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Introduction: Image guided superficial radiation therapy (IGSRT) is a novel technology which combines traditional superficial radiation therapy (SRT) with high resolution dermal ultrasound (HRDUS) to treat non-melanoma skin cancers (NMSC). Since development, IGSRT use has expanded dramatically in outpatient clinics. We review the IGSRT literature and state-of-the-art operating principles in US dermatologic practices. Methods: A literature search of electronic databases (Medline, Pubmed, Cochrane Library, Science Direct) combined with various authors' published and unpublished documents, procedures, and clinical experience with IGSRT were synthesized for this paper. Results: Studies have demonstrated IGSRT consistently delivers high cure rates (> 99%) with low complications for early stage (stage 0, I, or II) squamous cell and basal cell carcinomas. Control rates are statistically superior to non-image guided SRT and external beam radiation (XRT) as well as Mohs micrographic surgery (MMS). This improvement is attributed to in vivo dermal tumor visualization via HRDUS and using an interdisciplinary approach to deliver care. IGSRT use in the dermatologic clinic for early stage NMSCs has become common practice and continues to expand. Conclusion: While the safety and cosmetic benefits of SRT/XRT have been long documented, IGSRT represents a significant leap forward in efficacy (statistically significant) by adding in vivo dermal tumor imaging. Results rival and appear on one study to surpass tumor control obtained with MMS. A contributing factor to the success may be the availability and use of an interdisciplinary team approach that includes dermatologists, radiation therapists, radiation oncologists, and medical physicists. The high tumor control rates, minimal side effects, favorable cosmesis, and ability to treat multiple lesions per session using IGSRT are establishing this modality as a standard first-line therapy for early stage NMSCs in dermatology clinics. IGSRT may represent the most effective option for the non-surgical treatment of early stage NMSC to date. [ABSTRACT FROM AUTHOR]

Recently, photodynamic therapy (PDT) which involves a photosensitizer (PS), a special drug activated by light, and light irradiation has been widely used in treating various skin diseases such as port-wine stain as well as cancers such as melanoma and non-melanoma skin cancers. PDT comprises two general steps: the introduction of PS into the body or a specific spot to be treated, and the irradiation process using a light source with a specific wavelength to excite the PS. Although PDT is gaining great attention owing to its potential as a targeted approach in the treatment of skin cancers, several limitations still exist for practical use. One of the biggest challenges is the limited penetration of light owing to scattering, reflection, and absorption of light inside the skin layers. In addition, accidental light exposure of the target area causes additional cellular damage, which causes unexpected complications. To solve these issues, we introduced an optical microneedle–lens array (OMLA) to improve the efficiency and safety of PDT treatment. We designed and fabricated a novel optical microneedle–lens array with controlled dimensions to optimize light transmission. In addition, PS was coated uniformly over the tips of the OMLA using the dip coating method. Finally, we confirmed that the PS coated on the OMLA was released into the target area and subsequently generated radical oxygen by light irradiation. We expect that our proposed OMLA for PDT treatment can realize a new light-transmission platform optimized for PDT with targeting various types of skin cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-melanoma skin cancer (NMSC), strongly associated with prolonged ultraviolet (UV) radiation exposure, is the most prevalent type of skin cancer in Caucasians. The present review article summarizes the available evidence on the impact of NMSC incidence and cumulative sun exposure on systemic homeostasis, particularly focusing on oxidative stress, inflammation, and immune system response. Understanding these systemic alterations is crucial for unraveling the systemic burden of NMSC beyond skin damage. This complex interplay highlights the need for comprehensive care, including systemic therapies, effective photoprotection, and the potential role of targeted nutritional interventions to support overall health. The emergence of systemic therapies and photoprotection against non-melanoma skin cancer (NMSC) raises questions on the broader systematic impact of the disease. Personalized medicine involves a holistic patient approach, through which the evaluation of systemic biomarkers can reveal the interconnected aspects of patient health and tailored therapies. Cumulative UV exposure disrupts redox equilibrium and triggers inflammation and cutaneous immunosuppression, processes that contribute independently or via their interplay to cutaneous carcinogenesis. This systemic impact can be further reinforced by biomolecules derived from the NMSC microenvironment, fueling a continuous cycle of oxidative stress and inflammation in the organism. Regarding investigation of the systemic burden of NMSC, we conducted a narrative review focusing on parameters related to redox status, inflammation, and immune suppression observed in the blood components (serum, plasma, and erythrocytes) of NMSC patients. Our findings revealed an association of NMSC patients with perturbations of redox homeostasis, as evidenced by the decreased antioxidant activity, lower levels of non-enzymatic antioxidants, and increased byproducts of lipid, protein, and DNA oxidative damage. Additionally, NMSC patients presented augmented levels of pro-inflammatory interleukins, reduced anti-tumor biomolecule levels, and enhanced immune response markers, as well as elevated vitamin D levels. These systemic changes may lead to the association of NMSC with a higher risk of secondary malignancies in other organs. Overall, the findings of the present study suggest that NMSC affects systemic health beyond the skin, underscoring the need for a comprehensive and individualized approach to the management and monitoring of the patient. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer, particularly cutaneous squamous cell carcinoma (cSCC), is becoming more common, and advanced cases often require complex surgery that can affect both aesthetics and anatomical functionality. Neoadjuvant immunotherapy, which enhances the immune system to fight cancer before surgery, has recently shown promising results in improving outcomes. This systematic review evaluated studies on this topic to describe the efficacy of neoadjuvant immunotherapy in high-risk cSCC. Our review suggests that this approach not only reduces tumor burden but also leads to higher survival rates. However, the development of standardized treatment methods and further studies on this topic are needed to achieve better results in patient therapeutic management and a higher quality of life. Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer with increasing incidence worldwide. High-risk cSCCs often require extensive surgical treatments, which can impair anatomical function and aesthetics. Neoadjuvant immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as cemiplimab and pembrolizumab, has emerged as a promising approach to enhance tumor control and surgical outcomes. We performed a systematic review to evaluate the efficacy and safety of neoadjuvant immunotherapy in high-risk cSCC. Methods: A systematic review and proportional meta-analysis focusing on neoadjuvant immunotherapy for cSCC were conducted following PRISMA guidelines. MEDLINE and Scopus databases were searched up to September 2024 using predefined terms. Recorded findings were pathological/radiological response, 1-year disease-free survival (DFS), and overall survival (OS). Data extraction and risk-of-bias assessment were independently performed by two reviewers. Statistical analysis included fixed- and random-effects models, with heterogeneity assessed using Cochran's Q statistic and the I² index. Results: Nine studies met the inclusion criteria. The pooled pathologic response rate was 72.2% (95% CI: 57.7–84.6), and the radiological response rate was 54.8% (95% CI: 38.6–70.5), with moderate heterogeneity. Pooled 1-year DFS and OS proportions were 91.1% (95% CI: 85.0–95.3) and 90.6% (95% CI: 85.1–95.0), respectively, demonstrating homogeneity across studies. Adverse events were consistent with previously reported immune-related toxicities, with rare severe events. Conclusions: Neoadjuvant immunotherapy is a promising therapeutic strategy for high-risk cSCC, with high pathologic response rates and high survival outcomes. However, standardization of treatment protocols and further trials are needed to optimize efficacy, ensure safety, and assess long-term benefits. [ABSTRACT FROM AUTHOR]

Sunlight exposure plays an important role in human health, impacting processes such as mood, blood pressure regulation, and vitamin D3 production. Solar ultraviolet B radiation initiates vitamin D3 synthesis in the skin, which is subsequently metabolized into its biologically active form. UVB exposure plays a key role in enabling vitamin D3 synthesis, but it can also contribute to skin carcinogenesis, creating a complex interplay between its beneficial and harmful effects. Vitamin D deficiency, affecting over half the global population, is linked to a range of chronic diseases, including cancers, cardiovascular conditions, and autoimmune disorders. Simultaneously, excessive solar UVB exposure increases the risk of non-melanoma and melanoma skin cancers through mechanisms involving DNA damage and oxidative stress. This review examines the dual role of UVB radiation in health and disease, focusing on the mechanisms of cutaneous vitamin D3 synthesis, the epidemiology of skin cancer, and the protective roles of vitamin D3's photoproducts and its active metabolite, 1,25-dihydroxyvitamin D3. Understanding these interconnections is critical for developing strategies that balance adequate sun-induced vitamin D3 production with skin cancer prevention. [ABSTRACT FROM AUTHOR]

Arsenic (As) is a risk factor for non-melanoma skin cancer (NMSC). From a six-year follow-up study on 7000 adults exposed to As, we reported the associations of single-nucleotide variation in tumor tissue and gene expression. Here, we identify the associations of small deletions (DELs) and transcriptomic profiles in NMSC. Comparing the (a) NMSC tissue (n = 32) and corresponding blood samples from each patient, and (b) an independent set of non-lesional, healthy skin (n = 16) and paired blood, we identified NMSC-associated DELs. Differential expressions of certain gene pathways (TGF-β signaling pathway, IL-17 pathway, PD-L1 pathway, etc.) showed significant interactions with these somatic DELs and As exposure. In low-As-exposure cases, the DELs in APC were associated with the up-regulation of inflamed T-Cell-associated genes by a fold change (FC) of 8.9 (95% CI 4.5–17.6), compared to 5.7 (95% CI 2.9–10.8) without APC DELs; in high-As-exposure cases, the APC DELs were associated with an FC of 5.8 (95% CI 3.5–9.8) compared to 1.2 (95% CI −1.3 to 1.8) without APC DELs. We report, for the first time, the significant associations of somatic DELs (many in STR regions) in NMSC tissue and As exposure with many dysregulated gene pathways. These findings may help in selecting groups of patients for potential targeted therapy like PD-L1 inhibitors, IL-17 inhibitors, and TGF-β inhibitors in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides an overview of therapeutic approaches for advanced basal cell carcinoma (BCC), focusing on both locally advanced (laBCC) and metastatic (mBCC) disease. It entails a general overview of advanced BCC management and outlines approved systemic therapies, including hedgehog inhibitors (HHI) and immunotherapy. The review also explores ongoing research regarding emerging treatment strategies. Basal cell carcinoma (BCC) accounts for 80% of skin cancer cases. Although mostly curable by simple excision, the treatment of advanced disease can be challenging, as curative surgery or radiotherapy may not always be feasible. The scope of this review is to summarize current knowledge on molecular mechanisms in BCC pathogenesis, to elaborate on the definition of advanced/difficult-to-treat BCC, and to outline systemic treatment options. Particularly, pivotal trial data of the approved hedgehog inhibitors (HHI) sonidegib and vismodegib are compared. Concluding, we provide an overview of novel, particularly neoadjuvant and combined treatment approaches, both with hedgehog and immune-checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: Novel and highly effective drugs for non-melanoma skin cancer (NMSC) improve patient outcomes, but their high cost strains healthcare systems. Spain's decentralized public health system, managed by 17 autonomous communities (AaCc), raises concerns about equitable access. Methods: A cross-sectional survey (July–September 2023) was sent to Spanish Multidisciplinary Melanoma Group (GEM Group) members to assess access to new drugs. Findings: Fifty physicians from 15 Spanish AaCc responded to the survey. Access for drug with approved public reimbursement, Hedgehog inhibitors in basal-cell carcinoma and anti PD-L1 antibody in Merkel carcinoma, was observed in 84% and 86% of centers, respectively. For other EMA-approved treatments, but without reimbursement in Spain access decreased to 78% of centers. Heterogeneity in access was mainly observed intra regions. Conclusion: Unequal financial support for drugs for NMSC with creates a patchwork of access across Spanish hospitals, with variations even within the same AaCc. [ABSTRACT FROM AUTHOR]

Abstract Inflammatory bowel disease (IBD) is a multisystem condition that could affect the cutaneous systems, namely cutaneous extraintestinal manifestations (EIMs). It has been suggested that IBD is associated with erythema nodosum (EN), malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, the potential causal relationship between IBD and the mentioned above cutaneous EIMs is still unclear. This study aims to determine the effect of IBD on EN, MM and NMSC within a Mendelian randomization (MR) design. Summary-level data for IBD, EN, MM, NMSC were obtained from large-scale genome-wide association studies. We utilized five different methods, including the inverse variance weighted model (IVW), MR Egger, Weighted median, Simple mode, Weighted mode in the MR analysis, then the Cochran’s Q test, the MR-Egger pleiotropy test, the MR-PRESSO global pleiotropy test and leave-one-out sensitivity test were used to evaluate the heterogeneity and pleiotropy of identified IVs. To further ensure the validity of our findings, we evaluated the strength of the instrumental variables using the F-statistic and estimated the statistical power of our study. Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. MR analysis suggested that genetically determined IBD had a detrimental causal effect on NMSC (IVW: odds ratio [OR] = 1.002037, 95% confidence interval [CI] = 1.0001150–1.003962, P = 0.03776677), but not on EN (IVW: [OR] = 1.0937191, 95% [CI] = 0.9685831–1.235022, P = 0.1484349) and MM (IVW: [OR] = 0.9998064, 95% [CI] = 0.9994885–1.000124, P = 0.2326482). Besides, a positive causal effect of IBD on NMSC was verified in an independent validation dataset (IVW: [OR] = 1.002651, 95% [CI] = 1.0006524–1.004654, P = 0.009307506). The present study corroborated the causal relationship between IBD and NMSC. In contrast, our results showed no evidence of a causal association of IBD on EN and MM. These findings provide new insights into increasing attention to patients with IBD to prevent concurrent NMSC.

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are highly prevalent and a significant cause of morbidity. Image-guided superficial radiation therapy (IGSRT) uses integrated high-resolution dermal ultrasound to improve lesion visualization, but it is unknown whether efficacy varies by histology. This large retrospective cohort study was conducted to determine the effect of tumor histology on freedom from recurrence in 20,069 biopsy-proven NMSC lesions treated with IGSRT, including 9928 BCCs (49.5%), 5294 SCCs (26.4%), 4648 SCCIS cases (23.2%), and 199 lesions with ≥2 NMSCs (1.0%). Freedom from recurrence at 2, 4, and 6 years was 99.60%, 99.45%, and 99.45% in BCC; 99.58%, 99.49%, and 99.49% in SCC; and 99.96%, 99.80%, and 99.80% in SCCIS. Freedom from recurrence at 2, 4, and 6 years following IGSRT did not differ significantly comparing BCC vs. non-BCC or SCC vs. non-SCC but were slightly lower among SCCIS vs. non-SCCIS (p = 0.002). There were no significant differences in freedom from recurrence when stratifying lesions by histologic subtype. This study demonstrates that there is no significant effect of histology on freedom from recurrence in IGSRT-treated NMSC except in SCCIS. These findings support IGSRT as a first-line therapeutic option for NMSC regardless of histology.

Objectives: Skin cancer accounts for 2.2% of newly diagnosed cancer cases in Saudi Arabia, according to the Saudi Cancer Registry 2020. While studies indicate skin cancers primarily occur in the extremities, head, neck and mucosal regions, comprehensive data on prevalence, mortality, morbidity, treatment modalities and overall burden in Saudi Arabia are lacking. This scoping review aimed to analyze existing literature on skin cancer within the Saudi population, assess its prevalence and potential risk factors and identify knowledge gaps. We systematically searched PubMed, Web of Science, SCOPUS and Science Direct databases, utilizing the Rayyan QCRI tool for data organization and synthesis. The review included 15 studies encompassing 2,596 patients, of whom 1,378 (56.2%) were male. Our analysis revealed basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma as the most common types. BCC and SCC predominantly affected the head and neck, while melanoma more often impacted the extremities. Surgical intervention was the primary treatment approach. Key risk factors identified included occupational pesticide exposure, UV radiation susceptibility and genetic predisposition. This review highlights the need for a comprehensive nationwide screening program to evaluate the prevalence of skin-related issues in Saudi Arabia and address the identified knowledge gaps in skin cancer epidemiology and management. [ABSTRACT FROM AUTHOR]

Background/Objectives: Chronic inflammation and psychosocial factors significantly influence cancer progression and patient behavior in seeking medical care. Understanding their interplay is essential for enhancing early detection and developing personalized treatment strategies. This study aims to develop a comprehensive patient profiling model by comparing non-melanoma skin cancer (NMSC) and colorectal cancer (CRC). The goal is to identify common and distinct patterns in inflammation and psychosocial factors that affect disease progression and clinical presentation. Methods: We conducted a comparative analysis of patients diagnosed with NMSC and CRC, integrating clinical data with sociodemographic and psychological assessments. Advanced neural network algorithms were employed to detect subtle patterns and interactions among these factors. Based on the analysis, a cancer risk assessment questionnaire was developed to stratify patients into low-, moderate-, and high-risk categories. Results: Patients with low systemic inflammation and adequate vagal tone, supported by a stable family environment, demonstrated heightened sensitivity to subclinical symptoms, enabling earlier diagnosis and timely intervention. Conversely, patients with high systemic inflammation and reduced vagal tone, often influenced by chronic stress and unstable family environments, presented at more advanced disease stages. The developed risk assessment tool effectively classified patients into distinct risk categories, facilitating targeted preventive measures and personalized therapeutic strategies. Neural network profiling revealed significant interactions between biological and psychosocial factors, enhancing our understanding of their combined impact on cancer progression. Conclusions: The integrated profiling approach and the newly developed risk assessment questionnaire have the potential to transform cancer management by improving early detection, personalizing treatment strategies, and addressing psychosocial factors. This model not only enhances clinical outcomes and patient quality of life but also offers a framework adaptable to other cancer types, promoting a holistic and patient-centered approach in oncology. [ABSTRACT FROM AUTHOR]

Simple Summary: Image-guided superficial radiation therapy (IGSRT) is an emerging treatment option for non-melanoma skin cancers (NMSCs). The aim of this retrospective cohort study was to assess if there are relationships between patient comorbidities or socioeconomic status (SES) and outcomes from IGSRT treatment for their NMSCs. Data from 19,988 NMSCs revealed no difference in freedom from recurrence in less vs. more deprived neighborhoods (as a measurement of SES) or in patients without comorbidities vs. with many and/or severe comorbidities. This supports the use of IGSRT regardless of SES or comorbidities. Background: Non-melanoma skin cancers (NMSCs) are the most common cancers in the United States. Image-guided superficial radiation therapy (IGSRT) is an effective treatment for NMSCs. Patient comorbidities and socioeconomic status (SES) are known contributors to health disparities. However, the impact of comorbidities or SES on the outcomes of IGSRT-treated NMSCs has not yet been studied. This study evaluated freedom from recurrence in IGSRT-treated NMSCs stratified by SES and the number of comorbidities. Methods: This large retrospective cohort study evaluated associations between SES (via Area Deprivation Index (ADI)) or comorbidity (via Charlson Comorbidity Index (CCI)) and 2-, 4-, and 6-year year freedom from recurrence in patients with IGSRT-treated NMSC (n = 19,988 lesions). Results: Freedom from recurrence in less (ADI ≤ 50) vs. more (ADI > 50) deprived neighborhoods was 99.47% vs. 99.61% at 6 years, respectively (p = 0.2). Freedom from recurrence in patients with a CCI of 0 (low comorbidity burden) vs. a CCI of ≥7 (high comorbidity burden) was 99.67% vs. 99.27% at 6 years, respectively (p = 0.9). Conclusions: This study demonstrates that there are no significant effects of SES or comorbidity burden on freedom from recurrence in patients with IGSRT-treated NMSC. This supports the expansion of IGSRT in deprived neighborhoods to increase access to care, and IGSRT should be a consideration even in patients with a complex comorbidity status. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are highly prevalent and a significant cause of morbidity. Image-guided superficial radiation therapy (IGSRT) uses integrated high-resolution dermal ultrasound to improve lesion visualization, but it is unknown whether efficacy varies by histology. This large retrospective cohort study was conducted to determine the effect of tumor histology on freedom from recurrence in 20,069 biopsy-proven NMSC lesions treated with IGSRT, including 9928 BCCs (49.5%), 5294 SCCs (26.4%), 4648 SCCIS cases (23.2%), and 199 lesions with ≥2 NMSCs (1.0%). Freedom from recurrence at 2, 4, and 6 years was 99.60%, 99.45%, and 99.45% in BCC; 99.58%, 99.49%, and 99.49% in SCC; and 99.96%, 99.80%, and 99.80% in SCCIS. Freedom from recurrence at 2, 4, and 6 years following IGSRT did not differ significantly comparing BCC vs. non-BCC or SCC vs. non-SCC but were slightly lower among SCCIS vs. non-SCCIS (p = 0.002). There were no significant differences in freedom from recurrence when stratifying lesions by histologic subtype. This study demonstrates that there is no significant effect of histology on freedom from recurrence in IGSRT-treated NMSC except in SCCIS. These findings support IGSRT as a first-line therapeutic option for NMSC regardless of histology. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated tertiary lymphoid structures (TLSs) are functional immune-responsive aggregates, which have been reported to be associated with better prognosis in various tumors. However, their exact characteristics and prognostic value in extramammary Paget's disease (EMPD) remain unknown. Objective: To explore the features of TLSs in EMPD and their association with clinicopathological characteristics. Methods: In total, 171 EMPD patients from 2015 to 2023, retrospective, single center cohort were collected to assess the presence, maturation status, and location of TLSs by immunohistochemistry. Then, their clinicopathologic association and prognostic significance were further examined. Results: TLSs were detected in 97 cases (57%) of 171 EMPD patients, including high-density TLSs in 88 cases (91%), peritumoral TLSs (pTLSs) in 89 cases (92%), TLSs around appendages (aTLSs) in 23 cases (24%), and mature TLSs in 16 cases (16%). Secondary EMPD was more likely to produce TLS (Secondary: 16/21 [76%]; Primary: 81/150 [54%]; P = 0.06), and more likely to produce Mature TLS (Secondary: 5/10 [50%]; Primary: 11/80 [14%]; P = 0.02). The subjective symptoms of EMPD patients did not seem to correlate with the presence of TLS. EMPD patients with tumor invasion were more likely to form mature TLS (Invasion: 8/32 [25%]; In situ : 8/65 [12%]; P = 0.06), recurrent EMPD patients were more likely to form TLS (Recurrent: 34/50 [68%]; Initial: 63/121 [52%]; P = 0.06) especially mature TLS (Recurrent: 8/34 [24%]; Initial: 8/63 [13%]; P = 0.04). The depth of tumor invasion in EMPD patients with mature TLS was mostly less than or equal to 4mm (mature TLS+: 7/8 [88%]; TLS-: 6/17 [35%]; P = 0.05), aTLS were less common in EMPD patients with skin appendage invasion (aTLS+: 4/23 [17%]; aTLS-: 32/74 [43%]; P = 0.03). The same EMPD patients relapse after, the existence of TLS increased [TLS+ (initial): 9/17 (53%); TLS+ (recurrence):14/17 (82%); P =.07]. Limitations: Retrospective study design. Conclusions: Mature TLS is a positive prognostic factor for invasive EMPD and may serve as a new biomarker and therapeutic target for EMPD. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancer (NMSC) mainly includes basal cell carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma, showing a low mortality rate but the highest incidence worldwide. In recent decades, research has focused on understanding the pathogenesis and clinical treatments of NMSC, leading to significant advances in our knowledge of these diseases and the development of novel therapies, including immunotherapy. Nevertheless, the low to moderate objective response rate, high recurrence, and therapeutic resistance remain persistent challenges, which are partly attributable to the intratumoral heterogeneity. This heterogeneity indicates that tumor cells, immune cells, and stromal cells in the tumor microenvironment can be reshaped to a series of phenotypic and transcriptional cell states that vary in invasiveness and treatment responsiveness. The advent of single-cell RNA sequencing (scRNA-seq) has enabled the comprehensive profiling of gene expression heterogeneity at the single-cell level, which has been applied to NMSC to quantify cell compositions, define states, understand tumor evolution, and discern drug resistance. In this review, we highlight the key findings, with a focus on intratumoral heterogeneity and the mechanism of drug resistance in NMSC, as revealed by scRNA-seq. Furthermore, we propose potential avenues for future research in NMSC using scRNA-seq. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to provide an overview and analysis of the global disease burden of non-melanoma skin cancer using data from the Global Burden of Disease 2019 (GBD 2019) database. Material and methods: This study utilized the global GBD 2019 disease data. The data were categorized into various subgroups based on region, sociodemographic index (SDI), country, gender, and age. We analyzed incident cases, incidence rate, disability-adjusted life years (DALYs), DALY rate, as well as age-standardized indicators and their annualized percent change (EAPC). Results: The global burden of non-melanoma skin cancer exhibited an increasing trend from 1990 to 2019. The EAPC for the age standardized incidence rate (ASIR) was 1.13, and the EAPC for the age standardized DALY rate was 0.20. Geographic variations were observed, with the most substantial increase in ASIR observed in high-income North America (EAPC = 2.20), and a significant increase in the age standardized DALY rate in Central Asia (EAPC = 2.32). Countries with a high SDI had the highest ASIR and showed the most significant increasing trend (EAPC = 1.97). Overall, the burden of disease for nonmelanoma skin cancer increased in all countries globally from 1990 to 2019. The EAPC for incident cases, DALYs, and ASIR was greater than 0 in almost all countries worldwide, indicating an overall increasing trend. Conclusions: The global disease burden of non-melanoma skin cancer ex-hibited significant increasing changes from 1990 to 2019. Several countries in Asia, Africa, and North America experienced a severe disease burden. [ABSTRACT FROM AUTHOR]

Simple Summary: This case series study evaluates the use of reflectance confocal microscopy (RCM) for assessing treatment outcomes after superficial radiation therapy (SRT) in managing localized non-melanoma skin cancer (NMSC). Conducted between March 2020 and December 2023, this study included 29 patients with 38 lesions. Following RCM diagnosis, the patients underwent SRT, and outcomes were assessed at six months using RCM and clinical evaluation. The results showed 100% tumor clearance with no residual activity observed upon conducting follow-up RCM. Clinically, scarring and mild erythema were observed, with moderate to severe inflammation in six lesions. While the generalizability of the results of our study is limited by the size of the study population, our findings suggest that RCM and SRT may be effective in managing localized NMSC non-invasively, potentially offering an alternative to traditional surgical methods, particularly for elderly or surgically unsuitable patients. Background: Traditional treatment methods for non-melanoma skin cancer (NMSC) include surgical excision with histological evaluation, yet advancements such as reflectance confocal microscopy (RCM) and superficial radiation therapy (SRT) offer non-invasive management alternatives. This study aims to evaluate the use of RCM for the evaluation of treatment outcomes after SRT in managing localized NMSC. Methods: A prospective interventional case series study was conducted on patients treated for NMSC with SRT between March 2020 and December 2023. Suspected NMSC lesions were initially evaluated with a handheld dermoscope and then imaged at multiple depths using a VivaScope 1500 RCM. Two dermatologists trained in RCM reviewed the images. Confirmed NMSC lesions were biopsied and treated with SRT, followed by RCM imaging at six months post-treatment to assess cancer clearance, scarring, and inflammation. Results: Of the 38 lesions (composed of SCC (24) and BCC (14)) treated affecting the 29 patients, all lesions showed no residual tumor activity upon conducting follow-up RCM (100% clearance). Scarring and mild erythema were noted clinically. Six lesions demonstrated moderate to severe inflammation at a 6-month follow-up. Conclusions: This study demonstrates successful non-invasive management of localized NMSC using RCM and SRT. RCM was able to non-invasively demonstrate complete tumor clearance achieved by SRT with minimal adverse effects. These findings support considering the use of RCM and SRT as primary diagnostic, monitoring, and treatment options for NMSC without the need for biopsies, especially for elderly patients or those unsuitable for surgery due to medical conditions. [ABSTRACT FROM AUTHOR]

The non-melanoma skin cancers (NMSC) basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) account for the vast majority of global skin cancer diagnoses. Although mortality rate is low, tumour burden can cause significant morbidity from local compression and invasion. Aetiological factors include external influences, namely exposure to UV radiation as well as other carcinogens and individual predisposition to susceptibility from these external factors. Management consists mainly of surgical excision or one of numerous non-surgical methods, the choice of which should be tailored to individual tumour and patient factors. Newer immunological therapies may have a role in advanced or refractory cases. Guidance for management of NMSC in the United Kingdom (UK) is provided by the British Association of Dermatologists. [ABSTRACT FROM AUTHOR]

Purpose: Hydrochlorothiazide (HCTZ) exposure has been linked to increased skin cancer in Caucasian (white) populations, especially squamous cell carcinoma (SCC), but not basal cell carcinoma (BCC). This study aimed to evaluate and compare skin cancer risks associated with HCTZ‐ and other antihypertensives use. Methods: This retrospective cohort study utilized Taiwan's National Health Insurance Research Database. We identified patients aged 20 years and older, newly receiving antihypertensive medications between 2004 and 2015. We calculated the medication possession ratio (MPR) for the first 2 years of treatment to determine patient eligibility and treatment classification, whereby only patients with MPR above 80% were included. These were subsequently categorized by the type of antihypertensives they received, namely HCTZ, other thiazide diuretics, non‐thiazide diuretics or non‐diuretic antihypertensives. Cox proportional hazards model was used to evaluate skin cancer risks, and these were then classified as SCC or BCC. Results: Our study included 41 086, 27 402, 19 613, and 856 782 patients receiving HCTZ, other thiazide diuretics, non‐thiazide diuretics, and non‐diuretic antihypertensives, respectively. We found BCC risks were similar when comparing HCTZ with other thiazides (adjusted hazard ratio: 0.84; 95% CI: 0.54–1.33), non‐thiazide diuretics (0.93; 0.51–1.67), and non‐diuretic antihypertensives (0.91; 0.66–1.26). We observed a higher SCC risk in the HCTZ group, compared to other thiazides (1.24; 0.74–2.08), non‐thiazide diuretics (1.32; 0.70–2.51), and non‐diuretic antihypertensives (1.23; 0.87–1.73), although the confidence intervals (CIs) were wide and crossed the null. Conclusions: We concluded that skin cancer need not be of major concern to physicians when prescribing antihypertensives for an Asian population. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), are increasingly common and present significant healthcare challenges. Neutrophil extracellular traps (NETs), chromatin fibers expulsed by neutrophil granulocytes, can promote immunotherapy resistance via an impairment of CD8+ T cell-mediated cytotoxicity. Here, to identify a potential therapeutic target, we investigate the expulsion of NETs and their relation to CD8+ T cell infiltration in NMSC. Immunofluorescence staining for neutrophils (CD15) and NETs (H3cit), as well as immunohistochemistry for cytotoxic T cells (CD8+) on human cSCCs (n = 24), BCCs (n = 17) and MCCs (n = 12), revealed a correlation between neutrophil infiltration and ulceration diameter in BCC and MCC, but not in cSCC. In BCC and cSCC, neutrophil infiltration also correlated with the cross-sectional area (CSA). NETs were not associated with established risk factors but with the presence of an ulceration, and, in cSCC, with abscess-like structures. CD8+ T cell infiltration was not reduced in tumors that were NET-positive nor in those with a denser neutrophil infiltration. This study is the first to report and characterize NETs in NMSC. Thus, it gives an incentive for further research in this relevant yet understudied topic. [ABSTRACT FROM AUTHOR]

Background/Objectives: Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are non-melanoma skin cancers (NMSCs) and the most prevalent cancers in the United States. Image-guided superficial radiotherapy (IGSRT) is a relatively new treatment option that uses high-resolution dermal ultrasound integrated with superficial radiotherapy to improve tumor visualization. IGSRT is a clinically equivalent non-surgical alternative to Mohs micrographic surgery at 2 years of follow-up in early-stage NMSC, but larger cohort studies with longer follow-up periods that allow for analysis of patient outcomes by demographic and disease characteristics are needed. Methods: This large, retrospective cohort study was conducted to determine the effect of risk factors (tumor location, tumor stage, and sex) on 2-, 4-, and 6-year freedom from recurrence rates in 19,988 NMSC lesions treated with IGSRT, including lesions with complete treatment courses. Results: Overall freedom from recurrence rates were 99.68% at 2 years, 99.54% at 4 years, and 99.54% at 6 years; rates did not differ significantly by tumor location (head/neck versus other locations, p = 0.9) or sex (male versus female, p = 0.4). In contrast, there was a significant difference in freedom from recurrence rates when analyzed by tumor stage (p = 0.004). Conclusions: There was no significant effect of tumor location or sex on freedom from recurrence in IGSRT-treated NMSC. Although there was a significant difference according to tumor stage, freedom from recurrence rates exceeded 99% at all stages. [ABSTRACT FROM AUTHOR]

Background: Basal Cell Carcinoma (BCC) is the most common type of skin carcinoma and is considered an epidemic disease due to its increasing frequency in many countries. The most important problem of BCC is local invasion It grows in a "silent" way into immediately adjacent tissue. It rarely metastasizes. The early tumors are commonly small, translucent or pearly, raised and rounded areas located on a few dilated, superficial vessels. There are six subtypes of BCC that include nodular, pigmented, superficial, morphea form, cystic. The most important risk factor for basal cell carcinoma is exposure to UV-radiation. Outdoor workers with a long history of workrelated UV-exposure are at increased risk of developing BCC. Other risk factors include family history of skin carcinoma, light skin phototypes, advanced age. Objective: The current study investigated pathological and histological changes in tissue sections to identify the factors contributing to the infection frequency. Patients and Methods: Thirty-three BCC patients' samples have been collected from the main care center at al-Baquba Teaching Hospital of Diyala Province, Iraq. All patient groups were clinically diagnosed as BCC by dermatologists. Results: The study showed macroscopic and microscopic histological changes. An ulcerated macroscopic appearance of the lesion was shown. The tumor lesions are located on the face. It was noted that the percentage of patients was higher in men than women and higher in light skin than dark skin. The study also showed that the age group 66-74 years had a higher infection percentage, while the lower percentage was of the age group > 83 years. Conclusion: These findings pave the way for future research endeavors aimed at prevention, early detection, and targeted treatment strategies for this prevalent skin carcinoma. [ABSTRACT FROM AUTHOR]

Vismodegib and sonidegib are smoothened (SMO) inhibitors approved for the treatment of advanced basal cell carcinoma (aBCC). This study investigates the real-world experiences and outcomes associated with these therapies across multiple Italian centers. A retrospective, observational, multicenter study was conducted. Medical records of patients with local advanced basal cell carcinoma (laBCC) treated with SMO inhibitors outside of clinical trials from July 2019 to April 2024 were analyzed. A total of 57 patients were included in the study, with 19 (33.3%) receiving vismodegib and 38 (66.7%) receiving sonidegib. Vismodegib demonstrated a complete response (CR) in 31.6% of cases and a partial response (PR) in 26.3%. Sonidegib achieved a CR of 47.4% and a PR of 36.8%. The median treatment duration was 8 months for vismodegib and 12 months for sonidegib. Adverse events were more frequently reported with vismodegib. Treatment interruption due to adverse events occurred in 47.4% of vismodegib recipients and in 13.2% of those receiving sonidegib. The progression of the disease under treatment occurred in 7.9% of cases of patients under sonidegib and in 26.3% of cases under vismodegib. *************************************************************** *Appendix Authors list Valentina Benzecry Mancin,1 Veronica Benzi,2 Matteo Bianco,2,3 Alessandra Bulotta,4 Antonio Costanzo,2,3 Giuseppe Damiano,5 Nerina Denaro,6 Laura Eibenschutz,7 Barbara Merelli,8 Giulia Murgia,1 Alessandra Narcisi,3 Emanuela Passoni,1 Francesco Piscazzi,2,3 Vincenzo Russo5 1Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan; 2Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan; 3Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan; 4Department of Oncology, IRCCS San Raffaele, Milan; 5Unit of Immuno-Biotherapy of Melanoma and Solid Tumors, IRCCS Ospedale San Raffaele, Milan; 6Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan; 7Oncologic and Preventive Dermatology Unit, IFO-San Gallicano Dermatological Institute IRCCS, Rome; 8Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy

Abstract Background Skin cancer is the most common form of cancer in Ireland with over 13,000 new cases diagnosed annually. People with inflammatory bowel disease are at higher risk of developing skin cancer. Objectives The aim of this study is to assess inflammatory bowel disease (IBD) patients' awareness around skin cancer risk and photoprotection practices and to identify gaps in patient education regarding skin cancer prevention in IBD patients. Methods IBD patients >18 years old were invited to fill out a questionnaire while waiting for their outpatient appointment. Results A total of 87 patients (52% women) with IBD (Crohn's disease 62.8%, UC 35%,) were included. A total of 38 patients were diagnosed before age 25 (44%). Most patients were on active treatment for their IBD (96.5%, n = 85). Four patients had a personal history, and seven patients had a family history of skin cancer. Nearly half of participants (47.6%) were unaware or unsure of an increased risk of skin cancer associated with IBD and 42.5% were unaware or unsure of an increased risk with some IBD treatments. Behaviours around sun‐cream were generally good, however, other sun protective methods were suboptimal. Conclusions Only half (52.4%) of IBD patients surveyed were aware of a link between skin cancer and IBD. Skin cancer knowledge was generally good, however, photoprotection practices were suboptimal. This underscores the role of healthcare professionals in re‐enforcing sun safety information and skin cancer education in the IBD population.

Image-guided superficial radiation therapy (IGSRT) combines superficial radiation therapy (SRT) with full dermal visualization (FDV) via high-resolution dermal ultrasound (HRDUS) for the treatment of non-melanoma skin cancer (NMSC). The gold standard for IGSRT delivery includes a comprehensive cancer care model with support for dermatologists from a multidisciplinary team. When delivered in this model, IGSRT can achieve cure rates of 99% for treatment of NMSC. This paper focuses on the benefits of HRDUS used in conjunction with SRT for NMSC. Medical records from 7 dermatology clinics of 883 patients with 1507 cases of NMSC treated with IGSRT between 2017 and 2018 were retrospectively reviewed. In total, 92% of the NMSC lesions showed daily depth fluctuations, 60.32% of lesions did not require changes during therapy, and nearly 40% of lesions required at least one compensatory change during therapy. In total, 83% of NMSC lesions were labeled as high risk based on the 2024 NCCN guidelines. Increasing and decreasing tumor depth measurements during IGSRT inform dermatologists when adaptive changes in energy (kV), TDF, and dose will result in more efficacy and less toxicity, respectively.

Simple Summary: This research explored a new method to evaluate surgical margins when removing non-melanoma skin cancer, aiming to reduce the time patients need to stay in the hospital. Typically, surgeons use 3D histology to ensure all cancer tissues have been removed, but this process is time-consuming. This study suggests using ex vivo reflectance confocal microscopy (evRCM), which allows for quicker margin assessments. While evRCM showed high accuracy in confirming cancer-free areas, it was not as effective in detecting small remaining cancer cells as histology. Despite this limitation, evRCM significantly reduced patients' time in the hospital. These findings suggest that evRCM could become a valuable tool for improving the speed and accuracy of skin cancer surgery; however, its effectiveness is limited. Close collaboration between surgeons and pathologists is mandatory to achieve good patient outcomes. Background/Objectives: To ensure that non-melanoma skin cancer (NMSC) is completely removed in healthy tissue, micrographically controlled surgery (3D histology) is often performed, which can prolong the inpatient stay. This study examined ex vivo reflectance confocal microscopy (evRCM) for perioperative assessment of surgical margins, specifically in cases where re-excision was necessary due to incomplete removal of cutaneous tumor tissue. Methods: NMSC re-excisions were evaluated using evRCM by a cutaneous surgeon, with retrospective review by an independent pathologist when results differed from histology. Results: evRCM demonstrated high specificity (0.96; 95% CI, 0.90–0.99) but low sensitivity (0.20; 95% CI, 0.06–0.51). Unlike pathology, which discards outer surgical margins, evRCM examined the true surgical margins. Retrospective pathology analysis of the misdiagnosed cases confirmed that 25% (n = 2/8) were false negative and 75% (n = 6/8) were potentially false positive, resulting in a sensitivity of 0.2–0.8. Notably, evRCM led to a 113-day reduction in in-hospital stays, probably resulting in increased patient satisfaction and cost-effectiveness. Conclusions: evRCM was valuable for speeding up the assessment of surgical margins in patients with re-excised NMSC. Proper tissue preparation and assessment require interdisciplinary collaboration between cutaneous surgeons, pathologists, and physician assistants, emphasizing the need for standardized operating procedures. [ABSTRACT FROM AUTHOR]

Background: Innovative treatments for non‐melanoma skin cancers (NMSCs) are required to enhance patient outcomes. Aims: This review examines the effectiveness and safety of receptor tyrosine kinase inhibitors (RTKIs). Methods: A comprehensive review was conducted on the treatment potential of several RTKIs, namely cetuximab, erlotinib, gefitinib, panitumumab, and lapatinib. Results: The findings indicate that these targeted therapies hold great promise for the treatment of NMSCs. However, it is crucial to consider relapse rates and possible adverse effects. Further research is needed to improve treatment strategies, identify patient groups that would benefit the most, and assess the long‐term efficacy and safety, despite the favorable results reported in previous studies. Furthermore, it is crucial to investigate the potential benefits of integrating RTKIs with immunotherapy and other treatment modalities to enhance the overall efficacy of therapy for individuals with NMSC. Conclusions: Targeted therapies for NMSCs may be possible with the use of RTKIs. The majority of studies focused on utilizing epidermal growth factor receptor inhibitors as the primary class of RTKIs for the treatment of NMSC. Other RTKIs were only employed in experimental investigations. Research indicates that RTKIs could potentially serve as a suitable alternative for elderly patients who are unable to undergo chemotherapy and radiotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Actinic keratoses (AKs) are rough, scaly patches from UV exposure, increasing the risk of non-melanoma skin cancer (NMSC). This study examines AK incidence in Korea and its role as a risk factor for NMSC. Methods: A retrospective nationwide register-based cohort study analyzed 2,917 AK patients and 14,585 controls from 2002 to 2019. Patients diagnosed with AK were followed until NMSC occurrence, death, emigration, or December 2019. Results: AK incidence reached 44.8 per 100,000 person-years in 2019. The adjusted hazard ratio for NMSC in AK patients was 8.91 (95% confidence interval, 5.72–13.90). Higher NMSC risk was observed in female AK patients, those under 60 years, and those with lower income levels. The 16-year cumulative incidence of NMSC was 4.19% in AK patients versus 0.44% in controls. Conclusion: AK significantly increases the risk of NMSC in Koreans, highlighting the need for tailored surveillance and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Skin cancer shows geographic and ethnic variation. New Zealand—with a predominantly fair-skinned populations, high UV indices and outdoor lifestyles—has high rates of skin cancer. However, population prevalence data is lacking. This study aimed to determine the demographics and socioeconomic disease trends of non-melanoma skin cancer prevalence in New Zealand from a large targeted-screening study. Methods: A targeted screening programme was conducted among 32,839 individuals, Fitzpatrick Skin Types I to IV in Auckland, New Zealand during the 2008–2022 period. This data was analyzed retrospectively. Linear regression models were used to assess statistical trends of skin cancer prevalence over time, along with associated factors that included demographics, disease trends and overall prevalence. Results: A total of 32,839 individuals were screened and 11,625 skin cancers were detected. 16,784 individuals were females who had 4,378 skin cancers. 16,055 individuals were males who had 5,777 skin cancers. 54 males and 65 females had multiple skin cancers. The article presents detailed descriptions of tumour types and subtypes detected, age groups, demographic and socioeconomic information. regarding the non-melanoma skin cancers detected. Conclusion: Overall men have more non-melanoma skin cancer (NMSC) than females; however females develop more BCC on the lips. BCC is three times more common in the 31-50 age group, whereas SCC are significantly more prevalent after age 80. Prevalence of BCC has not changed over the 15-year timeframe of the study but SCC has increased. Older ages and higher incomes are associated with higher rates of NMSC in New Zealand. [ABSTRACT FROM AUTHOR]

Purpose: Long‐term use of hydrochlorothiazide increases the risk of non‐melanoma skin cancer. We aimed to evaluate potential changes in the use of hydrochlorothiazide in Switzerland after a direct healthcare professional communication (DHPC) in November 2018 by Swissmedic. Methods: We performed interrupted time‐series analyses using a large Swiss healthcare claims database (2015–2021). Within monthly intervals, we quantified the total number of claims and the total dispensed 'defined daily doses' (DDD) for preparations containing (1) hydrochlorothiazide, (2) angiotensin‐converting enzyme (ACE) inhibitors and angiotensin‐II‐receptor blockers (ARB), (3) calcium‐channel blockers (CCB) and (4) thiazide‐like diuretics per 10 000 persons. Using segmented linear regression, we quantified the pre‐DHPC trend, the immediate change and the post‐DHPC change in trend for total claims and DDD for the four drug classes weighted for the demographic distribution of the Swiss population. Results: ACE inhibitors and ARB were the most frequently claimed antihypertensive drugs with 300–400 claims per 10 000 persons, which increased by 5.4% during the study period. The average number of hydrochlorothiazide claims (157/10 000 persons in 2015) declined by 35% between 2015 and 2021. The decrease started prior to the DHPC, but the DHPC was associated with an immediate 6.1% decline and an accelerated decline in claims over time after the DHPC (similar results for DDD). This coincided with a 23% increase in claims of CCB (dihydropyridine type) over 7 years, whereas use of other antihypertensives increased less. Conclusion: Our results suggest that the DHPC by Swissmedic in 2018 accelerated a pre‐existing decline in the use of hydrochlorothiazide in Switzerland. [ABSTRACT FROM AUTHOR]

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-epi and publicly available human and/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity, while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPARδ has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs. [ABSTRACT FROM AUTHOR]

Since the scrotum is rarely exposed to sunlight, basal cell carcinoma (BCC) development in this area is an uncommon occurrence. As result, there is a scarcity of research covering this particular presentation, which poses a diagnostic and therapeutic challenge for clinicians. The objective of this systematic review is to provide a thorough overview of scrotal BCC, including a summary of its clinical characteristics, and microscopic subtypes. It also seeks to discuss the many techniques used in the management of this uncommon clinical presentation. Utilizing data from 1957 to October 2023, a systematic review of PubMed and Wiley Online Library was conducted to identify all cases of scrotal BCC with various presentations and managements. A total of 73 patients were included. The median patient age was 65.9 years (range 42 to 87). All studies were either case reports or case series. Our review shows that treatment with Mohs micrographic surgery (MMS), leads to a superior patient outcome based on anecdotal evidence in select cases. To deepen our understanding of Mohs surgery’s efficacy in treating scrotal BCC, it is imperative to conduct more robust research in the form of randomized clinical trials. [ABSTRACT FROM AUTHOR]

The keratinocyte carcinomas, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC), are the most common cancers in humans. Recently, an increasing body of literature has investigated the role of miRNAs in keratinocyte carcinoma pathogenesis, progression and their use as therapeutic agents and targets, or biomarkers. However, there is very little consistency in the literature regarding the identity of and/or role of individual miRNAs in cSCC (and to a lesser extent BCC) biology. miRNA analyses that combine clinical evidence with experimental elucidation of targets and functional impact provide far more compelling evidence than studies purely based on clinical findings or bioinformatic analyses. In this study, we review the clinical evidence associated with miRNA dysregulation in KCs, assessing the quality of validation evidence provided, identify gaps, and provide recommendations for future studies based on relevant studies that investigated miRNA levels in human cSCC and BCC. Furthermore, we demonstrate how miRNAs contribute to the regulation of a diverse network of cellular functions, and that large-scale changes in tumor cell biology can be attributed to miRNA dysregulation. We highlight the need for further studies investigating the role of miRNAs as communicators between different cell types in the tumor microenvironment. Finally, we explore the clinical benefits of miRNAs as biomarkers of keratinocyte carcinoma prognosis and treatment. [ABSTRACT FROM AUTHOR]

Skin cancer is the most common cancer type in the USA, with over five million annually treated cases and one in five Americans predicted to develop the disease by the age of 70. Skin cancer can be classified as melanoma or non-melanoma (NMSC), the latter including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). Development of BCC and SCC is impacted by environmental, behavioral, and genetic risk factors and the incidence is on the rise, with the associated number of deaths surpassing those caused by melanoma, according to recent reports. Substantial morbidity is related to both BCC and SCC, including disfigurement, loss of function, and chronic pain, driving high treatment costs, and representing a heavy financial burden to patients and healthcare systems worldwide. Clinical presentations of BCC and SCC can be diverse, sometimes carrying considerable phenotypic similarities to benign lesions, and underscoring the need for the development of disease-specific biomarkers. Skin biomarker profiling plays an important role in deeper disease understanding, as well as in guiding clinical diagnosis and patient management, prompting the use of both invasive and non-invasive tools to evaluate specific biomarkers. In this work, we review the known and emerging biomarkers of BCC and SCC, with a focus on molecular and histologic biomarkers relevant for aspects of patient management, including prevention/risk assessments, tumor diagnosis, and therapy selection. [ABSTRACT FROM AUTHOR]

Background: Seeding of skin cancer cells following diagnostic or therapeutic surgical procedures can occur and might cause local recurrences. As current preferred therapy for skin malignancy is surgical excision, seeding of tumour cells by manipulating malignant tissue or suturing can be another factor leading to recurrences. Objective: To evaluate whether genetic material and malignant cells adhere to standard suture materials. Methods: This prospective study included patients who underwent excision of skin lesions. Monofilament and braided sutures were examined. Sutures were passed through the observed tumour or healthy skin margins and were examined for DNA material and cells by cytological analysis, cell culture and characterization, and DNA analysis. Results: Twenty-two patients and 148 sutures were included. DNA quantification showed DNA material on all sutures, with no significant difference between braided and monofilament sutures. Cytological analysis showed that all slides prepared from cell blocks contained normal squamous and atypical cells. Cell culture and characterization showed viable cells adhering to the sutures under direct light microscopy. Cell cultures showed rapid proliferation of epithelial cells from squamous cell carcinoma specimens. Conclusion: Suture materials carry DNA material and cells, including malignant cells of cutaneous origin and may seed them at distant sites. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma is particularly common and its incidence is increasing. Effective treatment is needed to prevent local recurrence and metastasis. The aim of our systematic review was to assess the potential added value of Mohs micrographic surgery compared with conventional excision. The majority of included studies showed a lower risk of recurrence when Mohs micrographic surgery was used to treat cutaneous squamous cell carcinoma. In addition, Mohs micrographic surgery offers advantages for tumors located in aesthetically or anatomically challenging areas. However, this technique requires a certain level of expertise and additional time and resources. Background: The first-line treatment of the localized form of cutaneous squamous cell carcinoma (cSCC) remains surgical excision. Either conventional excision (CE) with margins or Mohs micrographic surgery (MMS) may be preferred, depending on the risk factors of cSCC, the characteristics of the tumor, and the available technical facilities. Methods: This article presents a systematic review of the current literature spanning from 1974 to 2023, comparing outcomes of cSCC treated with MMS versus cSCC treated with conventional excision. Results: Out of the 6821 records identified through the database search, a total of 156 studies were screened, of which 10 were included in the review. The majority of the included studies showed that treatment of cSCC with MMS consistently exhibits a significantly lower risk of recurrence compared to treatment with CE. In addition, MMS is emerging as the preferred technique for the resection of cSCC located in aesthetically or functionally challenging anatomical areas. Conclusion: The studies generally demonstrate that MMS is a safer and more effective treatment of cSCC than CE. Nevertheless, outcomes such as recurrence rates and cost-effectiveness should be assessed more precisely, in order to allow for a more tailored approach in determining the appropriate indication for the use of MMS. [ABSTRACT FROM AUTHOR]

Opinion statement: Neoadjuvant immunotherapy will change the standard of care for advanced resectable cutaneous squamous cell carcinoma (cSCC) and possibly other non-melanoma skin cancers. With pathological complete response rates around 50% for cSCC in early studies, neoadjuvant therapy allows patients the possibility of significant reduction in tumor size, de-escalation of adjuvant therapy, and improved long-term outcomes. Patients must be carefully selected to ensure that there is a margin of safety with respect to resectability, such that if a tumor progresses on neoadjuvant therapy, there remains a curative surgical option that is acceptable to the patient. The optimal treatment paradigm is an area of active research, with many researchers questioning whether adjuvant therapy, or even local therapy, is necessary in patients who seem to have a complete response. The ability to predict who will respond will become even more critical to answer, as a significant number of patients do not want to risk their disease progressing, especially in cosmetically sensitive areas of the head and neck. Recent studies in melanoma show promise for improved response rates using combination therapies, and these strategies may apply to cSCC as well. The use of LAG-3 inhibitors or mRNA vaccine technology may further improve the utility of neoadjuvant strategies. [ABSTRACT FROM AUTHOR]

Background: Non-melanoma skin cancer (NMSC) is the most common malignant tumor that poses a worldwide problem for health services. Three-dimensional total body photography (3D-TBP) is currently used as an adjunct to skin examination, particularly to monitor melanocytic lesions in patients at high risk of melanoma. Objectives: The authors investigate the efficacy and limitations of a skin examination for NMSC performed solely with 3D-TBP without patient contact. Methods: 130 patients with 167 skin lesions with suspected NMSC underwent skin examination with dermoscopy and subsequent surgery. In addition, a 3D-TBP was performed, which was subsequently assessed by an independent dermatologist and compared with the initial skin examination and histological findings. Results: Using 3D-TBP, a significantly lower sensitivity for the diagnosis of BCC (0.44 vs 0.77), a lower sensitivity for SCC (0.70 vs 0.78; p=0.754) and a significantly lower sensitivity for invasive skin tumors overall (0.66 vs 0.88; p

Non-melanoma skin cancer (NMSC) mainly includes basal cell carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma, showing a low mortality rate but the highest incidence worldwide. In recent decades, research has focused on understanding the pathogenesis and clinical treatments of NMSC, leading to significant advances in our knowledge of these diseases and the development of novel therapies, including immunotherapy. Nevertheless, the low to moderate objective response rate, high recurrence, and therapeutic resistance remain persistent challenges, which are partly attributable to the intratumoral heterogeneity. This heterogeneity indicates that tumor cells, immune cells, and stromal cells in the tumor microenvironment can be reshaped to a series of phenotypic and transcriptional cell states that vary in invasiveness and treatment responsiveness. The advent of single-cell RNA sequencing (scRNA-seq) has enabled the comprehensive profiling of gene expression heterogeneity at the single-cell level, which has been applied to NMSC to quantify cell compositions, define states, understand tumor evolution, and discern drug resistance. In this review, we highlight the key findings, with a focus on intratumoral heterogeneity and the mechanism of drug resistance in NMSC, as revealed by scRNA-seq. Furthermore, we propose potential avenues for future research in NMSC using scRNA-seq.