Does the effectiveness of biological medications in the treatment for psoriasis depend on the moment of starting therapy? A preliminary study.

Introduction: It is well known that biological medications acting on selected elements of the immune response are highly effective in psoriasis treatment. It is a common perception that psoriasis is a seasonal disorder with improvement in warmer months, however it has not been unequivocally confirmed. It is not known whether the time of year of starting systematic therapy for psoriasis influences treatment outcomes. Material and methods: Changes in psoriasis severity scores during treatment with biologics were investigated. The scores were recorded for 62 patients with moderate to severe psoriasis at the beginning, after 1, 4 and 7 months of the therapy. Patients were divided into two groups: those beginning the treatment in the cold period of the year (November-March) and in the warm period (May-September). The seasonal groups were also divided into subgroups according to the type of biologics used: interleukin inhibitors and tumor necrosis factor α (TNF-α) inhibitors. Results of the treatment were analysed using standard statistical tests of differences between samples. Results: After 1 and 4 months of the therapy, better efficacy of interleukin inhibitors was found in patients starting treatment in summer. The course of psoriasis improvement in patients taking TNF-α inhibitors resulted in consistent improvement regardless of the season. The outcome of the treatment after 7 months was similar for both seasonal groups and types of biologics used. Conclusions: Our understanding of the effectiveness of the treatments depending on the time of the year combined with the type of biologics used, may further improve results of the therapy.

Promising Immune Treatment of Advanced Cutaneous Squamous Cell Carcinoma with Cemiplimab-Real-World Experience in the Global SARS-CoV-2 Pandemic.

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent non-melanoma skin cancer. The standard curative treatment is surgical resection, but the treatment of locally advanced and metastatic disease apart from radiotherapy is currently based on cemiplimab. Cemiplimab has demonstrated efficacy in the treatment of advanced and metastatic cSCC in clinical trials, although real-world data are still limited. We present four cases of cSCC, which showed a tremendous response to cemiplimab-one patient achieved complete response and three of them achieved partial response. Immunotherapy with cemiplimab, a recently approved PD1 inhibitor, is an important addition to the cutaneous oncology therapeutic options that may be considered in patients with advanced disease not amenable to surgery or radiotherapy. In all four cases, the patients postponed visits to the doctor because of the fear of SARS-CoV-2 infection or for administrative and organizational reasons declared difficult access to doctors caused by the pandemic.

The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy.

The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient's immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our pilot, a single arm prospective study, enrolled patients with rectal cancer who qualified for neoadjuvant chemoradiotherapy. Blood samples for Flt-3L were collected before and every second week of chemoradiotherapy for a complete blood count every week. The kinetics of Flt-3L were assessed using Friedman's ANOVA. A multiple factor analysis (MFA) was performed to find relevant factors affecting levels of serum Flt-3L during chemoradiotherapy. FactoMineR and factoextra R packages were used for analysis. In the 33 patients enrolled, the level of Flt-3L increased from the second week and remained elevated until the end of treatment (p < 0.01). All patients experienced Grade ≥2 lymphopenia with a nadir detected mostly in the 5/6th week. MFA revealed the spatial partitioning of patients among the first and second dimensions (explained by 38.49% and 23.14% variance). The distribution along these dimensions represents the magnitude of early changes of Flt-3L. Patients with the lowest values of Flt-3L change showed the highest lymphocyte nadirs and lowest dose/volume parameters of active bone marrow. Our hypothesis-generating study supports the concept of early initiation of immuno-therapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred.

Risk Factors and Clinicopathological Features for Developing a Subsequent Primary Cutaneous Squamous and Basal Cell Carcinomas.

BACKGROUND: Patients with diagnosed keratinocyte carcinomas (KCs) have an increased risk of subsequent skin cancers development. Current studies indicate that patients with subsequent tumors should be followed up regularly. However, none of the studies indicate the connection between the specific subtypes and an increased risk for further KCs development. The study assesses the differences in the risk of developing a subsequent skin cancer after a previous diagnosis of KC, especially considering individual types of skin malignances, and identifies potential factors associated with an increased risk of new cutaneous tumor describing non-invasive diagnosis and monitoring. METHODS: Pathology and medical records were examined to identify the characteristics of patients with multiple KCs diagnosed between 1999 and 2019. RESULTS: The study group comprised 13,913 KCs occurring in 10,083 patients. Multiple KCs were observed in 2300 patients (22.8%). The analysis showed aggressive subtypes, multiple tumors, and male sex as significant prognostic factors. CONCLUSIONS: The most crucial risk factors for developing subsequent KC are being of a male gender, an aggressive tumor subtype, and previous history of multiple skin cancers. Basal cell carcinoma subtypes, such as infiltrative basosquamous, with aggressive growth patterns predispose not only to increased risk for the recurrence but are also expected to be at higher risk of subsequent KCs.

The role of inflammasomes in cutaneous pathology.

Inflammasomes are large intracellular multiprotein complexes, which constitute a novel part of the innate immune system. In response to danger signals from pathogens or other harmful agents, inflammasomes assemble resulting in production of the inflammatory cytokines. We discuss recent knowledge of the role of deregulated inflammasome activity in skin pathologies such as autoinflammatory diseases as well as common skin diseases such as psoriasis and atopic dermatitis. We also present an insight into the activation and effector mechanisms of inflammasomes in skin carcinogenesis. The complex influence of inflammasome on cutaneous disorders raises new challenges and opportunities for the treatment of skin diseases.

More Than Skin Deep - the Effects of Ultraviolet Radiation on Cathepsin K and Progerin Expression in Cultured Dermal Fibroblasts.

INTRODUCTION: Photoaging is a premature skin aging developing secondarily to the excessive exposure to ultraviolet radiation. Due to its complexity, an exact mechanism of photoaging has not been found yet; however, recent research has shown two new emerging players in this process - cathepsin K and progerin. AIM: To evaluate how different wavelengths of ultraviolet radiation (UVA, narrowband UVB and broadband UVB) influence cathepsin K and progerin protein and mRNA expression in dermal cultured fibroblasts. MATERIALS AND METHODS: Primary human dermal fibroblasts (Detroit 551, ATCC CCL-110) were cultured and irradiated with UVA, narrowband UVB (UVBnb) and broadband UVB (UVBwb). Fibroblasts were irradiated with 2 protocols: single high-dose exposure to UVR with protein/mRNA extraction immediately after exposure, 24 h after exposure and 48 h after exposure, and repeated (0 h, 24 h and 48 h) low-dose exposure to UVR with protein/mRNA extraction 48 h after first exposure. RESULTS: Single high doses of UVA, UVBwb and UVBnb resulted in decreased expression of cathepsin K and progerin protein/mRNA in all subsequent time points. Repeated exposure to low doses of UVA results in significant increase of progerin mRNA and significant decrease of progerin protein after 48 h, but repeated exposure to UVBwb and UVBnb resulted in decreased progerin mRNA and protein expression. Repeated exposure to UVA, UVBwb and UVBnb resulted in decreased cathepsin K protein and mRNA expression. CONCLUSION: The results suggest that there could be another progerin/cathepsin K regulatory pathway, which has not been described yet. Being contradictory with previous research, the influence of ultraviolet radiation on progerin and cathepsin K needs to be further elucidated.

Tumor of the Nose - A Rare Manifestation of a Metastatic Lung Cancer.

Lung cancer most often metastasizes to the central nervous system, bone and liver. Although metastases to the skin are quite rare, it is estimated that they may be the first clinical manifestation of this disease in 0.7%-12% of cases. Metastases to the skin are caused by adenocarcinoma (about 30%), squamous cell carcinoma (30%) and undifferentiated carcinoma (40%). Nasal tip metastases are extremely rare. They can be confused with more common skin problems, including non-melanoma skin cancers, rhinophyma, inflammatory tumors or infectious diseases. We report two patients with a tumor on the nose, which proved to be the first sign of the metastatic lung cancer.

Hippo Signaling Pathway as a New Potential Target in Non-Melanoma Skin Cancers: A Narrative Review.

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are the most frequently diagnosed cancers in humans, however, their exact pathogenesis is not fully understood. In recent years, it has been hypothesized that the recently discovered Hippo pathway could play a detrimental role in cutaneous carcinogenesis, but no direct connections have been made. The Hippo pathway and its effector, YAP, are responsible for tissue growth by accelerating cell proliferation, however, YAP upregulation and overexpression have also been reported in numerous types of tumors. There is also evidence that disrupted YAP/Hippo signaling is responsible for cancer growth, invasion, and metastasis. In this short review, we will explore whether the Hippo pathway is an important regulator of skin carcinogenesis and if it could be a promising target for future therapies.

AntiTNF-alpha therapy normalizes levels of lipids and adipokines in psoriatic patients in the real-life settings.

Studies have shown that the levels of pro-inflammatory adipokines in patients with psoriasis are higher than in general population. The aim of the study was to investigate the influence of 36-month therapy with TNF-α inhibitors (adalimumab, etanercept, infliximab) on the levels of adipokines (resistin, adiponectin, leptin) and lipids (TG, cholesterol, LDL, HDL) in 37 psoriasis patients and 30 healthy controls. The mean serum concentrations of adiponectin in patients from adalimumab, etanercept and infliximab group were similar to control group (p > 0.05, 142.71, 164.32, 129.35 and 174.44 µg/ml respectively). Resistin levels were higher in patients (p < 0.05, 4.48, 4.53 and 3.39 ng/ml respectively) than in controls (3.05 ng/ml). Mean leptin concentrations were significantly higher (p < 0.05) in the study group than in subjects without psoriasis (428.61, 523.24, 755.27 and 154.10 pg/ml respectively). A significant decrease in the mean resistin concentration was observed under the influence of biological therapy (p < 0.05). Decrease in serum leptin level was noted in etanercept and infliximab groups (p = 0.001 and p = 0.002 respectively). Improvement in all lipidogram parameters was noted in all examined groups (p < 0.05). Results may prove that biologic therapy affects the systemic inflammation associated with psoriasis and this effect persists with long-term therapy.

Ultraviolet Radiation and Chronic Inflammation-Molecules and Mechanisms Involved in Skin Carcinogenesis: A Narrative Review.

The process of skin carcinogenesis is still not fully understood. Both experimental and epidemiological evidence indicate that chronic inflammation is one of the hallmarks of microenvironmental-agent-mediated skin cancers and contributes to its development. Maintaining an inflammatory microenvironment is a condition leading to tumor formation. Multiple studies focus on the molecular pathways activating tumorigenesis by inflammation and indicate several biomarkers and factors that can improve diagnostic and prognostic processes in oncology and dermatology. Reactive oxygen species produced by ultraviolet radiation, oxidizers, or metabolic processes can damage cells and initiate pro-inflammatory cascades. Considering the potential role of inflammation in cancer development and metastasis, the identification of early mechanisms involved in carcinogenesis is crucial for clinical practice and scientific research. Moreover, it could lead to the progress of advanced skin cancer therapies. We focus on a comprehensive analysis of available evidence and on understanding how chronic inflammation and ultraviolet radiation can result in skin carcinogenesis. We present the inflammatory environment as complex molecular networks triggering tumorigenesis and constituting therapeutic targets.

Correlation of the ALA-PDT Treatment Efficacy and the HPV Genotype Profile of Genital Warts after Cryotherapy Failure and Podophyllotoxin Therapy in Male Patients.

BACKGROUND: Genital warts are the manifestation of the human papillomavirus (HPV) infection, which may last for weeks or months before the clinical presentation. The primary aim of the study was the correlation of the DNA HPV genotypes eradication with the treatment response in male patients with persistent genital warts. METHODS: Twenty-one male patients (age range: 22-58) after failure of cryotherapy and podophyllotoxin treatment were enrolled in the study. Genetic tests (Real Time - PCR method) analyzed the presence of DNA-HPV before and 6 months after four sessions (4 weeks apart) of photodynamic therapy with 5-aminolaevulinic acid (ALA-PDT). The treatment efficacy was evaluated before each PDT session and at the end of the study. RESULTS: The single HPV DNA type was present in 15/21 of the patients (13/15 HPV6). The high-risk HPV types were found in 8/21 subjects, of which 6/8 had several types. Six months after four sessions of PDT, complete response was found in 16/21 (76.19%; p = 0.0007) of patients, and DNA HPV clearance was found in 66.67% (p = 0.03). The eradication rate differed among patients with primary low-risk and high-risk HPV types-76.92% (10/13; p = 0.0003) and 50% (4/8; p = 0.05) respectively. CONCLUSION: ALA-PDT is an effective treatment even after the failure of previous modalities. The persistence of clinical lesions and high oncological risk HPV types should be an indication for treatment prolongation.

The incidence and clinical analysis of non-melanoma skin cancer.

Non-melanoma skin cancers (NMSCs) are the most common malignancies diagnosed in Caucasian populations. Basal cell carcinoma (BCC) is the most frequent skin cancer, followed by squamous cell carcinoma (SCC). Unfortunately, most European cancer registries do not record individual types of NMSC. To evaluate the incidence of primary BCCs and SCCs regarding age, sex, tumour site and tumour subtype to determine trends in epidemiology of both cancers. Retrospective analysis of BCCs and SCCs diagnosed and treated across seven sites in Poland from 1999 to 2019. We recorded 13,913 NMSCs occurring in 10,083 patients. BCC represented 85.2% of all cases. SCC patients were older than BCC patients (77.1 ± 11.3 years vs. 70.1 ± 12.3 years, p < 0.01). The nodular subtype was the most common subtype of BCC, followed by the superficial and infiltrative subtypes. The superficial BCC subtype was more common on photoprotected areas (p < 0.01), whereas the nodular BCC subtype occurred on the face (p < 0.01). The high-risk SCC subtypes were more common on face compared to low-risk SCC subtypes (p < 0.01). BCC and SCC are common malignancies developing at various ages and anatomical sites. These data underline the need for better registration policies regarding NMSC in order to improve prevention and treatment strategies for these tumours.

Effectiveness and safety of secukinumab in patients with moderate-to-severe plaque psoriasis - a real life retrospective study.

INTRODUCTION: Clinical experience indicates that secukinumab has significant efficacy in the treatment of moderate-to-severe psoriasis and psoriatic arthritis, demonstrating a rapid onset of action, sustained response, a favourable safety profile, and an improvement of patients' quality of life. AIM: To analyse the effects of skin lesions, signs and symptoms of arthritis, quality of life and safety of treatment in patients with psoriasis and psoriatic arthritis treated with secukinumab. MATERIAL AND METHODS: The study included 38 subjects, 21 with psoriasis (PV) and 17 with psoriatic arthritis (PsA) who received ≥ 1 dose of secukinumab. We assessed response to secukinumab treatment by the Psoriasis Area and Severity Index (PASI), body surface area (BSA), the Dermatology Life Quality Index (DLQI), moreover in patients with PsA, we also assessed 5-point Likert scale and joint tenderness and swelling. We evaluated the safety profile of secukinumab by assessing laboratory tests and monitoring adverse reactions. RESULTS: In patients with PV a statistically significant decrease in PASI (from 21.46 points to 0.84 point), BSA (from 22.38% to 0.8%), DLQI (from 20.57 points to 0.33 point) was observed. In patients with PsA a statistically significant decrease in PASI (from 13.41 points to 0.0 point), BSA (from 14.59% to 1.0%) and DLQI (from 17.76 points to 0.67 point) was observed. We noticed three incidences of adverse events. CONCLUSIONS: Our results prove that secukinumab offers a good therapeutic opportunity and may be a preferred treatment option for patients with moderate-to-severe psoriasis and psoriatic arthritis.

Clinical and epidemiological analysis of basosquamous carcinoma: results of the multicenter study.

Basosquamous carcinoma (BSC) is a rare non-melanoma skin cancer that shares the characteristic features of both basal and squamous cell carcinomas (BCC, SCC). Our research enables better characterization of BSC in comparison to high-risk subtypes of BCC and SCC. Paper includes a retrospective analysis of BSC cases regarding sex, age, number of tumors and anatomical distribution in comparison to BCC and SCC evaluating the differences and defining the implications. Histologically confirmed carcinomas recorded between 1999 and 2019 were studied. 181 diagnosed BSC cases were identified, making this study the largest cohorts of BSC patients reported worldwide. Most cases were reported on head and neck. Analysis of facial anatomic distribution shows that most commonly affected sites were the nose (43%) and the cheek (25%). The age at excision of metatypical BCC was higher than those of low-risk BCC (P < 0.05), however similar to high-risk BCC (P = 0.20). We revisited that the concept of BSC is the most similar to high-risk subtypes of BCC. Patients with diagnosed BSC have higher risk of second nonmelanoma skin cancer. Therefore, the frequency of follow-up examination should be adjusted to the individual risk of another skin cancer.

Primary Merkel Cell Carcinoma: A Retrospective Analysis of 31 Cases in Poland.

INTRODUCTION: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine cancer that typically arises in sun-exposed areas of the skin, especially in the elderly. Significant advances have recently been made regarding skin cancers, but data on cases of MCC are rather limited as these patients are frequently grouped together with other non-melanoma skin cancers (NMSC). Here, we performed an analysis of the clinical profile of patients with MCC in Poland to identify major factors influencing the prognosis. METHODS: Approximately 13,000 pathology and medical records were examined to identify patients with MCC diagnosed between 2010 and 2019. The management and outcomes of patients with histologically confirmed MCC were retrospectively evaluated. RESULTS: Thirty-one patients diagnosed with MCC were identified. The tumor occurred predominantly in women (61.3%) and in the elderly (mean 75.6 years). Twenty-nine patients had locoregional MCC and two had metastatic MCC at the time of diagnosis. Patients in stage I disease had excellent prognosis. In stages II and III, respectively 22.2% and 50.0% of patients developed metastases. Among patients who received chemotherapy with cisplatin and etoposide, 17% achieved partial remission with progression-free survival (PFS) of 8.0 months, and a further 50% achieved stable disease with PFS of 4.0, 4.5, and 4.5 months respectively. In 6 (19.4%) patients MCC coexisted with chronic lymphocytic leukemia (CLL). In all six cases CLL preceded MCC development. CONCLUSIONS: Female gender, tumor-free resection margins, and local disease were found to be independent prognostic factors in MCC progression. Patients with hematological malignancies, immunosuppression, and those with immune deficiencies should be closely followed up as they are predisposed to develop MCC.

NLRP1 and NLRP3 inflammasomes as a new approach to skin carcinogenesis.

Inflammasomes are key innate immune system receptors that detect pathogenic endo- and exogenous stressors like microorganisms or ultraviolet radiation (UVR) which activate the highly proinflammatory cytokines interleukin-1ß and interleukin-18. Inflammasomes are not only involved in inflammation, but also in carcinogenesis and tumor progression. Due to the dynamic increase in non-melanoma skin cancers (NMSC), it has become necessary to determine how UVR, which plays a key role in NMSC development, can regulate the structure and function of inflammasomes. In the present study, the regulatory mechanisms of NOD-Like Receptor Family Pyrin Domain Containing 1 and 3 inflammasome activation as well as an effective inflammasome-mediated immune response after UVR exposition are discussed. The differences and similarities between these molecular complexes that monitor cellular health, inflammation, and skin carcinogenesis are also highlighted. Despite numerous scientific data, more studies are still required to better understand the biology of inflammasomes in skin cancer development and to explore their therapeutic potential.