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.

Differences and Similarities in Epidemiology and Risk Factors for Cutaneous and Uveal Melanoma.

Both cutaneous melanoma (CM) and uveal melanoma (UM) represent important causes of morbidity and mortality. In this review, we evaluate the available knowledge on the differences and similarities between cutaneous melanoma and uveal melanoma, focusing on the epidemiological aspects and risk factors. Uveal melanoma is a rare condition but is the most prevalent primary intra-ocular malignant tumor in adults. Cutaneous melanoma, on the other hand, is significantly more common. While the frequency of cutaneous melanoma has increased in the last decades worldwide, the incidence of uveal melanoma has remained stable. Although both tumors arise from melanocytes, they are very distinct entities biologically, with complex and varied etiologies. Both conditions are encountered more frequently by individuals with a fair phenotype. ultraviolet-radiation is an important, well-documented risk factor for the development of CM, but has shown not to be of specific risk in UM. Although cutaneous and ocular melanomas seem to be inherited independently, there are reported cases of concomitant primary tumors in the same patient.

Clinicopathological characteristics and prognostic factors of atypical meningiomas with bone invasion: a retrospective analysis of nine cases and literature review.

BACKGROUND: Meningiomas are the most common primary neoplasms of the central nervous system in adults, arising from the arachnoid cap cells. Thus, grade 2 meningiomas are situated on the border between benignity and malignancy. Among the many prognostic factors that have been investigated in these tumors, bone invasion is one of them. OBJECTIVE: The aim of our study was to identify whether bone invasion influences tumor recurrence and progression-free survival (PFS) in patients with atypical meningiomas (AMs). PATIENTS, MATERIALS AND METHODS: Out of 81 patients with AMs followed over a period of five years, we identified nine patients with bone invasion. We analyzed their demographic, clinical, imaging, and pathological characteristics, such as age, gender, radiological aspects, morphological features, extent of resection, recurrence rate, and PFS over a follow-up period of 60 months. Bone invasion was determined based on preoperative, surgical, and pathological reports. RESULTS: Out of the nine patients with bone invasion, four had convexity meningiomas, four had parasagittal meningiomas and one had a falcine meningioma. Regarding tumor recurrence∕progression, most patients (n=6) recurred within the first 24 months after surgery. Our study showed that the early recurrence/progression of tumor (at 12 months) correlated with extensive presence of malignancy criteria, especially with the presence of 15-18 mitoses∕10 high-power fields, as well as with large foci of spontaneous necrosis, but also with tumor bone infiltration, extensive bone lamellae destruction, and tumor infiltration of adjacent muscle with its atrophy due to tumor compression. Patients with bone invasion had a PFS of 29.3 months, compared to patients without invasion who had a higher PFS (49.3 months). Significant statistical associations were observed between bone invasion and tumor recurrence (p=0.002) and PFS (p=0.004). CONCLUSIONS: Our study emphasizes the importance of a thorough histopathological examination of the surgical specimen, which can provide significant data for the assessment of the progression of an AM [World Health Organization (WHO) grade 2] with bone invasion. AM infiltration in adjacent bone and muscle increases the rate of tumor recurrence and decreases PFS over a follow-up period of 60 months.

Humps and bumps of head: review of meningiomas of the scalp.

Meningiomas are a type of tumor that arises from meningothelial cells and primarily develops in intracranial space, being some of the most common benign tumors of the central nervous system. However, meningiomas can rarely occur on the scalp and are called primary cutaneous meningiomas. Since the pathogenesis of these lesions is still uncertain, these tumors still pose challenges in terms of histopathological diagnosis. In this review, we will discuss the main cases of scalp meningiomas in the literature, their classification, pathological and immunohistochemical diagnosis, differential diagnosis with other scalp lesions and the most effective treatment. This study highlights the importance of immunohistochemistry in the differential diagnosis of skin lesions located on the scalp.

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.

Skin Dialogues in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic skin disorder associated with significant quality-of-life impairment and increased risk for allergic and non-allergic comorbidities. The aim of this review is to elucidate the connection between AD and most common comorbidities, as this requires a holistic and multidisciplinary approach. Advances in understanding these associations could lead to the development of highly effective and targeted treatments.

The Influence of Oncogenic Viruses in Renal Carcinogenesis: Pros and Cons.

Viral infections are major contributors to the global cancer burden. Recent advances have revealed that known oncogenic viruses promote carcinogenesis through shared host cell targets and pathways. The aim of this review is to point out the connection between several oncogenic viruses from the Polyomaviridae, Herpesviridae and Flaviviridae families and renal carcinogenesis, highlighting their involvement in the carcinogenic mechanism. We performed a systematic search of the PubMed and EMBASE databases, which was carried out for all the published studies on RCC in the last 10 years, using the following search algorithm: renal cell carcinoma (RCC) and urothelial carcinoma, and oncogenic viruses (BKPyV, EBV, HCV, HPV and Kaposi Sarcoma Virus), RCC and biomarkers, immunohistochemistry (IHC). Our analysis included studies that were published in English from the 1st of January 2012 to the 1st of May 2022 and that described and analyzed the assays used for the detection of oncogenic viruses in RCC and urothelial carcinoma. The virus most frequently associated with RCC was BKPyV. This review of the literature will help to understand the pathogenic mechanism of the main type of renal malignancy and whether the viral etiology can be confirmed, at a minimum, as a co-factor. In consequence, these data can contribute to the development of new therapeutic strategies. A virus-induced tumor could be efficiently prevented by vaccination or treatment with oncolytic viral therapy and/or by targeted therapy.

Diagnostics of HNSCC Patients: An Analysis of Cell Lines and Patient-Derived Xenograft Models for Personalized Therapeutical Medicine.

Head and neck squamous cell carcinomas (HNSCC) are very frequent worldwide, and smoking and chronic alcohol use are recognized as the main risk factors. For oropharyngeal cancers, HPV 16 infection is known to be a risk factor as well. By employing next-generation sequencing, both HPV-positive and negative HNSCC patients were detected as positive for PI3K mutation, which was considered an optimal molecular target. We analyzed scientific literature published in the last 5 years regarding the newly available diagnostic platform for targeted therapy of HNSCC HPV+/-, using HNSCC-derived cell lines cultures and HNSCC pdx (patient-derived xenografts). The research results are promising and require optimal implementation in the management of HNSCC patients.

Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms.

Kaposi's sarcoma is a rare disease with four known variants: classic, epidemic, endemic and iatrogenic (transplant-related), all caused by an oncogenic virus named Human Herpes Virus 8. The viral infection in itself, along with the oncogenic properties of HHV8 and with immune system dysfunction, forms the grounds on which Kaposi's Sarcoma may develop. Infection with HHV8 occurs through saliva via close contacts, blood, blood products, solid organ donation and, rarely, vertical transmission. Chronic inflammation and oncogenesis are promoted by a mix of viral genes that directly promote cell survival and transformation or interfere with the regular cell cycle and cell signaling (of particular note: LANA-1, v-IL6, vBCL-2, vIAP, vIRF3, vGPCR, gB, K1, K8.1, K15). The most common development sites for Kaposi's sarcoma are the skin, mucocutaneous zones, lymph nodes and visceral organs, but it can also rarely appear in the musculoskeletal system, urinary system, endocrine organs, heart or eye. Histopathologically, spindle cell proliferation with slit-like vascular spaces, plasma cell and lymphocyte infiltrate are characteristic. The clinical presentation is heterogenic depending on the variant; some patients have indolent disease and others have aggressive disease. The treatment options include highly active antiretroviral therapy, surgery, radiation therapy, chemotherapy, and immunotherapy. A literature search was carried out using the MEDLINE/PubMed, SCOPUS and Google Scholar databases with a combination of keywords with the aim to provide critical, concise, and comprehensive insights into advances in the pathogenic mechanism of Kaposi's sarcoma.

Merkel Cell Polyoma Virus and Cutaneous Human Papillomavirus Types in Skin Cancers: Optimal Detection Assays, Pathogenic Mechanisms, and Therapeutic Vaccination.

Oncogenic viruses are recognized to be involved in some cancers, based on very well-established criteria of carcinogenicity. For cervical cancer and liver cancer, the responsible viruses are well-known (e.g., HPV, HBV); in the case of skin cancer, there are still many studies which are trying to identify the possible viral etiologic agents as principal co-factors in the oncogenic process. We analysed scientific literature published in the last 5 years regarding mechanisms of carcinogenicity, methods of detection, available targeted therapy, and vaccination for Merkel cell polyomavirus, and beta human papillomavirus types, in relation to skin cancer. This review is targeted at presenting the recent findings which support the involvement of these viruses in the development of some types of skin cancers. In order to optimize the management of skin cancer, a health condition of very high importance, it would be ideal that the screening of skin cancer for these two analysed viruses (MCPyV and beta HPV types) to be implemented in each region's/country's cancer centres' molecular detection diagnostic platforms, with multiplex viral capability, optimal sensitivity, and specificity; clinically validated, and if possible, at acceptable costs. For confirmatory diagnosis of skin cancer, another method should be used, with a different principle, such as immunohistochemistry, with specific antibodies for each virus.

Comprehensive review on the pathophysiology, clinical variants and management of pemphigus (Review).

Pemphigus represents a group of chronic inflammatory disorders characterized by autoantibodies that target components of desmosomes, leading to the loss of intercellular adhesion between keratinocytes and causing intraepithelial blistering. The pemphigus group consists of four main clinical types with several variants: pemphigus vulgaris (with pemphigus vegetans and pemphigus herpetiformis as variants), pemphigus foliaceus, paraneoplastic pemphigus and IgA pemphigus (with two clinical variants: intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis). Genetic factors are involved in the pathogenesis, with HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more common in patients with pemphigus vulgaris, HLA class II DRB1*0344 and HLA Cw*1445 correlated with paraneoplastic pemphigus, and HLA-DRB1*04:01, HLA-DRB1*04:06, HLA-DRB1*01:01, HLA-DRB1*14, associated with a higher risk of developing pemphigus foliaceus. Autoantibodies are conducted against structural desmosomal proteins in the skin and mucous membranes, mainly desmogleins, desmocollins and plakins. Cell-mediated immunity may also play a role, especially in paraneoplastic pemphigus. Patients may present erythema, blisters, erosions, and ulcers that may affect the skin, as well as mucosal surfaces of the oral cavity, eyes, nose, leading to severe complaints including pain, dysphagia, and fetor. Oral mucosal postbullous erosive lesions are frequently the first sign of disease in pemphigus vulgaris and in paraneoplastic pemphigus, without skin involvement, making the diagnosis difficult. Treatment options classically include immunosuppressive agents, such as corticosteroids and corticosteroid-sparing agents such as azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate or dapsone. Newer therapies focus on blocking cell signaling events induced by pathogenic autoantibodies and/or targeting specific autoantibodies. The disease evolution is conditioned by the treatment with maximum doses of corticosteroids and the side effects associated with long-term immunosuppressive therapy, which is why patients need a multidisciplinary approach in following the treatment. In this review, we provide a comprehensive overview of the epidemiology, pathophysiology, clinical aspect, diagnosis and management of the main intraepidermal blistering diseases from the pemphigus group.

Use of imaging techniques for melanocytic naevi and basal cell carcinoma in integrative analysis (Review).

Early detection of skin cancer is essential in order to obtain an improved prognosis. Clinicians need more objective and non-invasive examination methods to support their decision whether to biopsy or not tumoral lesions. These may include several imaging techniques such as dermoscopy, videodermoscopy, also known as sequential digital dermoscopy (SDD), computer-aided diagnosis (CAD), total body photography, imaging and high-frequency ultrasonography (HFUS), reflectance confocal microscopy, multiphoton tomography, electrical impedance spectroscopy, Raman spectroscopy, stepwise two-photon-laser spectroscopy and quantitative dynamic infrared. This review summarizes the current developments in the field of melanocytic lesions, such as naevi and basal cell carcinoma (BCC) imaging techniques. The aim was to collect and analyze data concerning types, indications, advantages and disadvantages of modern imaging techniques for in vivo skin tumor diagnosis. Two main methods were focused on, namely videodermoscopy and HFUS, which can be included in daily dermatologists' practice. In skin tumors HFUS allows the assessment of tumoral lesions with depth smaller than 1.5 cm, being described a correlation between ultrasonographic depth and the histologic index.

Pemphigus vulgaris - approach and management.

The place of pemphigus vulgaris (PV) among autoimmune bullous dermatoses is well known. In pemphigus, IgG autoantibodies are directed against desmogleins 1 and 3, which are part of the cadherin family of cell-cell adhesion molecules. These structures are responsible for maintaining the intercellular adherence in stratified squamous epithelia, such as the skin and oral mucosa. The incidence of autoimmune bullous dermatoses is steadily increasing, being associated with a high degree of morbidity. The pathophysiology of these dermatoses is very well understood, complemented by recent genetic studies. The gold standard for the diagnosis of pemphigus vulgaris is the detection of autoantibodies or complement component 3 by direct immunofluorescence microscopy of a perilesional biopsy. Early diagnosis and initiation of treatment are necessary in order to achieve a favorable prognosis. Although the first line of treatment is corticotherapy, there are no clear guidelines on dosing regimens, and long-term adverse effects are important. Corticosteroid-sparing adjuvant therapies have been employed in the treatment of PV, aiming to reduce the necessary cumulative dose of corticosteroids. In addition, therapies with anti-CD20 antibodies are used, but antigen-specific immune suppression-based treatments represent the future.