive effect on the development of severe periodontal disease in psoriasis.

Genetic risk and protective factors of TNFSF15 gene variants detected using single nucleotide polymorphisms in Hungarians with psoriasis and psoriatic arthritis.

The aim of this study was to examine the role of single nucleotide polymorphisms (SNPs) and haplotypes of the tumor necrosis factor ligand superfamily member 15 (TNFSF15) gene in Hungarians with psoriasis and psoriatic arthritis. A case-control study was performed, and five TNFSF15 SNPs (rs3810936, rs6478108, rs6478109, rs7848647, rs7869487) were genotyped in 319 patients with psoriasis, 105 of whom also have psoriatic arthritis, and in 200 healthy individuals. Three haplotypes (A, B, C) based on these five SNPs were also analyzed. Our findings suggest that the rs6478109 SNP may be a genetic risk factor in psoriasis (p=0.0046), while haplotype C may be protective (p=0.0250). These results suggest that certain variants of the TNFSF15 gene contribute to the pathogenesis of the immune-mediated, multifactorial skin disease psoriasis, and that this difference is more readily apparent when groups of patients with and without psoriatic arthritis are examined separately.

Higher levels of autoantibodies targeting mutated citrullinated vimentin in patients with psoriatic arthritis than in patients with psoriasis vulgaris.

Antibodies against citrullinated proteins/peptides (ACPAs), and especially antibodies targeting mutated citrullinated vimentin (anti-MCVs), are novel biomarkers of rheumatoid arthritis (RA). Whereas ACPAs are specific and sensitive markers for RA, there have hardly been any reports relating to ACPAs in psoriatic arthritis (PsA) or in psoriasis without joint symptoms (PsO). The aim of the present study was to investigate the prevalence of anti-MCVs in PsA and PsO. Serum anti-MCV titers were measured in 46 PsA and 42 PsO patients and in 40 healthy controls by means of a commercial enzyme-linked immunosorbent assay. The potential correlations of the serum autoantibody levels with several clinical and laboratory parameters were examined. The anti-MCV levels in the PsA patients were significantly higher than those in the PsO group. Among the clinical variables, the presence of tender knee joints and nail psoriasis was significantly associated with anti-MCV positivity in the PsA patients. Higher anti-MCV titers in the PsO patients were associated with a more severe disease course and with the early onset of psoriatic skin symptoms. Our results suggest that anti-MCVs can be used as novel markers in the diagnosis of PsA and in a subset of PsO patients.

[Fluorescence diagnosis of non-melanoma skin cancer]. / Hámeredetu bordaganatok fluoreszcens diagnosztikája.

Photodynamic therapy involves - in dermatological practice usually exogenous - application of a photosensitizer then activation of accumulated protoporphyrin IX by light with an appropriate wavelength after a short incubation period. It is an evidence based method to treat certain non-melanoma skin cancers. During treatment when the excited protoporphyrin IX returns to base state, reactive oxygen species are formed leading to cell death in rapidly proliferating cells. Fluorescence of excited protoporphyrin IX can be used in diagnostics as well. In ultraviolet light, the photodamaged or neoplastic areas show coral red fluorescence which can clearly be distinguished from the much lower fluorescence of adjacent normal tissue. This process is suitable for exact determination of tumor margins so it can be used for planning surgical procedures or after photodynamic therapy at a follow up visit for the visualization of the therapeutic result. The present article reviews the literature of photodynamic diagnosis that is also used by the authors.

Successful treatment of multiple basaliomas with bleomycin-based electrochemotherapy: a case series of three patients with Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome is a rare multisystemic disease, characterized by numerous basal cell carcinomas. The ideal approach for patients with the syndrome would be a treatment with a high cure rate, minimal scarring, short healing time and mild side-effects. Electrochemo-therapy is a novel therapeutic option that ablates tumours with electrical current and simultaneously administered anticancer drugs. Three patients with Gorlin-Goltz syndrome were treated with electrochemotherapy using intravenous bleomycin. Clinical response was obtained in 98 (99%) of the lesions, 86 (87%) of them showed complete response. In 2 tumours, regression was confirmed with histological examination. Long-term cosmetic results were excellent. We consider electrochemotherapy to be an additional tool in the therapeutic armamentarium for Gorlin-Goltz syndrome, and suggest using it as early as possible in selected patients to avoid disfiguring scarring.