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There is limited data regarding the use of immunotherapy for patients with vulvar squamous cell carcinoma and coexisting autoimmune disease. Cemiplimab is a PD-1 inhibitor approved for use in patients with locally advanced and metastatic cutaneous squamous cell carcinoma. However, little is known about its efficacy in the setting of vulvar cancer. We present a case of advanced vulvar squamous cell carcinoma treated with induction chemotherapy and immunotherapy with cemiplimab followed by definitive chemoradiation in the setting of multiple autoimmune diseases. She achieved a complete clinical response and experienced no worsening of her autoimmune conditions despite cessation of her immunosuppressants and initiating an immune checkpoint inhibitor. We review existing data on neoadjuvant treatment of vulvar cancer and the use of cemiplimab in genital and inguinal squamous cell carcinomas. Ongoing exploration of cemiplimab’s efficacy in vulvar cancer and safety in immunosuppressed patients is critical.

Antibody-drug conjugates (ADCs) are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells, thereby attracting considerable attention in precise oncology therapy. Cetuximab (Cet) is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma (cSCC); however, its anti-tumor activity is limited to a single use. Cisplatin (CisPt) shows good curative effects; however, its adverse effects and non-tumor-targeting ability are major drawbacks. In this study, we designed and developed a new ADC based on a new cytotoxic platinum (IV) prodrug (C8Pt(IV)) and Cet. The so-called antibody-platinum (IV) prodrugs conjugates, named Cet-C8Pt(IV), showed excellent tumor targeting in cSCC. Specifically, it accurately delivered C8Pt(IV) into tumor cells to exert the combined anti-tumor effect of Cet and CisPt. Herein, metabolomic analysis showed that Cet-C8Pt(IV) promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells, thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum (IV) prodrugs conjugates.

Background/Purpose: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies worldwide. While several environmental risk factors for cSCC are well established, there is conflicting evidence on cigarette smoking (and its potential causal effect) and cSCC risk. Furthermore, it is unclear if these potential associations represent causal, modifiable risk factors for cSCC development. This study aims to assess the nature of the associations between cigarette smoking traits (smoking initiation, amount smoked, and lifetime smoking exposure) and cSCC risk using two-sample Mendelian randomization analyses. Methods: Genetic instruments, based on common genetic variants associated with cigarette smoking traits (P

Summary: Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician’s documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0–62.4) and 59.6% (95% CI, 51.3–67.5), respectively. ORR was 35.1% (95% CI, 27.5–43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.

Purpose: MicroRNAs (miRs) play multiple roles during cutaneous squamous cell carcinoma (CSCC) progression. Previous studies suggest miR-124 could inhibit cancer development in CSCC. Methods: Obtained 63 pairs of CSCC and adjacent tissues for analysis. Cultured HaCaT and two CSCC cell lines (A431 and SCL-1) in DMEM (10 % FBS). Transfected cells using Lipofectamine 2000 with various miR-124 mimics, inhibitors, or Snail family transcriptional repressor 2 (SNAI2) expression plasmid. Performed a series of assays, including real-time quantitative PCR, Western blot, CCK8, wound healing, transwell, and luciferase reporter gene assay, to examine the effects of miR-124 on CSCC cells. Results: An evident downregulation of miR-124 in CSCC tissues, which was related to advanced disease stage and nodal metastasis. Overexpressing miR-124 could reduce the proliferation, migration, and invasion abilities of CSCC cells. It was verified that miR-124 targets the SNAI2 in CSCC cells. Moreover, ectopic expression of SNAI2 rescued the suppressive effects on CSCC cells induced by miR-124 overexpression. Furthermore, miR-124 increased cell sensitivity to cisplatin. Besides, SNAI2 is a critical factor in the immune-related aspects of CSCC and its modulation may influence the response to immunotherapy. Conclusion: We demonstrate that miR-124 inhibits CSCC progression through downregulating SNAI2, and thus it may be a molecular candidate for treating CSCC in the clinic.

Objective: Cutaneous Squamous Cell Carcinoma (cSCC), a tumor with a significantly increasing incidence, is mostly diagnosed in the head region, where tumors have a worse prognosis and a higher risk of metastases. The presence of metastases reduces specific five-year survival from 99% to 50%. As the risk of occult metastases does not exceed 10%, elective dissection of the tributary parotid and neck lymph nodes is not recommended. Methods: We retrospectively analyzed a group of 12 patients with cSCC of the head after elective dissections of regional (parotid and cervical) nodes by means of superficial parotidectomy and selective neck dissection. Results: We diagnosed occult metastases neither in the cervical nor parotid nodes in any patient. None were diagnosed as a regional recurrence during the follow-up period. Conclucion: Our negative opinion on elective parotidectomy and neck dissection in cSCC of the head is in agreement with the majority of published studies. These elective procedures are not indicated even for tumors showing the presence of known (clinical and histological) risk factors for lymphogenic spread, as their positive predictive value is too low. Elective parotidectomy is individually considered as safe deep surgical margin. If elective parotidectomy is planned it should include only the superficial lobe. Completion parotidectomy and elective neck dissection are done in rare cases of histologically confirmed parotid metastasis in the parotid specimen. Preoperatively diagnosed parotid metastases without neck involvement are sent for total parotidectomy and elective selective neck dissection. Cases of clinically evident neck metastasis with no parotid involvement, are referred for comprehensive neck dissection and elective superficial parotidectomy. The treatment of concurrent parotid and cervical metastases includes total conservative parotidectomy and comprehensive neck dissection. Level of evidence: How common is the problem?Step 4 (Case-series)Is this diagnostic or monitoring test accurate? (Diagnosis)Step 4 (poor or non-independent reference standard)What will happen if we do not add a therapy? (Prognosis)Step 4 (Case-series)Does this intervention help? (Treatment Benefits)Step 4 (Case-series)What are the COMMON harms? (Treatment Harms)Step 4 (Case-series)What are the RARE harms? (Treatment Harms)Step 4 (Case-series)Is this (early detection) test worthwhile? (Screening)Step 4 (Case-series)

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.

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.

Resumen: La queratosis actínica (QA) es una afección cutánea caracterizada por la proliferación de queratinocitos mutados que pueden convertirse en carcinoma escamoso cutáneo. Las terapias disponibles, aunque efectivas, están asociadas con una alta frecuencia de reacciones cutáneas locales graves. Tirbanibulina, uno de los tratamientos para la QA actualmente en desarrollo, es un nuevo fármaco sintético de origen químico con potentes efectos antiproliferativos y antitumorales in vitro e in vivo con eficacia probada en el tratamiento de la QA, demostrada recientemente en dos ensayos clínicos de fase III. En la presente revisión se muestra el mecanismo de acción de tirbanibulina en base a la literatura relevante y los resultados de varios estudios preclínicos no publicados. Además, se plantea el escenario actual en cuanto a los tratamientos disponibles y cómo el mecanismo de acción novedoso de tirbanibulina encaja en el tratamiento de la QA. Abstract: Actinic keratosis (AK) is a skin condition characterized by the proliferation of mutated keratinocytes that can develop into squamous cell carcinoma. Available therapies, although effective, are associated with a high frequency of severe local skin reactions. Tirbanibulin, one of the treatments for AK currently in development, is a new synthetic chemical entity with anti-proliferative and anti-tumor effects, both in vitro and in vivo, with proved efficacy in the treatment of AK, which has been recently demonstrated in two phase III clinical trials. In the present review, the tirbanibulin mechanism of action, based on the relevant literature and the results of several unpublished preclinical studies, is shown. In addition, the current scenario regarding the available treatments and how the novel tirbanibulin mechanism of action fits into the treatment of AK is raised.

The aim of this study was to compare treatment modalities, pathological and clinical characteristics, and outcomes in patients with metastasis in a parotid gland. The medical records of 34 patients who received treatment for metastasis in the parotid gland over a twenty-year period were evaluated. Patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) metastasis were retrospectively reclassified using the P/N and N1S3 staging system. Patients with neck metastasis showed a significantly poorer prognosis (P = 0.025). Univariate analysis also revealed that extent of parotidectomy and type of neck dissection did not influence recurrence free survival (RFS) and overall survival (OS). When comparing the usefulness of the P/N and S1N3 staging systems, a positive correlation was observed between the P stage and the N1S3 stage in both RFS and OS. The extent of parotidectomy and concomitant neck dissection is still under discussion. Total parotidectomy and modified radical neck dissection did not improve RFS and OS. N1S3 is a less complex classification and possesses a higher predictive value when compared to the P/N staging system., Competing Interests: Declaration of competing interest There are no conflicts of interests in regard to this study., (Copyright © 2024 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Cutaneous squamous cell carcinoma (CSCC) is a malignant proliferation of cutaneous epithelium that has been observed to have an alarming rise in incidence. Numerous studies have demonstrated microRNAs (miRNAs or miRs) as important biomarkers in the diagnosis, prognosis, and treatment of CSCC. This study aims to investigate the effects of miR-203 on the behaviors of CSCC cells and possible mechanisms associated with protein regulator of cytokinesis-1 (PRC1) and Wnt/β-catenin signaling pathway. PRC1 was suggested as a target of miR-203 in squamous cell carcinoma cell line 1 (SCL-1) cells by dual-luciferase reporter gene assay. Based on the immunohistochemical staining and qRT-PCR, PRC1 was abundantly expressed while miR-203 was poorly expressed in CSCC tissues. miR-203 mimic or inhibitor was transfected into SCL-1 cells to upregulate or downregulate its expression. Upregulation of miR-203 downregulated PRC1 expression to block the Wnt/β-catenin signaling pathway. By conducting 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), scratch test, and Transwell and flow cytometric analyses, miR-203 was witnessed to restrain SCL-1 cell proliferation, migration, and invasion while accelerating their apoptosis. The rescue experiments addressed that inhibition of the Wnt/β-catenin signaling pathway conferred the anti-tumor effect of miR-203. These results establish a tumor-suppressive role for miR-203 in CSCC cell line SCL-1. Hence, miR-203 has promising potential as a therapeutic target for CSCC.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer caused by mutagenesis resulting from excess UVR or other types of oxidative stress. These stressors also upregulate the production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), through endoplasmic reticulum stress-initiated, sphingosine-1-phosphate (S1P) signaling pathway. Although CAMP has beneficial antimicrobial activities, it also can be proinflammatory and procarcinogenic. We addressed whether and how S1P-induced CAMP production leads to cSCC development. Our study demonstrated that (i) CAMP expression is increased in cSCC cells and skin from patients with cSCC; (ii) S1P levels are elevated in cSCC cells, whereas inhibition of S1P production attenuates CAMP-stimulated cSCC growth; (iii) exogenous CAMP stimulates cSCC but not normal human keratinocyte growth; (iv) blockade of FPRL1 protein, a CAMP receptor, attenuates cSCC growth as well as the growth and invasion of cSCC cells mediated by CAMP into an extracellular matrix-containing fibroblast substrate; (v) FOXP3+ regulatory T-cell (which decreases antitumor immunity) levels increase in cSCC skin; and (vi) CAMP induces endoplasmic reticulum stress in cSCC cells. Together, the endoplasmic reticulum stress-S1P-CAMP axis forms a vicious circle, creating a favorable environment for cSCC development, that is, cSCC growth and invasion impede anticancer immunity., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

There is limited data regarding the use of immunotherapy for patients with vulvar squamous cell carcinoma and coexisting autoimmune disease. Cemiplimab is a PD-1 inhibitor approved for use in patients with locally advanced and metastatic cutaneous squamous cell carcinoma. However, little is known about its efficacy in the setting of vulvar cancer. We present a case of advanced vulvar squamous cell carcinoma treated with induction chemotherapy and immunotherapy with cemiplimab followed by definitive chemoradiation in the setting of multiple autoimmune diseases. She achieved a complete clinical response and experienced no worsening of her autoimmune conditions despite cessation of her immunosuppressants and initiating an immune checkpoint inhibitor. We review existing data on neoadjuvant treatment of vulvar cancer and the use of cemiplimab in genital and inguinal squamous cell carcinomas. Ongoing exploration of cemiplimab's efficacy in vulvar cancer and safety in immunosuppressed patients is critical., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective(s): Vismodegib, a unique hedgehog pathway inhibitor, has been demonstrated to be effective in the treatment of non-operable and metastatic basal cell carcinoma (BCC). While effective, concerns regarding its role in the development of cutaneous squamous cell carcinoma (CSCC) remain. The primary objective is to describe a unique case of locally advanced BCC of the face and subsequent transformation to CSCC following treatment with vismodegib. Methods: Case report. Results: A 64-year-old Caucasian female presented with a 3-year history of a progressive and erosive lesion involving the entirety of her forehead with involvement of the left medial canthus and upper eyelid. Biopsies performed at the periphery of the lesion demonstrated superficial and nodular BCC. As surgical management would result in significant morbidity, the patient elected for treatment with oral vismodegib, 150 mg daily, with curative intent. Dramatic tumor response was experienced over an 18-month period; however, surveillance MRI demonstrated concern for tumor progression at the periphery of the mass without evidence of intracranial extension or metastases. Subsequent biopsies at the superior and left supraorbital margins demonstrated invasive SCC. Following immunohistochemistry analysis, intravenous nivolumab, 480 mg monthly was initiated; the patient remains progression-free after 18 months of therapy. Conclusion: This case highlights the importance of close surveillance in patients treated with vismodegib for non-operable BCC. Serial biopsies of new or suspicious appearing tumors should be performed given the potential for CSCC transformation.

Cutaneous squamous cell carcinoma (CSCC) accounts for ∼20%-25% of all skin tumors. Its precise incidence is often challenging to determine due to limited statistics and its incorporation with mucosal forms. While most cases have a favorable prognosis, challenges arise in patients presenting with locally advanced or metastatic forms, mainly appearing in immunocompromised patients, solid organ transplantation recipients, or those facing social difficulties. Traditionally, chemotherapy and targeted therapy were the mainstays for advanced cases, but recent approvals of immunotherapeutic agents like cemiplimab and pembrolizumab have revolutionized treatment options. These guidelines, developed by the Italian Association of Medical Oncologists (AIOM) using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, aim to guide clinicians in diagnosing, treating, and monitoring patients with CSCC, covering key aspects from primitive tumors to advanced stages, selected by a panel of experts selected by AIOM and other national scientific societies. The incorporation of these guidelines into clinical practice is expected to enhance patient care and address the evolving landscape of CSCC management., Competing Interests: Disclosure PQue reported consulting or advisory role for Roche/Genentech, Novartis, MSD, Bristol Myers Squibb, Pierre Fabre, Sanofi, Sun Pharma Advanced Research Company, Merck Serono; travel, accommodations, expenses from MSD Oncology, Sanofi/Regeneron. FB reported advisory role for SunPharma; speaker fee, travel/accommodations for presentations or lectures for Sanofi/Regeneron; honoraria as consultant for Roche, Novartis. PB reported consulting or advisory role for Merck, Sanofi, Merck Sharp & Dohme, Sun Pharma, Angelini, Molteni, Bristol-Myers Squibb, GSK; research funding by GSK, MSD, Sanofi, BMS. MDV reported consulting or advisory role for Novartis, MSD, Bristol Myers Squibb, Pierre Fabre, Immunocore. KP reported advisory board roles with Abbvie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi. PQua reported advisory board and speaker fee from Sanofi, SunPharma, IGEA. IZ reported advisory board and speaker fee from Sanofi, SunPharma, Philogen, Regeneron, Novartis, MSD, Cieffe Derma, La Roche Posay, BMS, Almirall. FS reported honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk, Sun Pharma, MSD, Pierre Fabre; participation on advisory board for Novartis, Philogen SunPharma, and MSD. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Declaration of Competing Interest CG has received grants from Italian Ministry of Health and BMS and Honoraria for presentations or lectures from AstraZeneca, BMS, Lilly, MSD, Roche, Sanofi, Takeda, Thermo Fisher; ML has received personal fees (advisory role and/or speaker honoraria) from Roche, Takeda, Sandoz, Eli Lilly, Pfizer, AstraZeneca, Novartis Exact Sciences and Ipsen; LDM has reported consulting fees from Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Eli Lilly, Seattle Genetics, Eisai, Pierre Fabre, and Daiichi Sankyo, speaker Honoraria from Roche, Novartis, Eli Lilly and MSD, travel grants from Roche, Pfizer and Celgene; FS has reported Honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk, Sun Pharma, MSD, Pierre Fabre and for advisory board for Novartis, Philogen, SunPharma, MSD.

Background: Little is known about whether UVB can directly influence epigenetic regulatory pathways to induce cutaneous squamous cell carcinoma (CSCC). This study aimed to identify epigenetic-regulated signalling pathways through global methylation and gene expression profiling and to elucidate their function in CSCC development. Methods: Global DNA methylation profiling by reduced representation bisulfite sequencing (RRBS) and genome-wide gene expression analysis by RNA sequencing (RNA-seq) in eight pairs of matched CSCC and adjacent normal skin tissues were used to investigate the potential candidate gene(s). Clinical samples, animal models, cell lines, and UVB irradiation were applied to validate the mechanism and function of the genes of interest. Findings: We identified the downregulation of the TGF-β/BMP-SMAD-ID4 signalling pathway in CSCC and increased methylation of inhibitor of DNA binding/differentiation 4 (ID4). In normal human and mouse skin tissues and cutaneous cell lines, UVB exposure induced ID4 DNA methylation, upregulated DNMT1 and downregulated ten-eleven translocation (TETs). Similarly, we detected the upregulation of DNMT1 and downregulation of TETs accompanying ID4 DNA methylation in CSCC tissues. Silencing of DNMT1 and overexpression of TET1 and TET2 in A431 and Colo16 cells led to increased ID4 expression. Finally, we showed that overexpression of ID4 reduced cell proliferation, migration, and invasion, and increased apoptosis in CSCC cell lines and reduced tumourigenesis in mouse models. Interpretation: The results indicate that ID4 is downregulated by UVB irradiation via DNA methylation. ID4 acts as a tumour suppressor gene in CSCC development. Funding: CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-3-021, 2017-I2M-1-017), the Natural Science Foundation of Jiangsu Province (BK20191136), and the Fundamental Research Funds for the Central Universities (3332019104).

Cutaneous squamous cell carcinoma is a common global cancer with Ultraviolet light recognized as the most significant risk factor. The other definite or plausible risk factors include immunosuppression, infection with oncogenic viruses, exposure to toxins, chemicals, chronic inflammatory skin disease and a high body mass index.This case highlights the rarity of the pathology in terms of size, the subtle transition of verrucous hyperplasia to cutaneous squamous cell carcinoma over a period of time and the fallibility of the frozen section report in deciding the optimum resection margins. The initial innocuous presentation represented a diagnostic challenge as it can be mistaken for other benign entities. A correlation between the history, clinical presentation, tumor biology and the histopathological characteristics helped us to unlock the jigsaw puzzle of approaching a rare condition with a modification in the surgical approach.

This study intends to address the impact of weekly hypofractionated radiation therapy with curative intent for cutaneous squamous cell carcinoma of the head and neck region in the elderly population., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Modified 5-aminolevulinic acid photodynamic therapy (M-PDT) is a novel therapeutic modality for cutaneous squamous cell carcinoma (cSCC) that is reported to be effective and well tolerated. However, the mechanisms underlying its antitumor effects are not fully understood. In this research, we investigated the effects of M-PDT on pyroptosis, a form of programmed cell death characterized by cell swelling, ruptures of cell membrane, and inflammatory cytokine release, in two human cSCC cell lines, SCL-1 and HSC-5. We found that M-PDT triggered pyroptosis in a dose-dependent manner, as evidenced by increased lactate dehydrogenase release, propidium iodide staining, and expression of pyroptosis-related proteins, such as NLR family pyrin domain containing 3 (NLRP3), N-terminal of gasdermin D (N-GSDMD), cleaved caspase-1, and mature interleukin 1 beta (IL-1B) in both cell lines. This process was inhibited by treatment with MCC950, an NLRP3-specific inhibitor, suggesting the involvement of the NLRP3 inflammasome in M-PDT-induced pyroptosis. We also demonstrated that M-PDT activated c-Jun N-terminal kinase (JNK) signaling, which is required for pyroptosis induction, as treatment with SP600125, a JNK inhibitor, suppressed the expression of pyroptosis-related proteins after M-PDT. JNK activation enhanced M-PDT-induced pyroptosis, highlighting the significance of the JNK pathway in M-PDT. Moreover, M-PDT increased intracellular reactive oxygen species (ROS) levels, which are responsible for JNK activation and pyroptosis induction. In summary, our results revealed that M-PDT triggers pyroptosis through ROS-mediated JNK activation and subsequent NLRP3 inflammasome activation in cSCC cells, providing a better understanding of the molecular mechanism of M-PDT and promoting its clinical application., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy arising in immunocompromised patients such as solid organ transplant recipients. In addition to an abundance in number, the morbidity and mortality of these tumors in this patient population exceeds that of immune competent individuals. Here, we used whole exome and bulk RNA sequencing to analyze mutation profiles between tumors arising in immunocompetent and immunosuppressed patients., Methods: DNA and RNA extracted from twenty formalin-fixed, paraffin embedded tumors and adjacent skin was sequenced. Bioinformatic analysis revealed tumor mutational burden, mutational signatures, microsatellite instability, and aberrant signaling pathways., Results: Similar median tumor mutational burden was found in both the tumors from the immunocompetent and the immunosuppressed cohorts. Mutation signature analysis revealed UVR signatures and evidence of azathioprine exposure. 50% of tumors from the immunosuppressed patients have mutations consistent with microsatellite instability, yet mismatch repair protein expression was preserved in the samples analyzed. Additionally, frequently mutated genes in this cohort belong to the extracellular matrix receptor interaction and calcium signaling pathways, suggesting these may be targets for future treatments of this disease., Conclusions: This study utilizes whole exome and bulk RNA sequencing to identify difference between cSCC arising in immunosuppressed and immunocompetent patients using the patient's photo exposed, but histologically normal appearing skin as the "germline" comparison. We demonstrate an enrichment in microsatellite instability in the tumors from immunosuppressed patients and differences in oxidative phosphorylation and epithelial-mesenchymal transition which may be targets for therapeutic intervention based on identification of mutations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The treatment of deep-invasive cutaneous squamous cell carcinoma (cSCC) is difficult. Sonodynamic therapy (SDT) has showed advantages in large penetration depth, small trauma, good repeatability, high targeting selectivity and effective protection for intact structure and function of tissues and organs., Objective: To study the efficacy and safety of 5-aminolevulinic acid SDT (ALA-SDT) in the treatment of cSCC., Methods: The absorption and transformation of ALA after co-incubation with cSCC were detected by UV-Vis and fluorescence absorption. The production of reactive oxygen species (ROS) when protoporphyrin IX (PpIX) excited with ultrasound was detected by ROS detection probe. Cytotoxicity of ALA-SDT to cSCC was detected with cytotoxicity indicators. The tumor volume changes and tumor weight of mice after ALA-SDT were detected. The effects of ALA-SDT on the growth of mice were evaluated through the changes in body weight of mice. Biosafety of treatment was further evaluated by histopathology to determine whether the tissues and organs of mice were affected after ALA-SDT., Results: ALA can be absorbed and converted into PpIX when incubated with cSCC cells and produces ROS with ultrasound irradiation. ALA-SDT showed a significant cytotoxicity on cSCC cells. With one session of ALA-SDT in vivo, tumor growth was slowed but not stopped and would proceed once treatment was ended. ALA-SDT had no significant effect on body weight changes and major tissues and organs of the mice., Conclusion: ALA-SDT could safely and reduce cSCC cells growth both in vitro and in vivo., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cutaneous squamous cell carcinoma (CSCC) is the most common malignant skin tumour in cats and the nature of the molecular mechanisms involved is poorly defined. Included among the molecular mechanisms in human and canine CSCCs is altered expression of E-cadherin/β-catenin. This study aimed to explore the immunohistochemical expression pattern of E-cadherin and β-catenin in 43 samples of feline CSCC by using a tissue microarray to elucidate whether expression of these molecules is dysregulated. Membrane expression of E-cadherin and membrane and cytoplasmic expression of β-catenin were significantly reduced in the CSCCs. Cytoplasmic expression of E-cadherin and nuclear expression of β-catenin were also found in some CSCCs. These findings indicate that altered expression of E-cadherin and β-catenin is a frequent event in feline CSCCs, suggesting that these molecules play an important role in acquisition of the malignant phenotype in feline patients with CSCC. The results also suggest the existence of a subpopulation of feline patients with CSCC in which the Wnt pathway may contribute to epidermal carcinogenesis., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: 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., Objective: We investigated the function of circ_TNFRSF21/miR-214-3p/CHI3L1 axis in cSCC., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Conflict of Interest The authors declare that there is no conflict of interest., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Although most cutaneous squamous cell carcinoma (cSCC) cases are generally nonlethal and manageable with surgical excision, there ares till significant hazards for patients who are ineligible for surgical resection. We sought to find a suitable and effective treatment for cSCC., Methods: We modified chlorin e6 by adding a hydrogen chain with a six-carbon ring to the benzene ring and named this new photosensitizer as STBF. We first investigated the fluorescence characteristics, cellular uptake of STBF and subcellular localization. Next, cell viability was detected by CCK-8 assay and the TUNEL staining was performed. Akt/mTOR-related proteins were examined by western blot., Results: STBF-photodynamic therapy (PDT) inhibits cSCC cells viability in a light dose dependent manner. The antitumor mechanism of STBF-PDT might be due to the suppression of the Akt/mTOR signaling pathway. Further animal investigation determined that STBF-PDT led to a marked reduction in tumor growth., Conclusions: Our results suggest that STBF-PDT exerts significant therapeutic effects in cSCC. Thus, STBF-PDT is expected to be a promising method for the treatment of cSCC and the photosensitizer STBF may be destined for a wider range of applications in photodynamic therapy., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Non-melanoma skin cancer (NMSC) is becoming ever more prevalent among older adults. However, older adults with NMSC are often underrepresented in clinical trials and guidelines on effective management is still unclear. The International Society of Geriatric Oncology (SIOG) created a multi-disciplinary task force to explore the potential in developing practical guidelines for the treatment of older patients with basal cell carcinoma (BCC) and skin (cutaneous) squamous cell carcinoma (cSCC)., Materials and Methods: A systematic literature search to identify relevant and up-to-date literature on treatment of NMSC in older adults was conducted on various databases including MEDLINE, Embase, CINAHL, Cochrane, and PubMed. The resulting papers were discussed by an expert panel, leading to a consensus recommendation., Results: A total of 154 articles were identified for the expert panel to utilise in generating consensus recommendations. A major focus on geriatric assessment and management options including surgery, radiotherapy, systemic therapy, clinical monitoring, and medical/medicophysical therapy were reviewed for recommendations., Discussion: Patient age should not be the sole deciding factor in the management of patients with NMSC. Assessment from a multidisciplinary team (MDT) is crucial, and the decision-making process should consider the patient's lifestyle, needs, and expectations. A comprehensive geriatric assessment should also be considered. Patients should feel empowered to advocate for themselves and have their views considered a part of the MDT discussion., Competing Interests: Declaration of Competing Interest Marthe Verhaert reports that her research institution has received speaker's fees through her from Pfizer, MSD, and Roche. Sandrine Aspeslagh reports being a member of an Advisory Board or Board of Directors for MSD, Sanofi, Roche, BMS, Pfizer, Ipsen, and Galapagos., (Copyright © 2023 Elsevier Ltd. All rights reserved.)