Nuclear Localization of Yes-Associated Protein is Associated With Tumor Progression in Cutaneous Melanoma.

Yes-associated protein (YAP), an effector molecule of the Hippo signaling pathway, is expressed at high levels in cutaneous melanoma. However, the role of YAP in melanoma progression according to cellular localization is poorly understood. Tissues from 140 patients with invasive melanoma were evaluated by immunohistochemistry. Flow cytometry, western blotting, viability assays, wound healing assays, verteporfin treatment, and xenograft assays were conducted using melanoma cell lines B16F1 and B16F10 subjected to YapS127A transfection and siYap knockdown. Nuclear YAP localization was identified in 63 tumors (45.0%) and was more frequent than cytoplasmic YAP in acral lentiginous and nodular subtypes (P =.007). Compared with cytoplasmic YAP melanomas, melanomas with nuclear YAP had higher mitotic activity (P =.016), deeper invasion (P <.001), and more frequently metastasized to lymph nodes (P <.001) and distant organs (P <.001). Patients with nuclear YAP melanomas had poorer disease-free survival (P <.001) and overall survival (P <.001). Nuclear YAP was an independent risk factor for distant metastasis (hazard ratio: 3.206; 95% CI: 1.032-9.961; P =.044). Proliferative ability was decreased in siYapB16F1 (P <.001) and siYapB16F10 (P =.001) cells and increased in YapS127AB16F1 (P =.003) and YapS127AB16F10 (P =.002) cells. Cell cycle analysis demonstrated relative G1 retention in siYapB16F1 (P <.001) and siYapB16F10 (P <.001) cells and S retention in YapS127AB16F1 cells (P =.008). Wound healing assays showed that Yap knockdown inhibited cell invasion (siYapB16F1, P =.001; siYapB16F10, P <.001), whereas nuclear YAP promoted it (YapS127AB16F, P <.001; YapS127AB16F1, P =.017). Verteporfin, a direct YAP inhibitor, reduced cellular proliferation in B16F1 (P =.003) and B16F10 (P <.001) cells. Proliferative effects of nuclear YAP were confirmed in xenograft mice (P <.001). In conclusion, nuclear YAP in human melanomas showed subtype specificity and correlated with proliferative activity and proinvasiveness. It is expected that YAP becomes a useful prognostic marker, and its inhibition may be a potential therapy for melanoma patients.

Exploring Molecular Genetic Alterations and RAF Fusions in Melanoma: A Belvarafenib Expanded Access Program in Patients with RAS/RAF-Mutant Melanoma.

BACKGROUND: Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). PATIENTS AND METHODS: Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. RESULTS: Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. CONCLUSIONS: Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib.

Squamous cell carcinoma of lip: Clinical feature analysis and suggestion of reconstruction algorithm.

Reconstruction of lips after squamous cell carcinoma (SCC) removal should restore functional and aesthetic roles; however, it remains a challenge. In this study we describe the clinical features of lip SCC and suggest a reconstruction algorithm. We retrospectively analyzed 34 patients with lip SCC who underwent reconstruction after Mohs micrographic surgery between January 2006 and March 2022. The mean age of the patients was 70.2 years. Seven tumors were on the upper lip and 27 tumors were on the lower lip. Twenty-five defects were located on the mucosal lip, eight defects involved both the mucosal and cutaneous lips, and one defect was confined to the cutaneous lip. Eighteen defects were smaller than 50% of the total lip size, and 16 were larger than 50%. Primary closure was mostly performed for defects smaller than 50% of the lip size (9/18 cases), and local flap, according to the location and size of the defects, was performed for larger defects. Thirteen patients experienced postoperative complications but improved within 1 year after surgery, except for one patient. We suggest a reconstruction algorithm with a 50% cut-off value. Defects smaller than 50% of the lip size could be reconstructed by primary closure. Even larger defects could be reconstructed by creation of a local flap from the remaining adjacent tissue with minimal postoperative complications.

Successful treatment of xanthoma disseminatum with pulsed dye laser: A case report.

Xanthoma disseminatum is a rare form of non-Langerhans cell histiocytosis with limited treatment options due to its unknown aetiology and diffuse skin lesions. This case report presents the successful treatment of a 31-year-old male with severe pan-facial xanthoma disseminatum lesions following a facial burn and traumatic brain injury resulting from a car accident. After 5 sessions of monthly pulsed dye laser treatment, there was a clinically significant reduction in the lesions. Over the course of 3 years, the patient underwent a series of monthly pulsed dye laser treatments, and the lesions were almost cleared. These findings suggest that pulsed dye laser therapy may offer an effective treatment option for managing xanthoma disseminatum. This is the first report on use of the pulsed dye laser for treatment of xanthoma disseminatum.

Comparison of full-thickness skin graft and punch grafting in the reconstruction of plantar defects.

Acral melanoma commonly occurs on weight-bearing areas of the sole. Reconstruction of such areas presents a surgical challenge due to limited availability and mobility of local skin. Thus, we aimed to compare the scar outcome of full-thickness skin graft (FTSG) and punch grafting in the reconstruction of plantar defects after melanoma surgery. We retrospectively reviewed six patients who underwent both FTSG for nonweight-bearing areas and punch grafting for weight-bearing areas. We compared results of FTSG and punch grafting within the same patient. Photos of completely healed scars were graded using the Stony Brook Scar Evaluation Scale (SBSES). The averages of the FTSG scores and the punch graft scores, as measured by the SBSES, were statistically compared. Punch grafting yielded a better outcome than FTSG, according to the SBSES. The average of the punch grafting scars was 4.67, which was significantly greater (p = 0.004) than that of FTSG scar scores at 1.83. For weight-bearing areas, punch grafting should be considered as the first option of reconstruction, with FTSG as a second option for nonweight-bearing areas. Overall, this combined approach provides an effective and safe method for reconstruction of extensive plantar wounds.

Looking Beyond the Hutchinson Sign: A Retrospective Study of Clinical Factors Indicating the Presence and Invasiveness of Nail Unit Melanoma in Patients With Longitudinal Melanonychia.

BACKGROUND: The data underlying this article are available in the article.Longitudinal melanonychia (LM) presents a challenge because nail unit melanoma (NUM) must be considered as a differential diagnosis. Because nail matrix biopsy may result in nail dystrophy, it is important to distinguish NUM from LM. OBJECTIVE: To provide evidence of previously reported clinical factors indicative of NUM in patients with LM. METHODS: This was a retrospective study of patients who presented with LM and had biopsy-confirmed NUM from 2005 to 2021. Benign LM was either confirmed by biopsy or considered benign if followed without the need for biopsy. Clinical factors associated with LM and NUM were compared by multivariate regression. RESULTS: A total of 177 patients (97 LM and 80 NUM) were included. Multivariate regression showed that high band color intensity (p = .0031), variegation (p = .0005), nail plate splitting (p = .0017), Hutchinson sign (p = .0027), and band change (p = .001) correlated with malignancy. Nail plate splitting was associated with Breslow thickness. CONCLUSION: Malignancy should be suspected and biopsy performed in patients with LM and high band color intensity, variegation, nail plate splitting, Hutchinson sign, and band change.

Proteasome Subunit Alpha Type-7 Expression Suppresses Cutaneous Squamous Cell Carcinoma Progression by Inhibiting Cancer-associated Cytokines.

BACKGROUND/AIM: Cutaneous squamous cell carcinoma (cSCC) is a common non-melanoma skin cancer, and its incidence is increasing. Proteasome subunit alpha type-7 (PSMA7) has been found to be aberrantly expressed in several cancers. However, whether it functions as a tumor suppressor or oncogene in the pathogenesis of cancers, particularly cSCC, remains controversial. Here, we aimed to investigate the functions of PSMA7 in cSCC pathogenesis. PATIENTS AND METHODS: Clinicopathological characteristics were evaluated in 131 patients with cSCC using tissue sections. The expression of PSMA7, nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and mitochondrial antiviral signaling protein (MAVS) was determined in cSCC tissue sections using immunohistochemical staining. The effect of PSMA7 expression on the biological behavior of cSCC cells was investigated in vitro. RESULTS: High immunoreactivity of PSMA7 (high-PSMA7) was detected in 53 (40.5%) patients with cSCC and was significantly associated with histologic grade (p=0.008) and favorable recurrence-free survival (p=0.018). The expression of PSMA7 and NOD1 (p=0.026) and MAVS (p=0.032) was negatively correlated in cSCC tissues. Contrary to the results of the cohort study, cell viability and invasiveness significantly decreased after PSMA7 down-regulation in cSCC cells in vitro. mRNA expression of tumor necrosis factor-alpha, interleukin-1 alpha (IL-1α), IL-6, and IL-8 were significantly increased after PSMA7 down-regulation in cSCC cells (all p=0.002). CONCLUSION: PSMA7-mediated degradation of NOD1 and MAVS as well as the subsequent reduction of the cancer-associated cytokine network may be a crucial mechanism of the antitumoral function of PSMA7 in patients with cSCC.

Mohs Micrographic Surgery With Digital Pathology Improves Surgical Quality and Efficiency: A Retrospective Cohort Study.

BACKGROUND: Mohs micrographic surgery, involving pathology of the surgical margin, has the lowest recurrence rate for skin cancer. Moreover, because of technological advances, digital pathology systems are gradually being adopted in hospitals. Yongin Severance Hospital was the first hospital to construct a fully digitalized pathology system in Korea. OBJECTIVE: To evaluate the efficiency and characteristics of the digital pathology system for Mohs micrographic surgery. METHODS: The medical records of 80 patients with skin cancer who underwent Mohs micrographic surgery from March 2020 to August 2022 were analyzed for the number of frozen margins, number of stages, operation time, and recurrence rate to compare cases based on the pathology system. RESULTS: Overall, 23 and 57 patients were examined using the conventional and digital pathology systems, respectively. The mean number of final stages was 0.494 lower ( p -value = .008), the time from the previous to the next stage was 0.687-fold shorter ( p = .002), and the rate of switching from positive to negative margins was 1.990 times higher ( p = .044) in the digital than the conventional group. LIMITATIONS: Retrospective single-center experience; short follow-up time. CONCLUSION: Digital pathology reduces operative time and increases accuracy in Mohs micrographic surgery.

Epidemiology and survival analysis of Merkel cell carcinoma in South Korea: a nationwide, multicenter retrospective study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, of which most research has been conducted in Caucasians. Therefore, the clinicopathological features and prognosis of Merkel cell carcinoma in Asians are still scarce. The aim of this study is to investigate the epidemiology and survival of MCC in South Korea and provide representative information regarding MCC in Asia. METHODS: This was a retrospective, nationwide, multicenter study conducted in 12 centers across South Korea. Patients with pathologically proven MCC were included in the study. The clinicopathological features and clinical outcomes of the patients were investigated. Overall survival (OS) was analyzed using the Kaplan-Meier method, and independent prognostic factors were identified using Cox regression analysis. RESULTS: A total of 161 patients with MCC were evaluated. The mean age was 71 years with a female predominance. OS was significantly different among the stages. Among clinicopathological features, multivariate Cox regression analysis demonstrated that only the stage at diagnosis was associated with poorer overall survival. CONCLUSIONS: The results of our study suggest that the incidence of MCC was higher in females than in males and that there was a higher rate of local disease at the time of diagnosis. Among the variable clinicopathological features, disease stage at diagnosis was the only significant prognostic factor for MCC in South Korea. The findings of this nationwide, multicenter study suggest that MCC has distinct features in South Korea compared with other countries.

Various Applications of Purse-String Suture and Its Cosmetic Outcome in Cutaneous Surgical Defects.

BACKGROUND: Purse-string suture is a simple technique to reduce wound size and to achieve complete or partial closure of skin defects. OBJECTIVE: To classify situations in which purse-string sutures can be utilized and to assess the long-term size reduction and cosmetic outcome of the final scar. METHODS: Patients (93 from Severance hospital and 12 from Gangnam Severance hospital) in whom purse-string sutures were used between January 2015 and December 2019 were retrospectively reviewed. Wound site, final reconstruction method, repair duration, final wound size, and Vancouver scar scale were assessed. RESULTS: A total of 105 patients were reviewed. Lesions were located on the trunk (48 [45.7%]), limbs (32 [30.5%]), and face (25 [23.8%]). Mean ratio of wound length/primary defect length was 0.79±0.30. Multilayered purse-string suture showed the shortest duration from excision to final repair (p<0.001) and most effectively minimized the scar size (scar to defect size ratio 0.67±0.23, p=0.002). The average Vancouver scar scale measured at the latest follow-up visit at least 6 months postoperatively was 1.62, and the risk of hypertrophic scarring was 8.6%. There was no significant difference in the Vancouver scar scale and the risk of hypertrophic scarring between the different surgical method groups. CONCLUSION: Purse-string sutures can be utilized in many stages of reconstruction to effectively reduce scar size without compromising the final cosmetic outcome.

Risk of recurrence of nail unit melanoma after functional surgery versus amputation.

BACKGROUND: Minimally invasive nail unit melanoma (NUM) can be treated with functional surgery (FS) instead of amputation. OBJECTIVE: To determine risk factors associated with recurrence in NUM. METHODS: We retrospectively reviewed patients with NUM between 2008 and 2022 at a tertiary referral center. Multivariable Cox regression models adjusted for male sex and Breslow thickness (BT) were generated. Receiver operating characteristic analysis was performed to determine optimal cut-off points of the BT for stratifying recurrence risk. RESULTS: We evaluated 140 NUM cases (33 amputation and 107 FS). The mean BT values were 3.14 ± 2.62 mm (amputation) and 0.70 ± 1.36 mm (FS). Recurrence occurred in 10 (30.30%) patients with amputation and 23 (21.5%) with FS. Distant disease occurred in 10 (30.30%) patients with amputation and 8 (7.48%) with FS. Male sex, greater BT, amelanotic color, ulcers, and nodules were associated with greater risk for recurrence or distant disease. A BT of 0.8 mm was deemed the optimal cut-off for stratifying recurrence risk after surgery (odds ratio, 5.32; 95% CI, 2.04-13.85). LIMITATIONS: Small sample. CONCLUSION: FS can be considered for NUM with a BT < 0.8 mm, providing an amputation-sparing benefit. However, NUM with risk factors for recurrence requires patient counselling and close follow-ups.

A nomogram combining clinical factors and biomarkers for predicting the recurrence of high-risk cutaneous squamous cell carcinoma.

BACKGROUND: Although determining the recurrence of cutaneous squamous cell carcinoma (cSCC) is important, currently suggested systems and single biomarkers have limited power for predicting recurrence. OBJECTIVE: In this study, combinations of clinical factors and biomarkers were adapted into a nomogram to construct a powerful risk prediction model. METHODS: The study included 145 cSCC patients treated with Mohs micrographic surgery. Clinical factors were reviewed, and immunohistochemistry was performed using tumor tissue samples. A nomogram was constructed by combining meaningful clinical factors and protein markers. RESULTS: Among the various factors, four clinical factors (tumor size, organ transplantation history, poor differentiation, and invasion into subcutaneous fat) and two biomarkers (Axin2 and p53) were selected and combined into a nomogram. The concordance index (C-index) of the nomogram for predicting recurrence was 0.809, which was higher than that for the American Joint Committee on Cancer (AJCC) 7th, AJCC 8th, Brigham and Women's Hospital, and Breuninger staging systems in the patient data set. CONCLUSION: A nomogram model that included both clinical factors and biomarkers was much more powerful than previous systems for predicting cSCC recurrence.

First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600-mutant advanced melanoma.

BACKGROUND: Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma. OBJECTIVE: To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation. METHODS: Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed. RESULTS: A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8+ T cells. LIMITATIONS: Analysis was conducted in a retrospective manner. CONCLUSION: Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

Implication of IL6-positive Cancer-associated Fibroblasts in Merkel Cell Carcinoma Pathogenesis: A Possible Modulator of Immune Microenvironment.

BACKGROUND/AIM: The role of cancer-associated fibroblasts (CAFs) in the pathogenesis of Merkel cell carcinoma (MCC) remains unknown. This study aimed to investigate the clinicopathological significance of CAF subpopulations and their association with tumor-infiltrating lymphocytes (TILs) in patients with MCC. MATERIALS AND METHODS: Clinicopathological features and the status of microenvironment fibrosis (MF) around tumor masses were evaluated in 20 MCC patient and tissue sections. Alpha-smooth muscle actin (α-SMA)-positive CAFs (α-SMA+CAFs), interleukin-6-positive CAFs (IL6+CAFs), CD4-positive TILs (CD4+TILs), and CD8-positive TILs (CD8+TILs) in MCC tissue samples were investigated using immunohistochemistry. RESULTS: In a total of 20 MCC patients, high-MF was detected in 12 (60%) patients which was significantly associated with worse progression-free survival (p=0.048), but not with overall survival. CD4+/CD8+ TILs were frequently detected in MCC tissues. High-intra-tumoral CD8+TIL was significantly associated with better overall and progression-free survival (p=0.04 and p=0.015) in our cohort. High-αSMA+ CAFs were detected in 11 (55.0%) patients and high-IL6+CAFs in 10 (50.0%) patients. A negative association was found between high-IL6+CAF and high-intra-tumoral CD8+TILs (p=0.005). Patients with high IL6+CAFs showed worse overall/progression-free survival than patients with low-IL6+CAFs (p=0.022 and p=0.035). CONCLUSION: IL6+CAFs may largely influence the tumor immune microenvironment of MCC by modulating distinct T-cell populations and functions. This study provides a possible therapeutic target to overcome resistance to immune therapies in MCC.

A Novel Method of Steroid Delivery to Improve the Efficacy of Intralesional Injection in Keloid Treatment.

BACKGROUND: Keloids are a chronic disease and cause pain, pruritus, and limitation of motion. Intralesional corticosteroid injection is the first-line treatment, but its effects can be limited, even with repeated injections. OBJECTIVE: To investigate the efficacy and safety of a tunneling method of corticosteroid injection compared with conventional intralesional injection. MATERIALS AND METHODS: A retrospective review was conducted of keloid patients treated with intralesional corticosteroid injection by conventional and tunneling methods. RESULTS: A total of 119 cases of keloid were included in the study. Among 78 patients treated with 20 mg/mL triamcinolone, the Investigators' Global Assessment effectiveness score and Observer Scar Assessment Scale (OSAS) score were significantly higher in the tunneling group than the conventional group at 1 month. At 6 months, the tunneling group showed significantly higher effectiveness in the OSAS score than the conventional group. In the tunneling group, the interval between treatments was significantly longer than in the conventional group. The occurrence of side effects was lower in the tunneling method group than in the conventional method group. CONCLUSION: This study reveals the benefits of the tunneling method over the conventional method for therapeutic effect and side effects in keloid treatment.

Implication of COPB2 Expression on Cutaneous Squamous Cell Carcinoma Pathogenesis.

The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was investigated by analyzing the Gene Expression Omnibus (GEO) database and through a retrospective cohort study of 95 cSCC patients. The effect of COPB2 expression on the biological behavior of cSCC cells was investigated both in vitro and in vivo. We found that COPB2 expression was significantly higher in cSCC samples than in normal skin samples. In our cohort, a considerable association was found between COPB2 expression and indicators of tumor immune microenvironment (TIME), such as histocompatibility complex class (MHC) I, and MHC II, CD4+/ CD8+ tumor-infiltrating lymphocytes. Additionally, COPB2 expression had an independent impact on worsened recurrence-free survival in our cohort. Furthermore, decreased proliferation, invasion, tumorigenic activities, and increased apoptosis were observed after COPB2 knockdown in cSCC cells. COPB2 may act as a potential oncogene and candidate modulator of the TIME in cSCC. Therefore, it can serve as a novel predictive prognostic biomarker and candidate immunotherapeutic target in cSCC patients.

Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma.

Acral melanoma commonly occurs in areas that are not exposed to much sunlight, such as the sole of the foot. Little is known about risk factors and mutational processes of plantar acral melanoma. Nuclear envelope rupture during interphase contributes to genome instability in cancer. Here, we show that the nuclear and micronuclear membranes of melanoma cells are frequently ruptured by macroscopic mechanical stress on the plantar surface due to weight-bearing activities. The marginal region of plantar melanoma nodules exhibits increased nuclear morphological abnormalities and collagen accumulations, and is more susceptible to mechanical stress than the tumor center. An increase in DNA damage coincides with nuclear membrane rupture in the tumor margin. Nuclear envelope integrity is compromised by the mechanosensitive transcriptional cofactor YAP activated in the tumor margin. Our results suggest a mutagenesis mechanism in melanoma and explain why plantar acral melanoma is frequent at higher mechanical stress points.

Incidence and Prevalence of Skin Cancers in South Korea from 2008 to 2016: A Nation-Wide Population Based Study.

Background: In South Korea, there have been few nationwide epidemiologic studies about premalignant actinic keratosis (AK), squamous cell carcinoma in situ (Bowen's disease), nonmelanoma skin cancer (NMSC), malignant melanoma of the skin (MM), Kaposi's sarcoma (KS), connective and soft tissue cancers, or mycosis fungoides (MF). Objective: Using a nationwide population-based study, we attempted to measure the incidence and the prevalence of the above-mentioned tumors in South Korea. Methods: The database we used included all claims in the Korean National Health Insurance program and the Korean Medical Aid program from 2008 to 2016. The International Classification of Diseases, 10th revision (ICD-10) was used to record diagnoses in this database. This data included AK, Bowen's disease, NMSC, MM, KS, connective and soft tissue cancers, and MF. Results: The age-standardized incidence and prevalence rate of AK, Bowen's disease, NMSC, MM, KS, connective and soft tissue cancers, as well as MF increased during the periods we investigated. The incidence and prevalence rate of AK and NMSC have increased two- to three-fold. In the case of Bowen's disease, MM, KS, connective and soft tissue cancers, or MF, we observed no significant tendency in age-standardized incidence or prevalence. Conclusion: We confirmed that the age-standardized incidence and prevalence rates of NMSC and AK tended to increase. These results might contribute to developing preventive and therapeutic strategies for skin cancers and may become a source for further studies.