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Melasma, which is thought to be associated with hyperactivation of melanocytes, is a common hyperpigmentary skin disorder. To treat this skin disorder, dermatologists can benefit from in vivo information of cellular morphometrics to evaluate pathologies of melasma and effectiveness of treatments. To acquire this useful information, we applied the in vivo slide-free label-free harmonic generation microscopy (HGM) to retrieve real-time HGM images and subsequent critical histopathological parameters. These in vivo quantitative parameters included melanin mass density (MMD), melanocyte dendricity score (MDS), melanophage density (MPD), and thickness of dermal papilla zone (DPZ). The statistical results from 33 recruited Asian female melasma patients showed that MMD, MDS, and MPD in melasma lesions were significantly higher than those in the surrounding normal skin; by contrast, the DPZ was lower. After treatment, the MMD, MPD, and DPZ restored toward the normal level; however, we observed no significant change of MDS. Our study indicates that these parameters are able to serve as clinical indices to evaluate the histopathological characteristics of melasma patients and the effectiveness of treatments.

Currently, only 14.7% of practicing dermatologists in Taiwan who work at medical centers are dedicated to innovative research. Dermatology departments appear to face steeper challenges with the recruitment and retention of physician-scientists than other medical specialties. The need to increase the number of physician-scientists is clear and can be achieved through the provision of good training programs, financial support, early mentorship, and sustained funding.

Background Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral cutaneous melanoma (NAM) in Asians are not well understood. Objectives To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma. Methods We performed comprehensive genomic profiling of 409 cancer-associated genes, using next-generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs. Results Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild-type (triple-WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell-cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell-cycle aberrations were independent prognostic factors of melanoma-specific survival. Conclusions This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians. What's already known about this topic? Mutation frequencies of driver genes vary between melanoma subtypes. Acral melanoma is the most common subtype of melanoma in Asians. KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype What does this study add? NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment. Melanomas with cell-cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration. What is the translational message? Cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival. These observations should be explored further for future drug development.

olmutinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC), especially for those harboring T790M mutations, the most common reason for other EGFR-TKI resistance. We describe three patients who developed acquired palmoplantar keratoderma (PPK) after taking olmutinib, an adverse event which has not been reported in previous generations of EGFR-TKIs. This article is protected by copyright. All rights reserved.

Background and Objectives Hair follicles are located at the interface of the external and internal environments and their cycling has been shown to be regulated by intra- and extra-follicular factors. The aim of this study is to examine whether or how hair follicles respond to visible light. Study Design/Materials and Methods We examined the effect of 3 mW red (630 nm, 1 J/cm2), 2 mW green (522 nm, 1 J/cm2), and 2 mW blue light (463 nm, 1 J/cm2) on telogen in mice for 3 weeks. The photobiologic effects of red light on cell proliferation of outer root sheath keratinocytes and dermal papilla cells were studied in vitro. Results We found that red light accelerated anagen entry faster than green and blue light in mice. Red light irradiation stimulated the proliferation of both outer root sheath keratinocytes and dermal papilla cells in a dose-dependent manner by promoting cell cycle progression. This stimulative effect was mediated via extracellular signal-regulated kinase phosphorylation in both cells. In a co-culture condition, dermal papilla cells irradiated by red light further enhanced keratinocyte proliferation, suggesting enhanced epithelial-mesenchymal interaction. In search for factors that mediated this paracrine effect, we found fibroblast growth factor 7 was upregulated in both mRNA and protein levels. The stimulative paracrine effect on keratinocytes was significantly inhibited by neutralizing antibody against fibroblast growth factor 7. Conclusions These results suggest that hair follicles respond to visible light in vivo. Red light may promote physiological telogen to anagen transition by directly stimulating outer root sheath keratinocytes and indirectly by enhancing epithelial-mesenchymal interaction in vitro. Lasers Surg. Med. 47:50–59, 2015. © 2014 Wiley Periodicals, Inc.

Background Higher CXCR4 expression enhances basal cell carcinoma (BCC) invasion and angiogenesis. The underlying mechanism of increased CXCR4 expression in invasive BCC is still not well understood. Objective To investigate the mechanisms involved in the regulation of CXCR4 expression in invasive BCC. Methods We used qRT-PCR, RT-PCR, Western blot, and flow cytometric analyses to examine different CXCR4 levels among the clinical samples, co-cultured BCC cells and BCC cells treated with recombinant transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). Immunohistochemical studies were used to demonstrate the correlation between TGF-β1 and CXCR4 expressions. The signal transduction pathway and transcriptional regulation were confirmed by treatments with chemical inhibitors, neutralizing antibodies, or short interfering RNAs, as well as luciferase reporter activity. Results Invasive BCC has higher TGF-β1 and CTGF levels compared to non-invasive BCC. Non-contact dermal fibroblasts co-culture with human BCC cells also increases the expression of CXCR4 in BCC cells. Treatment with recombinant human TGF-β1, but not CTGF, enhanced the CXCR4 levels in time- and dose-dependent manners. The protein level and surface expression of CXCR4 in human BCC cells was increased by TGF-β1 treatment. TGF-β1 was intensely expressed in the surrounding fibroblasts of invasive BCC and was positively correlated with the CXCR4 expression of BCC cells. The transcriptional regulation of CXCR4 by TGF-β1 is mediated by its binding to the TGF-β receptor II and phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2)-ETS-1 pathway. Conclusion TGF-β1 induces upregulation of CXCR4 in human BCC cells by phosphorylation of ERK1/2-ETS-1 pathway.

Background: Reports on the prevalence of different human papillomavirus (HPV) genotypes in male patients with anogenital HPV infection are limited. Methods: We retrospectively analyzed the HPV genotypes of 100 consecutive patients seen in our department with anogenital HPV infection during 2003e2006. History was gathered from the medical records. Results: The most common HPV genotypes among Taiwanese male patients for check of anogenital warts (in descending order) were HPV 6 (46%), HPV 11 (28%), HPV 16 (6%), HPV 33 (5%), HPV 66 (5%), HPV 18 (4%), HPV 53 (4%), and HPV 72 (4%). Coinfections with two, three, and four genotypes of HPV were present in 16%, 7%, and 1% of the patients, respectively. HPV 16 or 18 was found in 10% of cases, with 60% (6/10) coexisting with HPV 6/11. The presence of either HPV 6, 11, 16, or 18 was 77%. HPV 16 was more common in anal compared to genital warts, with an odds ratio of 3.65. Conclusion: The most common genotype of anogenital HPV infection in Taiwanese males was HPV 6, followed by HPV 11. Coinfection with more than one genotype of HPV as well as concurrent low- and high-risk HPV infection was not uncommon. Copyright 2012, Taiwanese Dermatological Association.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used to treat non–small cell lung cancer. Four major skin toxic effects with different incidences have been reported from clinical studies, including acneiform eruption (60%-94%), pruritus (16%-60%), xerosis (4%-38%), and paronychia (6%-12%). 1,2 However, a direct comparison of the incidences and severities of the 4 types of skin toxic effects for 3 different EGFR-TKIs in the same patient cohort has been lacking to date. Methods | This retrospective study was approved by the research ethics committee of National Taiwan University Hospital. We recruited patients within a named patient program for compassionate use before registration who had ever received afatinib treatment for non–small cell lung cancer between November 1, 2007, and April 30, 2013. Most of the pa

Background For preservation of integrity of appearance and function in a 66-year-old male with an extremely rare case of verrucous carcinoma developing from the subungium of his right thumb, intra-arterial infusion with methotrexate was used. Objective To evaluate the effectiveness of arterial infusion with methotrexate in this unusual nail bed cancer. Methods Right brachial arterial catheterization and infusion with methotrexate (50 mg) were used every 24 hours together with simultaneous intramuscular injection of 6 mg of leucovorin every 6 hours for 10 days. Results At 4 years, 8 months after therapy, the patient was in sustained complete remission with a functionally normal right thumb. Conclusion This case study suggests that intra-arterial infusion chemotherapy is a simple and effective method for thumb subungual verrucous carcinoma with the unique advantage of preservation of morphology and functional conditions. It can be considered an effective treatment option.

Importance Purpuric skin lesions have only rarely been reported in patients receiving epidermal growth factor receptor inhibitors. However, their clinical and histopathologic presentations have varied considerably. Objective To characterize purpuric skin eruptions caused by epidermal growth factor receptor inhibitors. Design, Setting, and Participants This prospective study enrolled 32 patients who presented to an integrated dermato-oncologic clinic in a tertiary referral medical center with purpuric skin lesions after using epidermal growth factor receptor inhibitors from January 1, 2013, through December 31, 2015. Exposures Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, erlotinib, and afatinib. Main Outcomes and Measures Clinical presentations, histopathologic features, laboratory examinations, and treatment outcomes of patients with purpuric drug eruptions. Results Thirty-two patients, 14 with purpuric drug eruptions without pustules (mean [SD] age, 60 [11] years; 12 female and 2 male) and 18 with purpuric drug eruptions with pustules (mean [SD] age, 64 [11] years; 12 female and 6 male), were identified. The median time to development of skin lesions was 3.5 months. The clinical presentations were characterized by purpuric macules, papules, and confluent plaques predominantly on the lower extremities. Pustules in various sizes could be found in 18 patients (56%). Eleven patients (34%) had skin lesions that covered places other than the lower extremities. Eczema craquele–like features developed in 13 patients (41%). Bacterial pathogens were frequently identified in these skin lesions. Among them,Staphylococcus aureuswas the most predominant and was found in 20 patients (63%), commonly in those with cutaneous pustules. Epidermal dysmaturation, neutrophil exocytosis, perivascular infiltration of lymphocytes and neutrophils, red blood cell extravasation, and plumping endothelium were the main histopathologic features. The expressions of filaggrin and human β-defensin 2 in lesional skin of these patients were markedly reduced. All patients improved after receiving at least 1 week of systemic antibiotic treatment; the doses of epidermal growth factor receptor inhibitors were also changed for 14 patients (44%). Conclusions and Relevance Purpuric drug eruptions caused by epidermal growth factor receptor inhibitors are uncommon and have characteristic clinical and histopathologic presentations. The role of bacterial pathogens in this reaction is important and requires further exploration.

In vivo harmonic generation microscopy (HGM) has been applied successfully in healthy human skin and can achieve a submicron resolution, similar to histopathologic examination, even at a penetration depth up to 270 μm. This study aims to investigate the clinical applicability of HGM imaging for differential diagnosis of nonmelanoma pigmented skin lesions. A total of 42 pigmented skin tumors, including pigmented basal cell carcinoma, melanocytic nevus, and seborrheic keratosis were evaluated by HGM ex vivo or in vivo. Based on the standard histopathologic characteristics, we established the corresponding HGM imaging criteria for each pigmented tumor. Diagnostic performance of HGM for differentiating nonmelanoma pigmented skin tumors was evaluated through the observers’ direct general assessment (overall evaluation) or the presence of two imaging criteria with the highest sensitivity and specificity (major criteria evaluation). Our results show that, based on the direct general assessment, the sensitivity is 92% [95% confidence interval (CI): 67 to 97%] and the specificity is 96% (95% CI: 83 to 99%); by major criteria evaluation, 94% sensitivity (95% CI: 70 to 99%) and 100% specificity (95% CI: 87 to 100%) are achieved. Our study indicates that HGM serves as a promising histopathological examination tool for noninvasive differential diagnostics of nonmelanoma pigmented skin tumors.

Background: Dapsone hypersensitivity syndrome (DHS) is a potentially life-threatening adverse drug reaction consisting of fever, hepatitis, exfoliative dermatitis, lymphadenopathy and hemolytic anemia. The incidence of DHS is estimated to be 2% in leprosy patients. Because the incidence of this drug eruption may be different in different ethnicities and diseases, we thought to investigate the incidence of DHS in non-leprosy patients. Methods: This is a retrospective study to examine the incidence, clinical manifestations and prognosis of DHS in non-leprosy patients who were given dapsone at the National Taiwan University Hospital between June 2001 and December 2005. Results: The incidence of DHS among non-leprosy patients was 1.66%. These patients ran a relatively benign course as compared with leprosy patients. Conclusion: The incidence of DHS among non-leprosy patients was compatible to that observed among leprosy patients. DHS in non-leprosy patients runs a favorable course with low morbidity in our study.

Administration of propylthiouracil therapy has been associated with a hypersensitivity syndrome that typically manifests as vasculitis. 1 Most cases of propylthiouracil therapy-induced antineutrophil cytoplasmic antibody (ANCA) positivity react to perinuclear ANCA (p-ANCA). 1 We describe a patient who presented with cutaneous manifestations of propylthiouracil therapy hypersensitivity vasculitis with ANCA positivity.

egression model showed that lymph node metastasis, advanced tage and IMP-3 expression predicted a poor outcome. The in vitro study confirmed that melanoma cells with higher igratory/invasive abilities have higher expression of IMP-3. Overxpression of IMP-3 in MeWo cells enhanced their migratory bility, while depletion of IMP-3 expression by RNA interference n A2058 melanoma cell line reduced the migration/invasion abiliies. These results provide evidence of direct involvement of IMP-3 n regulating melanoma biological behavior.

Background. For preservation of integrity of appearance and function in a 57-year-old male with a squamous cell carcinoma of his left big toe who had refused amputation, intra-arterial infusion with methotrexate was used. Objective. To evaluate the effectiveness of arterial infusion with methotrexate in this uncommon big toe cancer. Methods. Left external iliac arterial catheterization and infusion with methotrexate (50 mg) were used every 24 hours plus simultaneous intramuscular injection of 6 mg of leucovorin every 6 hours for 8 days. Results. At 7 years and 3 months after therapy, the patient was in sustained complete remission with a functionally normal left foot. Conclusion. This case study suggests that intra-arterial infusion chemotherapy is a simple and effective method for big toe squamous cell carcinoma with the unique advantage of preservation of organ and function. It can be considered as an effective alternative treatment.

IGF II mRNA-binding protein 3 (IMP-3) has been reported to be a marker of melanoma progression. However, the mechanisms by which it impacts melanoma are incompletely understood. In this study, we investigate the clinical significance of IMP-3 in melanoma progression and also its underlying mechanisms. We found that IMP-3 expression was much higher in advanced-stage/metastatic melanomas and that it was associated with a poor prognosis (P=0.001). Univariate analysis showed that IMP-3 expression was associated with stage III/IV melanomas (odds ratio=5.40, P=0.031) and the acral lentiginous subtype (odds ratio=3.93, P=0.0034). MeWo cells with overexpression of IMP-3 showed enhanced proliferation and migration and significantly increased tumorigenesis and metastatic ability in nude mice. We further demonstrated that IMP-3 could bind and enhance the stability of the mRNA of high mobility group AT-hook 2 (HMGA2). It was also confirmed that IMP-3 had an important role in melanoma invasion and metastasis through regulating HMGA2 mRNA expression. IMP-3 expression was positively correlated with HMGA2 expression in melanoma cells and also in melanoma tissues. Our results show that IMP-3 expression is a strong prognostic factor for melanoma, especially acral lentiginous melanoma.