Search Results (324)

Introduction: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer entity in Germany, following basal cell carcinoma. Its incidence has increased fourfold over the past three decades. Early diagnosis and treatment are essential for achieving favorable outcomes. Our study aims to identify prognostic factors based on real-world data to improve follow-up protocols and raise clinical vigilance. Methods: We conducted a retrospective, monocenter analysis with a total of 124 patients with at least one cSCC thicker than 3 mm, treated at the Department of Dermatology, University Medical Center Mainz, between 2010 and 2020. Tumor-specific criteria were correlated with patient-specific data, such as gender, age, immunosuppression, UV exposure and mortality. Results: A higher incidence of cSCC was found on UV-exposed skin (91.1%); however, tumors on non-UV-exposed skin were on average thicker (6.55 mm vs. 9.25 mm, p = 0.011) and associated with higher metastasis rates (10.6% vs. 63.3%, p < 0.001). Immunosuppression was strongly associated with a younger age at diagnosis (74 years vs. 81 years), a higher metastasis rate (29% vs. 10.8%, p = 0.021) and a worse 5Y-OS-rate (36.1% vs. 97.8%, p = 0.04). SLNB was performed in eight patients, with one positive SLN identified (12.5%). Local recurrence was observed in 18.1% (n = 21) of patients who did not experience SLNB, whereas no local recurrences (0%) were reported in patients with SLNB (p = 0.349). Discussion: Tumors on non-UV-exposed areas were thicker and more often metastatic, suggesting delayed detection or more aggressive tumor subtypes. Immunosuppression was associated with worse outcomes, underscoring the need for intensified follow-up. SLNB was rarely performed, and larger studies are needed to assess its role. Full article

Non-melanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), represents the most common type of cancer worldwide, particularly among Caucasians. While BCC is locally invasive with minimal metastatic potential, cSCC is a highly aggressive tumor with a significant potential for metastasis, particularly in elderly populations. Tumor development and progression and the metastasis of cSCC are influenced by a complex interplay between tumor cells and the tumor microenvironment. Recent research highlights the importance of various immune cell subsets, including T cells, tumor-associated macrophages (TAMs), and dendritic cells, in influencing tumor progression, immune evasion, and treatment resistance. This review outlines key regulatory mechanisms in the immune tumor microenvironment (TME) of cSCC and explores the role of cytokines, immune checkpoints, and stromal interactions. We further discuss the relevance of three-dimensional (3D) in vitro models such as spheroids, organoids, and tumor-on-chip systems as tools to mimic immune–tumor interactions with higher physiological relevance, such as macrophage activation and polarization against cSCC cells. Globally, 3D models offer new opportunities for immunotherapy screening and mechanistic studies. Understanding the immune landscape in cSCC through advanced modeling techniques holds strong clinical potential for improving diagnostic and therapeutic strategies. Full article

In recent years, a long list of relevant studies has highlighted the engagement of the nervous system in the fine-tuning of tumor development and progression. Several authors have shown that different types of nerve fibres (sympathetic, parasympathetic/vagal or somatosensory fibres) may contribute to tumor innervation affecting cancer initiation, progression and metastasis. A large presence of nerve fibres is frequently observed in tumors with respect to the corresponding healthy tissues. In this regard, it is worth noting that in some cases a reduced innervation may associate with slow tumor growth in a tissue-specific manner. Current studies have begun to shed light over the role played in this specific process by Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system. SCs observed in cancer tissues share strong similarities with repair SCs that appear after nerve injury. A large body of research indicates that SCs may have a role in shaping the microenvironment of tumors by regulating the immune response and influencing their invasiveness. In this review, we summarize data relevant to the role of peripheral innervation in general, and of SCs in particular, in defining the progression of different tumors: melanoma that originate in the skin with mainly sensory innervation; pancreatic and liver-derived tumors (e.g., pancreatic adenocarcinoma and cholangiocarcinoma) with mainly autonomous innervation. We conclude by summarizing data regarding hepatocarcinoma (with anatomical predominance of small autonomic nerve fibres) in which the potential relationship between innervation and tumor progression has been little explored, and largely remains to be defined. Full article

Malignant cutaneous melanoma is among the most aggressive forms of skin cancer, characterized by high metastatic potential and frequent resistance to standard therapies. Hydroxytyrosol, a phenolic compound derived from extra virgin olive oil, has shown promising anticancer properties in various models, yet its effects in 3D melanoma systems remain poorly understood. In this study, we used paired 3D spheroid models of non-tumorigenic (HEMa) and melanoma (C32) to assess the therapeutic potential of hydroxytyrosol. To evaluate the anti-tumoral effect of hydroxytyrosol, we performed cytotoxicity, metastasis, invasiveness, cell cycle arrest, apoptotic, and proteomic assays. Hydroxytyrosol treatment significantly impaired spheroid growth, reduced cell viability, and induced cell cycle arrest and apoptosis in C32 spheroids, with minimal cytotoxicity observed in HEMa models. Proteomic profiling further demonstrated that hydroxytyrosol selectively downregulated a network of oncogenic proteins, including ERBB2, ERBB3, ERBB4, VEGFR-2, and WIF-1, along with suppression of downstream PI3K-Akt and MAPK/ERK signaling pathways. In conclusion, compared to dabrafenib, hydroxytyrosol exerted a broader range of molecular effects and was more selective toward tumor cells. These findings support the use of hydroxytyrosol as a multi-targeted agent capable of attenuating melanoma progression through suppression of kinase signaling and tumor-stromal interactions. Full article

Background/Objectives: The gold standard of treatment for both melanoma and non-melanoma skin cancers is wide surgical resection to obtain oncological radicality, which occasionally results in functional or aesthetic impairment, potentially affecting quality of life. Despite the increased complexity of the technique, extended duration of hospitalization, and prolonged surgical operative times, microsurgery can facilitate the reconstruction of locally invasive skin cancers following ablative surgery and may yield superior functional and aesthetic outcomes. Consequently, microsurgical reconstruction is more likely to be necessary if a large skin tumor requires excision. However, the impact of this extensive and complex procedure on patients with skin cancer has not yet been fully elucidated. The objective of this research was to critically analyze the utilization of free flap reconstruction subsequent to skin cancer therapy. Through a comprehensive examination of published data, this study aimed to assess the potential benefits and drawbacks associated with this reconstructive approach. Methods: A systematic review of studies that were published from January 2004 to May 2024 was conducted using the MEDLINE online database search. To present an evidence summary and provide a systematic approach and quality assessment, the GRADE^® rating was applied to the results. Results: This review summarizes the oncological and clinical data, including previous interventions, adjuvant and neoadjuvant therapies, nodal status, distant metastasis, and follow-up time. Surgical outcome parameters such as healing time, flap survival, revision rate success, and minor and major complications were documented. Along with the findings, a quality assessment of the studies was also provided. Conclusions: This systematic review underscores the extensive use and efficacy of microsurgery for reconstruction after skin cancer excision; however, the literature remains limited by inconsistent reporting of oncological outcomes and the lack of a standardized approach to evaluate the impact of free flap reconstruction on both immediate and long-term cancer-specific results. Full article

Background/Objectives: Cutaneous melanoma is one of the aggressive forms of skin cancer originating from melanocytes. The high incidence of melanoma metastasis continues to rise, partly due to the complex nature of the molecular mechanisms driving its progression. While melanomas generally arise from melanocytes, we investigated whether aberrant keratinocyte differentiation pathways—like cornified envelope formation—discriminate primary melanoma from metastatic melanoma, revealing novel biomarkers in progression. Methods: In the present study, we retrieved four datasets (GSE15605, GSE46517, GSE8401, and GSE7553) associated with primary and metastatic melanoma tissues and identified differentially expressed genes (DEGs). Thereafter, an integrated meta-analysis and functional enrichment analysis of the DEGs were performed to evaluate the molecular mechanisms involved in melanoma metastasis, such as immune cell deconvolution and protein-protein interaction (PPI) network construction. Hub genes were identified based on four topological methods, including ‘Betweenness’, ‘MCC’, ‘Degree’, and ‘Bottleneck’. We validated the findings using the TCGA-SKCM cohort. Drug-gene interactions were evaluated using the DGIdb, whereas structural druggability was assessed using the ProteinPlus and AlphaFold databases. Results: We identified a total of eleven hub genes associated with melanoma progression. These included members of the keratin gene family (e.g., KRT5, KRT6A, KRT6B, etc.). Except for the gene CDH1, all the hub genes were downregulated in metastatic melanoma tissues. From a prognostic perspective, these hub genes were associated with poor prognosis (i.e., unfavorable). Using the Human Protein Atlas (HPA), immunohistochemistry evaluation revealed mostly undetected levels in metastatic melanoma. Additionally, the cornified envelope formation was the most enriched pathway, with a gene ratio of 17/33. The tumor microenvironment (TME) of metastatic melanomas was predominantly enriched in NK cell–associated signatures. Finally, several hub genes demonstrated favorable druggable potential for immunotherapy. Conclusions: Through integrated meta-analysis, this study identifies transcriptional, immunological, and structural pathways to melanoma metastasis and highlights keratin family genes as promising biomarkers for therapeutic targeting. Full article

Rafoxanide, originally developed as a veterinary anthelmintic for the treatment of parasitic infections in livestock, has recently emerged as a promising therapeutic prospect in oncology. This compound has demonstrated notable antineoplastic effects against a variety of cancers, including skin, gastric, colorectal, and lung cancers, as well as hematological malignancies such as multiple myeloma. Rafoxanide exerts its anticancer activity through multiple complementary mechanisms, including the induction of endoplasmic reticulum stress, cell cycle arrest, apoptosis, and immunogenic cell death. Furthermore, the drug has been reported to inhibit key oncogenic signaling pathways (e.g., STAT3, NF-κB, c-FLIP, survivin) that contribute to tumor growth and metastasis. Preclinical studies in murine models have demonstrated significant reductions in tumor volume of up to 50% and a tumor-free rate exceeding 80%, with effective doses ranging from 7.5 to 40 mg/kg. This multitargeted mode of action distinguishes rafoxanide from conventional therapies and may help overcome resistance mechanisms that often limit the efficacy of cancer treatments. In this review, we summarize and discuss the growing body of evidence supporting rafoxanide’s therapeutic potential in oncology, as well as its possible applications in cancer treatment. Full article

Skin cancers are associated with a significant psychological burden across all age groups, particularly as their global incidence continues to rise. Ultraviolet (UV) radiation—primarily UVA and UVB—remains the leading etiological factor, inducing DNA mutations in key genes such as TP53 and BRAF. Among skin cancers, basal cell carcinoma (BCC) is the most prevalent and typically indolent. In contrast, squamous cell carcinoma (SCC) tends to be more invasive, while melanoma is the most aggressive and prone to metastasis. Melanoma is especially concerning due to its rapid dissemination and its occurrence not only on the skin but also in ocular, mucosal, and nail tissues. These challenges, along with rising treatment resistance and mortality, underscore the urgent need for novel anticancer agents. Berberine—a plant-derived isoquinoline alkaloid—has attracted increasing attention for its broad-spectrum anticancer potential, including against skin cancers. In this review, we summarize current evidence regarding berberine’s mechanisms of action in melanoma and SCC, emphasizing both its preventive and therapeutic effects. We further explore its potential as an adjuvant agent in combination with conventional treatments, offering a promising avenue for enhancing the clinical outcomes of skin cancer therapy. Full article

Transient receptor potential classical or cation channels (TRPCs) are integral to tumor biology, particularly in maintaining Ca²⁺ homeostasis within cancer cells. TRPC5, a pH-sensitive member of this family, may act as a signaling molecule in the altered microenvironment of solid tumors, which are characterized by an inverted pH-gradient—with decreased extracellular and increased intracellular pH—that promotes tumor progression. This study addresses a gap in the field, as there is currently limited research on TRPC5, particularly regarding its potential role as a tumor marker. While TRPCs are known to be involved in cancer biology, the specific role of TRPC5 in solid tumors, including its potential role as a diagnostic marker, remains largely unexplored. This study is the first to examine TRPC5 expression profiles in common skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), and nevus cell nevi (NCN). Our findings reveal that the frequency of TRPC5 expression in BCC is significantly lower compared to SCC and epidermal portions of NCN and MM. These results suggest that TRPC5 could serve as an immunohistochemical marker to distinguish SCC from BCC. Additionally, this study lays the groundwork for future research into the role of TRPC5 in tumor progression and metastasis, especially since BCCs, which rarely metastasize, are predominantly negative for TRPC5. Full article

Background: Postoperative wound dehiscence is a major complication following spinal metastasis surgery, particularly in patients who receive preoperative radiotherapy or molecular-targeted therapy; however, preventive strategies remain limited. Objective: In this study, we aimed to identify the risk factors for postoperative wound dehiscence and evaluate the clinical utility of a novel curved skin incision (CSI) technique, designed to avoid irradiated areas, in comparison with the conventional midline incision (MI) technique. Methods: Logistic regression analysis was conducted on 107 patients who underwent MI between 2013 and 2018. Based on the results, we developed the CSI technique. Propensity score matching was performed to compare postoperative wound dehiscence in 29 matched pairs of patients treated with either CSI or MI from 2019 to 2021. Results: Preoperative radiotherapy and molecular-targeted therapy were found to be significant risk factors for wound dehiscence. CSI, which circumvents irradiated skin, was associated with a substantially lower rate of wound dehiscence than MI. Conclusions: The CSI technique offers a simple, reproducible, and effective surgical approach to reduce postoperative wound complications in high-risk patients. Its clinical benefit, especially for those with prior radiotherapy, suggests that it may serve as a valuable addition to standard spinal metastasis surgery. Full article

Protein kinase CK2 has emerged as a pivotal regulator of cellular processes involved in skin homeostasis, including cell proliferation, differentiation and inflammatory response regulation. In fact, CK2 activity dysregulation is implicated in the pathogenesis of different skin diseases, such as psoriasis, cancer and inflammatory dermatoses. CK2 overactivation fosters keratinocyte proliferation and pro-inflammatory cytokine production through the STAT3 and Akt pathways in psoriasis, thus contributing to epidermal hyperplasia and inflammation. In the realm of oncology, CK2 overexpression correlates with tumor progression, facilitating cell survival and metastasis in melanoma and non-melanoma skin cancers. Pharmacological inhibition of CK2 has demonstrated therapeutic potential, with CX-4945 (Silmitasertib) as the most studied adenosine triphosphate-competitive inhibitor (ATP-competitive inhibitor). Preclinical models reveal that CK2 inhibitors effectively mitigate pathological features of psoriasis, regulate keratinocyte differentiation, and suppress tumor growth in skin cancers. These inhibitors also potentiate the efficacy of conventional chemotherapeutics and exhibit anti-inflammatory effects in dermatological conditions. Future research will aim to enhance the specificity and delivery of CK2-targeting therapies, including topical formulations, to minimize systemic side effects. Combination therapies integrating CK2 inhibitors with other agents might offer synergistic benefits in managing skin diseases. This review underscores CK2’s critical role in skin and its therapeutic potential as a pharmacological target, advocating for innovative approaches to harness CK2 inhibition in dermatology. Full article

Metastatic melanoma is an aggressive skin cancer with a five-year survival rate of only 35%. Despite recent advances in immunotherapy, there is still an urgent need for the development of innovative therapeutic approaches to improve clinical outcomes of patients with metastatic melanoma. Prior research from our laboratory revealed that loss of the I-branching enzyme β1,6 N-acetylglucosaminyltransferase 2 (GCNT2), with consequent substitution of melanoma surface I-branched poly-N-acetyllactosamines (poly-LacNAcs) with i-linear poly-LacNAcs, is implicated in driving melanoma metastasis. In the current study, we explored the role of galectin-3 (Gal-3), a lectin that avidly binds surface poly-LacNAcs, in dictating melanoma aggressive behavior. Our results show that Gal-3 favors binding to i-linear poly-LacNAcs, while enforced GCNT2/I-branching disrupts this interaction, thereby suppressing Gal-3-dependent malignant characteristics, including extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway activation, BCL2 expression, cell proliferation, and migration. This report establishes the crucial role of extracellular Gal-3 interactions with i-linear glycans in promoting melanoma cell aggressiveness, placing GCNT2 as a tumor suppressor protein and suggesting both extracellular Gal-3 and i-linear glycans as potential therapeutic targets for metastatic melanoma. Full article

Background: Extramammary Paget’s disease (EMPD) is a rare cutaneous carcinoma that typically affects the elderly and is frequently observed in genital and perianal regions. We analyzed the outcomes and prognostic factors for EMPD after radiation therapy (RT). Methods: We analyzed data from 81 patients with non-metastatic EMPD who received either RT alone or in combination with surgery and/or chemotherapy. The median radiation dose was 56 Gy in 28 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) rates were calculated using the Kaplan–Meier method. Multivariate analyses were performed using the Cox proportional hazards model. Late adverse events were evaluated by NCI-CTCAE version 5.0. Results: The median age was 78 years, and the median follow-up period was 36 months. The three-year LC, PFS, and OS rates were 75%, 52%, and 80%, respectively. Multivariate analyses identified the presence of lymph node (LN) metastasis, the absence of surgery, and the omission of elective nodal irradiation (i.e., local irradiation only) as significant factors for unfavorable LC (p = 0.01, 0.02, and 0.006) and PFS (p = 0.001, 0.04, and 0.03). LN metastasis was also a significant factor for unfavorable OS (p = 0.005). One patient developed grade 2 skin infection, and another developed grade 3 lymphedema; no grade 4 or higher toxicity was observed. Conclusions: The present results revealed prognostic factors for EMPD after RT and suggest that the absence of surgery and omission of elective nodal irradiation worsened outcomes. A prospective study is needed to establish an optimal treatment strategy for this rare malignancy, which is common in the elderly. Full article

Background: Transoral robotic surgery (TORS) is a minimally invasive procedure that is performed with neck dissection (ND) and postoperative radiotherapy when necessary. This study aimed to review the methods of vascular ligation and ND in cases of TORS for oropharyngeal cancer in Japan. Methods: We enrolled 44 consecutive patients who underwent TORS for laryngopharyngeal cancer between December 2019 and December 2023. Of these, 35 patients who underwent TORS as a first-line treatment for oropharyngeal cancer were included in this study. We retrospectively collected patient data on age, sex, primary tumor location, clinical tumor–node classification, Eastern Cooperative Oncology Group performance status, history of irradiation to the neck, presence of anticoagulants, pathological results, tumor size, total operative duration, console time, length of skin incision operative result, estimated blood loss, late cervical lymph node metastasis, perioperative complications, postoperative hospital stay, postoperative bleeding, period until oral intake after surgery, and swallowing function. Intra- and postoperative outcomes of TORS, TORS + ND (IIa) + vascular ligation, and TORS + ND (II–IV) + vascular ligation. Results: Significant differences were found in operative duration, blood loss during ND, and skin incision length between TORS + ND (IIa) + vascular ligation and TORS + ND (II–IV) + vascular ligation. Console time and blood loss did not significantly differ between the two groups. Each group contained one case of postoperative bleeding. Conclusions: Safe and minimally invasive treatments can be established if vascular ligation and ND are implemented based on appropriate case selection. Full article

Background: The reconstruction of extensive full-thickness lower eyelid defects constitutes a challenge for plastic surgeons. Various techniques have been described to cater to patients’ specific defect needs, with the aim of achieving the best results. Materials and Methods: We performed a retrospective observational study assessing our experience with a combination of a single-stage procedure consisting of a hard palate graft and a Fricke flap for patients with complex lower lid resections undergoing immediate total reconstruction at our institution. Clinical data, histological type and results, size of tumor, recurrences, and post-operative complications were collected to evaluate outcomes. A Visual Analogue 10-point scale was administered to all patients to assess esthetic and functional outcomes. Results: Seven lower lid reconstructions were performed, with all patients receiving immediate reconstruction. The age of the patients ranged from 55 to 82. Five skin cancers were located on the right side and three on the left side. In all cases, histological diagnosis was non-melanoma skin cancers. The mean size of the tumor was 1.7 × 1.7. In all patients, negative surgical margins were obtained. All patients underwent 24-month follow up. No immediate complication from surgery was recorded within the first 30 days. During follow-up, lower lid ectropion was observed in one patient due to the development of a retracting scar. No local cancer recurrence or nodal metastasis were detected until 2 years follow-up. In only one case, adjuvant therapy was required. The aesthetic results were deemed satisfactory by all patients. Conclusions: According to our experience, the combination of a Fricke flap and hard palate graft is an excellent option for total lower eyelid reconstruction, with low morbidity and favorable outcomes, even in elderly and frail patients where satisfactory results were achieved in a single-stage procedure and short operative times. Full article