Precancerous Skin Lesions Research Articles

Increased microRNA 21 expression contributes to arsenic induced skin lesions, skin cancers and respiratory distress in chronically exposed individuals

More than 26 million people in West Bengal, India, are exposed to arsenic through drinking water, leading to several deleterious endpoints including precancerous and cancerous skin lesions and other non-dermatological health effects. Here, our aim was to identify whether miR21 is associated with such dermatological and non-dermatological health outcomes in chronically exposed humans. A total of 123 subjects from West Bengal were recruited for this study (45 exposed individuals with skin lesions, 38 exposed individuals without skin lesions and 40 unexposed individuals). The miR21 expression patterns in the lymphocytes were studied by quantitative realtime PCR and the effects on downstream targets were validated by Western blotting. Associations between the miR21 expression patterns and non-dermatological health effects were determined from epidemiological survey data. In vitro studies were done with low dose (0.05ppm) of chronic arsenic exposure to HaCaT cells for 15 passages. Interestingly, within the exposed group, the skin lesion individuals showed almost 4.5 fold up-regulation of miR21 compared to the no skin lesion group. The expression of the downstream targets of miR21 (PTEN and PDCD4) varied inversely, while the expression of pAKT and PI3K varied proportionately with its expression levels. Results of in vitro studies showed similar trends. Again miR21 was 2.03 fold up-regulated in the exposed individuals with respiratory diseases compared to the individuals without the same. This study for the first time shows that miR21 plays an important role in contributing to arsenic induced dermatological and non-dermatological health outcomes in an exposed population.

The Incidence of Precancerous and Cancerous Skin Lesions: A Retrospective Multicenter Study

The Incidence of Precancerous and Cancerous Skin Lesions: A Retrospective Multicenter Study

MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis.

The receptor tyrosine kinase MET is abundant in many human squamous cell carcinomas (SCCs), but its functional significance in tumorigenesis is not clear. We found that the incidence of carcinogen-induced skin squamous tumors was substantially increased in transgenic MT-HGF (mouse metallothionein-hepatocyte growth factor) mice, which have increased abundance of the MET ligand HGF. Squamous tumors also erupted spontaneously on the skin of MT-HGF mice that were promoted by wounding or the application of 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C. Carcinogen-initiated tumors had Ras mutations, but spontaneous tumors did not. Cultured keratinocytes from MT-HGF mice and oncogenic RAS-transduced keratinocytes shared phenotypic and biochemical features of initiation that were dependent on autocrine activation of epidermal growth factor receptor (EGFR) through increased synthesis and release of EGFR ligands, which was mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological inhibition of EGFR caused the regression of MT-HGF squamous tumors that developed spontaneously in orthografts of MT-HGF keratinocytes combined with dermal fibroblasts and implanted onto syngeneic mice. The global gene expression profile in MET-transformed keratinocytes was highly concordant with that in RAS-transformed keratinocytes, and a core RAS/MET coexpression network was activated in precancerous and cancerous human skin lesions. Tissue arrays revealed that many human skin SCCs have abundant HGF at both the transcript and protein levels. Thus, through the activation of EGFR, MET activation parallels a RAS pathway to contribute to human and mouse cutaneous cancers.

Solid nanoemulsion as antigen and immunopotentiator carrier for transcutaneous immunization

Imiquimod, a toll-like receptor 7 (TLR7) agonist, is an active pharmaceutical ingredient (API) established for the topical treatment of several dermal cancerous and precancerous skin lesions. Within this work, the immunostimulatory effect of imiquimod is further exploited in a transcutaneous immunization (TCI) approach based on a solid nanoemulsion (SN) formulation. SN contains a combination of imiquimod with the model peptide antigen SIINFEKL as a novel approach to omit needle and syringe and optimize dermal antigen administration.Excipients including sucrose fatty acid esters and the pharmaceutically acceptable oils MCT (middle chain triglycerides), avocado oil, jojoba wax and squalene are high pressure homogenized together with the antigen SIINFEKL. Freeze drying was performed to eliminate water and to achieve spreadable properties of the formulation for dermal administration. The influence of the different oil components was assessed regarding in vitro drug permeation in a Franz diffusion cell model using a murine skin setup. In vivo performance in terms of cytotoxic T-cell response was assessed in a C57BL/6 mouse model.Whereas Aldara® cream contains imiquimod in a dissolved state, the SN formulations carry the active in a suspended state. This resulted in a reduction of imiquimod permeation across murine skin from the SN when compared to Aldara® cream. In spite of this permeation rate reduction, each SN induced an in vivo immune response by specific T-cell lysis. A stabilized solid nanosuspension containing squalene/tocopherol exhibited a significantly higher performance (p⩽0.05) in comparison with Aldara® cream. MCT based SN exerted an in vivo effect comparable to Aldara®.In conclusion, anhydrous highly dispersed vehicles containing imiquimod in a submicron particle size distribution can represent promising formulations for TCI. The choice of the oil component has a strong influence on SN performance, independent of in vitro drug permeation.

Chemomodulatory Potential of Bartogenic Acid Against DMBA/Croton Oil Induced Two-Step Skin Carcinogenesis in Mice.

Barringtonia racemosa fruits are believed to be useful in cancer treatment in Ayurveda, the Indian system of medicine. In present study, bartogenic acid (BA), a triterpenoid constituent of Barringtonia fruits was evaluated for its cytotoxicity property using the human skin carcinoma cell line (SCC-13) and human peripheral blood mononuclear cells (PBMC). The chemopreventive efficacy of BA was evaluated against the DMBA/Croton oil-induced skin carcinogenesis in mice.BA was orally administered at the doses of 1, 2 or 4 mg/kg/day or applied topically every day for 12 weeks following DMBA application. The in vitro data from cell lines revealed that BA induces cytotoxicity against the SCC-13 cells (IC50=7.5 µM). It was found 4.05 times more selective to exert cytotoxicity against SCC-13 as compared to the PBMC (IC50=30.4 µM). The in vivo datacollected from mice model of DMBA/Croton oil-induced skin carcinogenesis revealed that BA administered orally or applied topically, both reduced the precancerous skin lesions andthe incidence of tumor bearing. The oral doses of BA (2 and 4 mg/kg) and topical treatment significantly reduced the incidence and number of skin papillomas. At these doses, BA also increased the activities of catalase and superoxide dismutase and induced an increase in glutathionecontent and inhibited lipid peroxidation in the skin. These findings reveal the chemopreventive efficacy of BA and also demonstrate that it contributes to the cytotoxic and antioxidative effects of Barringtonia racemosa fruits. The study also validates the traditional claims of Barringtonia fruits and provides a scientific basis of its chemopreventive property.

Favorable Immune Signature in CLL Patients, Defined By Antigen-Specific T-Cell Responses, Might Prevent Secondary Skin Cancers

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. The course of disease predisposes patients to the development of secondary malignancies, which might be due to a generalized immunosuppression induced by the disease and/or the therapies used for treatment. Skin cancer, including melanoma, is the most common secondary malignancy reported in these patients.In a recent study we reported on spontaneous memory T cell responses against CLL-associated antigens defined by HLA ligandome analysis in CLL patients. Moreover, retrospective analysis suggests a significant survival benefit for CLL patients showing immune reactions to more than one of the tested antigens (Kowalewski et. al., PNAS 2015).Here we analyzed our CLL patient cohort for the incidence of secondary malignancies, and in particular for skin cancers. A total of 15 CLL-associated HLA-peptides (6 A*02, 3 A*03, 6 B*07) were implemented for stimulation of HLA-matched PBMC obtained from CLL patients. 45 CLL patients (Binet A n=15, Binet B, n=15, Binet C n=15, median age, 33.3% (15/45) with prior CLL specific therapy) were analyzed for antigen-specific memory T-cell responses in IFNγ-ELISPOT assays. 13 patients (28.9%, response cohort) showed specific T cell response against > 1 antigen, while 32 patients (71.1%, negative cohort) showed none or only one immune response. The median age was 71 in the response cohort and 73 in the negative cohort. 40.0% (6/15) of CLL patients with Binet stage A and 33.3% (5/15) with stage B were classified as responders whereas only 13.3% (2/15) of patients with stage C showed >1 immune responses. Of the included CLL patients with prior therapy only one patient (8%) showed > 1 immune responses. In the analyzed CLL patient cohort 7 skin cancers (melanoma: n=2, squamous cell carcinoma: n=2, basal cell carcinoma: n=3), 3 precancerous skin lesions and 9 other secondary malignancies including renal cell carcinoma (n=2), colon (n=3), breast (n=2) and prostate cancer (n=2) were observed. In the negative cohort 34.4% (11/32) of the patients developed a secondary malignancy, while only 15.4% (2/13) in the immune response cohort presented with secondary neoplasms. Strikingly all skin cancers and precancerous skin lesions were observed in the non-immune responder cohort. Furthermore multiple secondary malignancies (e.g. squamous cell carcinoma and colon cancer) were only observed in the cohort that showed no immune response.Taken together our data suggest that a favorable immune signature in CLL patients, i.e. the ability to mount T-cell responses against CLL-associated antigens not only is associated with improved overall survival but also might protect these patients from the development of secondary skin cancers. DisclosuresNo relevant conflicts of interest to declare.

Design, Development and Characterization of Topical Microemulsions of 5-Fluorouracil for the Treatment of Non Melanoma Skin Cancer and its Precursor Lesions.

Treatment of non melanoma skin cancer and its precancerous skin lesions is associated with severe topical and systemic toxicity. So, it has become necessary to develop an efficient novel delivery system with less side effects and better patient compliance. Topical w/o microemulsion of 5-FU were prepared using sorbitan monooleate (Span 80), sorbitan trioleate (Span 85), polysorbate 80 (Tween 80), isopropyl alcohol (IPA) with different oils such as oleic acid, triacetin and isopropyl myristate (IPM). Evaluation tests of microemulsions like determination of thermodynamic stability, droplet size, viscosity, pH, conductivity and ex vivo release studies were performed. Spherical shape and Droplet size of microemulsion, which was around 100nm, was supported by Transmission electron microscopy. The lesser flux across skin for all microemulsion batches and higher skin retention of 5-FU loaded in microemulsion in comparison to topical 5-FU marketed cream resulted in better control over the drug release. Skin irritation studies on rats were performed to evaluate chronic toxicity of optimized microemulsion formulation on skin for 21 days and were compared with control group. Formalin (0.8%) was taken as standard irritant. Rat skin was observed for erythema and edema and the formulation was found safe for chronic use (p˃0.01). Histopathology studies showed the epidermal and dermal layers to be normal, showing the 5-FU microemulsion formulation to be safe for topical use. Better control of the drug release through skin can curtail topical and systemic toxicity which is supported by the skin irritation and histopathology studies.

Characteristics and outcomes of nonmelanoma skin cancer (NMSC) in children and young adults

Pediatric and young adult nonmelanoma skin cancer (NMSC) is rare and traditionally associated with predisposing heritable or congenital conditions. Clinical characteristics, outcomes, and iatrogenic risk factors have not been well described. We sought to characterize clinical features, potential risk factors, and gaps in care associated with NMSC in children and young adults. This was a retrospective chart review of children and young adults with squamous and basal cell carcinoma. We identified 28 patients with a total of 182 NMSC tumors. Of patients, 50% had predisposing conditions, and 46% had exposure to iatrogenic risk factors of prolonged immunosuppression, radiation therapy, chemotherapy, voriconazole use, or a combination of these. Of patients with iatrogenic risk factors, 62% developed subsequent cancerous or precancerous skin lesions. No patient was found to have chemotherapy or voriconazole exposure as a sole risk factor. Mean time to diagnosis of NMSC was 948 days with initial misdiagnosis in 36% of patients. The majority of patients underwent surgical excision. This was a retrospective single institution study with a small number of cases. Physicians should be aware of risk factors associated with NMSC in children and young adults to provide appropriate counseling and early diagnosis and treatment.

Quantitative Sonography of Basal Cell Carcinoma

A 30-MHz ultrasonic scanner was used to collect B-scan images together with appropriate radiofrequency echoes from diseased and healthy skin regions of patients with diagnosed basal cell carcinoma and pre-cancerous lesions (actinic keratosis). Radiofrequency data were processed to obtain the attenuation coefficient and statistics of the backscattered echo signal determination (K-distribution and effective density of scatterers [EDS]). The attenuation coefficient was significantly higher for patients with basal cell carcinoma than for healthy patients. Also, the pre-cancerous skin lesions had increased attenuation. The averaged EDS values for cancer lesions were significantly lower than those for pre-cancerous lesions and healthy skin. The successful differentiation between the tissue groups examined suggests the potential value of the attenuation coefficient and EDS for carcinoma characterization.

Actinic Keratosis Clinical Practice Guidelines: An Appraisal of Quality

Actinic keratosis (AK) is a common precancerous skin lesion and many AK management guidelines exist, but there has been limited investigation into the quality of these documents. The objective of this study was to assess the strengths and weaknesses of guidelines that address AK management. A systematic search for guidelines with recommendations for AK was performed. The Appraisal of Guidelines for Research and Evaluation (AGREE II) was used to appraise the quality of guidelines. Multiple raters independently reviewed each of the guidelines and applied the AGREE II tool and scores were calculated. Overall, 2,307 citations were identified and 7 fulfilled the study criteria. The Cancer Council of Australia/Australian Cancer Network guideline had the highest mean scores and was the only guideline to include a systematic review, include an evidence rating for recommendations, and report conflicts of interest and funding sources. High-quality, effective guidelines are evidence-based with recommendations that are concise and organized, so practical application is facilitated. Features such as concise tables, pictorial diagrams, and explicit links to evidence are helpful. However, the rigor and validity of some guidelines were weak. So, it is important for providers to be aware of the features that contribute to a high-quality, practical document.

A Pilot, Prospective, Open-Label Study on the Effects of a Topical Photorepair and Photoprotection Film-Forming Medical Device in Patients with Actinic Keratoses Evaluated by Means of Skin Analysis Camera Antera 3D

Background: Actinic keratosis (AK) is a very common precancerous skin lesion caused by chronic exposure to sunlight. UVA and UVB rays’ exposure is considered as the main pathogenic mechanism of keratinocytes alterations and malignant transformations. UVB and UVA cause direct alterations of DNA molecules, such as the formation of cyclobutane-pyrimidine dimers (CPD) and cellular structures damage, in particular membranes, trough free radicals formation. Eryfotona AK-NMSC (Ery) is a film-forming medical device (MD) class II indicated for the prevention and treatment of cancerization field in subjects with AK or non-melanoma skin cancers (NMSC). Ery is characterized by a photorepair action, thanks to its content in photolyase, an enzyme able repairing DNA CPD, and by high broadspectrum photoprotection (SPF 100+) (Repairsome). Controlled clinical studies have shown that this MD, both in the short and the long term, is able to induce in AK patients sub-clinical and clinical improvements at the cancerization field level. Study aim: In this pilot, prospective study, we evaluated the effects of 3-month application of this product in 11 subjects with AK through an objective assessment by skin camera ANTERA 3D instrument. The primary endpoints of the study were to evaluate: a) the evolution of the skin haemoglobin content (parameter related to the level of “vascularization” and inflammation of the skin lesions) at the level of a target AK lesion, identified and defined at baseline visit and b) the evolution of AK lesion area. Results: Ery treatment induced a statistically significant and clinically relevant reduction of AK target lesion area (a -75% reduction in comparison with baseline, range: -100%- 50%) and a significant haemoglobin content reduction as soon as after 1 month (-16%, p=0.01) and after 3 months of treatment (-34%, p=0.01) demonstrating an effect of normalization of this parameter at the AK target lesion level. The product was well tolerated. Conclusion: Data from this pilot study suggest that the use of a photorepair and photoprotection film-forming MD in subjects with AK is able to change in the short-medium term, an objectively-assessed parameter such as AK lesion area and the haemoglobin content via spectral analysis suggesting that this strategy could improve the skin area affected by the AK process.

MicroRNA-31 is overexpressed in cutaneous squamous cell carcinoma and regulates cell motility and colony formation ability of tumor cells.

Cutaneous squamous cell carcinoma (cSCC) is a malignancy of epidermal keratinocytes that is responsible for approximately 20% of skin cancer-related death yearly. We have previously compared the microRNA (miRNA) expression profile of cSCC to healthy skin and found the dysregulation of miRNAs in human cSCC. In this study we show that miR-31 is overexpressed in cSCC (n = 68) compared to healthy skin (n = 34) and precancerous skin lesions (actinic keratosis, n = 12). LNA in situ hybridization revealed that miR-31 was specifically up-regulated in tumor cells. Mechanistic studies of inhibition of endogenous miR-31 in human metastatic cSCC cells revealed suppressed migration, invasion and colony forming ability, whereas overexpression of miR-31 induced these phenotypes. These results indicate that miR-31 regulates cancer-associated phenotypes of cSCC and identify miR-31 as a potential target for cSCC treatment.

Introduction

Pediatric and young adult nonmelanoma skin cancer (NMSC) is rare and traditionally associated with predisposing heritable or congenital conditions. Clinical characteristics, outcomes, and iatrogenic risk factors have not been well described.We sought to characterize clinical features, potential risk factors, and gaps in care associated with NMSC in children and young adults.This was a retrospective chart review of children and young adults with squamous and basal cell carcinoma.We identified 28 patients with a total of 182 NMSC tumors. Of patients, 50% had predisposing conditions, and 46% had exposure to iatrogenic risk factors of prolonged immunosuppression, radiation therapy, chemotherapy, voriconazole use, or a combination of these. Of patients with iatrogenic risk factors, 62% developed subsequent cancerous or precancerous skin lesions. No patient was found to have chemotherapy or voriconazole exposure as a sole risk factor. Mean time to diagnosis of NMSC was 948 days with initial misdiagnosis in 36% of patients. The majority of patients underwent surgical excision.This was a retrospective single institution study with a small number of cases.Physicians should be aware of risk factors associated with NMSC in children and young adults to provide appropriate counseling and early diagnosis and treatment.

Präkanzerosen und Carcinomata in situ der Haut

Precancerous skin lesions and carcinomas in situ of the skin represent the early stages of epithelial skin tumors. There is no invasive tumor growth, so the basement membrane is completely intact. These lesions show a wide variation of clinical and histological appearances on the skin or mucosa. The precancerous and carcinoma in situ lesions that are described in this text are actinic keratosis, actinic cheilitis, cutaneous horns, arsenical keratosis, tar-induced dermatosis, X-ray irradiation-related keratosis, Bowen's disease, erythroplasia of Queyrat, bowenoid papulosis, intraepithelial neoplasia (vulvar, penile and anal). Because they all can progress into invasive carcinoma, therapy is mandatory. Many noninvasive therapeutic approaches exist nowadays in the form of gels, creams, photodynamic therapy and invasive techniques such as laser therapy and cryotherapy, curettage and excision of lesional skin. Depending on the treatment process, different rates of general clearance and recurrence of the lesions are discussed in this article.

Squamous Cell Carcinoma Developing after CO2 Laser Resurfacing

Skin resurfacing with the carbon dioxide (CO(2)) laser is currently a popular means of improving rhytides and scars and has been reported useful in the treatment for photodamaged skin, including precancerous and benign skin lesions, as well as superficial benign pigmented lesions. We describe a 68-year-old man who developed rapid squamous cell carcinoma (SCC) on the resurfaced areas 3 weeks following CO(2) laser resurfacing. Rapid occurrence of SCC should be considered a rare complication, and we recommend carefully considering CO(2) laser resurfacing after excision of an SCC and surveying any cancer recurrences. We report a rare complication of CO(2) laser resurfacing. This report suggests that additional work in this area is warranted.

CD10 Expression in Cutaneous Squamous Cell Carcinoma and Its Precursor Lesions: Evaluation Using Tissue Microarray

CD10 Expression in Cutaneous Squamous Cell Carcinoma and Its Precursor Lesions: Evaluation Using Tissue Microarray

Assessing hairdressers' knowledge of scalp and neck melanoma and their willingness to detect lesions and make referrals to dermatologists

Assessing hairdressers' knowledge of scalp and neck melanoma and their willingness to detect lesions and make referrals to dermatologists

Effects of a New Human Recombinant MnSOD in the Treatment of Photoaging and Actinic Keratosis

Physiological processes, as aerobic metabolism and inflammatory response, generate reactive oxygen species (ROS) that may induce cellular injury when their amount is increased and antioxidant defense mechanisms are overwhelmed. Also, ROS are generated following UV skin irradiation able to deplete the natural antioxidant defenses in the skin. The increase in exposure to UV may lead to photoaging and precancerous skin lesions (actinic keratosis). New antioxidant strategies in the prevention and therapy of skin lesions are urgently needed. In this study, we evaluated the antioxidant efficacy of a recombinant form of human manganese superoxide dismutase able to inhibit reactive oxygen species production in some patients affected by severe photoaging and actinic keratosis.

Techniques for fluorescence detection of protoporphyrin IX in skin cancers associated with photodynamic therapy.

Photodynamic therapy (PDT) is a treatment modality that uses a specific photosensitizing agent, molecular oxygen, and light of a particular wavelength to kill cells targeted by the therapy. Topically administered aminolevulinic acid (ALA) is widely used to effectively treat cancerous and precancerous skin lesions, resulting in targeted tissue damage and little to no scarring. The targeting aspect of the treatment arises from the fact that ALA is preferentially converted into protoporphyrin IX (PpIX) in neoplastic cells. To monitor the amount of PpIX in tissues, techniques have been developed to measure PpIX-specific fluorescence, which provides information useful for monitoring the abundance and location of the photosensitizer before and during the illumination phase of PDT. This review summarizes the current state of these fluorescence detection techniques. Non-invasive devices are available for point measurements, or for wide-field optical imaging, to enable monitoring of PpIX in superficial tissues. To gain access to information at greater tissue depths, multi-modal techniques are being developed which combine fluorescent measurements with ultrasound or optical coherence tomography, or with microscopic techniques such as confocal or multiphoton approaches. The tools available at present, and newer devices under development, offer the promise of better enabling clinicians to inform and guide PDT treatment planning, thereby optimizing therapeutic outcomes for patients.

A rapid and validated reverse phase liquid chromatographic method for determination of imiquimod from topical cream formulations

A Novel, rapid, accurate and precise reverse phase isocratic HPLC method has been developed for the determination of Imiquimod content in Imiquimod cream which is widely used for treatment of precancerous skin lesions known as actinic keratosis, a certain type of skin cancer and treatment of genital warts, known as Human Papilloma Virus (HPV). A mixture of 10 mM monobasic phosphate containing 0.1% triethylamine adjusted to pH 2.45 and acetonitrile in the ratio of 70:30 (v/v) was used as mobile phase. C-18 column of dimension 250 × 4.6 mm, 5 μ from Inertsil was used for analysis. Detector wavelength was kept at 245 nm and flow rate was kept 1.4 mL min−1. The retention time was observed at about 3.0 ± 0.1 min. The method has been validated as per ICH guidelines, with respect to specificity, linearity, accuracy, precision, robustness, solution stability and filter compatibility. Results for all the parameters were found within predetermined limits. The proposed method was applied to determine the content of Imiquimod in Imiquimod creams from different manufacturers. Content of the imiquimod was in good agreement with label claim of Imiquimod creams. This showed that proposed method is rapid, simple, precise, linear, robust, rugged and accurate which is useful and economic for routine analysis of Imiquimod content in Imiquimod cream.