The impact of the COVID-19 surge on phototherapy in Taiwan: Focusing on the patient profile, adherence, and attitude before and after the surge.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has caused changes in the medical practice. However, it is unclear whether the patients receiving phototherapy for their dermatoses have been affected. OBJECTIVES: This study aimed to identify the impact of the COVID-19 pandemic on phototherapy, focusing on the patient profile, adherence, and attitude before and after the surge. METHODS: The study encompassed the time 5 months prior to and after the surge of the COVID-19 pandemic (from May to July, 2021), resulting in the temporary closure of our phototherapeutic unit. RESULTS: Nine hundred eighty-one patients received phototherapy during this period. Vitiligo, psoriasis (Ps), and atopic dermatitis (AD) represented the groups with the highest patient numbers. For vitiligo, Ps and AD, 39.6%, 41.9%, and 28.4% of the patients resumed phototherapy after the pandemic-related shutdown (PRS). No significant difference was noted in age, gender, and number of weekly sessions between those who resumed or stopped phototherapy after PRS among three groups. Patients who resumed phototherapy after PRS tended to receive more weekly sessions of phototherapy than those who initiated after PRS. Additionally, patients who resumed phototherapy showed no significant difference in the number of weekly sessions before and after PRS. CONCLUSIONS: This study reveals a significant impact of the COVID-19 pandemic on patients undergoing phototherapy. Although the patient number remained similar before and after PRS, a significant portion of patients discontinued phototherapy after PRS. New strategies and continued education are needed to improve patient management in times of pandemic.

Low-dose tofacitinib with 308-nm excimer therapy successfully induced repigmentation in patients with refractory vitiligo.

Combining low-dose tofacitinib with 308-nm excimer may be an effective treatment for patients with nonsegmental vitiligo who were refractory to conventional therapies.

Effects of Solanum undatum extract (SR-T100) on photocarcinogenesis and photoaging of actinic keratosis.

SR-T100 gel, containing solamargine extracted from Solanum undatum (synonym: Solanum incanum), had good therapeutic effects on actinic keratosis (AK) in human and ultraviolet B-induced papilloma in mice. This study aimed to investigate the immunohistochemical changes in the human skin after SR-T100 treatment. An immunohistochemical study was performed and the changes in photocarcinogenesis and photoaging markers after 16-week SR-T100 gel treatment were documented. SR-T100 gel treatment for 16 weeks resulted in complete remission in nine AK lesions and partial remission in four AK lesions. SR-T100 gel abolished the expression of mutant p53 and SOX2 and restored the expression of NOTCH1. Additionally, SR-T100 gel improved wrinkling in human skin, while restoring the expression of lamin B1 and increasing synthesis of new elastic fibers. SR-T100 gel had therapeutic effects on photocarcinogenesis and photoaging of photodamaged skin with AK.

The effects of UVB irradiance on vitiligo phototherapy and UVB-induced photocarcinogenesis.

Phototherapy is the most commonly used modality for repigmenting vitiligo. Currently, UVB emitting devices, including narrow-band UVB (NBUVB) and excimer laser/light, are considered as the treatment of choice. While emitting wavelengths at close proximity, excimer lights emit higher irradiance (HI; W/m2 ) compared to NBUVB. Clinical reports have shown that excimer light is more efficacious in treating vitiligo compared to NBUVB, and we demonstrated that irradiance plays a critical role in promoting melanoblasts differentiation. UVB radiation from the sun is closely associated with photocarcinogenesis of the skin. Sunscreens were used to protect the skin by reducing UVB irradiance (low irradiance (LI) UVB). Sunscreen use was associated with skin cancer reduction in clinical trials. Paradoxically, sunscreen use was associated with increased sunburn episodes in the real-world settings. It was shown that UVB-induced sunburn depends on fluence (J/m2 ) but not irradiance of UVB radiation. We investigated the significance of irradiance in the context of UVB-induced carcinogenesis of the skin. For mice receiving equivalent fluence of UVB exposure, the LIUVB-treated mice showed earlier tumor development, larger tumor burden, and more epidermal keratinocytes harboring mutant p53 as compared to their HIUVB-treated counterparts. These results suggested that at equivalent fluence, LIUVB radiation has more photocarcinogenic potential on the skin compared to its HI counterpart. Since development of sunburn with or without sunscreen use indicates that certain threshold of UVB fluence has been received by the skin at LI and HI, respectively, sunburn episodes with sunscreen use (LIUVB) are more damaging to the skin compared to that without sunscreen (HIUVB) application. In summary, since irradiance plays an important role determining the biological effects of UVB radiation on the skin, future related studies should take this critical parameter into consideration.

The impact of irradiance on UVB-induced cutaneous immunosuppression: Implications on administering most efficient phototherapy.

BACKGROUND: Ultraviolet B (UVB) is commonly used for treating dermatologic conditions. Recently, high irradiance UVB (HIUVB) has been suggested to be more effective for treating skin conditions as compared to its low irradiance (LI) counterpart. The biological impact of UVB radiation emitted at different irradiance on cutaneous immunity remains obscure. OBJECTIVE: This study aimed to explore the impacts of UVB radiation administered at equivalent fluence (mJ/cm2) but different irradiance (mW/cm2) on cutaneous immune response. METHODS: Cultured bone marrow derived dendritic cell (BMDC) were treated with equivalent fluence of UVB radiation with HIUVB or LIUVB. The phenotypic and functional alterations of BMDCs were documented. Animal models were used to validate the in vitro results in vivo and explore the mechanisms involved. RESULTS: After equivalent fluence of UVB radiation, the HIUVB treated BMDC showed significantly lower MHCII and CD86 expressions, reduced capacity to stimulate T cell proliferation, and enhanced activation of aryl hydrocarbon receptor (AhR)-activated genes as compared to control while their LIUVB treated counterpart showed no significant change. Using animal model, the HIUVB induced significantly higher immune suppressive effect in mice as compared to their LIUVB counterpart after equivalent fluence of UVB treatment. The superior immune suppressive effect of HIUVB over LIUVB radiation was not observed when similar experiments were performed using AhR-deficient mice. CONCLUSION: We propose irradiance played an important role modulating UVB-induced cutaneous immune suppression. Future works on UVB phototherapy, both clinical and research, should incorporate this important parameter into consideration.

Mechanisms of repigmentation induced by photobiomodulation therapy in vitiligo.

Photobiomodulation (PBM) therapy is based on the exposure of biological tissues to low-level laser light (coherent light) or light-emitting diodes (LEDs; noncoherent light), leading to the modulation of cellular functions, such as proliferation and migration, which result in tissue regeneration. PBM therapy has important clinical applications in regenerative medicine. Vitiligo is an acquired depigmentary disorder resulting from disappearance of functional melanocytes in the involved skin. Vitiligo repigmentation depends on available melanocytes derived from (a) melanocyte stem cells located in the bulge area of hair follicles and (b) the epidermis at the lesional borders, which contains a pool of functional melanocytes. Since follicular melanoblasts (MBs) are derived from the melanocyte stem cells residing at the bulge area of hair follicle, the process of vitiligo repigmentation presents a research model for studying the regenerative effect of PBM therapy. Previous reports have shown favourable response for treatment of vitiligo with a low-energy helium-neon (He-Ne) laser. This review focuses on the molecular events that took place during the repigmentation process of vitiligo triggered by He-Ne laser (632.8 nm, red light). Monochromatic radiation in the visible and infrared A (IRA) range sustains matrix metalloproteinase (MMP), improves mitochondrial function, and increases adenosine triphosphate (ATP) synthesis and O2 consumption, which lead to cellular regenerative pathways. Cytochrome c oxidase in the mitochondria was reported to be the photoacceptor upon which He-Ne laser exerts its effects. Mitochondrial retrograde signalling is responsible for the cellular events by red light. This review shows that He-Ne laser initiated mitochondrial retrograde signalling via a Ca2+ -dependent cascade. The impact on cytochrome c oxidase within the mitochondria, an event that results in activation of CREB (cyclic-AMP response element binding protein)-related cascade, is responsible for the He-Ne laser promoting functional development at different stages of MBs and boosting functional melanocytes. He-Ne laser irradiation induced (a) melanocyte stem cell differentiation; (b) immature outer root sheath MB migration; (c) differentiated outer root sheath MB melanogenesis and migration; and (d) perilesional melanocyte migration and proliferation. These photobiomodulation effects result in perifollocular and marginal repigmentation in vitiligo.

Efficacy and safety of topical SR-T100 gel in treating actinic keratosis in Taiwan: A Phase III randomized double-blind vehicle-controlled parallel trial.

BACKGROUND: Currently available topical treatments for actinic keratosis (AK) are associated with substantial side-effects. OBJECTIVES: To evaluate the efficacy and safety of topical SR-T100 gel in treating AK. METHODS: A multicenter, randomized, double-blinded phase III trial was conducted. Patients with at least two clinically visible AK were enrolled and a punch biopsy was performed on one of the AK to confirm the diagnosis. This study consisted of up to 16-week treatment and 8-week post-treatment periods. Medication was applied daily with occlusive dressing. RESULTS: 123 subjects were recruited and 113 were randomized. 76 subjects were in the SR-T100 and 37 in the vehicle arms. In SR-T100 and vehicle groups, 32.39% and 17.14% of subjects achieved complete clearance, respectively. For 75% partial clearance of lesions, 71.83% and 37.1% of subjects achieved this goal in SR-T100 and vehicle group, respectively. When comparing SR-T100 to vehicle, the odds ratio of complete clearance was 2.14 (p = 0.111), and odds ratio of partial clearance was 4.36 (p < 0.001). Severe local reactions were reported by only one subject using SR-T100. CONCLUSION: The imitation of the study was that not all the treated AK lesions were confirmed by histopathology. The diagnostic uncertainty may contribute to the high partial clearance rate in the vehicle group since the clinical-diagnosed AK showed higher clearance rate compared to histopathology-confirmed AK. The use of occlusive dressing was another possible explanation for high placebo effects. The results suggested that topical SR-T100 gel may be an effective and safe treatment for field therapy of AK.

Combined Genetic Biomarkers and Betel Quid Chewing for Identifying High-Risk Group for Oral Cancer Occurrence.

We integrated genetic risk scores (GRS) and environmental factors for identifying high-risk subjects for oral squamous cell carcinoma (OSCC) occurrence by using case-control study. A total of 447 patients diagnosed with OSCC and 580 unrelated subjects were recruited from two medical centers in Taiwan. A multinomial logistic regression model was conducted to access interaction between GRS and betel quid (BQ) chewing. We employed ROC curve to compare the accuracy of OSCC occurrence. Four tag SNPs were found in NOTCH1, BRCA1, COL9A1, and HSPA13 genes that were significantly associated with OSCC occurrence. GRS was calculated by the four tag SNP risk alleles. The higher GRS (scores = 4) remained independently associated with risk of OSCC after adjustment for age, the use of alcohol, BQ, and cigarette: adjusted OR = 4.42 [95% confidence interval (95% CI), 1.34-14.55]. The GRS and BQ chewing interaction showed an increased risk for OSCC occurrence with adjusting for other substance use and age (OR = 70.77; 95% CI, 8.70-575.73). The synergy index was 16.58 (95% CI, 2.27-70.56), suggesting a positive additive interaction between GRS and BQ chewing. The areas under the ROC curves (AUROC) were 0.91 for combined GRS and BQ chewing with sensitivity of 88.6% and specificity of 86.7%. The AUROC of GRS and BQ chewing is above 90%, which may be valuable in identifying high-risk subjects. Early screening can allow the clinician to provide the appropriate intervention and to reduce the OSCC occurrence. Cancer Prev Res; 10(6); 355-62. ©2017 AACR.

Phototherapy and Combination Therapies for Vitiligo.

Vitiligo is a disease characterized by disappearance of melanocytes from the skin. It can negatively influence the physical appearance of affected individuals, and may profoundly affect a person's psychosocial function and quality of life. Therefore, vitiligo should not be considered as merely a condition that affects a patient's appearance, but needs to be actively treated in patients who seek medical help. Phototherapy has been used as the main treatment modality for patients with vitiligo. Different forms of phototherapy for vitiligo include broadband UVB, narrowband UVB, excimer light and excimer laser, and psoralen plus UVA.

Irradiance, but not fluence, plays a crucial role in UVB-induced immature pigment cell development: new insights for efficient UVB phototherapy.

Light exposure modulates development of living organisms. In the field of medicine, light has frequently been used for regenerative purposes. Excimer light (308 nm) has demonstrated superior efficacy in treating vitiligo, a condition requiring development of melanoblasts and a model for studying nerve cell regeneration, as compared to narrow-band ultraviolet B (NBUVB; 311 nm). Using mouse-derived melanoblast cells to examine the pro-differentiation effects of these two light sources, we demonstrated that at equivalent fluence, excimer light induces melanoblast differentiation, while NBUVB failed to so. Mechanistically, activation of aryl hydrocarbon receptor pathway and nuclear translocation of epidermal growth factor receptor are involved in pro-differentiation effects of excimer light. Reduction in irradiance by filter abrogated the effects of excimer light in melanoblasts, even when equivalent fluence was delivered by the same light source. As ultraviolet B (UVB) irradiation is closely associated pigment cell development, future therapy employing UVB for pigmentation purposes should incorporate irradiance as a crucial specification.

Induction of primitive pigment cell differentiation by visible light (helium-neon laser): a photoacceptor-specific response not replicable by UVB irradiation.

Solar lights encompass ultraviolet (UV), visible, and infrared spectrum. Most previous studies focused on the harmful UV effects, and the biologic effects of lights at other spectrums remained unclear. Recently, lights at visible region have been used for regenerative purposes. Using the process of vitiligo repigmentation as a research model, we focused on elucidating the pro-differentiation effects induced by visible light. We first showed that helium-neon (He-Ne) laser (632.8 nm) irradiation stimulated differentiation of primitive pigment cells, an effect not replicable by UVB treatment even at high and damaging doses. In addition, significant increases of mitochondrial DNA copy number and the regulatory genes for mitochondrial biogenesis were induced by He-Ne laser irradiation. Mechanistically, we demonstrated that He-Ne laser initiated mitochondrial retrograde signaling via a Ca(2+)-dependent cascade. The impact on cytochrome c oxidase within the mitochondria is responsible for the efficacy of He-Ne laser in promoting melanoblast differentiation. Taken together, we propose that visible lights from the sun provide important environmental cues for the relatively quiescent stem or primitive cells to differentiate. In addition, our results also indicate that visible light may be used for regenerative medical purposes involving stem cells.

Chronic arsenic exposure and its adverse health effects in Taiwan: a paradigm for management of a global environmental problem.

It was estimated that, nearly 100 million people are at risk for drinking arsenic (As)-contaminated drinking water. Although the WHO guideline recommends that levels of As in drinking water should not exceed 10 µm/L, it was estimated that more than 30 million people drink As-containing water at levels more than 50 µm/L in Bangladesh and India alone. Therefore, the adverse health effects resulting from chronic As exposure pose a global threat. In Taiwan, studies focusing on the health effects resulting from chronic As exposure through contaminated drinking water have been ongoing for more than 50 years. During the past half century, it was recognized that the impact of high As exposure on human health is much more complicated than originally anticipated. Chronic As exposure resulted in infamous blackfoot disease, which is unique to As endemic areas in Taiwan, and various diseases including cancers and non-cancers. Although the potential-biological outcomes have been well-documented, the pathomechanisms leading from As exposure to occurrence and development of the diseases remain largely unclear. One of the major obstacles that hindered further understanding regarding the adverse health effect resulting from chronic As exposure is documentation of cumulative As exposure from the distant past, which remains difficult as the present technologies mostly document relatively recent As exposure. Furthermore, the susceptibility to As exposure appears to differ between different ethnic groups and individuals and is modified by lifestyle factors including smoking habits and nutrition status. No consensus data has yet been reached even after comparing the study results obtained from different parts of the world focusing on associations between human As toxicity and genetic polymorphisms in terms of cellular detoxification enzymes, tumor suppressor proteins, and DNA repair pathway. With the availability of the new powerful "OMIC" technologies, it may now be possible to gain new path-breaking insights regarding this important environmental health issue. The lessons learned from the past half-century placed Taiwan in an experienced position to actively participate in the international collaborative projects using these novel technologies and standardized methods.

Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway.

BACKGROUND: The Solanum species herbs have been used to treat cancer for centuries; however, the underlying mechanisms and effectiveness in vivo remain unclear. OBJECTIVES: SR-T100, extracted from the Solanum incanum, contains solamargine alkaloid as the main active ingredient. Here, we investigated the apoptosis-inducing effects of SR-T100 for targeting squamous cell carcinoma (SCC) in vitro and in vivo. METHODS: We elucidated the mechanism by which SR-T100 induces apoptosis of human SCCs (A431, SCC4, SCC9, and SCC25) cells. The efficacy and safety issues were addressed regarding topical treatment of SR-T100 on UVB-induced cutaneous SCC of hairless mice and actinic keratoses (AKs) of human. RESULTS: SR-T100 induces apoptosis in human SCCs cell lines by up-regulating the expressions of tumor necrosis factor receptors (TNFRs) and Fas, and downstream adaptors FADD/TRADD of the TNF-α and Fas ligand signaling cascades. SR-T100 also triggered the mitochondrial apoptotic pathway, as up-regulated cytochrome c and Bax, down-regulated Bcl-X(L). Animal experiments showed that all papillomas (35/35) and 27 of 30 UVB-induced microinvasive SCCs in hairless mice disappeared within 10 weeks after once-daily application of topical SR-T100. Furthermore, 13 patients, who suffered with 14 AKs, were treated with once-daily topical SR-T100 gel and 10 AKs cured after 16 weeks, showing negligible discomforts. CONCLUSION: Our studies indicate that SR-T100 induces apoptosis of SCC cells via death receptors and the mitochondrial death pathway. The high efficacy of SR-T100 in our preclinical trial suggests that SR-T100 is a highly promising herb for AKs and related disorders.

Low-energy helium-neon laser therapy induces repigmentation and improves the abnormalities of cutaneous microcirculation in segmental-type vitiligo lesions.

Segmental vitiligo (SV) is a special form of vitiligo occurring in a dermatomal distribution, and an abnormality involving the sympathetic nerves supplying the affected dermatome is known to underlie this disorder. Previously, we have shown that SV is associated with an abnormal increase in cutaneous blood flow and adrenoceptor responses in the affected areas. Since SV is resistant to conventional forms of therapy, its management represents a challenge for dermatologists. Low energy helium-neon lasers (He-Ne laser, wavelength 632.8 nm) have been employed as a therapeutic instrument in many clinical situations, including vitiligo management and repair of nerve injury. The purpose of this study was to evaluate the effectiveness and safety of He-Ne lasers in treating SV, and determine their effects on the repair of sympathetic nerve dysfunction. Forty patients with stable-stage SV on the head and/or neck were enrolled in this study. He-Ne laser irradiation was administered locally at 3.0 J/cm2 with point stimulation once or twice weekly. Cutaneous microcirculatory assessments in six SV patients were performed using a laser Doppler flowmeter. The sympathetic adrenoceptor response of cutaneous microcirculation was determined by measuring cutaneous blood flow before, during and after iontophoresis with sympathomimetic drugs (phenylephrine, clonidine and propranolol). All measurements of microcirculation obtained at SV lesions were simultaneously compared with contralateral normal skin, both before and after He-Ne laser treatment. After an average of 17 treatment sessions, initial repigmentation was noticed in the majority of patients. Marked repigmentation (> 50%) was observed in 60% of patients with successive treatments. Cutaneous blood flow was significantly higher at SV lesions compared with contralateral skin, but this was normalized after He-Ne laser treatment. In addition, the abnormal decrease in cutaneous blood flow in response to clonidine was improved by He-Ne laser therapy. Our study showed that He-Ne laser therapy is an effective treatment for SV by normalizing dysfunctions of cutaneous blood flow and adrenoceptor responses in SV patients. Thus, the beneficial effects of He-Ne laser therapy may be mediated in part by a reparative effect on sympathetic nerve dysfunction.

Low-energy helium-neon laser induces locomotion of the immature melanoblasts and promotes melanogenesis of the more differentiated melanoblasts: recapitulation of vitiligo repigmentation in vitro.

Helium-neon laser (He-Ne Laser, 632.8 nm) is a low-energy laser that has therapeutic efficacy on various clinical conditions. Our previous study has demonstrated efficacy of He-Ne laser on vitiligo, a disease characterized by skin depigmentation. To regain skin tone on vitiligo lesions, the process began by the migration of the immature melanoblasts (MBs) to the epidermis, which was followed by their functional development to produce melanin. In this study, we investigated the physiologic effects of He-Ne laser irradiation on two MB cell lines: the immature NCCmelb4 and the more differentiated NCCmelan5. The intricate interactions between MBs with their innate extracelluar matrix, fibronectin, were also addressed. Our results showed that He-Ne laser irradiation enhanced NCCmelb4 mobility via enhanced phosphorylated focal adhesion kinase expression and promoted melanogenesis in NCCmelan5. In addition, He-Ne laser decreased the affinity between NCCmelb4 and fibronectin, whereas the attachment of NCCmelan5 to fibronectin increased. The alpha5beta1 integrin expression on NCCmelb4 cells was enhanced by He-Ne laser. In conclusion, we have demonstrated that He-Ne laser induced different physiologic changes on MBs at different maturation stages and recapitulated the early events during vitiligo repigmentation process brought upon by He-Ne laser in vitro.

Narrow-band UVB treatment of vitiligo in Chinese.

Narrow-band ultraviolet B (NBUVB) phototherapy has recently been reported to be an effective and safe treatment modality for vitiligo. In the present report, we evaluated the efficacy and safety of NBUVB therapy for vitiligo in Chinese patients. Seventy-two vitiligo patients treated from 2000 to 2003, were included retrospectively (male: female=33:39, mean age: 38.5). Among them, 61 were non-segmental type and 11 the segmental type. Treatments were given two to three times a week for a maximum period of one year with an initial dose of 0.2 J/cm2 and a 0-20% increment each session (mean accumulation dose: 155.3 J/cm2). Computer image analysis by Supervise classification was used to estimate the area of vitiligo involvement before and after treatment. An excellent response (75-100% area of repigmentation) was obtained in 9 patients (12.5%) and a good response (50-75%) in 24 (33.3%), a moderate response (25-50%) in 20 (27.8%), and a poor response (0-25%) in 19 (26.4%). In summary, 45.8% of our patients had more than 50% repigmentation. Burns were a side effect in 5 patients (7%) and transient erythema with itching or xerosis was noted in 5 patients (7%). These results indicate that NBUVB phototherapy is an effective and safe treatment choice for generalized vitiligo.