Πέμπτη 28 Μαρτίου 2019

Dermatologica Sinica

A memoriam for Stephen Katz, a Legend of physician scientist and master mentor in dermatology
Chih-Hung Lee

Dermatologica Sinica 2019 37(1):1-2



Advances in systemic treatment for adults with moderate-to-severe Atopic dermatitis
Yung-Tsu Cho, Chia-Yu Chu

Dermatologica Sinica 2019 37(1):3-11

Atopic dermatitis (AD) is generally considered a T-helper type 2-dominated disease. Adult AD is often more severe and less manageable by topical therapies and may require systemic immunosuppressants that bear notable side effects and organ toxicities. There is an unmet need for safe and effective long-term therapy in this population. Dupilumab, a fully human monoclonal antibody, dually inhibits interleukin (IL) IL-4 and IL-13 signaling and has demonstrated promising efficacy and acceptable safety profile in several Phase III trials, followed by recent Food and Drug Administration approval for the treatment of moderate-to-severe AD in adults whose disease is inadequately controlled with topical therapies. Dupilumab may also serve as a new treatment option when other systemic medications have failed or are inadvisable. Nevertheless, long-term safety data beyond 1 year and comparison with the existing therapies remain to be investigated. Other emerging agents targeting pruritogenic proteins, chronic inflammation, and epidermal hyperplasia are under vigorous clinical development. In particular, nemolizumab, blocking IL-31-mediated pruritus, has been reported in Phase II trials to provide symptom relief by interrupting the itch-scratch cycle. Accompanied by thorough characterization of different phenotype and endotype subsets, the era of precision medicine could bring new prospects in the optimal treatment of AD. 


Patient's perception and importance of clear/almost clear skin in moderate-to-severe plaque psoriasis: Results of clear about psoriasis survey in Taiwan
Yu-Huei Huang, Tsu-Man Chiu, Ji-Chen Ho, Chih-Chiang Chen, Rosaline Chung-Yee Hui, Po-Ju Lai, Tsen-Fang Tsai

Dermatologica Sinica 2019 37(1):12-18

Background: Psoriasis has been reported to impact patients' health-related quality of life. Limited data are available on patients' perception of this disease and the importance of clear/almost clear skin as a treatment goal in Taiwan. Objectives: A clear about Psoriasis worldwide survey was conducted among patients with moderate-to-severe psoriasis to assess patients' perspective on the impact of psoriasis on their personal and professional lives, treatment satisfaction, and the importance of achieving clear/almost clear skin. Here, we report the data for the Taiwanese patient population. Methods: A 20-min survey consisting of multiple choice questions and validated scales to assess disease severity and patient' quality of life was conducted between October 2015 and March 2016. Patients (age ≥18 years) with medically diagnosed moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] score ≥10 or PASI >5 to <10, plaques on visible or sensitive areas), not participated in any online surveys on psoriasis in the past 4 weeks were included in the survey. Results: Eighty-four respondents (male, 56%) with an average PASI score of 17.1 were analyzed. The majority of respondents (77%) had not achieved clear/almost clear skin and 71% believed that it is unachievable. Overall, 20% of patients did not feel comfortable telling their doctor that they want clear/almost clear skin, and 32% had never discussed it. Furthermore, 19% of patients were dissatisfied with their current treatment and 46% were uncertain if they were satisfied or dissatisfied. Overall, 96% of respondents experienced either discrimination or humiliation in daily life and 51% felt that psoriasis affected their professional life. Conclusions: The results of this survey demonstrate that, despite significant progress in the management of psoriasis, the treatment satisfaction level of patients remains suboptimal in Taiwan. The data highlight the need for patients to discuss their treatment goals with clinicians. 


Differential expression of PTEN and PDCD4 Tumor suppressors in melanoma and microRNA-21-positive melanoma cells and squamous carcinoma cells
Kao-Hui Liu, Woan-Ruoh Lee, Ya-Ju Hsieh, Chia-Lun Chou, Ming-Chung Jiang, Shing-Chuan Shen

Dermatologica Sinica 2019 37(1):19-27

Background:In vitro cell experiments show that microRNA-21 downregulates the PTEN and PDCD4 tumor suppressor and promote melanoma cell proliferation and invasion. We examined microRNA-21, PTEN, and PDCD4 expressions in various melanoma cells as well as in melanoma specimens to define the actual expression profile of these tumor regulators. Materials and Methods: The microRNA-21, PTEN, and PDCD4 expressions in human keratinocytes and melanoma cells were analyzed by reverse-transcription polymerase chain reaction (RT-PCR) and real-time RT-PCR and immunoblotting. PTEN and PDCD4 expressions in melanoma patients were analyzed by immunohistochemistry. Results: RT-PCR and quantitative real-time PCR assays showed that A375 melanoma cells, squamous cell carcinoma (SCC-25), and SCC-4 skin squamous carcinoma cells expressed a higher level of microRNA-21 than HaCaT human keratinocytes. This inconsistent staining pattern of PTEN and PDCD4 in a melanoma tumor mass is not understandable, because the expression level of microRNA-21 in melanoma specimens are different. The expression of PDCD4 was not inversely correlated with the levels of microRNA-21 in these cells. In addition, we also found that only A2058 cells expressed low PTEN level and that A375, SCC-25, and SCC-4 cells expressed high PTEN levels. Furthermore, expression of PDCD4 was higher in the highly malignant B16F10 mouse melanoma cells than in B16 F0 cells; by contrast, both B16F0 and B16F10 cells expressed PTEN at high levels. Conclusion: Although PDCD4 and PTEN are targets of microRNA-21-dependent inhibition, PTEN and PDCD4 expressions are regulated in a more complex manner in skin cancer; not all microRNA-21-positive skin cancers certainly lose their normal PTEN and PDCD4 tumor suppressor functions. 


Evaluation of anxiety sensitivity in patients with psoriasis
Hilal Kaya Erdogan, Ali Ercan Altinoz, Ersoy Acer, Zeynep Nurhan Saracoglu, Muzaffer Bilgin

Dermatologica Sinica 2019 37(1):28-32

Background/Objectives: Psoriasis is an inflammatory skin disease characterized by erythematous squamous plaques. It has negative physical, psychological, and social effects. Psychiatric comorbidities such as anxiety and depression can accompany to psoriasis. In our study, we aimed to evaluate the anxiety sensitivity (AS) in psoriasis patients. Methods: We included 89 psoriasis patients, 44 controls with nonpsychodermatological disease and 59 healthy volunteers to study. Dermatological examinations were performed, and the Psoriasis Area and Severity Index (PASI) values were calculated. Participants completed a sociodemographic information form, Beck Anxiety Inventory and AS Index-3. Results: Both the psoriasis group and the control group with nonpsychodermatological disease had higher anxiety scores than the healthy control group. Psoriasis patients were found to have higher AS scores than both control group with nonpsychodermatological disease and healthy controls. When the psoriasis group was divided into two groups according to the presence of systemic disease or psoriatic arthritis; there was no difference between the groups in terms of psychometric measurements. Furthermore, there was no significant correlation between PASI scores and disease duration and psychometric evaluations. Conclusion: Our study is the first to show that the AS of psoriasis patients is significantly higher than healthy controls and of those with nonpsychodermatological diseases. It is not clear that high AS in these patients is a predisposing factor to the disease or a consequence of the disease. 


Association of leptin, resistin, and high-molecular-weight adiponectin levels with psoriasis area and severity index scores, obesity, and insulin resistance in psoriasis patients
Emine Müge Acar, Nilsel İlter, Şehri Elbeg

Dermatologica Sinica 2019 37(1):33-39

Background: Psoriasis is frequently associated with obesity and cardiovascular diseases. Adipocytokines have been implicated in the pathogenesis of psoriasis and its cardiometabolic comorbidities. Objectives: The aim of this study was to assess the roles of leptin, resistin, and high-molecular-weight (HMW) adiponectin in psoriasis as well as their relationship with Psoriasis Area and Severity Index (PASI), obesity, and insulin resistance. Materials and Methods: Forty-six psoriasis patients and equivalent age-, sex-, and body mass index (BMI)-matched controls were recruited in this study. PASI, waist and hip circumferences, and waist/hip ratio (WHR) were recorded, and total body fat mass (TBFM) values were measured using a bioimpedance body composition analyzer. Fasting serum leptin, resistin, and HMW adiponectin levels were measured, and homeostasis model assessment values for insulin resistance (HOMA-IR) were calculated. Results: After the adjustment for anthropometric variables, leptin levels did not differ significantly between the groups (P = 0.736). The patient group showed significantly elevated resistin and lower HMW adiponectin levels (P = 0.007, P= 0.010, respectively). The correlation of serum leptin, resistin, and HMW adiponectin with PASI was not significant (r = −0.100, P= 0.506; r = −0.053, P= 0.726; r = −0.103, P= 0.494, respectively). HOMA-IR positively correlated with leptin and negatively correlated with HMW adiponectin (r = 0.426, P < 0.001; r = −0.393, P < 0.001, respectively). The correlation of leptin and resistin with BMI was direct while that of HMW adiponectin with BMI was inverse (r = 0.532, P < 0.001; r = 0.240, P= 0.021; r = −0.408, P < 0.001, respectively). No significant differences were detected regarding TBFM, and waist and hip circumferences (P = 0.187, P = 0.090, P= 0.543, respectively). However, WHR was significantly higher in the patient group (P = 0.015). Conclusion: Altered adipocytokine levels in psoriasis patients suggest a possible role of adipocytokines in the relationship between psoriasis and its metabolic comorbidities. Fat distribution is also different from the healthy population with similar TBFM values, and abdominal obesity, which is an independent cardiovascular risk factor, is more prevalent in psoriasis patients. 


Dermatoscopic assessment of nailfold capillary abnormalities in Behçet's disease and correlation of the findings with disease activity and severity
Duru Tabanlioglu-Onan, Pinar İncel-Uysal, Yıldız Hayran, Günay Şahin-Dalgiç, Mutlu Hayran, Ferda Artüz, Başak Yalçin

Dermatologica Sinica 2019 37(1):40-45

Background: A small number of studies used nailfold capillaroscopy (NC) in the evaluation of nailfold capillary changes in Behçet's disease (BD). The purpose of this study was to investigate the characteristics and frequency of nailfold capillary changes in BD by dermatoscopy and videodermatoscopy and to develop a scoring system for those capillary changes to predict the activity and severity of the disease. Methods: We performed NC on 40 BD patients and 20 healthy controls with dermatoscopy and videodermatoscopy. Capillary morphology, distribution, and density were analyzed qualitatively and quantitatively. We also assessed the activity and severity of the disease with BD Current Activity Form and BD Severity Score Classification and evaluated the relation of these scores with morphology scores and capillary density. Results: Capillary morphologic alterations were encountered significantly more in BD group (P < 0.05). Loss of continuity in capillary loops and irregularity of capillary distribution were significantly more frequent in BD group compared to healthy controls (P = 0.003 and P < 0.001). Morphology score was significantly higher in BD patients compared to control group (P < 0.001); however, we could not detect a significant relation between capillary morphology and density and the activity and severity of BD. Conclusion: Although we could not demonstrate a significant relation between capillary changes and the activity and severity of BD, we consider that NC performed with dermatoscopy can reflect the presence and extent of microvascular involvement and thereby might have diagnostic and prognostic value in BD. 


Childhood and adolescent psoriasis in Taiwan: A retrospective analysis from a single medical center
Hsi Yen, Hsing-Jou Su, Thi-Tuong Vi Tran, Pei-Lun Kuo, Julia Yu-Yun Lee, Tak-Wah Wong

Dermatologica Sinica 2019 37(1):46-49

There are limited studies regarding childhood and adolescent psoriasis in Taiwan. A total of 86 pathologically confirmed cases diagnosed from 1989 to 2017 were retrospectively reviewed. Mean disease onset age was 10.51 years, and plaque psoriasis was the most common type. Compared to studies on Caucasian and other Asian populations, we found a lower estimated prevalence, higher rate of psoriasis limited to the nail at presentation, and higher prevalence of psoriatic arthritis. The most common comorbidities were related to atopy and metabolic syndrome. Positive family history of psoriasis and psoriasis preceded by infection were significantly associated with moderate-to-severe disease. 


Idiopathic lymphoplasmacellular mucositis of the vulva in a patient with partial interferon-γ receptor 1 deficiency
Kuan-Yu Chen, Tseng-Tong Kuo, Ya-Ching Chang, Rosaline Chung-Yee Hui, Ya-Hui Chuang

Dermatologica Sinica 2019 37(1):50-52

We report a case of idiopathic lymphoplasmacellular mucositis (ILPM) of the vulva in a 48-year-old woman with partial interferon-γ receptor 1 (IFN-γR1) deficiency. The lesion had an unusual ulcerovegetative presentation. Remarkable response was observed with oral and topical steroids in the first 3 weeks. However, the lesion recurred after tapering oral steroids and continuous low-dose oral steroids were required to suppress recurrence. To the best of our knowledge, this is the first case report of ILPM in a patient with partial IFN-γR1 deficiency. ILPM should be included in the differential diagnosis of persistent vulvar ulcerovegetative lesions. 


Pigmented Basal-cell carcinoma of the upper lip: A report of a case and review of the literature
Natsuko Matsumura, Anna Furukawa, Kazuki Ueda, Akihiko Oyama, Toshiyuki Yamamoto

Dermatologica Sinica 2019 37(1):53-55

Basal-cell carcinoma (BCC) rarely occurs on the lip. We herein report a case of an 89-year-old male, who presented with a blackish nodule on the vermilion border and the outer mucosa of the right side of the upper lip. A diagnosis of pigmented BCC was made by histopathological examination. The patient was successfully treated by Abbe flap with excellent esthetic and functional results. We have reviewed 64 cases of lip BCCs previously reported. There was no gender predominance, and the upper lip was involved 1.5 times higher than the lower lip. There was no lymph node metastasis, and thus, lip BCC had a good prognosis. 


Anatomy Pathology

 IL‐8 and CXCR1 expression is associated with cancer stem cell‐like properties of clear cell renal cancer

ABSTRACT

Recent studies suggests that clear cell renal cell carcinoma ccRCC possesses a rare population of cancer stem cells (CSCs) that might contribute to tumor heterogeneity, metastasis and therapeutic resistance. Nevertheless, their relevance for renal cancer is still unclear. In this study, we successfully isolated CSCs from established human ccRCC cell lines. CSCs displayed high expression of the chemokine IL‐8 and its receptor CXCR1. While recombinant IL‐8 significantly increased CSC number and properties in vitro, CXCR1 inhibition using an anti‐CXCR1 antibody or repertaxin significantly reduced these features. After injection into immune‐deficient mice, CSCs formed primary tumors that metastasized to the lung and liver. All xenografted tumors in mice expressed high levels of IL‐8 and CXCR1. Further, IL‐8/CXCR1 expression significantly correlated with decreased overall survival in ccRCC patients. These results suggest that the IL‐8/CXCR1 phenotype is associated with CSC‐like properties in renal cancer.

 TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target

Abstract

Ten‐eleven translocation methylcytosine dioxygenase‐1, TET1, takes part in active DNA demethylation. However, our understanding of DNA demethylation in cancer biology and its clinical significance remain limited. This study showed that TET1 expression correlated with poor survival in advanced‐stage epithelial ovarian carcinoma (EOC), and with cell migration, anchorage‐independent growth, cancer stemness, and tumorigenicity. In particular, TET1 was highly expressed in serous tubal intraepithelial carcinoma (STIC), a currently accepted type II EOC precursor, and inversely correlated with TP53 mutations. Moreover, TET1 could demethylate the epigenome and activate multiple oncogenic pathways, including an immunomodulation network having casein kinase II subunit alpha (CK2α) as a hub. Patients with TET1highCK2αhigh EOCs had the worst outcomes, and TET1‐expressing EOCs were more sensitive to a CK2 inhibitor, both in vitro and in vivo. Our findings uncover the oncogenic and poor prognostic roles of TET1 in EOC and suggest an unexplored role of epigenetic reprogramming in early ovarian carcinogenesis. Moreover, the immunomodulator CK2α represents a promising new therapeutic target, warranting clinical trials of the tolerable CK2 inhibitor, CX4945, for precision medicine against EOC.

 Morpholino‐induced exon skipping stimulates cell‐mediated and humoral responses to dystrophin in mdx mice

Abstract

Exon skipping is a promising genetic therapeutic strategy for restoring dystrophin expression in the treatment of Duchenne muscular dystrophy (DMD). The potential for newly synthesized dystrophin to trigger an immune response in DMD patients, however, is not well established. We have evaluated the effect of chronic morpholino (PMO) treatment on skeletal muscle pathology and asked whether sustained dystrophin expression elicits a dystrophin‐specific autoimmune response. Here, two independent cohorts of dystrophic mdxmice were treated chronically with either 800 mg/kg/month PMO for 6 months (n=8) or 100 mg/kg/week PMO for 12 weeks (n=11). We found that significant muscle inflammation persisted after exon skipping in skeletal muscle. Evaluation of humoral responses showed serum‐circulating antibodies directed against de novo dystrophin in a subset of mice, as assessed both by Western blotting and immunofluorescent staining; however, no dystrophin‐specific antibodies were observed in the control saline‐treated mdx cohorts (n=8) or in aged (12‐month‐old) mdx mice with expanded "revertant" dystrophin‐expressing fibers. Reactive antibodies recognized both full‐length and truncated, exon‐skipped dystrophin isoforms in mouse skeletal muscle. We found more antigen‐specific T‐cell cytokine responses (e.g., IFN‐g, IL‐2) in dystrophin antibody‐positive mice than in dystrophin antibody‐negative mice. We also found expression of major histocompatibility complex class I on some of the dystrophin‐expressing fibers along with CD8+ and perforin‐positive T cells in the vicinity, suggesting an activation of cell‐mediated damage had occurred in the muscle. Evaluation of complement membrane attack complex (MAC) deposition on the muscle fibers further revealed lower MAC deposition on muscle fibers of dystrophin antibody‐negative mice than on those of dystrophin antibody‐positive mice. Our results indicate that de novo dystrophin expression after exon skipping can trigger both cell‐mediated and humoral immune responses in mdx mice. Our data highlight the need to further investigate the autoimmune response and its long‐term consequences after exon‐skipping therapy.

 Mis‐splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays

Abstract

Splicing disruption is a common mechanism of gene inactivation associated with germline variants of susceptibility genes. To study the role of BRCA2 mis‐splicing in hereditary breast/ovarian cancer (HBOC), we performed a comprehensive analysis of variants from BRCA2exons 2 to 9, as well as the initial characterization of the regulatory mechanisms of such exons. A pSAD‐based minigene with exons 2–9 was constructed and validated in MCF‐7 cells, producing the expected transcript (1016‐nt/V1‐BRCA2_exons_2‐9‐V2). DNA variants from mutational databases were analyzed by NNSplice and Human Splicing Finder softwares. To refine ESE‐variant prediction, we mapped the regulatory regions through a functional strategy whereby 26 exonic microdeletions were introduced into the minigene and tested in MCF‐7 cells. Thus, we identified nine spliceogenic ESE‐rich intervals where ESE‐variants may be located. Combining bioinformatics and microdeletion assays, 83 variants were selected and genetically engineered in the minigene. Fifty‐three changes impaired splicing: 28 variants disrupted the canonical sites, four created new ones, 10 abrogated enhancers, eight created silencers and three caused a double‐effect. Notably, nine spliceogenic‐ESE variants were located within ESE‐containing intervals. Capillary electrophoresis and sequencing revealed more than 23 aberrant transcripts, where exon skipping was the most common event. Interestingly, variant c.67G>A triggered the usage of a non‐canonical GC‐donor 4‐nt upstream. Thirty‐six variants that induced severe anomalies (>60% aberrant transcripts) were analyzed according to the ACMG guidelines. Thus, 28 variants were classified as pathogenic, five as likely pathogenic and three as variants of uncertain significance. Interestingly, 13 VUS were reclassified as pathogenic or likely pathogenic variants.

In conclusion, a large fraction of BRCA2 variants (~64%) provoked splicing anomalies lending further support to the high prevalence of this disease‐mechanism. The low accuracy of ESE‐prediction algorithms may be circumvented by functional ESE‐mapping that represents an optimal strategy to identify spliceogenic ESE‐variants. Finally, systematic functional assays by minigenes depict a valuable tool for the initial characterization of splicing anomalies and the clinical interpretation of variants.