New Treatment Horizons in Uveal and Cutaneous Melanoma.

Melanoma is a complex and heterogeneous malignant tumor with distinct genetic characteristics and therapeutic challenges in both cutaneous melanoma (CM) and uveal melanoma (UM). This review explores the underlying molecular features and genetic alterations in these melanoma subtypes, highlighting the importance of employing specific model systems tailored to their unique profiles for the development of targeted therapies. Over the past decade, significant progress has been made in unraveling the molecular and genetic characteristics of CM and UM, leading to notable advancements in treatment options. Genetic mutations in the mitogen-activated protein kinase (MAPK) pathway drive CM, while UM is characterized by mutations in genes like GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. Chromosomal aberrations, including monosomy 3 in UM and monosomy 10 in CM, play significant roles in tumorigenesis. Immune cell infiltration differs between CM and UM, impacting prognosis. Therapeutic advancements targeting these genetic alterations, including oncolytic viruses and immunotherapies, have shown promise in preclinical and clinical studies. Oncolytic viruses selectively infect malignant cells, inducing oncolysis and activating antitumor immune responses. Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic virus for CM treatment, and other oncolytic viruses, such as coxsackieviruses and HF-10, are being investigated. Furthermore, combining oncolytic viruses with immunotherapies, such as CAR-T cell therapy, holds great potential. Understanding the intrinsic molecular features of melanoma and their role in shaping novel therapeutic approaches provides insights into targeted interventions and paves the way for more effective treatments for CM and UM.

Role of arterial hypertension and angiotensin II in chronic kidney disease (Review).

Chronic kidney disease (CKD) is a major public health issue, due to its effect on the quality of life of patients and by the huge costs incurred in treating this disease. It is an irreversible process, characterized by the progressive loss of functional nephrons. CKD ultimately requires the support of renal function by dialysis or even renal transplantation. It has a multiple etiology, but the most common causes remain arterial hypertension and diabetes. High arterial blood pressure affects the target organs (kidneys) and this leads to a vicious circle involved in maintaining high blood pressure. Arterial hypertension is closely related to the renal pathology of CKD. The result of excessive activation of the renin angiotensin system (RAS) is increased angiotensin II (Ang II), which acts upon the systemic circulation and especially upon the kidneys. The outcome is high blood pressure and also the stimulation of proinflammatory and profibrotic effects in the kidneys. Collectively these ultimately lead to CKD. The aim of this review was to provide a brief overview of the pathophysiological associations between CKD, arterial hypertension, and Ang II.

Sentinel Lymph Node Biopsy in Cutaneous Melanoma, a Clinical Point of View.

Sentinel lymph node biopsy (SLNB) is a surgical procedure that has been used in patients with cutaneous melanoma for nearly 30 years. It is used for both staging and regional disease control with minimum morbidity, as proven by numerous worldwide prospective studies. It has been incorporated in the recommendations of national and professional guidelines. In this article, we provide a summary of the general information on SLNB in the clinical guidelines for the management of cutaneous malignant melanoma (American Association of Dermatology, European Society of Medical Oncology, National Comprehensive Cancer Network, and Cancer Council Australia) and review the most relevant literature to provide an update on the existing recommendations for SLNB.

Mucocutaneous lesions associated with SARS-CoV-2 infection (Review).

The ongoing COVID-19 pandemic, declared by the World Health Organisation in March 2020, with the emergence of new, possibly more contagious and more virulent strains, remains a research subject, with the complex systemic involvement better described and understood, but also with a variety of skin and mucosal lesions described in the literature. Mucocutaneous lesions associated with SARS-CoV-2 infection are still under investigation, due to their polymorphic clinical aspect and incompletely understood pathogenic mechanism. The cutaneous inflammatory, exanthematous and purpuric rashes, erythemato-purpuric enanthems, oral ulcers, lichenoid oral lesions, conjunctivitis, conjunctival pseudomembranes, or corneal lesions have been described in patients with COVID-19. Several classifications have been proposed based on the clinical pattern, histological findings, and possible pathogenic mechanisms. The pathogenic mechanism, the diagnostic criteria, the prognostic importance of these lesions are still being debated. The diverse clinical aspects of dermatological manifestations render the diagnosis difficult. However, several clinical patterns strongly associated with COVID-19, such as chilblains, papulovesicular exanthems, and febrile rash require increased awareness and changes to the investigation protocols for these conditions, to include testing for SARS-CoV-2. In the present review, the mucocutaneous findings associated with the novel coronavirus infection, reported thus far in the literature, was provided.

Phototherapy in dermatological maladies (Review).

Since the introduction of modern phototherapy in 1903 by Nobel Prize-winner Niels Ryberg Finsen, the usage of this therapy in the medical field has grown, techniques have been refined and developed, and it has gained widespread acceptance. Psoriasis vulgaris, parapsoriasis, lichen planus, atopic dermatitis, neonatal jaundice, urticaria, morphea, vitiligo, granuloma annulare and cutaneous T cell lymphoma are only a few dermatological indications that come along with satisfactory results. Most often, it is a 2nd or 3rd line therapy being an alternative in more severe or refractory diseases. Despite the side effects that may occur after phototherapy, which are often minor, the benefits can be significant. Unfortunately, the absolute contraindications limit the use of this type of treatment and implicitly the management of these patients. The current review aimed to combine the recommendations of phototherapy in dermatology, the types of phototherapy that can be suitable for certain dermatological diseases and to emphasize its importance in certain conditions that are associated with significant remission rates.

Update on the etiopathogenesis of psoriasis (Review).

Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders, involving hyperproliferative keratinocytes and infiltration of T cells, dendritic cells, macrophages, and neutrophils. Multiple factors appear to play important roles in the pathogenesis of psoriasis. These environmental (e.g., infectious agents and trauma), genetic, and immunologic factors are reviewed in this article. Although the pathogenesis of psoriasis remains to be established, data suggesting immune cell dysregulation in the skin are available. The involvement of the immune system, particularly T cells, in the etiopathogenesis of psoriasis is discussed in this review, indicating a potential justification for innovative treatment intervention. Besides describing pathogenic T cells, the aim of the review was to assess the function of newly identified antimicrobial peptides (AMPs), interleukin (IL)-23, IL-17, and tissue resident memory cells (TRMs), and their role in psoriasis. Furthermore, new insights were presented regarding TRMs, a recently identified subset of memory T cells, and the role they play in the local memory of disease, making them a potential new therapeutic target in psoriasis. Finally, current developments in T-cell research and cytokine-targeted therapy for psoriasis treatment are reviewed.

Adult female acne: Clinical and therapeutic particularities (Review).

Acne is a chronic inflammatory condition affecting the pilosebaceous unit that was traditionally viewed as a disease of the adolescence. However, over the past several years, an increasing number of adult women have been reported to suffer from this condition. The prevalence of adult female acne ranges between 12 and 54%. Two clinical types can be distinguished in this population, a 'retentional' and an 'inflammatory' type, which usually tend to overlap. In terms of evolution, three main subtypes can be identified: Persistent acne, which is the most frequent subtype, late-onset acne and recurrent acne. This type of acne is mainly mild-to-moderate in severity and may be refractory to conventional treatment. The etiopathogenesis is complex and has yet to be fully elucidated. It appears to involve an interaction among genetic predisposition, hormonal factors, and chronic activation of the innate immune system overlapping with external factors, such as daily stress, Western-type diet, use of tobacco and cosmetics. The treatment may be challenging and a holistic approach is required, with special attention to the individual needs and particularities of adult women. Both topical and systemic treatments are available, with hormonal therapies being of special value in this population. The aim of the present article was to provide up-to-date, evidence-based information on the clinical presentation, etiopathogenesis and treatment of adult female acne.

Cardiovascular comorbidities in psoriasis (Review).

Long considered a skin-limited condition, psoriasis is currently defined as a chronic, immune-mediated inflammatory disease, presenting, besides the skin changes, important systemic manifestations, the most common being: psoriatic arthritis, cardiovascular disease, metabolic syndrome, diabetes, inflammatory bowel disease and nonalcoholic steatohepatitis. It is a disease with a strong psycho-emotional and social impact, both through skin changes such as pruritic, scaly erythematous plaques, and through the association of comorbidities that influence morbidity and mortality. It has been shown that psoriasis is an independent cardiovascular risk factor, with patients developing ischemic heart disease/acute coronary syndrome, hypertension, peripheral arterial disease, or stroke. The chronic inflammatory status of psoriasis and the production of specific cytokines may be the etiopathogenic link to atherosclerosis and cardiovascular disease. Biological therapy may affect atherosclerosis, leading to the arrest of the evolution or even regressing the changes in the atheromatous plaque. The aim of this review was to re-evaluate the current knowledge regarding the cardiovascular comorbidities associated with psoriasis for optimal management of the patients.

Clinicopathological correlation of transient acantholytic dermatosis: A case report.

Transient acantholytic dermatosis (TAD) is a benign, non-familial, non-immune mediated acantholytic disorder of unknown etiology. The presence of polymorphous, unorganized, pruritic lesions on the trunk, associated with focal acantholysis and dyskeratosis, resembles a wide variety of dermatoses. The etiology of TAD (also known as Grover's disease) is unknown, and the success of treatment relies on the correct identification of the disease; however, some cases are refractory to all forms of therapy. For accurate diagnosis, a comprehensive literature review is required. Here, the case of a 55-year-old male with TAD displaying a Darier-like histopathological pattern was reported. The patient was successfully treated with retinoids and acitretin (Neotigason), as well as dapsone, an anti-inflammatory agent, as maintenance therapy. The presence of more than two histological findings, limited to small foci and clinical information, can diagnose Darier disease. The exact pathogenesis has not been elucidated, thus further studies of the pathogenesis of TAD are required.

Metabolic comorbidities of psoriasis (Review).

Psoriasis is a chronic inflammatory and immune-mediated condition, which is no longer considered as being limited to the skin, but may affect the entire body. Epidemiological studies have shown that certain disorders, including obesity, diabetes, liver abnormalities, elevated lipid levels in the blood and metabolic syndrome, may occur more frequently in patients with psoriasis compared with the general population. As psoriasis is a chronic disease, the frequently associated comorbidities must be identified early to ensure timely treatment and, possibly, their prevention. Comorbidities often manifest clinically 1-2 years after the onset of psoriasis and are commonly seen in patients with severe forms of the disease. The association between psoriasis and its comorbidities is not coincidental, but rather based on common pathophysiological mechanisms and risk factors that underlie the increased frequency of comorbidities in patients with psoriasis. The aim of the present review was to emphasize the important role of dermatologists in the early recognition of comorbidities in patients with psoriasis, with a focus on metabolic comorbidities, precisely because the dermatologists are usually the first medical contact due to the predominance of skin lesions. Therefore, these specialists have the responsibility to inform patients on the association between psoriasis and possible multiple comorbidities, devise prevention and treatment plans, or even redirect patients to other specialists.

Uveal melanoma diagnosis and current treatment options (Review).

Uveal melanoma is a rare condition accounting for only 5% of all primary melanoma cases. Still, it is the most frequently diagnosed primary intraocular malignant tumor in adults. Almost 90% of the tumors involve the choroid and only a small percentage affects the ciliary body or the iris. There is a consistent difference in incidence between different regions with individuals of northern European descent having a significantly higher risk as compared to Hispanics, Asians, and Blacks. Among the many risk factors, mutations in the G protein subunit alpha Q (GNAQ) or G protein subunit alpha 11 (GNA11) genes and different receptors are highly suggestive. While iris melanoma can easily be noticed by the patient itself or diagnosed at a routine slit-lamp evaluation, a consistent percentage of posterior uveal tumors are incidentally diagnosed at funduscopic evaluation as they can evolve silently for years, especially if located in the periphery. Uveal melanoma classifications rely on the tumor size (thickness and basal diameter) and also on intraocular and extraocular extension. The differential diagnosis with pseudomelanomas is carried out according to the tumor aspect and position. Iris melanoma has a better prognosis and a lower mortality rate as compared to choroidal melanoma that has a much higher rate of metastasis (50% of the patients) and a subsequent limited life expectancy from 6 to 12 months. While conservative therapeutic options for the primary tumor, relying on different surgical excision techniques and/or irradiation therapies, offer good local tumor control, the treatment options for metastatic disease, although numerous, are still inadequate in preventing a fatal outcome.

Management of psoriasis in children (Review).

Psoriasis is a common long-lasting, inflammatory disease that mainly affects the skin. The incidence of this condition has increased significantly over time and at this point, it affects approximately 1% of children. Psoriasis can appear at any age, including childhood and adolescence, with a higher frequency in girls, an earlier onset being associated with severe psoriasis. The pathology is the result of the interaction between genetics and trigger factors such as infections, stress, diet, obesity, and chemical irritants. Paradoxically, tumor necrosis factor (TNF)-α inhibitors (infliximab, adalimumab) may induce psoriasis in children. Psoriasis is a long-term condition with periods of exacerbation; thus, the quality of life can be affected and patients should receive psychosocial support. Although most children have mild disease and topical treatment is efficient, some cases are challenging to treat. The aim of this review was to provide an overview of the current knowledge concerning the epidemiology, etiology, pathogenesis, clinical features, comorbidities, and treatment of psoriasis in children and also to emphasize the need for a multidisciplinary approach to this complex pathology.

Hypersensitivity reactions to monoclonal antibodies: Classification and treatment approach (Review).

The present paper aims to review the topic of adverse reactions to biological agents, in terms of the incriminating mechanisms and therapeutic approach. As a result of immunomodulatory therapy, the last decade has achieved spectacular results in the targeted treatment of inflammatory, autoimmune, and neoplastic diseases, to name a few. The widespread use of biological agents is, however, associated with an increase in the number of observed adverse drug reactions ranging from local erythema to systemic reactions, including life-threatening immunologically mediated events, which justifies the need for a deeper understanding of this subject. Rapid desensitization to biological agents emerges as a treatment strategy for anaphylactic (immediate or delayed) hypersensitivity reactions as well as for severe infusion reactions. Drug desensitization is the administration of progressively increasing doses of the specific preparation until reaching the therapeutic dose in order to induce immunological tolerance and is indicated when the drugs are indispensable to the therapeutic regimen of individuals with hypersensitivity reactions to the preparation, with no reasonable alternatives.

Immunohistochemical study of CD117 in various cutaneous melanocytic lesions.

The aim of the present study was to carried out a comparative immunohistochemical evaluation of CD117 (c-Kit), a biomarker that evaluates both tumor progression and prognosis, in different melanocytic lesions, to emphasize the significance of this biomarker in malignant melanoma (MM). The study was performed on 55 cases, represented by a control group, which included 5 cases of simple nevi and 5 cases of dysplastic nevi, as well as a study group consisting of 35 cases of primary MM and 10 metastases (one intestinal, 3 cutaneous - one satellite and two distant as well as 6 in the lymph nodes). The study group included 15 cases of superficial spreading melanoma (SSM), 10 cases of nodular melanoma (NM), 3 lentigo maligna melanoma (LMM), 3 cases of acral lentiginous melanoma (ALM) and 4 cases of amelanotic MM. CD117 was found to be massively involved in the process of tumorigenesis of cutaneous malignancies, being immunohistochemically undetectable in benign neural lesions, but densely expressed in dysplastic lesions and in situ melanoma areas. In invasive cutaneous MMs, CD117 expression tended to decrease with neoplasia progression proceding into the tumorigenic, vertical growth phase, being lower in the profound dermal component of tumors and in nodular MMs. To eliminate the epidermal barriers and gain a proliferative advantage to allow the transition to the vertical growth phase, it seems that MM should lose expression of c-Kit. Cutaneous metastases were found to express CD117 at a level comparable to their primary tumors, suggesting that other mechanisms interfere directly with the metastatic process and not loss of c-Kit expression by itself. CD117 overexpression in cutaneous melanocytic lesions correlates significantly with increased immunostaining intensity, suggesting that the immunohistochemical evaluation of CD117 may be a good method for screening patients, who could benefit from personalized therapy with tyrosine kinase inhibitors.

Influence of unilateral intravitreal bevacizumab injection on the incidence of symptomatic choroidal neovascularization in the fellow eye in patients with neovascular age-related macular degeneration (Review).

Neovascular age-related macular degeneration (neovascular ARMD) represents only 10% of ARMD cases but is responsible, if untreated, for quick and severe central vision loss due to major macular changes. The presence of choroidal neovascularization (CNV) in one eye is associated with an approximately 10% risk of CNV development in the fellow eye each year. Intravitreal anti-VEGF therapy has quickly evolved as the standard treatment in neovascular ARMD in the last decade due to significant anatomical and functional improvements, especially in the early stages. In many reports an improvement in the untreated fellow eye was mentioned and systemic exposure was soon confirmed for all anti-VEGF agents after unilateral intravitreal injection. In particular, bevacizumab intravitreal injection is followed by a consistent reduction of serum VEGF levels and the drug was shown to have the longest serum half-life raising important debates about its safety. Once bevacizumab was detected in the fellow eye of an animal model after unilateral injection, the possible influence on fellow eye conversion rate into neovascular ARMD was questioned. Although comparative studies have not found statistically significant differences between drugs regarding the incidence of symptomatic CNV in the fellow eye during treatment, we observed, on a retrospective 36-month evaluation, a reduced incidence of symptomatic CNV in the fellow eye that might be explained by the consistent systemic exposure of bevacizumab.

Intraocular pressure changes during and after silicone oil endotamponade (Review).

Silicone oil (SIO) has rapidly become an indispensable adjunct in vitreoretinal surgery. Constant improvements in purity and also in viscosity have not totally prevented specific complications that may occur during endotamponade. Results of in vitro studies that suggested that higher viscosity silicone oil might be superior in terms of stability and safety are confirmed in real life only if endotamponade lasts for more than 6 months. Intraocular pressure changes induced by the silicone oil endotamponade or oil extraction are documented from its very first use and are potentially threatening vision. The purpose of this review is to update current knowledge on the incidence, risk factors, pathogenesis, and management of secondary silicone oil glaucoma. Also, in a retrospective evaluation on cases with complex retinal detachments that underwent 23G vitrectomy and high viscosity SIO endotamponade, we have noticed that a considerable number of cases developed significant intraocular pressure changes during SIO endotamponade and after SIO removal, especially in early postoperative period.

Involvement of proinflammatory cytokines in angiotensin II-induced hypertension in rat.

Rightfully considered as essential for hydro-electrolytic homeostasis, angiotensin II (Ang II) is the main product of the renin-angiotensin system (RAS). Ang II is one of the most important factors that contribute to the regulation of systemic arterial blood pressure (ABP). This major role is based on the effects exerted by RAS: Upon the kidney (RAS involvement in the control of salt and water excretion), upon the brain (RAS involvement in the control of water intake), and upon the sympathetic nervous system. It is currently known that there is a tight bidirectional link between high ABP and chronic kidney disease (CKD). Ang II causes vasoconstriction in the renal microvasculature, predominantly in the preglomerular arterioles. High ABP affects the target organs (eyes, brain, heart, kidneys) and it is known both as a cause and as an effect of CKD. Thus, there is a positive feedback mechanism that contributes even more to the increase in ABP and the progression of CKD. Along with its main hemodynamic effects, Ang II has direct proinflammatory actions, that also affect the structure and function of the kidney and heart. This study investigated the role of RAS and Ang II in the inflammation that accompanies the hypertension experimentally induced by Ang II in rats. Our data support the hypothesis that anti-inflammatory medication might alleviate the morphological and/or functional changes of the kidneys and heart that are related to Ang II-induced hypertension.

Ocular cicatricial pemphigoid (Review).

Ocular cicatricial pemphigoid is a particular form of mucous membrane pemphigoid and it is characterized by a chronic bilateral conjunctivitis with relapsing-remitting periods. Without therapy 75% of the cases develop visual loss due to major ocular complications (e.g. severe dry-eye syndrome, corneal erosions, corneal keratinization, entropion, symblepharon). Pathogenesis remains uncertain and probably linked to an autoimmune type II hypersensitivity response in patients with a genetic predisposition and exposure to different environmental triggers. With a worldwide distribution, no racial predilection and an estimated incidence that largely varies from 1/10,000-1/60,000, ocular cicatricial pemphigoid predominantly affects women aged ~60 years. Conjunctival biopsy with direct immunofluorescence is the gold standard in diagnosis confirmation, but up to 40% of the patients have a negative biopsy result that does not rule out the diagnosis. The skin and many other mucous membranes (e.g. oral, trachea, esophagus, pharynx, larynx, urethra, vagina and anus) may be involved. The disease grading relies on Foster staging system (based on clinical signs) and Mondino and Brown system (based on the inferior fornix depth loss). The differential diagnosis includes atopy, allergies, trauma, chemical burns, radiation, neoplasia, infectious, inflammatory and autoimmune etiologies. The main goals of the treatment are to stop disease progression, to relieve symptoms and to prevent complications. With long-term systemic therapy 90% of the cases can be efficiently controlled. While Dapsone is the first-line treatment in mild to moderate disease in patients without G6PD deficiency, more severe cases require immunosuppressant therapy with azathioprine, mycophenolate mofetil, methotrexate or cyclosporine. Cyclophosphamide, biologics (etanercept or rituximab) and intravenous immunoglobulin therapy are usually reserved for recalcitrant disease and unsatisfactory results to conventional therapy. Dry eye syndrome requires constant lubricating medication and topical steroids, cyclosporine-A and tacrolimus. Surgery should be planed only in quiescent phase as minor conjunctival trauma can significantly worsen the disease.

A novel approach regarding the anti-aging of facial skin through collagen reorganization.

The needle shaping technique can be used to perform subcutaneous microtransplants, enabling the 'lifting' of the skin. This prospective cohort study aimed to examine the effects of needle shaping on facial skin tone, volume and histological structure. A total of 54 women underwent the needle shaping procedure performed by inserting a tiny acupuncture needle combined with mixed electrical currents. The overall treatment was completed within 4 sessions of 2 months apart, once every 15 days. Maintenance was ensured by 2 sessions (no longer than 15 days apart) every 6 months. Macroscopic skin appearance was evaluated by a specialized dermatologist and the satisfaction of the patients was assessed. The microscopic structure of the skin dermis was evaluated by optic and scanning electron microscopy. I-chrome staining demonstrated more compact dermis-collagen fibers which were larger and thicker as compared to the controls. Scanning electron microscopy demonstrated an increased dermis thickness as compared to pre-treatment. All patients that answered to the follow up reported satisfaction during assessment. The satisfaction of the patients was very good and excellent in 45% of cases. The results of the needle-shaping procedure are natural with no scaring or down time. Moreover, the result is lasting even for 1 year, depending always on the subject's lifestyle and general health condition.

Molecular and cellular stratagem of brain metastases associated with melanoma.

Tumors of the central nervous system are the most prevalent complications of melanoma, especially in the late stage of disease. Melanoma, lung and breast cancer are the leading cause of secondary tumors in the brain, the majority of them having a poor outcome. Brain dissemination is developed in half of stage IV melanomas and these cases can increase up to 75%, having a major impact on the quality of life. This review will focus on recent findings that provide new ways to potentially prevent brain metastases in malignant melanoma. The key of these findings is based on the heterogeneity of the melanoma and of the brain metastases at genetic levels. This new era of technologies provides new tools in understanding the dissemination mechanisms of malignant cells. The cellular and molecular changes, the immune status of the patient and the blood-brain barrier permeability are key regulators of cancer cell dissemination. Understanding these mechanisms can render new hope in preventing brain metastases by focusing on melanoma and new pharmacologic approaches.