Changes in the Use of Hydrochlorothiazide and Other Antihypertensive Drugs in Switzerland in Association With the Swissmedic Safety Alert Regarding Non-melanoma Skin Cancer: An Interrupted Time-Series Analysis Using Swiss Claims Data.

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.

Therapeutic targeting of siRNA/anti-cancer drug delivery system for non-melanoma skin cancer. Part I: Development and gene silencing of JAK1siRNA/5-FU loaded liposome nanocomplexes.

Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 101 µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p < 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene in vitro, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.

Mohs micrographic technique in high-risk basal cell carcinoma: a 3D prediction of safety margins.

OBJECTIVE: Compared with standard excision with a two-dimensional histological examination, Mohs micrographic surgery offers a lower recurrence rate and a greater extent of healthy tissue sparing for the treatment of high-risk basal cell carcinoma (BCC). The aims of this study were to first quantify the healthy tissue spared through the micrographic technique compared to traditional surgery for high-risk tumours. Then, to speculate, through the analysis of the distal micrographic resection margin, the adequate width of safety margins for standard excision. METHOD: A cohort of patients with high-risk BCC was treated with Mohs surgery. Safety margins, tumours residual final breach and hypothetical standard excision safety margins areas were recorded. RESULTS: A total of 96 patients were included. A reduction of 27.96% (95% Confidence Interval (CI): 17.90-38.02) of healthy skin removed was observed using a micrographic method compared to the standard approach. Standard excision with a 6mm safety margin was associated with 86.46% (95% CI: 79.62-93.30) of complete excision. Greater margins were not associated with a statistically significant improvement of complete excision. CONCLUSION: Mohs surgery should be considered the gold standard operative treatment for high-risk BCC. However, if micrographic techniques are not feasible, the standard excision with a predetermined margin of 6 mm, should be considered as the best option.

Geographical differences in hydrochlorothiazide associated risk of skin cancer balanced against disability related to hypertensive heart disease.

BACKGROUND: Hypertension affects 25-30% of the world population. Hydrochlorothiazide (HCTZ) is among the most used and cheapest medications but was in 2018 labeled with a warning stating increased risk of non-melanoma skin cancer (NMSC). This study describes geographical differences in the association between HCTZ and NMSC in a perspective of hypertensive heart disease (HHD). METHODS: We conducted a systematic literature search (PubMed, Embase, Clinicaltrial.gov, and Clinicaltrial.eu) using PICO/PECO acronyms including case-control, cohort, and randomized controlled trials. We constructed a rate ratio of disability-adjusted life years (DALY) for HHD/NMSC in global burden of disease (GBD) regions. RESULTS: No increased risk of NMSC with use of HCTZ was found in Taiwan, India, and Brazil. A small (hazard ratio (HR)/odds ratio (OR) ≤ 1.5) but significantly increased risk was seen in Canada, USA, and Korea. An increased risk (1.5 < HR/OR ≤ 2.5) in Iceland, Spain, and Japan and a highly increased risk (HR/OR > 2.5 in UK, Denmark, Netherlands, and Australia. HHD is associated with a more than 10-fold DALY rate compared with NMSC in 13 of 21 GBD regions corresponding 77.2% of the global population. In none of these 13 regions were there an increased risk of HCTZ-associated NMSC. CONCLUSIONS: Despite limited information from many countries, our data point to large geographical differences in the association between HCTZ and NMSC. In all GBD regions, except Australasia, HHD constitutes a more than 5-fold DALY rate compared to NMSC. This disproportionate risk should be considered before avoiding HCTZ as part of the antihypertensive treatment.

Lack of genetic association of non-melanoma skin cancer and pseudoexfoliative glaucoma.

BACKGROUND: Prior research has shown a positive association of pseudoexfoliative glaucoma (PXG) in patients with non-melanoma skin cancer (NMSC), likely due to an increase in ultraviolet exposure associated with both. However, the role of NMSC as a genetic risk factor for PXG has not been examined. Thus, the goal of this study is to utilize Mendelian randomization with genome-wide association studies to evaluate for genetic causality while controlling for environmental confounders. METHODS: We conducted a MR using the inverse variance weighted method (MR-IVW) as our primary analysis. Genomic data was sourced from GWASs for patients with NMSC (10,382 cases, 208,410 controls) and PXG (1,515 cases and 210,201 controls), originating from the FinnGen Biobank. RESULTS: Despite previous association of history of NMSC with occurrence of PXG, we found no evidence for a causal association between SNPs associated with NMSC and risk of PXG following MR analysis (MR-IVW, odds ratio (OR): 0.98, 95% CI: 0.85-1.14, P = 0.87). CONCLUSION: Here, we found no evidence for a causal association between SNPs associated with NMSC and the risk of PXG following a MR analysis.

The Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association with Tumor Stromal Inflammation.

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.

Cutaneous Squamous Cell Carcinoma on the Eyebrow of a Woman: A Rare Case Report.

The exact incidence of cutaneous squamous cell carcinoma (CSCC) or nonmelanoma skin cancer is unknown, and it is believed that the rate of occurrence is increasing with the growing elderly population and sun exposure, and it is more prevalent in males than in females. In this article, we describe the case of an 81-year-old woman who presented with a lesion on the right upper eyebrow. The patient had been consulting a dermatologist and undergoing treatment for three months. However, the lesion did not show any signs of improvement, and the dermatologist speculated that it might be a common wound that was healing slowly because of her diabetes. Imaging revealed an ulcerating skin lesion on the right upper eyebrow without connection to the deeper structures. Surgical intervention was chosen with the patient's consent. This rare case of CSCC on a woman's eyebrow showed that skin cancer can occur in unusual locations and in people without risk factors.

Non-melanoma skin cancer burden in Spain: a nationwide analysis of incidence trends (1990-2019).

Non-melanoma skin cancer (NMSC) is the most -common skin cancer in Spain, yet national data on its incidence trends are limited. To analyse the trends in NMSC incidence in Spain from 1990 to 2019, examining variations by sex, age, period, and birth cohort. Data on NMSC incidence was sourced from the Global Health Data Exchange. Age-standardized incidence rates (ASIRs) were calculated using the direct method. Trends and average annual percentage changes were identified using Joinpoint regression analysis. Age-period-cohort analysis was applied to assess age-specific, period-specific, and cohort-specific relative risks. From 1990 to 2019, Spain reported 2,302,399 NMSC cases. ASIRs significantly declined post-2005, with men exhibiting slightly higher rates than women. Joinpoint analysis revealed distinct trends between genders, with men experiencing an initial rise followed by a decline, while women exhibited periods of increase interspersed with decline. APC analysis showed a net decrease in age-adjusted NMSC rates for both sexes. Local drift analysis showed a downward trend in most age groups, indicating a broad decrease at the population level. However, no decrease was observed in young men (20-24 years). Both sexes showed an increased risk of NMSC between 1990 and 2002, followed by a decrease. In particular, those born at the beginning of the 21st century showed a significant decrease in NMSC risk compared with earlier cohorts, suggesting a possible cohort effect. A comprehensive analysis of NMSC trends in Spain highlights the need for ongoing research and interventions to address the evolving burden.

Micro RNA Dysregulation in Keratinocyte Carcinomas: Clinical Evidence, Functional Impact, and Future Directions.

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.

Biomarkers in Cutaneous Keratinocyte Carcinomas.

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.

Access to systemic treatment of non-melanoma skin cancer in Spain: a survey analysis.

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.

Recent Research Trends Against Skin Carcinoma - An Overview.

Skin cancer is a prevalent and sometimes lethal cancer that affects a wide range of people. UV radiation exposure is the main cause of skin cancer. Immunosuppression, environmental factors, and genetic predisposition are other contributing variables. Fair-skinned people and those with a history of sunburns or severe sun exposure are more likely to experience this condition. Melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) are the three main forms. Melanoma poses a bigger hazard because of its tendency for metastasis, while SCC and BCC have limited metastatic potential. Genetic mutations and changes to signalling pathways such as p53 and MAPK are involved in pathogenesis. Early diagnosis is essential, and molecular testing, biopsy, dermoscopy, and visual inspection can all help. In addition to natural medicines like curcumin and green tea polyphenols, treatment options include immunotherapy, targeted therapy, radiation, surgery, and chemotherapy. Reducing the incidence of skin cancer requires preventive actions, including sun protection and early detection programs. An overview of skin cancers, including their forms, pathophysiology, diagnosis, and treatment, highlighting herbal therapy, is given in this review.

The Impact of Education Level on Basal Cell Carcinoma Development Risk.

BACKGROUND: Basal cell carcinoma (BCC) stands as the most common skin malignancy, with its high incidence rate and associated costs rising annually. The origin of BCC is related to environmental, genetic, and phenotypic factors. Among these, the most important risk factor is exposure to UV light triggering keratinocyte carcinogenesis, causing cumulative cellular damage that leads to BCC development. Individuals' educational background and awareness of skin cancer risk factors may influence the development of BCC. Lack of knowledge about risk factors (like chronic UV exposure, sunburn, artificial solar beds, and fair skin color), prevention methods, and jobs involving outdoor activities may be associated with BCC formation. AIM: The aim of the study was to analyze recent trends and the risk factors associated with BCC, while also revealing any potential link between BCC and the patient's education level and awareness of skin cancer risk factors. DESIGN AND METHODS: A hospital-based case-control study was conducted, involving a total of 141 individuals. Among them, 47 were clinically and histologically confirmed BCC patients, while the remaining participants served as controls. The control group comprised 94 individuals matched for age and gender. Data on various factors including gender, age, residency, education level, Fitzpatrick skin type, outdoor activities, use of solariums, and UV therapy, as well as awareness of potential BCC triggers, were collected using an adapted questionnaire and subjected to analysis. The collected data underwent statistical evaluation. RESULTS: Most of the BCCs (n = 52; 71.2%) were located in sun-exposed areas (p < 0.001), with a female/male ratio of 1.35 to 1. The nodular type of BCC was the most common form (n = 49; 67.2%). The percentage of patients in the study group with Fitzpatrick phototypes I and II (n = 38; 80.9%) was significantly higher than in controls (n = 50; 53.2%, p = 0.002). The percentage of persons with higher education levels (bachelor's degree, master's degree, and post-diploma) was significantly less prevalent among cases compared to controls (n = 20 (42.6%) vs. n = 58 (61.7%), respectively (p = 0.033)). Notably, BCC patients with low education levels exhibited significantly lesser awareness concerning genetic factors and chronic solar radiation.  Conclusions: Coexistence of factors, such as a medical history of skin cancer, having Fitzpatrick skin types I and II, engaging in outdoor work exposed to the sun, knowledge that genetic factors are risk factors of skin cancer, and knowledge that stress is a risk factor of skin cancer, are significant predictors of the disease. A lower level of education and limited awareness about risk factors can also be a risk factor for BCC. It is essential to raise awareness about potential triggers and preventive measures within the population to reduce the incidence of the disease.

Impact of the COVID-19 Pandemic on the Surgical Management of Head and Neck Non-Melanoma Skin Cancers in a Maxillofacial Center of Cluj-Napoca.

Background: The COVID-19 era has been a bleak period for both cancer and non-cancer patients, with delayed non-emergency treatments, such as for non-melanoma skin cancer (NMSC). This study aimed to evaluate how the treatment of NMSC patients was influenced by the management of the COVID-19 pandemic in an Eastern European Maxillofacial Surgery center. Materials and Methods: A total of 176 patients with a histopathological diagnosis of head and neck NMSC who were surgically treated in Cluj-Napoca Emergency County Hospital between 2016 and 2022 were included in this study, and divided into two samples, pre-pandemic (2016-2019) and COVID-19 (2020-2022) periods. Results: The pandemic presented with a decrease of 46.15% in patients' hospitalization, with wealthy and educated patients being prevalent. Even if the waiting time for surgery was increased, the stage of cancer and preference method for reconstruction did not differ. Despite the lower addressability of NMSC patients during the pandemic, there were no changes in surgical treatment. Conclusions: During COVID-19, the number of patients was reduced, with a longer waiting time for surgery, but without any changes in tumor stage and treatment preferences. However, the benefit of removing a cancer tumor is higher compared to the risk of developing COVID-19 infection during hospitalization.

Therapeutic Approaches for Non-Melanoma Skin Cancer: Standard of Care and Emerging Modalities.

Skin cancer encompasses a range of cutaneous malignancies, with non-melanoma skin cancers (NMSCs) being the most common neoplasm worldwide. Skin exposure is the leading risk factor for initiating NMSC. Ultraviolet (UV) light induces various genomic aberrations in both tumor-promoting and tumor-suppressing genes in epidermal cells. In conjunction with interactions with a changed stromal microenvironment and local immune suppression, these aberrations contribute to the occurrence and expansion of cancerous lesions. Surgical excision is still the most common treatment for these lesions; however, locally advanced or metastatic disease significantly increases the chances of morbidity or death. In recent years, numerous pharmacological targets were found through extensive research on the pathogenic mechanisms of NMSCs, leading to the development of novel treatments including Hedgehog pathway inhibitors for advanced and metastatic basal cell carcinoma (BCC) and PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC). Despite the efficacy of these new drugs, drug resistance and tolerability issues often arise with long-term treatment. Ongoing studies aim to identify alternative strategies with reduced adverse effects and increased tolerability. This review summarizes the current and emerging therapies used to treat NMSC.

Mohs Micrographic Surgery for Cutaneous Squamous Cell Carcinoma.

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.

Systematic review of approaches to detection and classification of skin cancer using artificial intelligence: Development and prospects.

In recent years, there has been a significant improvement in the accuracy of the classification of pigmented skin lesions using artificial intelligence algorithms. Intelligent analysis and classification systems are significantly superior to visual diagnostic methods used by dermatologists and oncologists. However, the application of such systems in clinical practice is severely limited due to a lack of generalizability and risks of potential misclassification. Successful implementation of artificial intelligence-based tools into clinicopathological practice requires a comprehensive study of the effectiveness and performance of existing models, as well as further promising areas for potential research development. The purpose of this systematic review is to investigate and evaluate the accuracy of artificial intelligence technologies for detecting malignant forms of pigmented skin lesions. For the study, 10,589 scientific research and review articles were selected from electronic scientific publishers, of which 171 articles were included in the presented systematic review. All selected scientific articles are distributed according to the proposed neural network algorithms from machine learning to multimodal intelligent architectures and are described in the corresponding sections of the manuscript. This research aims to explore automated skin cancer recognition systems, from simple machine learning algorithms to multimodal ensemble systems based on advanced encoder-decoder models, visual transformers (ViT), and generative and spiking neural networks. In addition, as a result of the analysis, future directions of research, prospects, and potential for further development of automated neural network systems for classifying pigmented skin lesions are discussed.

Surgical Management of Patients with Parotid Involvement from Non-Melanoma Skin Cancer of the Head and Neck.

We conducted a retrospective, longitudinal study on a single-center series of patients who underwent parotidectomy in the management of advanced head and neck non-melanoma skin cancer (hnNMSC). The aim of this study was to identify prognostic factors associated with worse outcomes. Forty-one men and nine women were included. The mean age at the time of surgery was 78.9 years. The 5-year overall survival, disease-specific survival, locoregional recurrence-free survival, and distant metastasis-free survival calculated with Kaplan-Meier curves were 39.9%, 56.3%, 58.6%, and 82.1%, respectively. A univariate analysis showed that the status of the margins, facial nerve direct involvement, lymph vascular invasion, and histological grading were associated with worse outcomes (p < 0.05). Positive margins were associated with worse disease-specific survival also in a multivariate analysis (p = 0.001, HR = 32.02, and CIs 4.338 to 351.3). Because the resection in free margins is the most important prognostic factor, early diagnosis or, in the case of advanced disease, extensive surgical resection with concomitant reconstruction is needed. Adjuvant therapy is indicated in selected cases.

High-Risk Non-Melanoma Skin Cancers: Biological and Therapeutic Advances.

Nonmelanoma skin cancers (NMSCs) are the most common cancers, with high-risk NMSCs sharing features such as poor histologic differentiation, invasion into deeper layers, and anatomic location. NMSC includes basal cell carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. Herein, the authors describe advances in understanding the genetic mechanisms of malignant transformation and the composition of tumor microenvironment for these cancers. They summarize recent therapeutic advances, including targeted therapy and immunotherapy for NMSCs. Effective skin protection against ultraviolet radiation-induced carcinogenesis remains an urgent unmet need for NMSC prevention. The authors highlight immune-based interventions as novel strategies to address this need.