Search Results (365)

The Kindlin family of scaffold proteins plays key roles in integrin-mediated processes. Kindlin-1 and -2, encoded by the FERMT1 and FERMT2 genes, respectively, are expressed in the epidermis. Kindlin-1 plays protective roles against the development of cutaneous squamous cell carcinomas (cSCCs) in epidermal keratinocytes. However, the role of Kindlin-2 in transformed epidermal keratinocytes has remained virtually unexplored. In this study, we used siRNA approaches to generate Kindlin-2-depleted cells in three isogenic transformed keratinocyte lines. PM1, MET1, and MET4 cells model, respectively, a precancerous lesion, a primary cSCC, and a metastatic lesion of the latter. MET1 cells express both Kindlin-1 and -2. However, Kindlin-1 was not detectable in PM1 and MET4 cells. FERMT2 silencing in PM1 and MET4, but not in MET1 cells, reduced proliferation and the ability to adhere to culture surfaces and spreading. Furthermore, Kindlin-2-depleted PM1 and MET4, but not MET1 cells, exhibited decreased numbers of focal adhesions, as well as an altered F-actin and microtubule cytoskeletal organization. Significantly, FERMT2 silencing reduced the directional migration in all three cell types. These findings are consistent with the concept that, in the absence of other Kindlin orthologues, Kindlin-2 plays a prominent role in the modulation of the proliferation, spreading, focal adhesion assembly, and motility of transformed keratinocytes, as exemplified by PM1 and MET4 cells. 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

Background: Huriez syndrome is a rare hereditary skin disorder marked by early-onset sclerodactyly, hyperkeratosis of the palms and soles, and nail dysplasia. A key concern is the early and aggressive development of cutaneous squamous cell carcinoma (SCC), typically affecting the dorsal aspects of the hands. Methods: This narrative review summarizes clinical features, genetic aspects, and oncologic implications of Huriez syndrome. A systematic search was conducted in PubMed and Scopus, including English-language articles published up to May 2025. Relevant case reports and small case series were analyzed. Results: Seven patients (58.3%) underwent multiple surgeries due to recurrent or bilateral disease. Six patients (50%) required amputations, including finger, hand, and arm amputations, with no foot amputations reported. Reconstruction after oncological resection was performed in six patients (50%) using skin grafts (3), pedicled flaps (2), or free flaps (1). Amputation was mainly for advanced disease, with radial forearm flaps used for reconstruction. All flaps remained disease-free. Five cases (41.6%) had a history of local recurrence. Conclusions: The early diagnosis of Huriez syndrome is crucial to enable the surveillance and timely treatment of SCC. A multidisciplinary team including dermatologists, oncologists, plastic surgeons, and geneticists is recommended. Further research is needed to clarify genetic mechanisms and develop early detection strategies to improve outcomes. Full article

Background: Long non-coding RNAs (lncRNAs) are increasingly recognized as pivotal regulators in both inflammatory and neoplastic skin disorders. Their implications in numerous biological processes, including gene expression, immune responses, and epidermal homeostasis, suggest potential applications as diagnostic and prognostic markers, as well as therapeutic targets. Methods: We conducted a literature search on lncRNAs involved in both psoriasis and cutaneous squamous cell carcinoma (cSCC), highlighting overlapping pathogenic mechanisms. Results: Several lncRNAs, such as HOTAIR, MALAT-1, H19, and uc.291, display dysregulated expression in both psoriasis and cSCC, influencing keratinocyte proliferation and apoptosis, immune modulation, cytokine signaling, and the synthesis of epidermal proteins. Conclusions: The intersection of lncRNA function in chronic inflammation and skin carcinogenesis underscores their role in mediating the transition from psoriatic inflammation to tumorigenesis, offering new insights into disease susceptibility; further investigation through functional studies and clinical validation are required. The study of lncRNA-mediated molecular pathways is particularly relevant given the increased risk of non-melanoma skin cancers and lymphoproliferative disorders among patients with chronic and severe forms of psoriasis. Full article

Cutaneous neoplasia is among the most common illnesses in dogs and can pose significant risks. Accurate morphological diagnosis of these conditions is vital for effective treatment and management. In this retrospective study, a total of 3746 canine skin biopsies were submitted to a veterinary reference diagnostic laboratory and evaluated using histopathology. The variables assessed included age, sex, breed, lesion, location, and histopathological diagnosis. Non-neoplastic lesions accounted for 61% of all analyzed samples, while neoplastic tumors accounted for 39%. When looking at age, dogs ranging 3–6 years and 7–9 years had at least six times higher risk of developing malignant neoplasia compared to those aged 0–2 years. Among the malignant neoplasms, mast cell tumors, hemangiosarcoma, and squamous cell carcinoma were the most observed, representing 30%, 18%, and 12% of cases, respectively. The breeds most frequently affected by malignant neoplasms included Pit Bull Terriers, Boxers, and mixed breeds, all of which comprised the majority of mast cell tumor cases at 50.54%. These findings are novel in this field and may assist small animal veterinarians in making preliminary diagnoses, while also helping pet owners understand the importance of skin cancer and its early detection. Full article

Background: Cutaneous squamous cell carcinoma (SCC) is the most common primary malignant tumor of the hand, and its aggressive nature can lead to significant morbidity, particularly when affecting critical structures like the thumb. SCC in this location may arise in the periungual area or the pulp and frequently presents with non-specific symptoms such as swelling, nail deformity, or discharge, features that closely mimic common benign conditions. Methods: A retrospective study analyzed patients with neglected or misdiagnosed SCC of the thumb treated at the Hand and Microsurgery Unit of the Jewish Hospital, Rome, between 2015 and 2025. Patient demographics, duration from symptom onset to diagnosis, initial misdiagnoses, and imaging findings (X-rays, MRI, CT scans, lymph node sonography) were reviewed. Surgical interventions, histopathological grading, and postoperative management were documented, with long-term follow-up focusing on disease progression and patient survival. Results: Sixteen patients were included in the study. The mean age at surgery was 73.6 years (range: 55–93 years), with a mean delay of 8.2 months from symptom onset to diagnosis in 87.5% of cases. Initial misdiagnoses included verruca vulgaris, onychomycosis, paronychia, and osteomyelitis. Imaging consistently revealed soft tissue involvement, bony invasion, and occasional metastasis. Surgical approaches ranged from wide resection to amputation, with thumb reconstruction in selected cases and hand amputation in severe presentations. Long-term follow-up (mean 4.6 years) showed high morbidity, a reduction in hand function and QoL, and a 50% mortality rate, with two cases due to metastatic disease (12.5%). Conclusions: Thumb SCC presents diagnostic and therapeutic challenges, exacerbated by late diagnosis and initial misdiagnoses. Multidisciplinary management involving early recognition, comprehensive imaging, appropriate surgical interventions, and vigilant follow-up is crucial for optimizing outcomes. Full article

Background/Objectives: Tumor-immune system interactions shape the progression of cutaneous squamous cell carcinoma (cSCC). Serum biomarkers for risk stratification remain limited. Complement factor H (CFH) regulates the alternative complement pathway. It has been linked to immunosuppression and cSCC development in tissue-based studies. We investigated whether serum CFH is associated with tumor aggressiveness and may help predict immunotherapy outcomes in advanced cSCC. Methods: In this retrospective, single-center study, pre-treatment serum CFH levels were measured in 104 cSCC patients (62 high-risk and 42 advanced) using ELISA. Associations with clinical characteristics, disease stage, and response to cemiplimab were analyzed. Subgroup comparisons considered immune status and inflammatory comorbidities. Results: Advanced cSCC patients had significantly higher CFH levels than high-risk patients (OR 0.13, p = 0.026), independent of tumor diameter or invasion depth. Among advanced cSCC cases, lower baseline CFH was associated with more prolonged progression-free survival (median 19.8 vs. 3.07 months, p = 0.029; HR 0.29, p = 0.014), independent of covariates including immunosuppression. CFH levels during therapy did not predict treatment response. ROC analysis showed moderate discriminatory ability with CFH alone (AUC 0.625), which improved when combined with clinical variables in a multivariable risk model (AUC 0.767). Conclusions: Serum CFH is an independent predictor of cemiplimab response and reflects biological aggressiveness in cSCC beyond conventional high-risk features. These findings support the use of CFH in clinical risk models and warrant external validation in multicenter cohorts. Full article

Background/Objectives: Non-melanoma skin cancer (NMSC) is among the most common cancers in the United States, with solar ultraviolet (UV) radiation being a primary etiological factor. T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase activated by solar UV, has been implicated in skin carcinogenesis. This study aimed to investigate the mechanistic role of TOPK in solar UV-induced skin damage and tumor development. Methods: RNA sequencing (RNA-seq) was performed on skin tissues from wild-type (WT) and TOPK knockout (KO) mice, with or without solar UV exposure, to identify TOPK-regulated genes and pathways. Follow-up experiments using Western blotting, immunofluorescence, and luciferase assays were conducted in vitro and in vivo. Functional assays included 3D spheroid and Transwell co-culture systems involving cutaneous squamous cell carcinoma (cSCC) and fibroblast cells. Results: TOPK deletion altered gene expression profiles and inhibited solar UV-induced activation of multiple signaling pathways, including cytokine–cytokine receptor interaction, PI3K/AKT, MAPKs, PKG, cAMP, and calcium signaling. RNA-seq and protein analyses identified interleukin-19 (IL19) as a key downstream effector suppressed by TOPK deletion. In cSCC and fibroblast cells, TOPK knockdown reduced IL19 expression and secretion. IL19 promoted cSCC growth and activated PI3K/AKT, ERK, and TOPK pathways. Additionally, chronic TGFβ exposure increased IL19 expression and activated fibroblasts, as indicated by elevated αSMA and FAPα levels. Conclusions: These findings establish TOPK as a central regulator of solar UV-induced skin carcinogenesis, partially via modulation of IL19 signaling and fibroblast activation. Targeting TOPK may offer a novel strategy for the prevention and treatment of NMSC. Full article

Background/Objectives: Actinic keratosis (AK) occurs on sun-damaged skin and is considered a precursor to squamous cell carcinoma (SCC). Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) and red light, is a common treatment for AK. However, its clinical efficacy for invasive tumors such as SCC is limited by the poor penetration and distribution of the photosensitizer. Cold atmospheric plasma (CAP), a partially ionized gas, increases skin permeability and exhibits anti-cancer properties through the generation of reactive oxygen species (ROS). In a previous study, CAP showed promising synergistic effects when combined with ALA-PDT for the treatment of SCC cells in vitro. The present study investigated the effects of combining CAP with ALA-PDT on cutaneous AK and SCC induced by ultraviolet B (UV-B) irradiation in SKH1 hairless mice. Methods: We compared various application sequences (CAP-ALA–red light, ALA–red light–CAP, and ALA-CAP–red light) against conventional ALA-PDT using visual, histological, and molecular assessments of the affected skin. Results: The results demonstrated that combined treatments strongly inhibited the growth of UV-B-induced skin lesions. TUNEL staining revealed increased apoptosis following both single and combined therapies, while Ki-67 staining indicated reduced keratinocyte proliferation and diminished DNA damage in treated areas. mRNA expression analysis showed the upregulation of apoptosis-related genes (p16^INK4a, p21^CIP1) alongside enhanced anti-tumor immune responses (IL-6, IL-8) in the affected tissue samples. Notably, the combined treatment enhances the therapeutic effect, whereas the sequence of application does not seem to be relevant for therapeutic efficacy in vivo. Conclusions: Overall, these results suggest that CAP may enhance the anti-tumor effect of conventional ALA-PDT, supporting previous findings on SCC cells. Full article

Background: Actinic keratoses (AKs) are common pre-neoplastic lesions that may progress to cutaneous squamous cell carcinoma (cSCC). Photodynamic therapy (PDT) is an effective field-directed treatment for AK, but its impact on key biomarkers remains unclear. This study evaluates the clinical, dermatoscopic, and immunohistochemical effects of PDT on AK, with a focus on proliferation (Ki67, p53) and inflammation (COX-2) markers, to assess its efficacy in delaying carcinogenesis. Methods: In our prospective one-center study, we enrolled 31 patients with AK, with no history of previous AK treatment. They underwent three PDT sessions at four-week intervals, with follow-up eight weeks after the final session. Clinical, dermatoscopic, and immunohistochemical analyses of Ki67, p53, and COX-2 expression were performed before and after treatment. Results: Clinically, 54.8% of patients achieved complete lesion clearance, with no residual severe AK lesions. Ki67 and p53 immunoexpression significantly decreased post-PDT (p < 0.05), confirming its antiproliferative effect. COX-2 expression also declined significantly (p < 0.05), supporting PDT’s anti-inflammatory role. However, COX-2 remained stable or increased in 35.48% of cases, possibly due to inflammation-induced regeneration. There is a positive correlation between the reduction in Ki67, p53, and COX-2 immunoexpression and the decrease in AK severity (both according to Olsen grade and dermatoscopic grade). Conclusions: PDT effectively reduces AK severity, proliferation, and inflammation markers, potentially delaying carcinogenesis. However, residual biomarker expression suggests that additional treatment sessions or combination therapies may be necessary for complete lesion clearance. Further studies are required to optimize PDT protocols. Full article

The aim of this study was to develop a baseline [¹⁸F]FDG PET/CT model to predict immunotherapy response in advanced cutaneous squamous cell carcinoma (cSCC) and noninvasively determine tumor grade, thereby enhancing early patient stratification. We retrospectively analyzed 59 patients with histologically confirmed advanced cSCC submitted to immunotherapy with cemiplimab. All underwent [¹⁸F]FDG PET/CT at baseline and after approximately 12 weeks. Clinical response was assessed through PET findings integrated with clinical and dermatological evaluation, and patients were classified as responders (complete/partial metabolic response or stable disease) or non-responders (progression or toxicity-related discontinuation). Tumors were also classified as low to intermediate (G1–G2) or poorly differentiated (G3). Machine learning models (Random Forest and Extreme Gradient Boosting) were trained to predict treatment response and tumor grade. Clinical benefit was observed in 46/59 patients (77.9%), while 13 (22.1%) were non-responders. Histology showed 64.4% (n = 38) G1–G2 and 35.6% (n = 21) G3 tumors. The PET-based model best predicted clinical benefit (AUC = 0.96, accuracy = 91% cross-validation; AUC = 0.88, accuracy = 82% internal validation). For tumor grade prediction, the CT-based model achieved a higher AUC of 0.80 (accuracy 73%), whereas the PET-based model reached an AUC of 0.78 but demonstrated a slightly higher accuracy of 77%. Radiomic analysis of baseline [¹⁸F]FDG PET enables the discriminative prediction of immunotherapy response and tumor grade in advanced cSCC, with PET-based models outperforming CT-based ones. Full article

Nanotechnology offers alternative approaches to the discovery of anticancer drugs. Hydrophobic bioactive components can be included in the cores of amphiphilic nanocarriers, which leads to the formation of a water-dispersible product with improved bioavailability, facilitated excretion, and reduced systemic toxicity in the treated organisms. This study was aimed at the formation of polymer nanocarriers, loaded with anticancer drug precursor podophylotoxin (PPT) or PPT-containing juniper leaf extracts, seeking to study their antineoplastic activity in A-431 epidermoid carcinoma cells and HaCaT normal keratinocytes. The amphiphilic, biodegradable, and biocompatible MPEG-b-PLA diblock copolymer was self-assembled in aqueous media into nanosized particles, whose physicochemical characteristics were studied by dynamic light scattering, transmission electron microscopy, and other methods. High encapsulation efficiency was determined for the PPT component-loaded micelles. DNA fragmentation, cell cycle arrest, nuclear condensation, membrane lipid order assessment, reactive oxygen species, and apoptosis induction by the loaded nanocarriers in A-431 or HaCaT cells were analyzed by the comet assay, FACS, Hoechst DNA staining, Laurdan generalized polarization, and other methods. As a result of various cellular processes induced by the PPT component-loaded nanoparticles, effector caspase-3 and caspase-7 activation showed selectivity towards tumor cells compared to the normal cells. The newly obtained PPT-containing nanoparticles have applications as potential drugs in the prospective nanomedicine. Full article

Background: A previous published Phase 2 trial using 2–4 doses of neoadjuvant cemiplimab in stage II–IV resectable cutaneous squamous cell carcinoma (CSCC) demonstrated that a complete pathological (pCR) rate of 51% and major pathological response (mPR) rate of 13% could be achieved with durable disease control. Methods: In this open-label, single-institution phase II trial (NCT05878288), patients with stage II–IV resectable CSCC received up to four doses of neoadjuvant cemiplimab prior to surgery. The primary endpoint of the study was to perform comprehensive molecular profiling. The focus of this report are the secondary clinical endpoints of pCR rate, mPR (defined as <10% viable tumour) rate, overall response rate (ORR) using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, immune-modified RECIST (imRECIST) and Immune PET Response Criteria in Solid Tumours (iPERCIST), disease-free survival (DFS), overall survival (OS), safety, and to describe changes in planned surgery. Results: Eleven patients were enrolled, with all proceeding with surgery. An ORR and pCR rate of 73% (8/11; 95% CI 0.39–0.93) was achieved, whilst 3/11 patients progressed on treatment. On pre-operative imaging, all 8/11 pCR patients demonstrated a partial response (RECIST 1.1), whilst 6/8 achieved a complete metabolic response and 2/8 a partial metabolic response (iPERCIST). Median follow-up was 10.2 (IQR 6.7–16.4) months. DFS was 91% (95% CI 0.57–1) and OS was 100% (95% CI 0.68–1), with one non-responder patient who developed recurrent locoregional and distant metastatic disease. There were no unexpected safety signals. Pathological features of response to neoadjuvant immunotherapy most commonly were granulomatous inflammation with keratin, fibrosis and inflammation. No cases with a dense inflammatory infiltrate were observed. Neoadjuvant immunotherapy did not impact the intra-operative planning and execution of surgery, but in the eight pCR cases, it reduced the extent of required surgery, whilst in the three non-responder cases, surgery was more extensive than originally planned. Conclusions: The DISCERN trial confirms that an excellent complete response rate can be achieved with four doses of neoadjuvant immunotherapy in stage II–IV CSCC. Proposed refinements to the pathological assessment of response and metabolic response criteria in CSCC for the neoadjuvant context are provided. Full article

The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks of metastasis and recurrence, underscores the importance of identifying novel therapies and validated biomarkers to augment patient management, particularly in the context of well-established and advanced disease. Following a brief overview of the well-recognized epidemiology, clinical features, and diagnosis of cSCC, the current review is focused on risk factors, most prominently excessive exposure to ultraviolet radiation (UVR) as a cause of persistent, pro-tumorigenic mutagenesis, and immune suppression. The next phase of the review encompasses an evaluation of the search for key driver mutations in the pathogenesis of cSCC, including the role of these and other mutations in the formation of immunologically reactive neoepitopes. With respect to additional mechanisms of tumorigenesis, immune evasion is prioritized, specifically the involvement of cell-free and infiltrating cellular mediators of immune suppression. Prominent amongst the former are the cytokine, transforming growth factor-β1 (TGF-β1), the prostanoid, prostaglandin E2, and the emerging immune suppressive nucleoside adenosine. In the case of the latter, tumor-infiltrating and circulating regulatory T cells have been implicated as being key players. The final sections of the review are focused on an update of the immunotherapy of established and advanced disease, as well as on the search for novel, reliable lesional and systemic biomarkers with the potential to guide patient management. Full article

Background/Aim: Perineal, pelvic and urogenital reconstruction presents a challenge, not only due to defect size but also due to high morbidity resulting from surgery and post-operative complications. The purpose of this study is to review the surgical approach and evaluate the results regarding pelvic/perineal reconstruction after advanced tumor resection. Patients and Methods: The total number of patients was 34 (11 males, 23 females). The histology varied, including sixteen rectal-anal squamous cell carcinomas, five Buschke-Lowenstein tumors, four vulvar-vaginal carcinomas, four sacral chordomas, two cutaneous squamous cell carcinomas, two soft tissue sarcomas and a case of Paget’s disease. Most patients had previously been treated with colectomies and/or gynecological resections and received a full dose of radiotherapy. Reconstruction was performed with the following flaps: oblique/vertical rectus abdominis myocutaneous flap (ORAM/VRAM), gracilis myocutaneous flap, inferior gluteal artery perforator flap (IGAP), internal pudendal artery perforator flap (IPAP) and lotus petal flaps. Results: Most patients had a relatively uncomplicated post-operative course. Surgical site infection and wound dehiscence occurred more commonly with the thigh flaps rather than the abdominal flaps. However, the aggression and the frequent recurrences of these tumors had as a result, only 15 out of 34 patients achieved a five-year disease-free survival. Conclusions: Pelvic and perineal defects are usually massive and the use of myocutaneous flaps to eliminate the dead space is of paramount importance. Although these are mainly salvage operations with a low survival rate, they promote patients’ quality of life. A frequent challenge is the simultaneous achievement of tumor radical resection and pelvis functionality. Full article