Psoriasis: What Is New in Markers of Disease Severity?

Introduction. Psoriasis is a chronic inflammatory skin disease and is the result of the interaction between numerous external and internal factors. Psoriasis presents a wide range of skin manifestations encompassing individual lesions varying from pinpoint to large plaques that can evolve into generalised forms. The lesions mirror the pathophysiological mechanisms involved in psoriasis pathogenesis, such as inflammation, dysregulation of immune response, uncontrolled proliferation of keratinocytes and angiogenesis. In this article, we present the latest advances achieved regarding markers that correlate with psoriasis severity. Material and method. We have performed a narrative review on markers of psoriasis severity, including articles published between March 2018-March 2023. Results. We have identified four categories of markers: inflammation markers, oxidative stress markers, hormonal markers and cancer-related markers. The main focus was on inflammation biomarkers, including immunomodulatory molecules, haematological parameters, inflammatory cells and costimulatory molecules. Conclusions. The analysed data indicate that markers associated with inflammation, oxidative stress and hormones, and cancer-related markers could be useful in assessing the severity of psoriasis. Nevertheless, additional research is required to ascertain the practical importance of these biomarkers in clinical settings.

A Panel of Potential Serum Markers Related to Angiogenesis, Antioxidant Defense and Hypoxia for Differentiating Cutaneous Squamous Cell Carcinomas from Actinic Keratoses.

Cutaneous squamous cell carcinoma (cSCC) arising from the malignant proliferation of epidermal keratinocytes is the second most common skin cancer. Actinic keratosis (AK), which is considered cSCC in situ, may progress into invasive tumors. Currently, there are no serum markers that can differentiate cSCC from AK. The aim of our study was to assess angiogenesis and oxidative stress in patients with cSCC and patients with AK and find reliable serum markers useful in the diagnosis of cSCC. We have determined the serum levels of a group of proangiogenic factors (MMP-2, MMP-9, VEGF, FGF2), the total antioxidative status/capacity (TAS/TAC), ImAnOx, a marker of oxidative stress, and HIF-1 alpha, an indicator of hypoxia. We have identified higher serum levels of MMP-2. MMP-9, VEGF, FGF2 and HIF-1 alpha and lower levels of ImAnOx in cSCC patients compared to AK patients and controls. There were no statistically significant differences between AK patients and controls. We have found positive correlations between proangiogenic markers and HIF-1 alpha and negative correlations between proangiogenic markers and ImAnOx. Our results suggest that MMP-2, MMP-9, VEGF, FGF2, ImAnOx and HIF-1 may be promising markers for differentiating AK from cSCC, and there is a link between angiogenesis, oxidative stress and hypoxia.

Disturbances in Nitric Oxide Cycle and Related Molecular Pathways in Clear Cell Renal Cell Carcinoma.

It is important to note that maintaining adequate levels of nitric oxide (NO), the turnover, and the oxidation level of nitrogen are essential for the optimal progression of cellular processes, and alterations in the NO cycle indicate a crucial step in the onset and progression of multiple diseases. Cellular accumulation of NO and reactive nitrogen species in many types of tumour cells is expressed by an increased susceptibility to oxidative stress in the tumour microenvironment. Clear cell renal cell carcinoma (ccRCC) is a progressive metabolic disease in which tumour cells can adapt to metabolic reprogramming to enhance NO production in the tumour space. Understanding the factors governing NO biosynthesis metabolites in ccRCC represents a relevant, valuable approach to studying NO-based anticancer therapy. Exploring the molecular processes mediated by NO, related disturbances in molecular pathways, and NO-mediated signalling pathways in ccRCC could have significant therapeutic implications in managing and treating this condition.

Mast Cell Activation Syndrome Update-A Dermatological Perspective.

Mast cells (MCs) are infamous for their role in potentially fatal anaphylaxis reactions. In the last two decades, a more complex picture has emerged, as it has become obvious that MCs are much more than just IgE effectors of anaphylaxis. MCs are defenders against a host of infectious and toxic aggressions (their interactions with other components of the immune system are not yet fully understood) and after the insult has ended, MCs continue to play a role in inflammation regulation and tissue repair. Unfortunately, MC involvement in pathology is also significant. Apart from their role in allergies, MCs can proliferate clonally to produce systemic mastocytosis. They have also been implicated in excessive fibrosis, keloid scaring, graft rejection and chronic inflammation, especially at the level of the skin and gut. In recent years, the term MC activation syndrome (MCAS) was proposed to account for symptoms caused by MC activation, and clear diagnostic criteria have been defined. However, not all authors agree with these criteria, as some find them too restrictive, potentially leaving much of the MC-related pathology unaccounted for. Here, we review the current knowledge on the physiological and pathological roles of MCs, with a dermatological emphasis, and discuss the MCAS classification.

Apprising Diagnostic and Prognostic Biomarkers in Cutaneous Melanoma-Persistent Updating.

The incidence of melanoma, a very aggressive skin cancer, has increased over the past few decades. Although there are well-established clinical, dermoscopic and histopathological criteria, the diagnosis is often performed late, which has important implications on the patient's clinical outcome. Unfortunately, melanoma is one of the most challenging tumors to diagnose because it is a heterogeneous neoplasm at the clinical, histopathological, and molecular level. The use of reliable biomarkers for the diagnosis and monitoring of disease progression is becoming a standard of care in modern medicine. In this review, we discuss the latest studies, which highlight findings from the genomics, epitranscriptomics, proteomics and metabolomics areas, pointing out different genes, molecules and cells as potential diagnostic and prognostic biomarkers in cutaneous melanoma.

Viral Infections Confined to Tattoos-A Narrative Review.

Since ancient times, people have tattooed their skin for various reasons. In the past, tattoos were associated with low social status; nowadays, tattoos are very popular and are considered a form of art. However, tattoos are associated with various clinical problems, including immune reactions, inflammatory disorders, infections, and even skin cancer. Epidemiological and clinical data of infections on tattoos are scarce. Tattoo-related infections are mostly bacterial; only a few localized viral infections have been reported so far and are caused by molluscum contagiosum virus (MCV), human papillomavirus (HPV), and herpes simplex virus (HSV). In most cases, the lesions were strictly confined to the area of the tattoo. In this review, we have analysed reported cases of viral infections localized on tattoos and discussed the possible mechanisms involved in the occurrence of these infections.

Effectiveness of Platelet-Rich Plasma Therapy in Androgenic Alopecia-A Meta-Analysis.

Platelet-rich plasma (PRP) represents a novel therapy tested and is used more and more frequently in dermatology and cosmetic surgery for a variety of conditions, including androgenic alopecia (AGA), a common condition with a complex pathogenesis involving genetic factors, hormonal status and inflammation. We performed an extensive literature search which retrieved 15 clinical trials concerning the use in AGA of PRP therapy, alone or in combination, in male, female or mixed patient groups. A quantitative statistical meta-analysis of n = 17 trial groups proved significant increases in hair density from 141.9 ± 108.2 to 177.5 ± 129.7 hairs/cm2 (mean ± SD) following PRP (p = 0.0004). To the best of our knowledge, this is the first meta-analysis that proved a statistically significant correlation between the number of PRP treatments per month and the percentage change in hair density (r = 0.5, p = 0.03), as well as a negative correlation between the mean age of treatment group and the percentage change in hair density (r = -0.56, p = 0.016). Other factors considered for analysis were the PRP preparation method, amount used per treatment, hair diameter, terminal hairs and pull test. We conclude that PRP represents a valuable and effective therapy for AGA in both males and females if patients are rigorously selected.

Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.

Serum Sialylation Changes in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma Patients.

Cutaneous squamous cell carcinoma (cSCC), a malignant proliferation of the cutaneous epithelium, is the second most common skin cancer after basal cell carcinoma (BCC). Unlike BCC, cSCC exhibits a greater aggressiveness and the ability to metastasize to any organ in the body. Chronic inflammation and immunosuppression are important processes linked to the development of cSCC. The tumor can occur de novo or from the histological transformation of preexisting actinic keratoses (AK). Malignant cells exhibit a higher amount of sialic acid in their membranes than normal cells, and changes in the amount, type, or linkage of sialic acid in malignant cell glycoconjugates are related to tumor progression and metastasis. The aim of our study was to investigate the sialyation in patients with cSCC and patients with AK. We have determined the serum levels of total sialic acid (TSA), lipid-bound sialic acid (LSA), beta-galactoside 2,6-sialyltransferase I (ST6GalI), and neuraminidase 3 (NEU3) in 40 patients with cSCC, 28 patients with AK, and 40 healthy subjects. Data analysis indicated a significant increase in serum levels of TSA (p < 0.001), LSA (p < 0.001), ST6GalI (p < 0.001), and NEU3 (p < 0.001) in the cSCC group compared to the control group, whereas in patients with AK only the serum level of TSA was significantly higher compared to the control group (p < 0.001). When the cSCC and AK groups were compared, significant differences between the serum levels of TSA (p < 0.001), LSA (p < 0.001), ST6GalI (p < 0.001) and NEU3 (p < 0.001) were found. The rate of synthesis of sialoglycoconjugates and their rate of enzymatic degradation, expressed by the ST6GalI/NEU3 ratio, is 1.64 times lower in the cSCC group compared to the control group (p < 0.01) and 1.53 times lower compared to the AK group (p < 0.01). The tumor diameter, depth of invasion, and Ki67 were associated with higher levels of TSA and LSA. These results indicate an aberrant sialylation in cSCC that correlates with tumor aggressiveness.

Current Perspectives on the Role of Matrix Metalloproteinases in the Pathogenesis of Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common skin malignancy, which rarely metastasizes but has a great ability to infiltrate and invade the surrounding tissues. One of the molecular players involved in the metastatic process are matrix metalloproteinases (MMPs). MMPs are enzymes that can degrade various components of the extracellular matrix. In the skin, the expression of MMPs is increased in response to various stimuli, including ultraviolet (UV) radiation, one of the main factors involved in the development of BCC. By modulating various processes that are linked to tumor growth, such as invasion and angiogenesis, MMPs have been associated with UV-related carcinogenesis. The sources of MMPs are multiple, as they can be released by both neoplastic and tumor microenvironment cells. Inhibiting the action of MMPs could be a useful therapeutic option in BCC management. In this review that reunites the latest advances in this domain, we discuss the role of MMPs in the pathogenesis and evolution of BCC, as molecules involved in tumor aggressiveness and risk of recurrence, in order to offer a fresh and updated perspective on this field.

Neuroendocrine Factors in Melanoma Pathogenesis.

Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects.

Complex Interaction Among Immune, Inflammatory, and Carcinogenic Mechanisms in the Head and Neck Squamous Cell Carcinoma.

Inflammation is deeply involved in the development of most types of cancer. Many studies focus on the interaction between immune-inflammatory mechanisms and tumorigenesis in the head and neck squamous cell carcinoma (HNSCC). In this chapter, we emphasize the complexity of processes underlying this interaction and discuss the mechanisms of carcinogenesis in HNSCC with a special focus on metabolic changes, inflammation, and the immune landscape. Unveiling complex connections between immuno-inflammatory processes and tumor initiation, promotion, and progression will open new directions in the reliable identification of predictive factors and therapeutic targets in HNSCC.

Posttranslational Modifications Pattern in Clear Cell Renal Cell Carcinoma.

Posttranslational modifications are dynamic enzymatic-mediated processes, regulated in time and space, associated with cancer development. We aimed to evaluate the significance of posttranslational modifications in the pathogenesis of clear cell renal cell carcinoma. The authors developed a prospective, observational study during a period of three years and included 55 patients with localized renal cell carcinoma and 30 heathy subjects. Glycosylation, nitration and carbonylation, thiol-disulfide homeostasis, methylation, phosphorylation and proteolytic cleavage were evaluated in the serum of the evaluated subjects in the present study. Our results showed some characteristics for early ccRCC: high production of cytokines, substrate hypersialylation, induced nitrosative and carbonylic stress, arginine hypermethylation, thiol/disulfide homeostasis (TDH) alteration, the regulatory role of soluble receptors (sRAGE, sIL-6R) in RAGE and IL-6 signaling, the modulatory effect of TK-1and TuM2-PK in controlling the level of phosphometabolites in neoplastic cells. These data could be the initial point for development of a panel of biomarkers such as total sialic acid, orosomucoids, nitrotyrosine, carbonylic metabolites, ADMA, SDMA, and thiol-disulfide equilibrium for early diagnosis of ccRCC. Moreover, they could be considered a specific disease PTM signature which underlines the transition from early to advanced stages in this neoplasia, and of a therapeutic target in kidney oncogenesis.

Recent Advances in Signaling Pathways Comprehension as Carcinogenesis Triggers in Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common malignant skin tumor. BCC displays a different behavior compared with other neoplasms, has a slow evolution, and metastasizes very rarely, but sometimes it causes an important local destruction. Chronic ultraviolet exposure along with genetic factors are the most important risk factors involved in BCC development. Mutations in the PTCH1 gene are associated with Gorlin syndrome, an autosomal dominant disorder characterized by the occurrence of multiple BCCs, but are also the most frequent mutations observed in sporadic BCCs. PTCH1 encodes for PTCH1 protein, the most important negative regulator of the Hedgehog (Hh) pathway. There are numerous studies confirming Hh pathway involvement in BCC pathogenesis. Although Hh pathway has been intensively investigated, it remains incompletely elucidated. Recent studies on BCC tumorigenesis have shown that in addition to Hh pathway, there are other signaling pathways involved in BCC development. In this review, we present recent advances in BCC carcinogenesis.

Antiganglioside Antibodies and Inflammatory Response in Cutaneous Melanoma.

INTRODUCTION: Endogenously produced antiganglioside antibodies could affect the evolution of cutaneous melanoma. Epidemiological and experimental evidence suggest "chronic inflammation" to be one of the hallmarks in skin cancers. The aim of the study was to characterize the relation between antiganglioside antibodies and inflammation in cutaneous melanoma focusing on gangliosides GM1, GM2, GM3, GD1a, GD1b, GT1b, GQ1b. Material and Method. We performed an observational study that included 380 subjects subdivided into three groups: patients with metastatic melanoma (170 cases), patients with primary melanoma (160 cases), and healthy subjects (50 subjects). The assessment of antiganglioside antibodies, IgG, and IgM classes, against -GM1, -GM2, -GM3, -GD1a, -GD1b, -GT1b, -GQ1b was performed using immunoblot technique (EUROLine kit). RESULTS: The presence of IgG and IgM antiganglioside antibodies in primary melanoma was (%), as follows: anti-GM1 (5.0 and 13.1), -GM2 (1.8 and 18.1), -GM3 (0.6 and 5.6), -GD1a (0.6 and 15.0), -GD1b (3.7 and 10.7), -GT1b (0.0 and 13.1), -GQ1b (0.0 and 5.0). In metastatic melanoma, the level of antiganglioside antibodies was significantly lower compared with primary melanoma (p < 0.05), while in the control group they were absent. Antiganglioside antibodies anti-GM1 and -GD1a were positively correlated, while anti-GM3, -GD1b, and -GT1b were negatively associated with the inflammatory markers, interleukin 8 (IL-8), and C reactive protein (CRP). CONCLUSIONS: Tumour ganglioside antigens generate an immune response in patients with primary melanomas. The host's ability to elaborate an early antiganglioside response could be considered as a defence mechanism, directed toward eliminating a danger signal from the tumour microenvironment. Antiganglioside antibodies associated with inflammation markers could be used as diagnostic, monitoring, and treatment tools in patients with cutaneous melanoma.

The Role of Beta HPV Types and HPV-Associated Inflammatory Processes in Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer with a complex but not fully understood pathogenesis. Recent research suggests the role of beta human papillomavirus (HPV) types and HPV-associated inflammatory processes in cSCC development. Beta HPV types are components of the normal flora; however, under the influence of certain cofactors, the virus may trigger a malignant process. Dysregulation of the immune system (chronic inflammation and immunosuppression), environmental factors (ultraviolet radiation), and genetic factors are the most important cofactors involved in beta HPV-related carcinogenesis. In addition, the oncoproteins E6 and E7 of beta HPV types differ biochemically from their counterparts in the structure of alpha HPV types, resulting in different mechanisms of action in carcinogenesis. The aim of our manuscript is to present an updated point of view on the involvement of beta HPV types in cSCC pathogenesis.

Tumour Microenvironment in Skin Carcinogenesis.

Tumour microenvironment is a complex system comprising cells and molecules that will provide the necessary conditions for tumour development and progression. Cells residing in the tumour microenvironment gain specific phenotypes and specific functions that are pro-tumorigenic. Tumour progression is in fact a combination between tumour cell characteristics and its interplay with tumour microenvironment. This dynamic network will allow tumour cells to grow, migrate and invade tissues. In the present chapter, we are highlighting some traits that characterise tumour microenvironment in basal cell carcinoma, squamous cell carcinoma and cutaneous melanoma. In skin cancers, there are some common tumour microenvironment characteristics such as the presence of tumour-associated macrophages and regulatory T lymphocytes that are non-tumour cells promoting tumorigenesis. There are also skin cancer type differences in terms of tumour microenvironment characteristics. Thus, markers such as macrophage migration inhibitory factor in melanoma or the extraordinary diverse genetic make-up in the cancer-associated fibroblasts associated to squamous cell carcinoma are just a few of specific traits in skin cancer types. New technological advances for evaluation of tumour environment are presented. Thus, non-invasive skin imaging techniques such as reflectance confocal microscopy can evaluate skin tumour inflammatory infiltrates for density and cellular populations. Analysing tumour micromedium in depth may offer new insights into cancer therapy and identify new therapy targets.

The Relationship between the Soluble Receptor for Advanced Glycation End Products and Oxidative Stress in Patients with Palmoplantar Warts.

BACKGROUND AND OBJECTIVES: Warts are the most common lesions caused by human papillomavirus (HPV). Recent research suggests that oxidative stress and inflammation are involved in the pathogenesis of HPV-related lesions. It has been shown that the soluble receptor for advanced glycation end products (sRAGE) may act as a protective factor against the deleterious effects of inflammation and oxidative stress, two interconnected processes. However, in HPV infection, the role of sRAGE, constitutively expressed in the skin, has not been investigated in previous studies. MATERIALS AND METHODS: In order to analyze the role of sRAGE in warts, we investigated the link between sRAGE and the inflammatory response on one hand, and the relationship between sRAGE and the total oxidant/antioxidant status (TOS/TAS) on the other hand, in both patients with palmoplantar warts (n = 24) and healthy subjects as controls (n = 28). RESULTS: Compared to the control group, our results showed that patients with warts had lower levels of sRAGE (1036.50 ± 207.60 pg/mL vs. 1215.32 ± 266.12 pg/mL, p < 0.05), higher serum levels of TOS (3.17 ± 0.27 vs. 2.93 ± 0.22 µmol H2O2 Eq/L, p < 0.01), lower serum levels of TAS (1.85 ± 0.12 vs. 2.03 ± 0.14 µmol Trolox Eq/L, p < 0.01) and minor variations of the inflammation parameters (high sensitivity-CRP, interleukin-6, fibrinogen, and erythrocyte sedimentation rate). Moreover, in patients with warts, sRAGE positively correlated with TAS (r = 0.43, p < 0.05), negatively correlated with TOS (r = -0.90, p < 0.01), and there was no significant correlation with inflammation parameters. There were no significant differences regarding the studied parameters between groups when we stratified the patients according to the number of the lesions and disease duration. CONCLUSIONS: Our results suggest that sRAGE acts as a negative regulator of oxidative stress and could represent a mediator involved in the development of warts. However, we consider that the level of sRAGE cannot be used as a biomarker for the severity of warts. To the best of our knowledge, this is the first study to demonstrate that sRAGE could be involved in HPV pathogenesis and represent a marker of oxidative stress in patients with warts.

Photodynamic therapy: A hot topic in dermato-oncology.

Photodynamic therapy (PDT) is a modern, non-invasive therapeutic method used for the destruction of various cells and tissues. It requires the simultaneous presence of three components: a photosensitizer (PS), a light source and oxygen. Precancerous skin lesions are conditions associated with a high likelihood of malignant transformation to squamous cell carcinoma. Data available so far indicate that PDT is a promising treatment method which can be successfully employed in several medical fields including dermatology, urology, ophthalmology, pneumology, cardiology, dentistry and immunology. Numerous authors therefore have studied this technique in order to improve its efficacy. As a result, significant advancement has been achieved with regard to PSs and drug delivery systems. Substantial progress was also obtained with respect to PDT for the treatment of precancerous skin lesions, several authors focusing their efforts on the study of daylight-PDT and on identifying methods of decreasing technique-related pain. This review reports on the most recent findings in PDT, with emphasis on cutaneous precancerous lesions.