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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.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used as a treatment for non-small-cell lung cancer. There have been some reports of EGFR-TKIs being associated with vascular adverse events. We found that EGFR-TKIs decreased the proliferation of HMEC-1s (immortalized human dermal microvascular endothelial cells) and HMVECs (human dermal microvascular endothelial cells), and also inhibited the phosphorylation of EGFR and ERK. We examined the mRNA expression profile of erlotinib-treated HMEC-1s and identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most consistently up-regulated transcript and protein. IQGAP1 was also overexpressed and co-localized with endothelial cells in the lesional skin. Notably, increased IQGAP1 expression was associated with decreased transendothelial electrical resistance and increased vascular permeability in vitro. Erlotinib treatment enriched the staining of IQGAP1 and reduced the intensities of α-catenin at the sites of cell-cell contact. In conclusion, erlotinib induces adherens junction dysfunction by modulating the expression of IQGAP1 in dermal endothelial cells. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND The prevalence of psychiatric comorbidities in patients with chronic urticaria (CU) in a national population is largely unknown. OBJECTIVES To investigate the prevalence of psychiatric disorders and psychiatric medication use in patients with CU in Taiwan. METHODS Data were sourced from Taiwan's National Health Insurance Research Database for 2011. Patients who had a primary/secondary International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of 708·1, 708·8 or 708·9 during 2011 with at least two outpatient visits and an antihistamine prescription were identified as CU cases. Patients with CU were classified into three disease severity groups according to their medication types. Psychiatric disorders were identified by patients having three outpatient visits with a primary or secondary diagnosis of a given psychiatric disease. Psychiatric medication use was defined by having at least four outpatient visits with prescriptions for anxiolytics, antidepressants or sleeping pills in 2010 or 2011. RESULTS Of the 167 132 patients with CU, 82·5% had mild CU, 17·0% had moderate CU and 0·4% had severe CU. Patients with CU had a higher prevalence of psychiatric disorders and psychiatric medication prescription than control groups. The relative risk (RR) of psychiatric disorders was 1·43 for patients with mild, 1·50 for patients with moderate and 2·32 for patients with severe CU vs. the controls (P < 0·001). For psychiatric medication prescription, the RRs were 1·95, 2·70 and 2·09, respectively, vs. controls (P < 0·001). CONCLUSIONS Patients with CU had a higher prevalence and risk of psychiatric disorders and psychiatric medication prescription than control groups. What's already known about this topic? Previous studies have shown a high prevalence of psychiatric comorbidities in patients with chronic urticaria (CU), with rates ranging from 35% to 60%. Anxiety, depression and somatoform disorders have been reported as the most prevalent mental disorders in patients with CU. What does this study add? Patients with CU had a higher prevalence of psychiatric disorders and psychiatric medication use than control groups in the general population. The relative risk (RR) of psychiatric disorders was 1·43 for those with mild CU, 1·50 for those with moderate CU and 2·32 for those with severe CU vs. controls. The RR for psychiatric medication use was 1·95 for those with mild CU, 2·70 for those with moderate CU and 2·09 for those with severe CU vs. controls. Mental health evaluations and management are important elements in CU management.

Atopic dermatitis is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions. It is considered one of the most common chronic conditions, with an estimated global prevalence of nearly 230 million. As in the rest of the world, prevalence of atopic dermatitis has been increasing in Asian countries over the last few decades. This increased prevalence in Asian countries has been attributed to factors such as rapid urbanization, increasingly Westernized lifestyles, and improved standards of living and education. As a result, it is important to understand the increasing burden of disease in Asian countries and the differences between the countries in terms of epidemiology, diagnostic criteria, management, quality of life and economic burden.

Background/purpose This report describes the 2014 consensus of the Taiwanese Dermatological Association regarding the definition, classification, diagnosis, and management of urticaria. This consensus is distributed to practices throughout Taiwan to provide recommendations for diagnostic and therapeutic approaches for common subtypes of urticaria, in order to improve the quality of life of urticaria patients. The consensus, thus, serves as an important reference for dermatologists throughout Taiwan. Methods All the consensus contents were voted on by the participating dermatologists, with approval by no less than 75% being required for inclusion. The consensus provides a comprehensive overview of urticaria, including recent advances in identifying its causes and the processes by which it develops. Results All the consensus meeting attendees agreed to a definition of urticaria, which states that it is characterized by the sudden appearance of wheals (also known as hives), angioedema, or both. Most of the experts (16 out of 19, or 84.2%) agreed that chronic urticaria is defined as the sudden occurrence of wheals and/or angioedema for a period of ≥ 6 weeks. In addition, the consensus attendees also approved the Urticaria Activity Score system or the Urticaria Activity Score for 7 days system as the recommended method for assessing disease activity in spontaneous urticaria. Conclusion It was also determined that the treatment goal for patients with any form of urticaria should be complete cessation of suffering from all urticaria symptoms. The recommended treatment algorithms for chronic spontaneous urticaria and acute urticaria were finally proposed and approved by 100% (19/19) and 84.2% (16/19) of the consensus attendees, respectively.

Cutaneous adverse drug reactions (cADRs) encompass many types of clinical presentations, ranging from benign maculopapular eruption (MPE) to severe cutaneous adverse reactions (SCARs). The relationship between viral reactivation and drug eruptions has been widely observed and has provided a new direction for researchers to explore. In recent years, a number of studies have focused in particular on sequential human herpes virus (HHV) reactivation in drug reaction with eosinophilia and systemic symptoms (DRESS), and these studies have provided crucial evidence demonstrating that clinical presentations can be closely related to the dynamics of viral activity. The DRESS patients with long-term sequelae tended to present with viral activation, including sequential changes in serum cytokines, chemokines, and immune cells. Moreover, other cADRs might also be influenced by the reactivation of different viruses. In this study, we discuss recent progress in understanding the role of viral reactivation in cADRs and the possible pathomechanism underlying the drug-induced immune response.

This article aims to present current COVID-19 vaccination considerations for patients on immunotherapeutics for the management of immune-mediated dermatological diseases and summarize the recommendations relevant to clinical practice in Taiwan. These Taiwan Dermatological Association (TDA) recommendations are intended to be dynamic in nature and serve as an interim guide to optimize patient care at this current juncture. It is expected that our clinical practice would continually evolve and be informed by new evidence that emerges in this pandemic.

Background: Plasmacytoid dendritic cells (pDCs) are implicated in the reactivation of human herpesvirus 6 (HHV-6) in drug reaction with eosinophilia and systemic symptoms (DRESS). Objectives: We aimed at identifying the alterations of circulating pDCs, basophils, and myeloid dendritic cells (mDCs) during the active stage of drug eruptions and the relationship between pDC alteration and HHV-6 reactivation in DRESS patients. Methods: Nine DRESS patients and twelve patients of other drug eruptions (ODE, including five cases of maculopapular eruptions (MPEs), five cases of Stevens–Johnson syndrome, and two cases of fixed drug eruption) were prospectively recruited. Blood samples were collected weekly for 2 consecutive weeks for flow cytometry of pDC, basophil, mDC, and detection of HHV-6 reactivation by serum anti-HHV-6 immunoglobulin G, or whole blood HHV-6 viral DNA by quantitative polymerase chain reaction. Results: The HHV-6 reactivation was exclusively seen in DRESS, and the pDC levels decreased in DRESS compared with ODE (P = 0.002) and (MPE, P = 0.021), with the timing of such decrease preceding HHV-6 reactivation. Conclusion: The decrease of pDC levels is significantly more common in DRESS patients and occurs before HHV-6 reactivation. The chronological sequence implies that the decrease of pDC may be crucial in the pathogenesis of viral reactivation.

Background Chronic urticaria (CU) is a condition characterized by recurrent itchy hives and/or angioedema for ≥6 weeks. Most of the data about CU come from western countries with very little information available about CU in Asia, Africa, and the Middle East. Methods AWARE-AMAC is a 24-month prospective, observational, real-world, non-interventional study in patients aged ≥18 years from Asia, the Middle East, and Africa (AMAC) with CU refractory to H1-antihistamines (H1-AH). The main objective was to describe the real-world experience with CU, including clinical characteristics, presence of angioedema, treatment patterns (shifts between treatment classes and changes within a treatment class), investigator-assessed disease control, and the impact on quality of life. Subgroups of interest were type of CU at Baseline and treatment class (based on 2013 urticaria guidelines). There were no mandatory visits and diagnostic/monitoring procedures additional to routine practice, except the patient diary (7-day Urticaria Activity Score) and patient reported outcome assessments. Results The focus of the current manuscript is on patients with chronic spontaneous urticaria (CSU), who formed 98% of the sample. Patients were predominantly female (69.6% female, mean age ± SD 39.8 ± 13.29 years). Time since current diagnosis (Mean ± SD) was 28.6 ± 49.06 months. Amongst patients with CSU, 31.0% had comorbid chronic inducible urticaria (CINDU) and 46.4% had a history of angioedema. 91.9% received H1-AH therapy (±other treatments). The most frequently prescribed treatment classes at Baseline were any/combination of medications, not classified under the other 7 treatment classes, named "Others" (30.5%) followed by, omalizumab (OMA; 23.6%) and second-generation H1-AH monotherapy (sgAH; 15.1%). At Month 12, the most prescribed treatment classes (>15%) for patients were OMA (23.5%) and "Other" (21.3%); 19.7% received "No drug". At Month 24, OMA (22.5%), and "Other" (17.9%) were most frequently prescribed; 28.6% received "No drug". Overall, 79.5% of patients had some type of change in treatment. Over the study period, improvement in self-reported QoL increased, which was mirrored by better disease control. Conclusion In AMAC countries, the non-recommended "Other" treatment class played a major role in the initial management of CU patients. High usage of H1-AH (±other treatments) and OMA was observed. Treatment changes were observed in a majority of patients. Treatment escalation from sgAH was mostly via OMA. Improvement of disease control and QoL was achieved during the study period. Trial registration Observational study (NA).

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions characterized by different extents of epidermal necrosis and mucosal breakdown. A limited number of studies have reported the long-term patterns of SJS and TEN complications in patient populations over long follow-up periods. The aim of this retrospective study was to collect data on long-term sequelae in patients admitted for SJS, SJS/TEN overlap, or TEN between 1998 and 2012. Among all 102 patients eligible for analysis, the 2 most common sequelae were cutaneous and ocular problems, both with incidences of 44.1%. Visceral organ involvement was observed in 2 patients with irreversible deterioration of chronic kidney disease and in one patient with interstitial lung disease. Autoimmune disease was present in 6 patients: Sjögren's syndrome or Sjögren-like syndrome in 5 patients and concomitant systemic lupus erythematosus and Hashimoto thyroiditis in one patient.

Background/Objective This report describes the 2014 consensus of the Taiwanese Dermatological Association (TDA) regarding the treatment of atopic dermatitis (AD). The TDA consensus is distributed to practices throughout Taiwan to provide recommendations for therapeutic approaches for AD patients to improve their quality of life. Methods The information in the consensus was agreed upon by a panel of national experts at TDA AD consensus meetings held on March 16, May 4, and June 29, 2014. The consensus was in part based on the 2013 Asia–Pacific AD guidelines and the guidelines of the American Academy of Dermatology, with modification to reflect the clinical practice in Taiwan. Results The amendments were drafted after scientific discussions focused on the quality of evidence, risk, and benefits; all the consensus contents were voted on by the participating dermatologists, with approval by at least 75% for inclusion. Conclusion The consensus provides a comprehensive overview of treatment for AD, with some local and cultural considerations for practitioners in Taiwan, especially the use of wet dressings/wraps, systemic immunomodulatory agents, and complementary therapies.

Background/objective Contact dermatitis to topical medicaments is commonly encountered in daily practice of dermatologists. The incidence and ranking of common allergens in topical medicaments may vary depending on local prescription and self-medication behavior. The objective of this study is to investigate the clinical features and common allergens of contact dermatitis to topical medicaments in Taiwan. Methods From 1978 to 2005, a total of 3717 patients had been patch tested in our Contact Dermatitis Clinic. Any case with suspected contact allergy to topical medicaments receiving patch testing was included in this study. Results During this period, a total of 608 patients were included and 603 of them completed the patch tests. Of the 603 patch-tested patients, 397 (66%) were positive for at least one antigen, and all patch tests were negative in 206 (34%). Patients with positive patch testing were characterized by younger age and location on the limbs and skin folds, while sex and atopy were not different among the two groups. A total of 1076 positive reactions to identifiable medicaments or main ingredients were recorded in 397 patients with positive patch testing. Among these positive reactions, 701/1076 counts (65%) were read as relevant. Traditional herbal medicaments (50%), antiseptics (21%), vehicle ingredients (9%), antibiotics (8%), corticosteroids (2%), anesthetics (2%), and nonsteroidal anti-inflammatory drugs (1%) were the most common sensitizers in this study, and the common concomitant allergens were fragrance (52%) and metal (20%). Conclusion The results emphasized the special cultural consideration in Taiwanese patients with contact dermatitis to topical medicaments.

Background/aims Ultraviolet light-signature mutations in the telomerase reverse transcriptase ( TERT ) gene promoter have been identified in cutaneous melanomas, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs). Whether these mutations also occur in periocular tumours, including periocular sebaceous carcinomas (PSCs) and in situ tumours, has not been studied. Methods DNA extraction, PCR and Sanger sequencing were used to determine the frequency of TERT promoter mutations in periocular tumours. The presence of mutations was correlated with histological evidence of solar elastosis. Results Sixty-three tumours were analysed. TERT promoter mutations were identified in 18 of 22 BCCs (82%), 6 of 10 SCCs (60%), 1 of 2 in situ SCCs (50%), 4 of 9 grade III conjunctival intraepithelial neoplasia (CIN III) (44%) and 0 of 20 PSCs (0%). For BCCs, TERT promoter mutations were not associated with the histological risk categories of the tumours. For CIN III cases, all of the three lesions with solar elastosis had TERT promoter mutations, whereas the mutation was found in only one of the six CIN III cases without solar elastosis. Conclusions We demonstrate that ultraviolet light-signature TERT promoter mutations are very common in periocular BCCs, SCCs and CIN III lesions, indicating important roles of ultraviolet light in the pathogenesis of these tumours. In addition, the mutations are present in in situ stage. By contrast, no TERT promoter mutation is found in PSCs.

Background Treatment guidelines for chronic spontaneous/idiopathic urticaria (CSU) are available; however, only 50% of patients are well controlled with approved doses of H1-antihistamines, and certain patients remain symptomatic despite receiving up to 4× the approved dose of H1-antihistamines plus H2-antihistamines and/or leucotriene-receptor antagonists. Objectives To highlight real-life clinical practice in Taiwan and to understand the unmet medical needs of CSU patients. Methods A nationwide cross-sectional, observational survey of 50 dermatologists and 200 CSU patients was conducted between June 2013 and November 2013. Face-to-face interviews of dermatologists and online interviews of CSU patients were conducted independently. Results Dermatologists reported that dermographism and blood tests were the most commonly used diagnostic methods to confirm the diagnosis. The key driving factor for most clinic-based dermatologists (70%) in choosing a treatment was ‘response to my medicines’, and most preferred H1-antihistamines and steroids for treating CSU patients, whereas most hospital-based dermatologists (85%) gave higher priority to ‘severity and impact of the conditions’. Patients were reported to have high psychological pressures and significant impact of CSU on their daily activity. In addition, CSU patients were not satisfied with their current treatment and 69% of patients switched their first-consulted physician. Furthermore, lack of information and concerns about side-effects were major factors which held back patients from seeking Western treatment. Conclusions There is an unmet medical need of CSU patients in Taiwan highlighting gaps among guidelines, real-life clinical practice, patients' perceptions and patients' knowledge of their disease.

Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a syndrome involving multiple systems. Liver injury is the most common visceral manifestation. Objective The purpose of this study was to investigate the types of liver injury and factors associated with DRESS. Methods A retrospective cohort study was conducted in Taiwan using a DRESS database compiled from December 2000 to March 2013. Results Seventy-two cases were included in this study. Among them, 62 (86.1%) cases involved liver injury, 6 of which (9.7%) were liver injury before skin presentation. The distribution of liver injury patterns at initial presentation was 23 cholestatic type (37.1%), 17 mixed type (27.4%), and 12 hepatocellular type (19.4%). Patients with hepatocellular-type injuries were younger, with a median age of 31.5 ( P = .044). Individuals with liver function results more than 10 times the upper limit were more likely to have fever ( P = .026), took more time to recover, and had fewer eosinophils in the dermis ( P = .002). Limitations The study was a retrospective cohort study with limited cases. Conclusions Liver injury is common in DRESS and frequently associated with atypical lymphocytosis. The cholestatic type is the most common type. Patients with cholestatic-type injuries were older and more frequently had interface changes in skin pathology.

Background Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV-6, HHV-7, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined. Methods A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum-specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples. Results Among the various cADRs, HHV-6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)-1β, IL-2, IL-6, interferon-γ, tumor necrosis factor-α, were significantly lower in DRESS patients with HHV-6 reactivation when compared to those without HHV-6 reactivation. In addition, these mediators were significantly lower before and during HHV-6 reactivation, compared to cytokine levels after HHV-6 reactivation in the same patient. Conclusion HHV-6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV-6 reactivation.

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.

Dermatologic adverse events (dAEs) are common with the use of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. First- and second-generation agents (erlotinib, gefitinib, and afatinib) are frequently associated with acneiform rash, pruritus, xerosis, and paronychia; the incidence and characterization of these dAEs have been well described. However, there is evidence that the dAE profile is different with third-generation EGFR-TKIs. Herein, we describe the dAEs associated with third-generation EGFR-TKIs and our clinical experience with osimertinib, a third-generation EGFR-TKI approved by the U.S. Food and Drug Administration for the treatment of metastatic, EGFR T790M mutation-positive non-small cell lung cancer in patients whose disease has progressed on or after EGFR-TKI therapy. Case summaries of patients from two of our institutions who received osimertinib and were referred to a dermatologist for dAEs are also presented. Overall, the evidence suggests that osimertinib is associated with less severe and less frequent dAEs than first- and second-generation EGFR-TKIs and that therefore a different approach is warranted. Finally, we outline dAE management approaches for osimertinib in the context of those typically employed with first- and second-generation EGFR-TKIs. Implications for Practice Appropriate prevention and management of dermatologic adverse events (dAEs) associated with the use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) may help patients to continue therapy and lessen any negative impact on their quality of life. EGFR-TKIs are frequently associated with acneiform rash, pruritus, xerosis, and paronychia; however, dAEs associated with third-generation EGFR-TKIs are lower in frequency and severity. Before therapy, health care providers should discuss the potential osimertinib-associated dAEs and encourage patients to report their dAEs. Patients should also be educated on prophylactic measures to minimize the severity of dAEs and the importance of adherence to the treatment regimen.

BACKGROUND: Adherence to topical corticosteroids (TCS) is essential for the effective treatment of atopic dermatitis but can be limited by concerns about their use. This study examined the feasibility of applying the validated TOPICOP score for assessing TCS phobia across different countries.METHODS: This was a prospective multicentre feasibility study conducted in 21 hospitals in 17 countries. Patients >3 months of age with atopic dermatitis or their parents or legal representatives completed a validated translation of the TOPICOP questionnaire in the country's native language. Respondents also completed questionnaires collecting opinions about the feasibility and acceptability of the TOPICOP questionnaire.RESULTS: A total of 1564 participants in 15 countries were included in the analysis. 81% of respondents considered the questions clear or very clear, and 79% reported that it took less than 5 minutes to complete. Each of the individual items in the TOPICOP questionnaire was considered to be not at all difficult to answer by 49% to 74% of participants. The mean global TOPICOP score was 44.7%±20.5. Mean TOPICOP subscores were 37.0±22.8% for knowledge and beliefs, 54.7±27.8% for fears and 50.1±29.1% for behaviours. Global scores and subscores differed between countries, although the subscores did not always vary in parallel, suggesting different levels of TCS phobia and different drivers for each country.CONCLUSIONS: The TOPICOP score can be feasibly applied across countries and may therefore be useful for obtaining qualitative and quantitative data from international studies and for adapting patient education and treatment.

The pathogenesis of melanomas emerging in plantar surfaces remains unclear; however, mechanical stress has been reported to increase the formation of melanomas. In this study, we conducted a multicenter retrospective analysis of 153 acral melanomas diagnosed between 2000 and 2015 in Taiwan. The male-to-female ratio of the patients in question was 1:1.28, and the mean age at diagnosis was 68 years. We examined whether melanomas which developed in different areas of the patients’ soles differed in their associations with various clinicopathological characteristics and survival. Testing by goodness of fit indicated that stress-bearing areas were significantly more conducive to the generation of melanomas than non-stress-bearing areas (P P P

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments.

Background Melanoma is a heterogeneous group of diseases with distinct sets of genetic changes. Recurrent and mutually exclusive C>T or CC>TT transition mutations were identified in the promoter region of the reverse transcriptase catalytic subunit of the telomerase gene (TERT) in melanoma recently, and it was suggested that they enhanced the expression of TERT gene and played important roles in the melanoma pathogenesis. These mono or di-nucleotide transitions were ultraviolet (UV)-signature mutations. Methods In this study, polymerase chain reaction and direct sequencing of TERT promoter using formalin-fixed and paraffin-embedded tissue was performed to investigate whether these UV-signature mutations were also present in acral lentiginous melanoma. Results TERT promoter mutation was identified in only 2 of the 32 cases (6%) of acral lentiginous melanomas while it was identified in 3 of the 9 cases (33%) of non-acral cutaneous melanomas. The difference was statistically significant (p = 0.028). Conclusions The rarity of TERT promoter mutation in the acral lentiginous melanoma was consistent with the supposed role of UV light in the melanoma pathogenesis and also corroborated the view that acral lentiginous melanomas have a different pathogenesis with the melanomas from sun-exposed sites.

Sarcoidal alopecia is a subtype of plaque-forming cutaneous sarcoidosis that may resemble discoid lupus erythematosus (DLE). Because the clinical appearance of the two lesions is similar, the correct diagnosis may be missed. The systemic involvement and progressive nature of sarcoidosis, make it important to differentiate sarcoidal alopecia from DLE, so that proper treatment can be initiated and potential long-term sequelae avoided. We present the case of a 57-year-old Taiwanese woman with sarcoidal alopecia of the scalp that mimicked DLE.

Background Generalized bullous fixed drug eruption (GBFDE), a particular form of fixed drug eruption (FDE), is characterized by widespread blisters and erosions and can be confused with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Objective We sought to analyze specific features of GBFDE and differentiate it from SJS/TEN. Methods We retrospectively studied patients with GBFDE and SJS/TEN during a period of 10 years. GBFDE was defined as typical FDE lesions with blisters involving at least 10% body surface area on at least 3 of 6 different anatomic sites. Clinical presentations; histopathological features; immunohistochemical patterns of cluster-of-differentiation (CD)3, CD4, CD8, CD56, Fas, Fas ligand, granzyme B, perforin, granulysin, and forkhead box P3 (Foxp3); and serum granulysin levels were compared. Results Twenty-three cases of GBFDE were collected. Patients with GBFDE had shorter latent periods, less mucosal involvement, more eosinophil infiltration, and dermal melanophages. Lesional infiltrates in GBFDE had more dermal CD4 + cells including Foxp3 + regulatory T cells, fewer intraepidermal CD56 + cells, and fewer intraepidermal granulysin + cells. The serum level of granulysin in GBFDE was also significantly lower than in SJS/TEN. Limitations The number of cases in this study is small. Conclusion GBFDE is a distinct disease distinguishable from SJS/TEN by particular features such as granulysin, CD56, and Foxp3 expressions.

Background/Objectives Paraneoplastic pemphigus (PNP) is a rare mucocutaneous disease with a high mortality rate. It is defined by polymorphic mucocutaneous manifestations, particular histological features, characteristic results of direct and indirect immunofluorescence examinations, presences of specific autoantibodies, and associations with underlying neoplasms. However, currently, there is no existing study regarding the characteristics of PNP patients in Taiwan. In this study, we report a case series and try to determine the specific presentations of PNP patients in Taiwan. Materials and methods PNP patients treated in a referral center in northern Taiwan from 1998 to 2012 were retrospectively recruited. The clinical manifestations, histopathological features, findings of direct and indirect immunofluorescence, results of immunoblotting, and all relevant clinical information were collected. Results Eleven patients were identified with an average age of 62 years. Polymorphic mucocutaneous manifestations were observed in almost all patients. The most common presentation was pemphigus-like lesions, followed by lichen planus-like lesions. All patients had recalcitrant oral mucosal lesions. Five and four patients had genital and eye involvements, respectively. The mostly associated neoplasm is Castleman’s disease, followed by malignant thymoma. Acantholysis is the mostly observed histological features, followed by lichenoid dermatitis and interface dermatitis. Depositions of immunoglobulins or complements on the surface of keratinocytes or along basement membrane zone were found in eight and seven patients, respectively. Respiratory symptoms presented in eight patients. Despite intensive treatments, seven patients expired. Conclusion PNP in Taiwanese patients has a high association with Castleman’s disease or malignant thymoma. Complete laboratory examinations and thorough investigations for occult neoplasms are mandatory to establish a diagnosis in patients with clinical suspicions of PNP.

The editors were made aware of concerns by a reader regarding potential manipulation of data in [this article][1] ([1][2]). An internal review by the editors determined that the same RT-PCR bands appear to be duplicated in the A549/HIF-1α and MDA-MB-231/GAPDH panels in Fig. 1B. In addition, it

Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) involves a unique and severe adverse drug reaction. Patients present with fever, rash, lymphadenopathy, hematological abnormalities, systemic illness, and may suffer from prolonged cour- ses. Although the precise pathogenesis of DRESS/DIHS is not fully understood, it is widely considered to be an immunological reaction to a drug or drug metabolites. In this review article, we discuss the his- torical aspects of nosology, variable clinical and histopathological features, advantages and disadvantages of using an international Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) and Japanese DIHS criteria, pathogenesis, treatment, and long-term sequelae of DRESS/DIHS. Early recognition of this syn- drome, withdrawal of suspected culprit drugs, and adequate supportive care are mainstays of improving patient prognosis and reducing morbidities and mortality. Moreover, some DRESS/DIHS patients may develop long-term sequelae, especially autoimmune diseases and end organ failure. Physicians should be aware of these possibilities in patients after DRESS/DIHS and cautiously follow-up symptoms and lab- oratory tests for early detection of these sequelae.

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 The development of autoimmune sequelae is one of the characteristic features of drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome; however, the incidence of sequelae and prognosis of patients with DRESS are unknown. Objective We sought to investigate the incidence of sequelae, including less well-known sequelae, and long-term prognosis in patients with DRESS/drug-induced hypersensitivity syndrome. Methods A retrospective cohort study was conducted at a medical center in northern Taiwan using a DRESS/drug-induced hypersensitivity syndrome database. Patients who were followed up for at least 1 year were included in the study. Results Nine patients died before interview, whereas 43 patients completed a specially designed questionnaire. The overall cumulative incidence of long-term sequelae was 11.5% (6 of 52 patients). Four patients developed autoimmune diseases, specifically Graves disease (n = 2), type 1 diabetes mellitus (n = 1), and autoimmune hemolytic anemia (n = 1). Alopecia areata was also noted in 1 of the 2 patients with Graves disease. The other 2 patients developed renal failure after visceral involvement and required lifetime hemodialysis. Limitations Our study included a small number of patients. Further, viral studies were not performed. Conclusion The sequelae of DRESS can be divided into 2 major types that appear to occur in different age groups: young patients tend to develop autoimmune diseases, whereas elderly patients are more vulnerable to end-organ failure.

Objective:To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai).Methods:We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate ofHLA-B*15:02andHLA-A*31:01of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)–induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database.Results:We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association betweenHLA-B*15:02and OXC-SJS (p= 1.87 × 10−10; odds ratio 27.90; 95% confidence interval [CI] 7.84–99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values ofHLA-B*15:02for OXC-SJS/TEN were 0.73% and 99.97%, respectively.HLA-A*31:01was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p= 0.003; relative risk 0.212; 95% CI 0.077–0.584).Conclusions:Our findings suggest thatHLA-B*15:02is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptiveHLA-B*15:02screening should be evaluated further.

Summary Hidradenoma papilliferum (HP) is a benign epithelial tumor most commonly seen in the vulva. It is proposed to be derived from the anogenital mammary–like glands and is histologically very similar to the mammary intraductal papilloma (IP). Approximately 60% of mammary IPs have activating mutations in either PIK3CA or AKT1 , with each gene accounting for 30% of cases. In this study, we screened the mutation statuses of PIK3CA , AKT1 , RAS , and BRAF in 30 HPs. The results showed that activating mutations in either PIK3CA or AKT1 were identified in 20 tumors (67%); 19 tumors had PIK3CA mutations (63%; 13 in exon 20 and 6 in exon 9), and 1 had an AKT1 E17K mutation (3%). BRAF V600E mutation was found in an HP that also had a PIK3CA H1047R mutation. No RAS mutation was found. The mutation status was not correlated with the degree of epithelial cell hyperplasia. We conclude that although there might be site-related variations in the mutation frequencies of PIK3CA and AKT1 genes, HP is histologically and also genetically very similar to the mammary IP, suggesting that HP can be viewed as the extramammary counterpart of mammary IP.

CCN family protein 2 (CCN2), also known as connective tissue growth factor, is a secreting protein that modulates multiple cellular events. We previously demonstrated the metastasis-suppressive effect of CCN2 in lung cancer cells. In this study, we investigate the role of CCN2 in anoikis, a form of programmed cell death that is critical in suppressing cancer metastasis. CCN2 binds to the epidermal growth factor receptor (EGFR) and triggers ubiquitination by inhibiting the formation of the β-pix/Cbl complex, resulting in the degradation of EGFR. Binding of CCN2 to EGFR suppresses the phosphorylation of c-Src and extracellular signal-regulated kinase but increases the expression of death-associated protein kinase, which leads to anoikis. Overall, our findings provide evidence validating the use of CCN2 as an anti-metastatic therapy in lung cancer patients, and prospect a potential therapeutic synergy between CCN2 and the anti-EGFR antibody for the treatment of lung cancer.