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To explore the relationship between miR-20a and CCND1 protein in cutaneous squamous cell carcinoma (CSCC), as well as the possible signaling pathway molecular mechanism involved. Methods: Skin cancer tissues and adjacent normal skin tissues of the CSCC patients were collected, respectively. Results: The expression levels of miR-20a and CCND1 genes in tissues were analyzed by qRT-PCR. In order to investigate the effect of miR-20a on SCL-1 cells of CSCC cell line, SCL-1 cells were divided into control group (non-transfection), miR-NC group (transfection of miR-NC) and miR-20a mimics group (transfection of miR-20a mimics). In order to investigate the relationship between CCND1 and PI3K/AKT signaling pathway, SCL-1 cells were divided into control group (non-transfection), si-NC group (transfection of si-NC) and si-CCND1 group (transfection of si-CCND1). In order to explore the interaction between miR-20a and CCND1 and its effect on CSCC cells, SCL-1 cells were divided into miR-NC group (transfection of miR-NC), miR-20a mimics group (transfection of miR-20a mimics), and mimics+pcDNA group (co-transfected miR-20a mimics and pcDNA) and mimics+CCND1 group (co-transfected miR-20a mimics and pcDNA-CCND1). The protein expression levels of p-AKT, AKT, p-PI3K, PI3K and GSK-3 were analyzed by Western blot. Cell proliferation was detected by MTT. The apoptosis was detected by flow cytometry. Cell migration and invasion were analyzed by Transwell. Dual luciferase reporter assay was used to analyze the targeting relationship between miR-20a and CCND1. The expression level of miR-20a in CSCC cancer tissues and SCL-1 cell were low, and the expression level of CCND1 in CSCC cancer tissues and SCL-1 cell were high. Compared with control group and miR-NC group, the proliferation level and the number of invasion and migration of SCL-1 cells in the miR-20a mimics group were decreased (P<0.05), the apoptosis level of SCL-1 cells was increased (P<0.01), and the protein phosphorylation levels of PI3K and AKT were decreased (P<0. 01). Target Scan Human database analysis result and dual luciferase reporter assay results showed that miR-20a had a targeting relationship with CCND1. Compared with control group and si-NC group, the protein expression levels of CCND1 and GSK-3茁 and the protein phosphorylation levels of PI3K and AKT in SCL-1 cells in the si-CCND1 group were decreased (P<0.01). Compared with miR-20a mimics group or mimics+pcDNA group, the proliferation level and the number of invasion and migration of SCL-1 cells in mimics+CCND1 group were increased (P<0.05), while the apoptosis level of SCL-1 cells was decreased (P<0.01), and the protein phosphorylation levels of PI3K and AKT were increased (P<0.01). Conclusion: Overexpression of miR-20a may inhibit the activation of PI3K/AKT signaling pathway by targeting the expression level of CCND1, thereby inhibiting the proliferation, invasion and migration of CSCC cells, and promoting the apoptosis of cancer cells. [ABSTRACT FROM AUTHOR]

Closure of a circular tissue defect in the head-neck-face region is challenging because most transposition flaps are rhombic or triangular. For a tension-less closure, both rhombic transposition flap and the circular tissue defect need to be engineered maintaining strict geometric calculations. The present illustration demonstrates a modified rhombic transposition flap with greater freedom in rotation and mobility for closing a moderate-sized circular defect resulting from wide local excision of cutaneous squamous cell carcinoma in the mid-face. The circular shape of the primary tissue defect did not need to be altered. The authors revisited an earlier published technique in the process, adding their own modification to the rhombic transposition flap. [ABSTRACT FROM AUTHOR]

Simple Summary: The effectiveness and safety of immune checkpoint inhibitors in the treatment of patients with advanced cutaneous squamous cell carcinoma were evaluated in a real-world population, including patients who would have typically been excluded from clinical trials. We identified 36 patients with advanced cutaneous cell carcinoma treated with immune checkpoint inhibitors between 2017 and 2022 at a single Cancer Center in Canada; ten patients had hematological malignancy, two patients had autoimmune disease on immune suppressive drug, two patients were solid organ transplant recipients, and four patients had poor performance status. The results showed that immune checkpoint inhibitors, specifically cemiplimab and pembrolizumab, were effective and safe for advanced cutaneous squamous cell carcinoma patients, regardless of age, immune status, or performance status. Immune checkpoint inhibitors exhibit a high response rate, prolonged duration of response, and a favorable toxicity profile; these characteristics position them as a preferred therapeutic option, particularly suitable for patients with comorbidities that might otherwise preclude the utilization of conventional systemic treatments. Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions that would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. Of the 36 patients identified, the best overall response (BOR) to ICI was a partial response (PR) in 41.7%, a complete response (CR) in 27.8%, and stable disease in (SD) 13.9%. The progression-free survival (PFS) rate for 1 year was 58.1%; the median PFS was 21.3 months (95% CI 6.4–NE). The 1-year overall survival (OS) was 76.7%, and the median OS was 38.6 months (95% CI 25.4–NE). Immune-compromised patients, ECOG performance 2–3, and age ≥ 75 years were not significantly associated with PFS or OS. IrAE grades 3–4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefits with ICI regardless of age, immune status or ECOG performance status. We acknowledge the small sample size and retrospective methodology as the main limitations of our study. [ABSTRACT FROM AUTHOR]

Purpose: To describe tumor response and cranial nerve function outcomes after administration of anti-PD-1 to patients with cutaneous squamous cell carcinoma (CSCC) with perineural spread to cranial nerves (CN) extending into the cavernous sinus. Methods: Electronic patient records from a single institution were queried for patients with CSCC of the head and neck causing diplopia (ICD-10 H53.2) who were treated with anti-PD-1. Data extracted included demographics, duration of anti-PD-1 therapy, immune-mediated adverse reactions, tumor response per adapted RECIST v1.1, and changes in CN function and symptoms (e.g., pain). All patients were prescribed cemiplimab 350 mg IV q3 weeks. Results: Four patients met inclusion criteria. They had varying degrees of pain and sensory deficits in branches of the trigeminal nerve (CN V). One, 2, 3 and 1 patients had baseline involvement of CN III, IV, VI and VII, respectively. MRI confirmed perineural cavernous sinus involvement in all patients. Duration of anti-PD-1 therapy ranged 15–60 weeks. All patients experienced an objective anti-tumor response to anti-PD-1; partial response n = 2, complete response n = 2. At a median follow-up of 22 months, responses were ongoing in all patients. All patients demonstrated improvement in ocular motility deficits and pain with resolution of symptoms in 3 and 1 patients, respectively. Conclusion: Administration of anti-PD-1 to patients with CSCC with perineural spread into the cavernous sinus can generate durable anti-tumor regressions and restore CN function, while sparing the morbidity associated with surgical resection and/or radiotherapy. Our findings add to emerging literature supporting this treatment approach for this patient population. [ABSTRACT FROM AUTHOR]

Background: To evaluate the role of definitive weekly hypofractionated radiotherapy (RT) for the treatment of surgery‐ineligible elderly patients with cutaneous squamous cell carcinoma of the head and neck region (cHNSCC). Methods: Eligible elderly patients (aged ≥75 years) with cHNSCC were included. Patients received definitive weekly hypofractionated RT, using megavoltage electrons, to a total dose of 56–64 Gy (8 Gy per fraction). Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR). Secondary endpoints included duration of response (DOR), progression‐free survival (PFS), overall survival (OS), pain response, tolerability, and safety. Results: A total of 19 patients with 27 lesions were included and treated with definitive weekly hypofractionated RT. All patients received the prescribed total dose. ORR was 92.6%, including 70.4% of lesions with a CR and 22.2% with a PR. Median DOR was 12 months. No severe toxicity occurred. Conclusions: Our study confirmed the satisfying efficacy and acceptable toxicity of definitive weekly hypofractionated RT for cHNSCC in elderly patients. Our results establish weekly hypofractionated scheduleas a promising treatment option for elderly patients with cHNSCC. [ABSTRACT FROM AUTHOR]

Background: The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, paralleling the aging of the population. cSCC predominantly affects chronically sun-exposed areas, such as the head and neck region. At our tertiary center, a multidisciplinary approach to non-melanoma skin cancer is provided for locally advanced cSCC. Methods: We retrospectively revised all patients with locally advanced/metastatic cSCC treated with anti-PD1 antibody (Cemiplimab) at our Institution from January 2020 to March 2023 (minimum follow-up of 4 months on treatment). Results: Overall, we consecutively treated 20 ultra-octogenarian patients, of whom 15 were males and 5 were females (median age: 86.9 years). Despite age, a median number of concomitant drugs, and comorbidities, efficacy, and safety were superimposable with the available literature. No patients reported treatment-related adverse events of grade 3 or higher. Grade 2 adverse events were reported in 25% of patients. Overall, the response rate was 65%, with 50% partial responses and 20% long-lasting stable disease. The median duration of response was 14 months. The G8 elderly score was assessed in all patients, and the median score was 12 (range 9–14). Conclusions: Among ultra-octogenarian patients, a clinical benefit from Cemiplimab was obtained in most, including tumor shrinkage and pain relief. Cemiplimab confirmed its effectiveness in elderly patients in a real-life setting, with no new safety concerns. [ABSTRACT FROM AUTHOR]

Objective To explore the expression and significance of INHBA in cutaneous squamous cell carcinoma. Methods Immunohistochemistry, RT-PCR and western blot methods were used to measure the expression levels of INHBA in 17 cases of normal skin (NS), 30 cases of actinic keratosis (AK) and 30 cases of cutaneous squamous cell carcinoma (cSCC). Results The immunohistochemical staining indicated that the positive staining of INHBA was brown-yellow particles in the cytoplasm/nucleus, with positive rates of 23.53%, 66.67% and 86.67%, respectively, in NS, AK and cSCC (χ2=27.10,P=0.001). The relative expression levels of INHBA mRNA in NS, AK and cSCC were 1.097±0.083, 1.328±0.041, 1.731±0.064, respectively (F=48.53, P

Abstract Background Topical anticancer drugs offer a potential therapeutic modality with high compliance for treating cutaneous squamous cell carcinoma (cSCC). However, the existing topical treatments for cSCC are associated with limited penetrating ability to achieve the desired outcome. Therefore, there remains an urgent requirement to develop drugs with efficient anticancer activity suitable for treating cSCC and to overcome the skin physiological barrier to improve the efficiency of drug delivery to the tumor. Results We introduced lycorine (LR) into the topical treatment for cSCC and developed a cell-penetrating peptide (CPP)-modified cationic transfersome gel loaded with lycorine-oleic acid ionic complex (LR-OA) (LR@DTFs-CPP Gel) and investigated its topical therapeutic effects on cSCC. The anti-cSCC effects of LR and skin penetration of LR-OA transfersomes were confirmed. Simultaneously, cationic lipids and modification of R5H3 peptide of the transfersomes further enhanced the permeability of the skin and tumor as well as the effective delivery of LR to tumor cells. Conclusions Topical treatment of cSCC-xenografted nude mice with LR@DTFs-CPP Gel showed effective anticancer properties with high safety. This novel formulation provides novel insights into the treatment and pathogenesis of cSCC.

Abstract Background Endoplasmic reticulum stress (ER stress) may destroy endoplasmic reticulum homeostasis (ER homeostasis) and leads to programmable cell death. Unfolded protein response (UPR) originally stimulated by ER stress is critical for the survival of tumor cells through trying to re-establish ER homeostasis as an adaption to harsh microenvironment. However, mechanisms involving key regulators in modulating UPR remain underexplored. Methods The expression of LINP1 in cutaneous squamous cell carcinoma (cSCC) tissues and cell lines was assessed. Subsequently, LINP1 was knocked out, knocked down or overexpressed in cSCC cells. CCK-8 assays, colony forming assays, transwell migration assays and invasiveness measurement by matrigel-coated transwell were performed to examine the role of LINP1 in cSCC development through gain-of-function and loss-of-function experiments. Transcriptomic sequencing (RNA-Seq) was conducted and indicated the key downstream signaling events regulated by LINP1 including UPR and apoptosis signaling. Furthermore, the direct interaction between LINP1 and eIF2α to modulate UPR and apoptosis was confirmed by RNA pulldown, RNA immunoprecipitation (RIP), ChIP-qPCR and in vitro phosphorylation assays. Results In this study, LncRNA in non-homologous end joining pathway 1 (LINP1) was identified to be one of the top ten highest-expressed LncRNAs in cSCC, the second most common cancer in the world. Functional studies using in vitro and in vivo models revealed that LINP1 functions as an oncogene to promote cell proliferation, colony formation, migration and invasiveness while inhibiting cell apoptosis in cSCC. Transcriptomic sequencing after knockdown of LINP1 indicated LINP1 negatively regulates UPR-related pathways involving key effectors for activating UPR and the apoptosis following the prolonged UPR. Mechanistic study showed LINP1 physically interacts with eIF2α to inhibit its phosphorylation for avoiding unmitigated UPR. Loss of LINP1 followed by enhanced eIF2α phosphorylation led to overactivated UPR and induced DDIT3 expression, contributing to ER stress-induced apoptosis and suppression of cSCC development. Conclusions Our findings demonstrate a novel regulatory hierarchy of UPR by demonstrating LINP1 as a critical modulator for eIF2α phosphorylation and a suppressor of UPR-mediated apoptosis, which suggests a novel therapeutic target for cSCC treatment.

Resumen: El cáncer de piel al igual que otros tumores internos está compuesto por células transformadas de crecimiento incontrolado. El crecimiento tumoral ha sido objeto de estudio desde hace décadas. En este artículo se repasan las distintas formas de medición del crecimiento tumoral cutáneo y se establecen las bases para el desarrollo de una estimación del tiempo de duplicación tumoral que pueda ser útil en el manejo de los pacientes con cáncer de piel. Abstract: Skin cancer, like other cancers, is characterized by the uncontrolled growth of transformed cells. Tumor growth has been studied for decades. We review different methods for measuring skin tumor growth and propose a new system for estimating tumor doubling time that could be useful in the management of skin cancer.

ObjectiveWe analyzed the incidence of facial nerve sacrifice during parotidectomy for metastatic cutaneous squamous cell carcinoma (CSCC).Study designWe retrospectively reviewed the charts of patients with cutaneous squamous cell carcinoma.SettingWe used our CSCC institutional database, which includes patients treated at the University of California-Davis from 2001 to 2018.MethodsWe evaluated patients who presented with biopsy-proven head and neck CSCC who underwent parotidectomy as a part of surgical treatment. We assessed the frequency of facial nerve sacrifice required in patients with normal preoperative facial nerve function with metastatic disease to the parotid. We evaluated the association between sacrifice and high-risk tumor variables using multivariate analysis.ResultsWe identified 53 patients with parotid metastasis and normal preoperative facial nerve function. Thirteen percent of patients required sacrifice of the main trunk of the facial nerve and 27% required sacrifice of a branch of the facial nerve. All patients who underwent facial nerve sacrifice had extracapsular spread (ECS). Perineural invasion (PNI) in the primary tumor (odds ratio [OR], 9.11; P = .041) and location of metastasis within the parotid body (OR, 6.6; P = .044) were independently associated with facial nerve sacrifice.ConclusionPatients with regionally metastatic CSCC to the parotid gland frequently require sacrifice of all or a component of the facial nerve despite normal preoperative function. The likelihood of nerve sacrifice is highest for tumors with PNI and metastatic disease within the body of the parotid.

Overexpression of the 14-3-3ε protein is associated with suppression of apoptosis in cutaneous squamous cell carcinoma (cSCC). This antiapoptotic activity of 14-3-3ε is dependent on its binding to CDC25A; thus, inhibiting 14-3-3ε – CDC25A interaction is an attractive therapeutic approach to promote apoptosis in cSCC. In this regard, designing peptide inhibitors of 14-3-3ε – CDC25A interactions is of great interest. This work reports the rational design of peptide analogs of pS, a CDC25A-derived peptide that has been shown to inhibit 14-3-3ε–CDC25A interaction and promote apoptosis in cSCC with micromolar IC50. We designed new peptide analogs in silico by shortening the parent pS peptide from 14 to 9 amino acid residues; then, based on binding motifs of 14-3-3 proteins, we introduced modifications in the pS(174–182) peptide. We studied the binding of the peptides using conventional molecular dynamics (MD) and steered MD simulations, as well as biophysical methods. Our results showed that shortening the pS peptide from 14 to 9 amino acids reduced the affinity of the peptide. However, substituting Gln176 with either Phe or Tyr amino acids rescued the binding of the peptide. The optimized peptides obtained in this work can be candidates for inhibition of 14-3-3ε – CDC25A interactions in cSCC.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2–5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan–Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51–4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.

Background: Skin cancer is one of the most frequent types of cancer, and cutaneous squamous cell carcinoma (cSCC) constitutes 20% of non-melanoma skin cancer (NMSC) cases. PTCH1, a tumor suppressor gene involved in the Sonic hedgehog signaling pathway, plays a crucial role in neoplastic processes. Methods: An analytical cross-sectional study, encompassing 211 cSCC patients and 290 individuals in a control group (CG), was performed. A subgroup of samples was considered for the relative expression analysis, and the results were obtained using quantitative real-time PCR (qPCR) with TaqMan® probes. The functional, splicing, and disease-causing effects of the proposed variants were explored via bioinformatics. Results: cSCC was predominant in men, especially in sun-exposed areas such as the head and neck. No statistically significant differences were found regarding the rs357564, rs2236405, rs2297086, and rs41313327 variants of PTCH1, or in the risk of cSCC, nor in the mRNA expression between the cSCC group and CG. A functional effect of rs357564 and a disease-causing relation to rs41313327 was identified. Conclusion: The proposed variants were not associated with cSCC risk in this Mexican population, but we recognize the need for analyzing larger population groups to elucidate the disease-causing role of rare variants.

Extra-anogenital giant cSCCs are rare but have worse outcomes compared to smaller tumors. Prompted by limited data, the authors conducted a retrospective study to gather more information about giant cSCCs to optimize clinical care. We identified seven cases of giant cSCCs from a review of cSCC cases treated in the Unit of Dermatosurgery between 2016 and 2022. Most patients were male (85.71%) with a mean age of 80.29 ± 12.22 years. UV radiation was the most common risk factor (five cases) followed by smoking (three cases) and hidradenitis suppurativa (one case). Most giant cases were located in the head area (71.4%) and the diameter of lesions ranged from 6 to 18 cm. All patients corresponded to tumor stage T3, and 42.86% of patients had lymph node metastases. Surgical excision was the treatment of choice in most cases (85.71%), while a combination of cemiplimab and RP1 was used in some cases due to the ineffectiveness of treatment or contraindications to other therapies. The authors emphasize the importance of early detection and prevention of modifiable risk factors, such as UV radiation, and a multidisciplinary approach to treatment. Other therapies, including immunotherapy, may become increasingly important.

Background: The usage of immunotherapy to treat skin malignancies in transplant patients requires weighing the risk of acute organ transplant rejection with the potential reduction of antitumor efficacy by transplant immunosuppression. Reducing the duration of immune checkpoint inhibitor treatment may help prevent acute transplant rejection and late immune-related adverse events. Case presentation: An allogenic kidney transplant patient who developed regionally metastatic cutaneous squamous cell carcinoma received four cycles of pembrolizumab with complete response to therapy. Therapy was discontinued due to fatigue, significant cancer response, and to reduce the risk of acute graft rejection. His renal function remained stable, and he achieved subsequent durable response after treatment discontinuation. Conclusion: Organ transplant recipients with complete response to immunotherapy for cutaneous squamous cell carcinoma may continue to respond despite early treatment cessation. This may reduce the risks of late immunerelated adverse events and acute graft rejection. [ABSTRACT FROM AUTHOR]

Introduction of immunotherapy has radically changed the therapeutic scenario in patients affected by locally advanced and/or metastatic cutaneous squamous cell carcinoma patients. If it is well consolidated the role of immunotherapy in the setting of a disease not amenable to curative surgery and/or radiation, how to integrate immune checkpoint inhibitors in the curative setting is still under evaluation. Surgery combined or not with adjuvant radiotherapy remains the mainstay of curative treatment in localized cutaneous squamous cell carcinoma; however, promising data with neoadjuvant or perioperative immunotherapy could pave the way towards a treatment de-escalation according to the response achieved. On the other side, data on adjuvant treatment with pembrolizumab and cemiplimab after surgery and radiation are still awaited. Several questions related to the activity and safety of immunotherapy in real world setting still remain without answer, and several points need to be better explored. In the current review we will explore the updated literature on the use of immunotherapy in cutaneous squamous cell carcinoma, and we will show the current challenges in its use.

BackgroundImmune checkpoint inhibitors (ICI) are standard of care therapy for patients with cutaneous malignancies, the most frequently diagnosed cancers in solid organ transplant (SOT) recipients. The activity and rate of allograft rejection in SOT recipients with advanced skin cancers treated with ICI is understudied.MethodsWe conducted a retrospective analysis of SOT recipients with advanced melanoma, cutaneous squamous cell carcinoma (cSCC), and merkel cell carcinoma (MCC) who were treated with ICI. Unpublished cases from our institution and published cases from the literature were aggregated. Demographics, type of immunosuppressive therapy, type of ICI(s) administered, prior systemic therapies, tumor response to ICI, and evidence of organ rejection and/or failure were recorded. Objective response rates (ORR) and rates of graft rejection and failure are reported.ResultsNinety patients were identified; four patients from our institution and 86 unique patients from a literature review. ORR to first-line ICI for the entire cohort was 41.1% (37/90). ORR by tumor type was 31% (18/58), 64.3% (18/28), and 25.0% (1/4) for melanoma, cSCC, and MCC, respectively. The rate of graft rejection was 37.8% (34/90) with 61.8% (21/34) of these cases progressing to graft failure. Number of immunosuppressive agents (0, 1, 2, or 3) was inversely associated with rate of graft failure.ConclusionsIn this retrospective analysis, ICIs demonstrate clinical activity in SOT recipients with cutaneous malignancies; however, the rate of graft rejection is high. Treatment plans should be individualized through thorough interdisciplinary discussion. Immunosuppressive modifications may be considered prior to starting treatment, but when feasible, enrollment on clinical trials is preferred.

Summary: Background: Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer, affecting more than 2 million people worldwide yearly and metastasising in 2–5% of patients. However, current clinical staging systems do not provide estimates of absolute metastatic risk, hence missing the opportunity for more personalised treatment advice. We aimed to develop a clinico-pathological model that predicts the probability of metastasis in patients with cSCC. Methods: Nationwide cohorts from (1) all patients with a first primary cSCC in The Netherlands in 2007–2008 and (2) all patients with a cSCC in 2013–2015 in England were used to derive nested case–control cohorts. Pathology records of primary cSCCs that originated a loco-regional or distant metastasis were identified, and these cSCCs were matched to primary cSCCs of controls without metastasis (1:1 ratio). The model was developed on the Dutch cohort (n = 390) using a weighted Cox regression model with backward selection and validated on the English cohort (n = 696). Model performance was assessed using weighted versions of the C-index, calibration metrics, and decision curve analysis; and compared to the Brigham and Women's Hospital (BWH) and the American Joint Committee on Cancer (AJCC) staging systems. Members of the multidisciplinary Skin Cancer Outcomes (SCOUT) consortium were surveyed to interpret metastatic risk cutoffs in a clinical context. Findings: Eight out of eleven clinico-pathological variables were selected. The model showed good discriminative ability, with an optimism-corrected C-index of 0.80 (95% Confidence interval (CI) 0.75–0.85) in the development cohort and a C-index of 0.84 (95% CI 0.81–0.87) in the validation cohort. Model predictions were well-calibrated: the calibration slope was 0.96 (95% CI 0.76–1.16) in the validation cohort. Decision curve analysis showed improved net benefit compared to current staging systems, particularly for thresholds relevant for decisions on follow-up and adjuvant treatment. The model is available as an online web-based calculator (https://emc-dermatology.shinyapps.io/cscc-abs-met-risk/). Interpretation: This validated model assigns personalised metastatic risk predictions to patients with cSCC, using routinely reported histological and patient-specific risk factors. The model can empower clinicians and healthcare systems in identifying patients with high-risk cSCC and offering personalised care/treatment and follow-up. Use of the model for clinical decision-making in different patient populations must be further investigated. Funding: PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.

Cutaneous squamous cell carcinoma (cSCC) is a highly invasive disease with the potential to metastasize and cause fatality. Therefore, it is crucial to understand the mechanism behind cSCC in order to devise effective strategies to combat this disease. We investigated the function of circ_TNFRSF21/miR-214-3p/CHI3L1 axis in cSCC. The features of circ_TNFRSF21 was characterized using Sanger sequencing, and RNase R/actinomycin D treatment. Genes and M1/M2 markers levels were assessed by qRT-PCR and IHC. The proliferation, migration, and invasion of cells were evaluated by CCK-8, colony formation, EdU incorporation, and transwell assays. Tumor growth and metastasis in vivo were evaluated by nude mouse xenograft model. Interactions of circ_TNFRSF21/miR-214-3p and miR-214-3p/CHI3L1 were validated by RNA immunoprecipitation and dual luciferase assay. Circ_TNFRSF21 and CHI3L1 expression were elevated in both human cSCC tissues and cells, whereas miR-214-3p was reduced. Circ_TNFRSF21 silencing or miR-214-3p overexpression suppressed cSCC cell proliferation, migration, invasion, and M2 macrophage polarization. Circ_TNFRSF21 functioned as a sponge for miR-214-3p while miR-214-3p directly targeted CHI3L1. Knockdown of miR-214-3p reversed the effects of circ_TNFRSF21 knockdown on cSCC development, while CHI3L1 upregulation reversed the effects of miR-214-3p overexpression. Furthermore, knockdown of circ_TNFRSF21 inhibited cSCC tumor growth and metastasis in vivo. Circ_TNFRSF21 plays a significant role in cSCC progression by enhancing cell proliferation, migration, invasion, and M2 macrophage polarization through inhibiting miR-214-3p and subsequent disinhibition of CHI3L1. These findings deepen our understanding of the molecular mechanism of cSCC and propose the circ_TNFRSF21/miR-214-3p/CHI3L1 axis as promising diagnosis markers or therapeutic targets for cSCC. • Circ_TNFRSF21 was increased in cSCC tissues and cells but miR-214-3p was reduced. • Circ_TNFRSF21 promoted cSCC cell proliferation, invasion, and migration and M2 macrophage polarization. • Circ_TNFRSF21 sponged miR-214-3p to disinhibit CHI3L1 expression. • miR-214-3p inhibitor blocked sh-circ_TNFRSF21'roles on cSCC development and CHI3L1 reduced the effects of miR-214-3p mimics. • Knockdown of circ_TNFRSF21 inhibited cSCC growth and metastasis in vivo. [ABSTRACT FROM AUTHOR]

Cancer is a progressive disease of multi-factorial origin that has risen worldwide, probably due to changes in lifestyle, food intake, and environmental changes as some of the reasons. Skin cancer can be classified into melanomas from melanocytes and nonmelanoma skin cancer (NMSC) from the epidermally-derived cell. Together it constitutes about 95% of skin cancer. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) are creditworthy of 99% of NMSC due to the limited accessibility of conventional formulations in skin cancer cells of having multiple obstacles in treatment reply to this therapeutic regime. Despite this, it often encounters erratic bioavailability and absorption to the target. Nanoparticles developed through nanotechnology platforms could be the better topical skin cancer therapy option. To improve the topical delivery, the nano-sized delivery system is appropriate as it fuses with the cutaneous layer and fluidized membrane; thus, the deeper penetration of therapeutics could be possible to reach the target spot. This review briefly outlooks the various nanoparticle preparations, i.e., liposomes, niosomes, ethosomes, transferosomes, transethosomes, nanoemulsions, and nanoparticles technologies tested into skin cancer and impede their progress tend to concentrate in the skin layers. Nanocarriers have proved that they can considerably boost medication bioavailability, lowering the frequency of dosage and reducing the toxicity associated with high doses of the medication. [ABSTRACT FROM AUTHOR]

Long intergenic noncoding ribonucleic acid (lncRNA) 460 is reportedly associated with carcinogenesis and progression in various types of cancer. However, the mechanisms underlying its action in cutaneous squamous cell carcinoma (CSCC) remain unclear. LINC00460 mRNA expression was analysed using data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cell growth, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), transwell migration and invasion assays after inducing LINC00460 knockdown. A xenograft tumour model was used to determine the effects of LINC00460 on tumour growth and metastasis in vivo. To examine the interaction between LINC00460 and ELAVL1, RNA pulldown and RNA immunoprecipitation assays were performed. LINC00460 was found to be significantly upregulated in CSCC tissues and cell lines. Functionally, LINC00460 knockdown inhibited cell proliferation, migration, and invasion in vitro. Consistent with this, when LINC00460 expression decreased, CSCC tumorigenesis and metastasis in vivo were inhibited. Mechanistically, LINC00460 binds to embryonic lethal abnormal vision like RNA binding protein 1 (ELAVL1) and enhances its stability by inhibiting the β-transducin repeats-containing protein (β-TrCP)-mediated ubiquitination of ELAVL1. Moreover, the effect of LINC00460 silencing on the proliferation, migration, and invasion of CSCC cells could be reversed by overexpressing ELAVL1. Our findings demonstrated that LINC00460 plays a critical role in regulating ELAVL1 function. This highlights the potential targets for the clinical diagnosis and treatment of CSCC. [ABSTRACT FROM AUTHOR]

Aim: We aimed to investigate the presence of human papillomavirus type 197 (HPV197) in patients with cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Materials & methods: 58 formalin-fixed paraffin-embedded tissue samples, including 12 SCC and 46 BCC and the adjacent non-tumoral skin of the same patient were analyzed for the presence of HPV197E6 gene, using a quantitative real-time PCR assay. Results: The HPV197E6 gene was identified in 12 tumor samples (7 BCC and 5 SCC), but not in the control group. Conclusion: Based on these results, a high copy number of HPV197E6 gene provides additional support for the role of HPV197 in skin cancer. The skin is one of the most common sites of cancer. Several risk factors have been studied for skin cancer, including viral infections. The human papillomavirus (HPV) is one of the most studied viruses in cancer research. In this study, we investigated the role of HPV197, a recently discovered HPV, in skin cancer. Of 58 tissue samples examined, 12 skin cancer samples contained HPV197, while HPV was not detected in any of the non-tumoral skin tissues. This suggests that the HPV197 virus may be a risk factor for skin cancer. [ABSTRACT FROM AUTHOR]

Most skin tumors are not fatal, but if not treated in a timely manner, they can lead to significant morbidity. Due to the COVID-19 pandemic and in order to create more capacities for the treatment of COVID-19-positive patients as well as to contain the spread of the virus, the healthcare system was reorganized worldwide, leading to decreased access to preventive screening programs. The aim of this study was to evaluate the impact of the pandemic on healthcare accessibility to cutaneous squamous cell carcinoma patients in Serbia. This retrospective study was conducted at the Clinic for Burns, Plastic, and Reconstructive Surgery, University Clinical Center of Serbia in Belgrade. Patient demographics and pathohistological findings of tumors of patients living in and outside the capital in the period before, during, and after the pandemic were compared. The two groups did not show any differences regarding the largest tumor diameter prior and during the pandemic; however, this difference became extremely noticeable after the pandemic (15 mm vs. 27 mm; p < 0.001). While cSCCs are commonly slow-growing tumors, the impact of the COVID-19 pandemic is not negligible. This study found a population at a significant risk of cSCC metastasis, with additional evidence likely to emerge in the upcoming years. [ABSTRACT FROM AUTHOR]

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of skin cancer, showing a rapid increasing incidence worldwide. Although most cSCC can be cured by surgery, a sizeable number of cases are diagnosed at advanced stages, with local invasion and distant metastatic lesions. In the skin, neurotrophins (NTs) and their receptors (CD271 and Trk) form a complex network regulating epidermal homeostasis. Recently, several works suggested a significant implication of NT receptors in cancer. However, CD271 functions in epithelial tumors are controversial and its precise role in cSCC is still to be defined. Methods: Spheroids from cSCC patients with low-risk (In situ or Well-Differentiated cSCC) or high-risk tumors (Moderately/Poorly Differentiated cSCC), were established to explore histological features, proliferation, invasion abilities, and molecular pathways modulated in response to CD271 overexpression or activation in vitro. The effect of CD271 activities on the response to therapeutics was also investigated. The impact on the metastatic process and inflammation was explored in vivo and in vitro, by using zebrafish xenograft and 2D/3D models. Results: Our data proved that CD271 is upregulated in Well-Differentiated tumors as compared to the more aggressive Moderately/Poorly Differentiated cSCC, both in vivo and in vitro. We demonstrated that CD271 activities reduce proliferation and malignancy marker expression in patient-derived cSCC spheroids at each tumor grade, by increasing neoplastic cell differentiation. CD271 overexpression significantly increases cSCC spheroid mass density, while it reduces their weight and diameter, and promotes a major fold-enrichment in differentiation and keratinization genes. Moreover, both CD271 overexpression and activation decrease cSCC cell invasiveness in vitro. A significant inhibition of the metastatic process by CD271 was observed in a newly established zebrafish cSCC model. We found that the recruitment of leucocytes by CD271-overexpressing cells directly correlates with tumor killing and this finding was further highlighted by monocyte infiltration in a THP-1-SCC13 3D model. Finally, CD271 activity synergizes with Trk receptor inhibition, by reducing spheroid viability, and significantly improves the outcome of photodynamic therapy (PTD) or chemotherapy in spheroids and zebrafish. Conclusion: Our study provides evidence that CD271 could prevent the switch between low to high-risk cSCC tumors. Because CD271 contributes to maintaining active differentiative paths and favors the response to therapies, it might be a promising target for future pharmaceutical development. [ABSTRACT FROM AUTHOR]

Background: The landscape of systemic therapies for advanced non-melanoma skin cancers has been revolutionized by the advent of immunotherapy. Cemiplimab is the only immune checkpoint inhibitor (ICI) approved by the European Medicine Agency for recurrent/metastatic cutaneous squamous cell carcinoma (cSCC). Its excellent efficacy outcomes are achieved due to its good tolerability profile. The drug-related hypersensitivity reaction (HSR) is a well-known issue in oncology, but it is rarely reported in respect to immune checkpoint inhibitors. Cemiplimab is among the agents with the best infusion tolerability profiles. Clinical practice guidelines in this field are lacking. Results: We report on the successful management of a severe infusion reaction induced by Cemiplimab in a patient with cSCC based on a desensitization protocol, which led to adequate treatment delivery and prolonged clinical benefit. A review of the available literature on HSR rates and its management with ICIs, and on drug desensitization (DD) protocols and their efficacy, was conducted to highlight the limited knowledge on this topic and its importance. Conclusion: Our experience highlights the need for a DD protocol in order to improve the treatment of HSRs, particularly when elicited by an immunotherapy agent, preventing treatment discontinuation and preserving its efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-melanoma skin cancer affects a significant portion of the population in the United States, with over one million cases diagnosed each year. Skin cancers in the head and neck are considered high risk for locoregional spread and recurrence, requiring close monitoring and multidisciplinary management by head and neck surgeons, oncologists, radiation oncologists, and many others. In this study, we performed an extensive literature review to summarize current knowledge regarding the etiology, disease course, and management of head and neck skin cancers in immunocompromised patients. We draw attention to the role of newly developed immunotherapies being used in this subset of patients. The incidence of non-melanoma skin cancer (NMSC) continues to rise, and more than one million cases are diagnosed in the United States each year. The increase in prevalence has been attributed to increased lifespan and improvements in survival for conditions that increase the risk of these malignancies. Patients who are immunocompromised have a higher risk of developing NMSC compared to the general population. In immunosuppressed patients, a combination of prevention, frequent surveillance, and early intervention are necessary to reduce morbidity and mortality. In this review, we collate and summarize current knowledge regarding pathogenesis of head and neck cutaneous SCC and BCC within immunocompromised patients, examine the potential role of the immune response in disease progression, and detail the role of novel immunotherapies in this subset of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell cancer is a common form of cancer. Caught early, it is usually curable. However, 3–5% develop into a metastatic form with a very poor prognosis. All efforts to find biomarkers, in blood or in the tumor itself, for early identification of this group of patients have so far failed. This study describes a novel method based on fine needle aspiration that enables the identification of lymphocyte markers in tumor-draining lymph nodes. By focusing on lymph nodes as a key organ for a well-functioning immune system, it might be possible to, early on, find biomarkers related to future metastatic development. Cutaneous squamous cell cancer (cSCC) is the second most common form of skin cancer, characterized by abnormal, accelerated growth of squamous cells. When caught early, most cSCCs are curable. About 5 percent of the cSCC cases have advanced to such an extent, generally metastatic, that they are far more dangerous, with very poor prognosis and challenging to treat. All efforts to find biomarkers, in blood or in the tumor itself, for early identification of patients with a risk for metastasis have so far failed. The present study describes a novel method that enables the identification of lymphocyte markers in tumor-draining lymph nodes. Six patients with advanced cSCC were analyzed using a combination of a sentinel lymph node biopsy (SLNB) protocol, fine needle aspiration (FNA), and flow cytometry. Immunological results from the sentinel nodes were combined with corresponding data from peripheral blood and unfixed tumor tissues. The result demonstrates a striking difference between the subsets of T-cells from the three compartments. Our interpretation of this first pilot study is that the ability to follow specific immunological markers on lymphocytes in tumor-draining lymph nodes will enable the identification of novel prognostic biomarkers not detectable in material from blood and tumor tissues. [ABSTRACT FROM AUTHOR]

Cutaneous basal and squamous cell carcinoma reflect the first and second most common type of non-melanoma skin cancer, respectively. Especially cutaneous squamous cell carcinoma has the tendency to metastasize, finally resulting in a rather poor prognosis. Therapeutic options comprise surgery, radiation therapy, and a systemic or targeted chemotherapy. There are some good treatment results, but overall, the response rate of newly developed drugs is still modest. Drug repurposing represents an alternative approach where already available and clinically approved substances are used, which originally intended for other clinical benefits. In this context, we tested the effect of the naturally occurring polyphenolic aldehyde (±) gossypol with concentrations between 1 and 5 µM on the invasive squamous cell carcinoma cell line SCL-1 and normal human epidermal keratinocytes. Gossypol treatment up to 96 h resulted in a selective cytotoxicity of SCL-1 cells (IC50: 1.7 µM, 96 h) compared with normal keratinocytes (IC50: ≥ 5.4 µM, 96 h) which is mediated by mitochondrial dysfunction and finally leading to necroptotic cell death. Taken together, gossypol shows a high potential as an alternative anticancer drug for the treatment of cutaneous squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

It is well established that immunosuppressed patients are at increased risk for poor outcomes (PO) from cutaneous squamous cell carcinoma (cSCC), including local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Defining PO risk is challenging but may be beneficial in guiding management. We aimed to define PO risk factors and evaluated their importance in immunosuppressed versus immunocompetent patients. We conducted a 4-year single-center retrospective review of patients with cSCC. Patient and tumor characteristics were evaluated in those that experienced PO. Immunosuppressed patients were ~ 11-fold more likely than immunocompetent patients to develop PO (10/85 vs. 15/1332, p < 0.0001). Among those with PO, immunosuppressed patients had diminished relapse free (p = 0.026) and progression free (p < 0.001) survival compared to immunocompetent. Immunosuppression was significantly associated with LR (p < 0.00001). Immunosuppressed patients were also more likely to develop NM, DM and experience DSD (p = 0.027). Mohs Appropriate Use Criteria was associated with NM, DM and DSD (p = 0.029), with area H tumors more likely to result in metastasis and death. In conclusion, immunosuppressed patients are more likely to develop LR, metastasis, and DSD from cSCC compared to immunocompetent patients. Immunosuppressed status was an independent risk factor for PO in this cohort and further considered for its inclusion in prognostication schema is warranted. [ABSTRACT FROM AUTHOR]

Background: Anti-PD1 agents are currently recommended as first-line treatment in advanced cutaneous squamous cell carcinoma (acSCC) by updated European guidelines. Although acSCC frequently affects elderly patients with multiple comorbidities, this subset of patients is often excluded of registration clinical trials. Purpose: To assess anti-PD-1 efficacy and safety in elderly acSCC patients in real-life conditions and describe this specific population with oncogeriatric evaluation tools. Methods: A multicenter retrospective study including acSCC patients at least 70 years old treated with PD-1 inhibitors was conducted in French referral centers. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety data, time to response (TTR), duration of response (DOR), overall survival (OS), and progression-free survival (PFS). Results: 63 patients were included. ORR was 57.1% (95% CI 44.0–69.5), median TTR and DOR were 3 and 5.5 months respectively. Median OS was not reached (95% CI 12.5 months-not reached) at data cut-off after a median follow-up of 8 months while median PFS was 8 months. (95% CI 5 months-not reached). Grade 3–5 adverse effects occurred in 47.6% of patients. 41.3% of patients experienced degradation of ECOG performance status during anti-PD-1 treatment. Nutritional state worsened in 27% of patients and 57.1% lost weight during treatment. Conclusion: In this particular subset of acSCC patients PD-1 inhibitors obtain results similar to those obtained in younger populations included in pivotal clinical trials, with acceptable safety. A specific oncogeriatric evaluation at treatment initiation and during follow-up appears important in this setting most notably to help manage toxicity. [ABSTRACT FROM AUTHOR]

Background: Many classifications exist to select patients with "high-risk" head and neck cutaneous squamous cell carcinoma (HNCSCC). Objective: To compare the performance of the Brigham and Women's Hospital (BWH) classification with the performance of the American Joint Committee on Cancer 8th Edition (AJCC8), the Union for International Cancer Control 8th Edition (UICC8), and the National Comprehensive Cancer Network (NCCN) classifications. Methods: In this single-center retrospective study, HNCSCC resected in a tertiary care center were classified as "low-risk" or "high-risk" tumors according to the four classifications. Rates of local recurrence (LR), lymph node recurrence (NR), and disease-specific death (DSD) were collected. The performance of each classification was then calculated in terms of homogeneity, monotonicity, and discrimination and compared. Results: Two hundred and seventeen HNCSCC from 160 patients, with a mean age of 80 years, were included. For predicting the risk of any poor outcome and risk of NR, the BWH classification had the best specificity and positive predictive value. However, its concordance index was not significantly higher than that of the AJCC8 and UICC8 classifications. The NCCN classification was the least discriminant. Conclusions and Relevance: This study suggests that the BWH classification is the most appropriate for predicting the risk of poor outcomes in patients with HNCSCC when compared with the NCCN, UICC8, and AJCC8 classifications. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, we describe the recent studies that define the genetic alterations and composition of the stroma of oral and cutaneous squamous cell carcinomas (OSCC and CSCC, respectively). Mutations in tumor suppressor genes and protooncogenes cooperate in determining the differentiation, aggressiveness, and metastatic potential of these types of cancers. Driver mutations in tumor suppressor genes are more frequently observed in OSCC than CSCC. We also describe the differential composition of the tumor microenvironment and how this influences the aggressiveness of each tumor type. Although both OSCC and CSCC tumors are highly infiltrated by immune cells, high levels of tumor-infiltrating lymphocytes have been more frequently reported as predictors of good responses in OSCC than CSCC. Squamous cell carcinomas arise from stratified squamous epithelia. Here, a comparative analysis based on recent studies defining the genetic alterations and composition of the stroma of oral and cutaneous squamous cell carcinomas (OSCC and CSCC, respectively) was performed. Both carcinomas share some but not all histological and genetic features. This review was focused on how mutations in tumor suppressor genes and protooncogenes cooperate to determine the differentiation, aggressiveness, and metastatic potential of OSCC and CSCC. In fact, driver mutations in tumor suppressor genes are more frequently observed in OSCC than CSCC. These include mutations in TP53 (encoding pP53 protein), CDKN2A (encoding cyclin dependent kinase inhibitor 2A), FAT1 (encoding FAT atypical cadherin 1), and KMT2D (encoding lysine methyltransferase 2D), with the exception of NOTCH (encoding Notch receptor 1), whose mutation frequency is lower in OSCC compared to CSCC. Finally, we describe the differential composition of the tumor microenvironment and how this influences the aggressiveness of each tumor type. Although both OSCC and CSCC tumors are highly infiltrated by immune cells, high levels of tumor-infiltrating lymphocytes (TILs) have been more frequently reported as predictors of better outcomes in OSCC than CSCC. In conclusion, OSCC and CSCC partially share genetic alterations and possess different causal factors triggering their development. The tumor microenvironment plays a key role determining the outcome of the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Cetuximab remains a viable treatment for patients with advanced cutaneous squamous cell carcinoma who fail or are ineligible for immunotherapy. When used immediately following the progression of anti-PD1 therapy, cetuximab demonstrated particularly rapid and durable responses in our single institution retrospective experience. These findings should be validated in larger, prospective studies. However, if results are confirmed, cetuximab should be considered the preferred second-line agent after the failure of ICI. Future research should explore how ICI impacts subsequent anti-EGFR therapy, determine the ideal sequencing strategy when these agents are used and define if combination therapy using ICI with cetuximab is better than using either agent alone. Anti-PD1 therapy demonstrated impressive, prolonged responses in advanced cutaneous squamous cell carcinoma (CSCC). Therapy for ICI-refractory/ineligible disease remains unclear. We performed a retrospective analysis in locally-advanced/metastatic CSCC using cetuximab across three cohorts: immediately after ICI failure (A), not immediately following ICI failure (B), or without prior ICI (C). The primary endpoint was the overall response rate (ORR). Secondary endpoints included disease-control rate (DCR), progression-free survival (PFS), overall survival (OS), time-to-response (TTR) and toxicity. Twenty-three patients were included. In cohort A (n = 11), the ORR was 64% and DCR was 91%, with six ongoing responses at data cutoff. In cohort B (n = 2), all patients had progression as the best response. At a median follow-up of 21 months for A and B, TTR and PFS were 2.0 and 17.3 months, respectively. The median OS was not reached. In cohort C (n = 10), the ORR and DCR were 80%, including five ongoing responses at the data cutoff. At a median follow-up of 22.4 months, the TTR, PFS and OS were 2.5, 7.3 and 23.1 months, respectively. Cetuximab was well tolerated in all cohorts. In summary, cetuximab is effective in patients with failure/contraindications to ICI. Cetuximab immediately after ICI failure yielded particularly fast, durable responses. If confirmed, this could be the preferred therapy following ICI failure. [ABSTRACT FROM AUTHOR]

Background: Cutaneous squamous cell carcinoma (CSCC) is a severe malignancy derived from the skin. Mounting evidence suggests that circular RNAs (circRNAs) participate in diverse biological functions in human cancers, containing CSCC. However, the biological functions and underlying mechanism of hsa_circ_0005085 in CSCC have not been clearly studied. Methods: Expression levels of hsa_circ_0005085, microRNA‐186‐5p (miR‐186‐5p), and Laminin subunit gamma 1 (LAMC1) were detected by reverse transcription‐quantitative polymerase chain reaction. Cell counting kit‐8 assay, colony formation assay, and 5‐Ethynyl‐2′‐deoxyuridine assay were used to assess cell proliferation. Transwell assay was conducted to detect cell migration and invasion. Cell apoptosis was analyzed by flow cytometry. Protein expression of LAMC1, E‐cadherin, Snail, and slug were assessed using western blot assay. Using bioinformatics software, the binding between miR‐186‐5p and hsa_circ_0005085 or LAMC1 was predicted, followed by verification using a dual‐luciferase reporter and RNA‐Immunoprecipitation. The mouse xenograft model was established to investigate the role of hsa_circ_0005085 in vivo. Results: Hsa_circ_0005085 level was downregulated in CSCC tissues and cells. Overexpression of hsa_circ_0005085 inhibited cell proliferation, migration, invasion, epithelial‐mesenchymal transition (EMT), and promoted cell apoptosis in CSCC. MiR‐186‐5p could restore the effect of hsa_circ_0005085 overexpression on CSCC cells, and the knockdown of LAMC1 reversed the regulation of the miR‐186‐5p inhibitor. In mechanism, hsa_circ_0005085 served as a sponge for miR‐186‐5p to regulate LAMC1 expression. Overexpression of hsa_circ_0005085 reduced growth of tumor via miR‐186‐5p/LAMC1 axis in vivo. Conclusion: In our study, hsa_circ_0005085 might inhibit CSCC development by targeting the miR‐186‐5p/LAMC1 axis, which might provide a promising therapeutic target for CSCC. [ABSTRACT FROM AUTHOR]

A 90-year-old man presented for evaluation of an incompletely excised squamous cell carcinoma above the right brow, with pathology demonstrating tumor extending to resection margins with perineural invasion. A cord of tumor was noted to extend past the orbital rim and towards the posterior orbit. Mohs excision versus coordinated resection and reconstruction with colleagues in the head and neck surgery and craniofacial plastic surgery departments were considered. Multidisciplinary consensus was to proceed with radical resection in the operating room followed by adjuvant radiation therapy. One year later, the patient presented to our Mohs unit with a 3cm eroded multinodular plaque. Following an in-depth discussion regarding the options of further surgery versus systemic treatment, the patient and his family opted to pursue consultation with a medical oncology consultant to discuss restaging and potential systemic therapy. A PET scan with concurrent CT revealed a hypermetabolic right temporal scalp mass without evidence of bony invasion or extension into the nodal basin. Immunotherapy with cemiplimab was started at a dose of 350mg IV every three weeks. After 7 cycles, the patient demonstrated complete clinical resolution with a repeat PET scan showing interval near resolution of abnormal metabolic activity.

Abstract Background Prognostic factors for initial response of advanced cutaneous squamous cell carcinoma to cemiplimab treatment are lacking. Il-6 has been found to affect immune cell populations which impact tumor development. The aim was to investigate the prognostic significance of IL-6 serum levels before and during treatment. Methods Serum levels of IL-6 were correlated with clinical outcomes in a retrospective study. Results Overall, 39 patients were enrolled. High serum levels of IL-6 (> 5.6 pg/ml) were associated with poorer survival (45.1% vs 0 deaths; OS: 16.1 ± 1.5 vs 20.8 ± 0 months, 95% CI 13,046 to 19,184) and shorter PFS (10.3 ± 1.9 vs 18.9 ± 1.5 months; 95% CI 3433 to 10,133) in patients with advanced CSCC treated with cemiplimab. In addition, patients whose IL-6 level increased after treatment with cemiplimab, independently of the basal level, had a poorer response to treatment than patients whose level was reduced or stable after immunotherapy. Conclusions Serum levels of IL-6 at baseline and changes after cemiplimab immunotherapy may have a prognostic significance in patients with advanced cutaneous squamous cell carcinoma.

Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4) has been implicated in keratinocyte development and several types of cancer. A well-defined role for NFATC4 in cutaneous squamous cell carcinoma (CSCC) has not yet been established. In this study, NFATC4 gene function in CSCC development was examined. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure the mRNA expression of NFATC4 in CSCC tissues and controls. A431 and Colo16 cell proliferation, invasion, and apoptosis were measured by CCK-8 assay, transwell invasion, and flow cytometry, respectively, after an NFATC4 expression lentivirus infection. Animal models were applied to validate the function of the NFATC4 gene. (1) CSCC tissues showed a significant decrease in NFATC4 expression compared to controls. (2) Overexpression of NFATc4 suppresses A431 and Colo16 cell proliferation and invasion but promotes cell apoptosis. (3) Mouse models overexpressing NFATC4 showed reduced tumourigenesis. It was suggested that NFATC4 might be a tumour suppressor gene in CSCC.

Abstract Cutaneous squamous cell carcinoma (CSCC) is a common cancer in humans and is the second major type of skin cancer that causes death in humans. In this article, we investigated the effects of alkannin on CSCC progression. We revealed that alkannin curbed CSCC cell viability in a dose‐dependent manner and accelerated CSCC cell apoptosis. In addition, alkannin expedited macrophage M1 polarization while curbing M2 polarization. Moreover, alkannin elevated phosphatase and tensin homolog (PTEN) abundance in CSCC cells. The results of bioinformatics analysis revealed that alkannin might modulate CSCC via PTEN. Downregulation of PTEN reversed the effects of alkannin on apoptosis of CSCC cells and M1/M2 polarization of macrophages. Alkannin reduced CSCC tumor growth in a mouse xenograft model. In conclusion, alkannin curbed the advancement of CSCC by expediting apoptosis and facilitating M1 polarization of macrophages by upregulating PTEN. These data may offer a therapeutic approach against CSCC.

Dan Li,1 Liwen Ma,1 Jun Bao,1 Lei Cao,2 Wei Min3 1Department of Dermatology, the Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 2Clinical Immunology Laboratory, the First Affiliated Hospital of Soochow University, Soochow University, Suzhou, People’s Republic of China; 3Department of Dermatology, the First Affiliated Hospital of Soochow University, Soochow University, Suzhou, People’s Republic of ChinaCorrespondence: Wei Min, Email minwei@suda.edu.cnBackground: Increasing evidence has indicated that several B7 family members play critical roles in the progress of many cancers. However, the clinical significance of the B7 family in cutaneous squamous cell carcinoma (cSCC) is still elusive. The purpose of this study is to investigate the potential role of B7-H1 biomolecules (PD-L1) in regulating the tumorigenesis and progression of cSCC, the most common non-melanoma skin cancer.Methods: We collected transcriptome data of cSCC patients from TCGA databases (n = 496) and subjected the transcription data to bioinformatical analysis. Differential expression of B7-H1 genes with a grade-dependent pattern was identified. We collected paraffin sections of skin squamous carcinoma and analyzed by immunohistochemical staining. We further examined the PD-L1 levels of CD14+ cells in peripheral blood of each cSCC patient and normal subjects by flow cytometry.Results: It was found that higher expression of PD-L1 was associated with poor prognosis of cSCC patients and shorter overall survival. These observations were further verified in the clinical paraffin sections and in peripheral blood T cells.Conclusion: Our study reveals that PD-L1 is a potential prognostic marker in clinical prognosis for cSCC patients and could be valuable for cSCC treatment.Keywords: PD-L1, cutaneous squamous cell carcinoma, tumour progression, immunotherapy

Cutaneous squamous cell carcinoma (cSCC) is one of the most common types of skin cancer. The incidence of the skin cancer is increasing year by year and seriously affects the quality of life of patients. Therefore, finding new targeted markers is of great significance for diagnosis and treatment. In recent years, the role of long non-coding RNA in diseases has been paid more attention. It is involved in the development of diseases through influencing transcription, epigenetics, and regulating competitive endogenous RNA networks. In cSCC, its related LncRNAs are abnormally expressed and affect tumor phenotypes through molecular, gene, signal pathway and other ways. In this review, we summarize studies on the role of seven common long non-coding RNA in cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma accounts for 20 % of all malignant non-melanoma skin tumors, which is one of the most common cancers worldwide. Antitumor treatment is usually very effective: cure rate reaches 90 %, while local recurrence rate is 25 %. The main treatment option for primary skin cancers is surgery. The most significant risk factors for locoregional recurrence include tumor location (head and neck), size (>2 cm), depth of invasion (>4 mm), tumor differentiation grade, perineural invasion, immune system disorders (immunosuppression), severe concomitant diseases, and previous treatment.In patients with advanced cutaneous squamous cell carcinoma, 1-year, 2-year, and 3-year survival rates are 50–80, 30–35 and 15–16 %, respectively. Radiotherapy is a radical treatment option that increases the 5-year survival rate to 90 % and ensures good cosmetic results in 80 % of cases. There are 3 main variants of radiotherapy for cutaneous squamous cell carcinoma: sole radiotherapy according to a radical program, adjuvant radiotherapy in combination with surgery, and palliative radiotherapy. most frequently, radiotherapy is used as part of adjuvant postoperative treatment and is not initially considered as a sole conservative treatment for cutaneous squamous cell carcinoma patients below 45 years of age with resectable tumors, especially high-risk tumors. palliative radiotherapy is an affordable and effective method for combating painful symptoms; moreover, it often provides long-term local control.

Abstract Background Although determining the recurrence of cutaneous squamous cell carcinoma (cSCC) is important, currently suggested systems and single biomarkers have limited power for predicting recurrence. Objective In this study, combinations of clinical factors and biomarkers were adapted into a nomogram to construct a powerful risk prediction model. Methods The study included 145 cSCC patients treated with Mohs micrographic surgery. Clinical factors were reviewed, and immunohistochemistry was performed using tumor tissue samples. A nomogram was constructed by combining meaningful clinical factors and protein markers. Results Among the various factors, four clinical factors (tumor size, organ transplantation history, poor differentiation, and invasion into subcutaneous fat) and two biomarkers (Axin2 and p53) were selected and combined into a nomogram. The concordance index (C-index) of the nomogram for predicting recurrence was 0.809, which was higher than that for the American Joint Committee on Cancer (AJCC) 7th, AJCC 8th, Brigham and Women’s Hospital, and Breuninger staging systems in the patient data set. Conclusion A nomogram model that included both clinical factors and biomarkers was much more powerful than previous systems for predicting cSCC recurrence.

Abstract Background Bowen's disease is a cutaneous squamous cell carcinoma (CSCC) in situ. If left untreated, BD may progress to invasive CSCC. CSCC is one of the most common cutaneous carcinoma in the elderly and the advanced, metastasis CSCC usually have a poor outcomes. However, the mechanisms of invasion and metastasis from Bowen’s disease to CSCC is complicated and still unclear. Objectives The aim of this study was to explore the biomarkers and molecular alterations in Bowen’s disease development process via analyzing the proteomics changes in tissues of CSCC, Bowen disease and healthy skin. Methods A total of 7 individuals with CSCC (5 for proteomics study and 2 for validation), 7 individuals with Bowen disease (5 for proteomics study and 2 for validation) and 7 healthy controls (5 for proteomics study and 2 for validation) presented to the Department of Dermatology, Yijishan Hospital, the First Affiliated Hospital of Wannan Medical College between January 2021 and December 2021 were enrolled. The proteomics analysis was performed to screen differentially expressed proteins/gens (DEPs/DEGs) in the lesions of CSCC, Bowen disease and healthy skin tissues. The transcriptomic data (GSE32628) of CSCC was selected and downloaded from the GEO database. The common DEGs in our proteomics results and GSE32628 between CSCC and healthy skin tissues were selected. And then, the common DEGs which significantly up or down-regulated between CSCC and Bowen disease in our proteomics results were further screened to identify using Western blot methods in the validation group. CSCC A431 cells were transfected with SERPINB1 small interfering RNA (si-SERPINB1) or small interfering RNA negative control (si-NC). To explore the effect of SERPINB1 silencing on migration and invasion ability of A431 cells. Results A total of 501 proteins were differentially expressed between the CSCC and healthy skin tissues, with 332 up-regulated and 169 down-regulated at least 1.5-fold with a P value