Total body topical 5-fluorouracil for extensive non-melanoma skin cancer.
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ABSTRACT:
SUBMITTER: van Ruth S
PROVIDER: S-EPMC2795156 | biostudies-other | 2006 Jun
REPOSITORIES: biostudies-other
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Project description:Chemically crosslinked hydrogels based on poly(N-vinylcaprolactam) (PNVCL) were synthetized by a photoinitiated chemical method. A galactose-based monomer, 2-lactobionamidoethyl methacrylate (LAMA), and N-vinylpyrrolidone (NVP) were added with the aim to improve the physical and chemical properties of hydrogels. The effects of both comonomers on the swelling ratio (Q), volume phase transition temperature (VPTT), glass transition temperature (Tg), and Young's moduli by mechanical compression below and above the VPTT were studied. Gold nanorods (GNRDs) and 5-fluorouracil (5FU) were embedded into the hydrogels, to study the drug release profiles with and without the excitation of GNRDs by irradiation in the near-infrared region (NIR). Results showed that the addition of LAMA and NVP increased the hydrogels' hydrophilicity, elasticity, and VPTT. The loading of GNRDs in the hydrogels changed the release rate of 5FU when irradiated intermittently with an NIR laser. The present study reports on the preparation of a hydrogel-based platform of PNVCL-GNRDs-5FU as a potential hybrid anticancer hydrogel for chemo/photothermal therapy that could be applied against skin cancer for topical 5FU delivery.
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Project description:(1) Background: Non-melanoma skin cancer is the most frequently diagnosed cancer in humans. The process of skin carcinogenesis is still not fully understood. However, several studies have been conducted to better explain the mechanisms that lead to malignancy; (2) Methods: We reviewed the more recent literature about the pathogenesis of non-melanoma skin cancer focusing on basal cell carcinomas, squamous cell carcinoma and actinic keratosis; (3) Results: Several papers reported genetic and molecular alterations leading to non-melanoma skin cancer. Plenty of risk factors are involved in non-melanoma skin cancer pathogenesis, including genetic and molecular alterations, immunosuppression, and ultraviolet radiation; (4) Conclusion: Although skin carcinogenesis is still not fully understood, several papers demonstrated that genetic and molecular alterations are involved in this process. In addition, plenty of non-melanoma skin cancer risk factors are now known, allowing for an effective prevention of non-melanoma skin cancer development. Compared to other papers on the same topic, our review focused on molecular and genetic factors and analyzed in detail several factors involved in non-melanoma skin cancer.
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Project description:Purpose of reviewThe therapeutic landscape for non-melanoma skin cancer (NMSC) has recently expanded with the development of effective and targeted immunotherapy. Here, we provide an overview of the role of immunotherapy in the management of advanced cutaneous carcinomas.Recent findingsSeveral agents were recently U.S. Food and Drug Administration (FDA)-approved for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma, Merkel cell carcinoma, and basal cell carcinoma. However, recent approvals in tissue-agnostic indications may also benefit other NMSCs including cutaneous adnexal solid tumors with high tumor mutation burdens or microsatellite instability. Furthermore, while FDA-approved indications will likely continue to expand, continued studies are needed to support the role of immunotherapy in the neoadjuvant, adjuvant, and refractory settings. Immunotherapy is emerging as the standard of care for several advanced NMSCs not amenable to surgery and radiation. Ongoing evaluation of the clinical trial landscape is needed to optimize enrollment and ensure continued innovation.
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Project description:Prospective epidemiologic studies that investigated the association between body mass index (BMI) and non-melanoma skin cancer (NMSC) yielded inconsistent findings. A dose-response meta-analysis was conducted to quantitatively summarize the evidence. PubMed and Embase databases were searched for relevant studies. Study-specific relative risk (RR) and 95% confidence interval (CI) for an increase in BMI of 5?kg/m2 was computed with the generalized least squares trend estimation, and these risk estimates were combined with the random-effects model. Nine publications were included in the final analyses, consisting of 18 independent cohorts with 22 risk estimates (971,795 participants and 50,561 NMSC cases). Results of the dose-response analyses showed a nonlinear inverse relationship between BMI and NMSC (RR?=?0.88, 95% CI: 0.85-0.91, I2?=?71.2%, P-nonlinearity <0.001), which persisted when limiting to the studies with adjustment for important potential confounders including sun exposure and sensitivity factors. The risk estimates were very similar for squamous cell carcinoma and basal cell carcinoma. Sex appeared a source of heterogeneity (P-difference?=?0.06), with a weaker, but still significant inverse association in men than in women. This dose-response meta-analysis suggests a nonlinear inverse association between BMI and NMSC.
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Project description:IntroductionSeveral studies have shown an increased risk of cancer after non melanoma skin cancers (NMSC) but the individual risk factors underlying this risk have not been elucidated, especially in relation to sun exposure and skin sensitivity to sunlight.PurposeThe aim of this study was to examine the individual risk factors associated with the development of subsequent cancers after non melanoma skin cancer.MethodsParticipants in the population-based New Hampshire Skin Cancer Study provided detailed risk factor data, and subsequent cancers were identified via linkage with the state cancer registry. Deaths were identified via state and national death records. A Cox proportional hazard model was used to estimate risk of subsequent malignancies in NMSC patients versus controls and to assess the potential confounding effects of multiple risk factors on this risk.ResultsAmong 3584 participants, risk of a subsequent cancer (other than NMSC) was higher after basal cell carcinoma (BCC) (adjusted HR 1.40 [95% CI 1.15, 1.71]) than squamous cell carcinoma (SCC) (adjusted HR 1.18 [95% CI 0.95, 1.46]) compared to controls (adjusted for age, sex and current cigarette smoking). After SCC, risk was higher among those diagnosed before age 60 (HR 1.96 [95% CI 1.24, 3.12]). An over 3-fold risk of melanoma after SCC (HR 3.62; 95% CI 1.85, 7.11) and BCC (HR 3.28; 95% CI 1.66, 6.51) was observed, even after further adjustment for sun exposure-related factors and family history of skin cancer. In men, prostate cancer incidence was higher after BCC compared to controls (HR 1.64; 95% CI 1.10, 2.46).ConclusionsOur population-based study indicates an increased cancer risk after NMSC that cannot be fully explained by known cancer risk factors.
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Project description:Combating melanoma via topical route is a highly challenging task due to low selectivity, poor efficacy and impeding biological environment of the skin. In the present study, we engineered a chitosan based pH responsive biodegradable nanogel (FCNGL), encapsulated with 5-FU that was effective even at very low drug doses (0.2% w/v) against melanoma. The FCNGL was synthesized by ion gelation technique exhibited nano-size particle distribution and sustained drug release kinetics. Hemolysis and coagulation analysis revealed high safety whereas MTT and apoptosis assays exhibited the efficacy of FCNGL. DMBA-Croton oil Swiss albino mice model was employed for in vivo assessment followed by gamma scintigraphic screening. Tumor burden and pharmacokinetic antioxidant stress levels along with whole-body gamma scintigraphy imaging using 99 mTc labelled nanogel exhibited selective accumulation in melanoma tumor nodules. The pH responsive behaviour of the nanogels resulted in triggered release of 5-FU in slightly acidic microenvironment, resulting in selective drug accumulation at the melanoma site. Immunohistochemistry (IHC) analysis of tumor showed improvement of subcutaneous layer alignment and regeneration of the epithelial skin layer when compared with standard 5% 5-FU and control mice group. Overall our preclinical data using the FCNGL portends to be a promising platform for efficient and sustained delivery of 5-FU for topical chemotherapy that can result in high efficacy, patient compliance and safety in the clinical set up.
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Project description:Mitochondrial DNA (mtDNA) damage, predominantly encompassing point mutations, has been reported in a variety of cancers. Here we present in human skin, the first detailed study of the distribution of multiple forms of mtDNA damage in nonmelanoma skin cancer (NMSC) compared to histologically normal perilesional dermis and epidermis. We present the first entire spectrum of deletions found between different types of skin tumours and perilesional skin. In addition, we provide the first quantitative data for the incidence of the common deletion as well as the first report of specific tandem duplications in tumours from any tissue. Importantly, this work shows that there are clear differences in the distribution of deletions between the tumour and the histologically normal perilesional skin. Furthermore, DNA sequencing of four mutation 'hotspot' regions of the mitochondrial genome identified a previously unreported somatic heteroplasmic mutation in an SCC patient. In addition, 81 unreported and reported homoplasmic single base changes were identified in the other NMSC patients. Unlike the distribution of deletions and the heteroplasmic mutation, these homoplasmic mutations were present in both tumour and perilesional skin, which suggests that for some genetic studies the traditional use of histologically normal perilesional skin from NMSC patients may be limited. Currently, it is unclear whether mtDNA damage has a direct link to skin cancer or it may simply reflect an underlying nuclear DNA instability.
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Project description:Densely labelled segmentation data for digital pathology images is costly to produce but is invaluable to training effective machine learning models. We make available 290 hand-annotated histopathology tissue sections of the 3 most common skin cancers; basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and intraepidermal carcinoma (IEC). These non-melanoma skin cancers constitute over 90% of all skin cancer diagnoses and hence this dataset gives an opportunity to the scientific community to benchmark analytic methodologies on a significant portion of the dermatopathology workflow. The data represents typical cases of the three cancer types (not requiring a differential diagnosis) across shave, punch and excision biopsy contexts. Each image is accompanied with a segmentation mask which characterizes the section into 12 tissue types, specifically: keratin, epidermis, papillary dermis, reticular dermis, hypodermis, inflammation, glands, hair follicles and background, as well as BCC, SCC and IEC. Included also are cancer margin measurements to work towards automated assessment of surgical margin clearance and tumour invasion. This leaves open many opportunities for researchers to utilize or extend the dataset, building upon recent work on image analysis problems in skin cancer (Thomas et al., 2021).
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Project description:Background: Mohs micrographic surgery (MMS) is the gold standard treatment for high-risk facial non-melanoma skin cancer. However, patients' access to MMS is limited by cost. The muffin technique micrographic surgery (MTMS) is an alternative micrographic technique wherein the entire excised margin is evaluated post-operatively by a pathologist using paraffin-embedded material. Herein, we describe the implementation and the preliminary results of MTMS in an academic dermatology center. Objective: To describe the MTMS and outline its efficacy and safety in a real-world clinical academic setting. Methods: A retrospective chart review was conducted of all patients with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) who underwent MTMS at the University of Alberta Dermatology Center from June 2016 until July 2019. Results: A total of 69 patients were included (64 BCCs and 5 SCCs). 68.1% of surgeries had clear margins following the first incision, 100% after second round re-excisions. There were no observed cases of tumor recurrence after a median 40 months of follow-up. There were no major adverse events or complications. Conclusions: MTMS is a superior alternative to simple excision of skin cancer by providing full margin control and residual tumor mapping.
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Project description:A milieu of cytokines and signaling molecules are involved in the induction of UV-induced immune suppression and thus the etiology of non-melanoma skin cancer (NMSC). Targeting the UV-induced immunosuppression pathway, and using a large population based study of NMSC, we have investigated the risk associated with functional variants in 10 genes (IL10, IL4, IL4R, TNF, TNFR2, HTR2A, HRH2, IL12B, PTGS2, and HAL). The most prominent single genetic effect was observed for IL10. There was increasing risk for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with increasing number of variant IL10 haplotypes (BCC: p(trend)?=?0.0048; SCC: p(trend)?=?0.031). Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (OR(BCC)?=?1.5, 95% CI 1.1-1.9; OR(SCC)?=?1.4, 95% CI 1.0-1.9), and these associations were largely confined to women (OR(BCC)?=?2.2, 95% CI 1.4-3.4; SCC: OR(SCC)?=?1.8, 95% CI 1.1-3.0). To examine how combinations of these variants contribute to risk of BCC and SCC, we used multifactor dimensionality reduction (MDR) and classification and regression trees (CART). Results from both of these methods found that in men, a combination of skin type, burns, IL10, IL4R, and possibly TNFR2 were important in both BCC and SCC. In women, skin type, burns, and IL10 were the most critical risk factors in SCC, with risk of BCC involving these same factors plus genetic variants in HTR2A, IL12B and IL4R. These data suggest differential genetic susceptibility to UV-induced immune suppression and skin cancer risk by gender.
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