Comparison of racial distribution of photodermatoses in USA academic dermatology clinics: A multicenter retrospective analysis of 1080 patients over a 10-year period.

BACKGROUND: Previous studies at single academic institutions have identified variations in the prevalence of photodermatoses among racial groups. The purpose of the study was to compare the distribution of photodermatoses between Whites and Blacks at four academic medical centers in the USA. METHODS: A retrospective chart review was performed at four institutions' general dermatology clinics using diagnoses consistent with the International Classification of Disease (ICD), Ninth and Tenth Revisions, codes related to photodermatoses between August 2006 and August 2016. A total of 9736 charts were manually reviewed and classified. Analyses were performed analyzing the frequency of photodermatoses between Whites and Blacks in the pooled data. RESULTS: There were 1,080 patients with photodermatoses identified. Statistically significant differences in the frequency of photodermatoses between Whites and Blacks were identified for polymorphous light eruption (more common in Blacks), photoallergic contact dermatitis, phototoxic drug eruption, phytophotodermatitis, porphyria, and solar urticaria (more common in Whites). The most commonly diagnosed photodermatoses were polymorphous light eruption (total 672), and photodermatitis not otherwise specified (total 189). CONCLUSION: Our study demonstrated significantly higher proportions of polymorphous light eruption in Blacks, and higher proportions of photoallergic contact dermatitis, phototoxic drug eruptions, phytophotodermatitis, porphyrias, and solar urticaria in Whites.

The Immune System and Pathogenesis of Melanoma and Non-melanoma Skin Cancer.

Tumor development is the result of genetic derangement and the inability to prevent unfettered proliferation. Genetic derangements leading to tumorigenesis are variable, but the immune system plays a critical role in tumor development, prevention, and production. In this chapter, we will discuss the importance of the immune system as it relates to the development of skin cancer-both melanoma and non-melanoma skin cancers (NMSC).

PEGylated Dendrimers as Drug Delivery Vehicles for the Photosensitizer Silicon Phthalocyanine Pc 4 for Candidal Infections.

Fungi account for billions of infections worldwide. The second most prominent causative agent for fungal infections is Candida albicans (C. albicans). As strains of fungi become resistant to antifungal medications, new treatment modalities must be investigated to combat these infections. One approach is to employ photodynamic therapy (PDT). PDT utilizes a photosensitizer, light, and cellular O2 to produce reactive oxygen species (ROS), which then induce oxidative stress resulting in apoptosis. Silicon phthalocyanine Pc 4 is a photosensitizer that has exhibited success in clinical trials for a myriad of skin diseases. The hydrophobic nature of Pc 4, however, poses significant formulation and delivery challenges in the use of this therapy. To mitigate these concerns, a drug delivery vehicle was synthesized to better formulate Pc 4 into a viable PDT agent for treating fungal infections. Utilizing poly(amidoamine) dendrimers as the framework for the vehicle, ∼13% of the amine chain ends were PEGylated to promote water solubility and deter nonspecific adsorption. In vitro studies with C. albicans demonstrate that the potency of Pc 4 was not hindered by the dendrimer vehicle. Encapsulated Pc 4 was able to effectively generate ROS and obliterate fungal pathogens upon photoactivation. The results presented within describe a nanoparticulate delivery vehicle for Pc 4 that readily kills drug-resistant C. albicans and eliminates solvent toxicity, thus, improving formulation characteristics for the hydrophobic photosensitizer.

Activated T cells exhibit increased uptake of silicon phthalocyanine Pc 4 and increased susceptibility to Pc 4-photodynamic therapy-mediated cell death.

Photodynamic therapy (PDT) is an emerging treatment for malignant and inflammatory dermal disorders. Photoirradiation of the silicon phthalocyanine (Pc) 4 photosensitizer with red light generates singlet oxygen and other reactive oxygen species to induce cell death. We previously reported that Pc 4-PDT elicited cell death in lymphoid-derived (Jurkat) and epithelial-derived (A431) cell lines in vitro, and furthermore that Jurkat cells were more sensitive than A431 cells to treatment. In this study, we examined the effectiveness of Pc 4-PDT on primary human CD3(+) T cells in vitro. Fluorometric analyses of lysed T cells confirmed the dose-dependent uptake of Pc 4 in non-stimulated and stimulated T cells. Flow cytometric analyses measuring annexin V and propidium iodide (PI) demonstrated a dose-dependent increase of T cell apoptosis (6.6-59.9%) at Pc 4 doses ranging from 0-300 nM. Following T cell stimulation through the T cell receptor using a combination of anti-CD3 and anti-CD28 antibodies, activated T cells exhibited increased susceptibility to Pc 4-PDT-induced apoptosis (10.6-81.2%) as determined by Pc 4 fluorescence in each cell, in both non-stimulated and stimulated T cells, Pc 4 uptake increased with Pc 4 dose up to 300 nM as assessed by flow cytometry. The mean fluorescence intensity (MFI) of Pc 4 uptake measured in stimulated T cells was significantly increased over the uptake of resting T cells at each dose of Pc 4 tested (50, 100, 150 and 300 nM, p < 0.001 between 50 and 150 nM, n = 8). Treg uptake was diminished relative to other T cells. Cutaneous T cell lymphoma (CTCL) T cells appeared to take up somewhat more Pc 4 than normal resting T cells at 100 and 150 nm Pc 4. Confocal imaging revealed that Pc 4 localized in cytoplasmic organelles, with approximately half of the Pc 4 co-localized with mitochondria in T cells. Thus, Pc 4-PDT exerts an enhanced apoptotic effect on activated CD3(+) T cells that may be exploited in targeting T cell-mediated skin diseases, such as cutaneous T cell lymphoma (CTCL) or psoriasis.

The photodynamic antibacterial effects of silicon phthalocyanine (Pc) 4.

The emergence of antibiotic-resistant strains in facultative anaerobic Gram-positive coccal bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), is a global health issue. Typically, MRSA strains are found associated with institutions like hospitals but recent data suggest that they are becoming more prevalent in community-acquired infections. It is thought that the incidence and prevalence of bacterial infections will continue to increase as (a) more frequent use of broad-spectrum antibiotics and immunosuppressive medications; (b) increased number of invasive medical procedures; and (c) higher incidence of neutropenia and HIV infections. Therefore, more optimal treatments, such as photodynamic therapy (PDT), are warranted. PDT requires the interaction of light, a photosensitizing agent, and molecular oxygen to induce cytotoxic effects. In this study, we investigated the efficacy and characterized the mechanism of cytotoxicity induced by photodynamic therapy sensitized by silicon phthalocyanine (Pc) 4 on (a) methicillin-sensitive Staphylococcus aureus (MSSA) (ATCC 25923); (b) community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) (ATCC 43300); and (c) hospital acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) (PFGE type 300). Our data include confocal image analysis, which confirmed that Pc 4 is taken up by all S. aureus strains, and viable cell recovery assay, which showed that concentrations as low as 1.0 µM Pc 4 incubated for 3 h at 37 °C followed by light at 2.0 J/cm2 can reduce cell survival by 2-5 logs. These results are encouraging, but before PDT can be utilized as an alternative treatment for eradicating resistant strains, we must first characterize the mechanism of cell death that Pc 4-based PDT employs in eliminating these pathogens.

Silicon phthalocyanine 4 phototoxicity in Trichophyton rubrum.

Trichophyton rubrum is the leading pathogen that causes long-lasting skin and nail dermatophyte infections. Currently, topical treatment consists of terbinafine for the skin and ciclopirox for the nails, whereas systemic agents, such as oral terbinafine and itraconazole, are also prescribed. These systemic drugs have severe side effects, including liver toxicity. Topical therapies, however, are sometimes ineffective. This led us to investigate alternative treatment options, such as photodynamic therapy (PDT). Although PDT is traditionally recognized as a therapeutic option for treating a wide range of medical conditions, including age-related macular degeneration and malignant cancers, its antimicrobial properties have also received considerable attention. However, the mechanism(s) underlying the susceptibility of dermatophytic fungi to PDT is relatively unknown. As a noninvasive treatment, PDT uses a photosensitizing drug and light, which, in the presence of oxygen, results in cellular destruction. In this study, we investigated the mechanism of cytotoxicity of PDT in vitro using the silicon phthalocyanine (Pc) 4 [SiPc(OSi(CH3)2(CH2)3N(CH3)2)(OH)] in T. rubrum. Confocal microscopy revealed that Pc 4 binds to cytoplasmic organelles, and upon irradiation, reactive oxygen species (ROS) are generated. The impairment of fungal metabolic activities as measured by an XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt) assay indicated that 1.0 µM Pc 4 followed by 670 to 675 nm light at 2.0 J/cm(2) reduced the overall cell survival rate, which was substantiated by a dry weight assay. In addition, we found that this therapeutic approach is effective against terbinafine-sensitive (24602) and terbinafine-resistant (MRL666) strains. These data suggest that Pc 4-PDT may have utility as a treatment for dermatophytosis.

The immune system and skin cancer.

Carcinogenesis involves multiple mechanisms that disturb genomic integrity and encourage abnormal proliferation. The immune system plays an integral role in maintaining homeostasis and these mechanisms may arrest or enhance dysplasia. There exists a large body of evidence from organ transplantation literature supporting the significance of the immune suppression in the development of skin cancer. Nonmelanoma skin cancers are the most frequent neoplasms after organ transplantation, with organ transplant recipients having a 65-fold increase in squamous cell carcinoma incidence and 10-fold increase in basal cell carcinoma incidence. Similarly, UV-radiation (UVR) induced immunosuppression is correlated with the development of cutaneous malignancies in a dose-dependent manner. This was first shown several decades ago by Margaret Kripke, when transplanted tumors were rejected in mice with competent immune systems, but grew unchecked in immunosuppressed specimens. After UV exposure, chromophores initiate a cascade that leads to immunosuppression via derangement of Langerhans cells' antigen-presenting capacity. UV-irradiated Langerhans cells present antigens to Th2 cells, but fail to stimulate Th1 cells. A subset of T regulatory cells, specific for the antigen encountered after UVR, is also stimulated to proliferate. In general UV irradiation leads to a greater number of T regulatory cells and fewer effector T cells in the skin, shiftingthe balance from T-cell-mediated immunity to immunosuppression. These regulatory cells have the phenotype CD4+, CD25+, Foxp3+, CTLA-4+. These and many other changes in local immunity lead to a suppressed immune state, which allow for skin cancer development.

Acute effects of fractional laser on photo-aged skin.

BACKGROUND: Nonablative fractional photothermolysis (FP) laser treatment has shown clinical efficacy on photo-aged skin. Few studies have examined the molecular responses to FP. OBJECTIVE: To characterize the dynamic alterations involved in dermal matrix remodeling after FP laser treatment. METHODS: A single multipass FP treatment was performed. Baseline, day 1, and day 7 biopsies were obtained. Biopsies were sectioned and stained for histology and immunofluorescence confocal microscopic. Heat shock protein-70 (HSP-70) and matrix metalloproteinase-1 (MMP-1) expression and extracellular matrix (ECM) autofluorescence were examined. Quantitative real-time polymerase chain reaction (qRT-PCR) experiments were performed probing for collagen 1A1 (COL1A1) and COL3A1. RESULTS: All three patients were Caucasian women aged 49, 62, and 64 with Fitzpatrick skin types II, III, and IV. Transient neutrophilic infiltration found on day 1. Protein expression of HSP-70 and MMP-1 were up-regulated on day 1, reverting to baseline by day 7. ECM autofluorescence decreased from baseline to day 7. qRT-PCR showed a minor decrease in COL1A1 and COL3A1 messenger RNA 1 day after treatment. Variable results between patients receiving equal treatment were evident.

Effects of pimecrolimus versus triamcinolone on Langerhans cells after UV exposure.

BACKGROUND/PURPOSE: Pimecrolimus is a topical immunomodulator for atopic dermatitis. Concerns regarding malignancy risk resulted in its black box warning in 2006. The purpose of this study is to determine the effects of pimecrolimus on Langerhans cells (LC), mediators of the cutaneous immunity UV-irradiated skin. METHODS: A RCT was conducted investigating pimecrolimus 1% cream vs triamcinolone 0.1% cream on UV-irradiated epidermal LC on 20 healthy volunteers. Punch biopsies were stained with antibodies to CD1a, HLADR and CD83. RESULTS: Triamcinolone caused more depletion in UV-irradiated CD1a(+) epidermis relative to pimecrolimus treatment. (P=0.030). Using HLA-DR as a pan-marker for APCs, pimecrolimus caused marginally less depletion than triamcinolone (P=0.013). Using anti-CD83 as a maturation marker, UV-irradiated skin treated with pimecrolimus showed more mature LC than skin treated with triamcinolone (P=0.00090). CONCLUSION: UV-induced changes in LC are minimally affected by pimecrolimus, compared with triamcinolone.

Silicon phthalocyanine (Pc 4) photodynamic therapy is a safe modality for cutaneous neoplasms: results of a phase 1 clinical trial.

BACKGROUND: Photodynamic therapy (PDT) is a non-invasive treatment for non-melanoma skin cancer. However, PDT systems currently used clinically have limitations such as pain and superficial tissue penetration. The silicon phthalocyanine Pc 4 is a second-generation photosensitizer with peak absorption in the far red at 675 nm. OBJECTIVE: To assess the safety and tolerability of topically applied Pc 4 followed by red light (Pc 4-PDT) in treating cutaneous neoplasms. STUDY DESIGN/MATERIALS AND METHODS: Forty three adults with a diagnosis of neoplasms including actinic keratoses, Bowen's disease, squamous cell carcinoma, basal cell carcinoma, or mycosis fungoides were treated with a single administration of Pc 4-PDT and followed for 14 days. The study utilized a light and Pc 4 dose escalation design in sequential groups of three subjects each. RESULTS: Pc 4-PDT was well tolerated with no significant local toxicity or increased photosensitivity. It has promising biologic effects, particularly in mycosis fungoides where 14 of 35 subjects demonstrated a clinical response, which correlates with Pc 4-PDT-induced apoptosis, as measured by increased active caspase-3 in the treated skin lesions. CONCLUSIONS: Pc 4-PDT is a safe and tolerable treatment modality that effectively triggers apoptosis in cutaneous neoplasms such as mycosis fungoides.

Topical application of green and white tea extracts provides protection from solar-simulated ultraviolet light in human skin.

BACKGROUND: Tea polyphenols have been found to exert beneficial effects on the skin via their antioxidant properties. AIMS: We sought to determine whether topical application of green tea or white tea extracts would prevent simulated solar radiation-induced oxidative damages to DNA and Langerhans cells that may lead to immune suppression and carcinogenesis. METHODS: Skin samples were analysed from volunteers or skin explants treated with white tea or green tea after UV irradiation. In another group of patients, the in vivo immune protective effects of green and white tea were evaluated using contact hypersensitivity to dinitrochlorobenzene. RESULTS: Topical application of green and white tea offered protection against detrimental effects of UV on cutaneous immunity. Such protection is not because of direct UV absorption or sunscreen effects as both products showed a sun protection factor of 1. There was no significant difference in the levels of protection afforded by the two agents. Hence, both green tea and white tea are potential photoprotective agents that may be used in conjunction with established methods of sun protection.

The Effect of Shift Work and Poor Sleep on Self-Reported Skin Conditions: A Survey of Call Center Agents in the Philippines.

Night shift workers may have a disrupted circadian rhythm, which may contribute to the development of skin disease. The purpose of this study was to determine whether there is a significant difference in the prevalence and severity of self-reported skin disease between "regular" day shift workers compared to "graveyard" night shift workers. We conducted surveys from 630 call center agents in Manila, the Philippines, and they were analyzed regarding demographics, medical history, dermatologic history, lifestyle, and sleep. No difference was found in the prevalence of skin disease between shifts. However, night shift workers were worse sleepers. When compared to good sleepers, poor sleepers had a higher prevalence of skin disease with worse severity. Graveyard shift workers with poor sleep may have increased skin disease severity.

Monitoring Pc 4 photodynamic therapy in clinical trials of cutaneous T-cell lymphoma using noninvasive spectroscopy.

Silicon phthalocyanine Pc 4 photodynamic therapy (Pc 4-PDT) has emerged as a potentially effective treatment for cutaneous T-cell lymphoma (CTCL). Noninvasive reflectance and fluorescence spectroscopy before, during, and after PDT may provide useful dose metrics and enable therapy to be tailored to individual lesions. We present the design and implementation of a portable bedside spectroscopy system for initial clinical trials of Pc 4-PDT of CTCL. Reflectance and fluorescence spectra were obtained from an early stage CTCL patient throughout the course of the PDT treatment. Preliminary patient data show a significant effect of Pc 4 on the tissue absorption, modest Pc 4 photobleaching, and heterogeneity of Pc 4 within and between the lesions.

UV protective effects of DNA repair enzymes and RNA lotion.

Solar UV radiation is known to cause immune suppression, believed to be a critical factor in cutaneous carcinogenesis. Although the mechanism is not entirely understood, DNA damage is clearly involved. Sunscreens function by attenuating the UV radiation that reaches the epidermis. However, once DNA damage ensues, repair mechanisms become essential for prevention of malignant transformation. DNA repair enzymes have shown efficacy in reducing cutaneous neoplasms among xeroderma pigmentosum patients. In vitro studies suggest that RNA fragments increase the resistance of human keratinocytes to UVB damage and enhance DNA repair but in vivo data are lacking. This study aimed to determine the effect of topical formulations containing either DNA repair enzymes (Micrococcus luteus) or RNA fragments (UVC-irradiated rabbit globin mRNA) on UV-induced local contact hypersensitivity (CHS) suppression in humans as measured in vivo using the contact allergen dinitrochlorobenzene. Immunohistochemistry was also employed in skin biopsies to evaluate the level of thymine dimers after UV. Eighty volunteers completed the CHS portion. A single 0.75 minimum erythema dose (MED) simulated solar radiation exposure resulted in 64% CHS suppression in unprotected subjects compared with unirradiated sensitized controls. In contrast, UV-induced CHS suppression was reduced to 19% with DNA repair enzymes, and 7% with RNA fragments. Sun protection factor (SPF) testing revealed an SPF of 1 for both formulations, indicating that the observed immune protection cannot be attributed to sunscreen effects. Biopsies from an additional nine volunteers showed an 18% decrease in thymine dimers by both DNA repair enzymes and RNA fragments, relative to unprotected UV-irradiated skin. These results suggest that RNA fragments may be useful as a photoprotective agent with in vivo effects comparable to DNA repair enzymes.

Apoptosis mechanisms related to the increased sensitivity of Jurkat T-cells vs A431 epidermoid cells to photodynamic therapy with the phthalocyanine Pc 4.

To examine the clinical applicability of Pc 4, a promising second-generation photosensitizer, for the photodynamic treatment of lymphocyte-mediated skin diseases, we studied the A431 and Jurkat cell lines, commonly used as surrogates for human keratinocyte-derived carcinomas and lymphocytes, respectively. As revealed by ethyl acetate extraction and absorption spectrophotometry, uptake of Pc 4 into the two cell lines was linear with Pc 4 concentration and similar on a per cell basis but greater in Jurkat cells on a per mass basis. Flow cytometry showed that uptake was linear at low doses; variations in the dose-response for uptake measured by fluorescence supported differential aggregation of Pc 4 in the two cell types. As detected by confocal microscopy, Pc 4 localized to mitochondria and endoplasmic reticulum in both cell lines. Jurkat cells were much more sensitive to the lethal effects of phthalocyanine photodynamic therapy (Pc 4-PDT) than were A431 cells, as measured by a tetrazolium dye reduction assay, and more readily underwent morphological apoptosis. In a search for molecular factors to explain the greater photosensitivity of Jurkat cells, the fate of important Bcl-2 family members was monitored. Jurkat cells were more sensitive to the induction of immediate photodamage to Bcl-2, but the difference was insufficient to account fully for their greater sensitivity. The antiapoptotic protein Mcl-1 was extensively cleaved in a dose- and caspase-dependent manner in Jurkat, but not in A431, cells exposed to Pc 4-PDT. Thus, the greater killing by Pc 4-PDT in Jurkat compared with A431 cells correlated with greater Bcl-2 photodamage and more strongly to the more extensive Mcl-1 degradation. Pc 4-PDT may offer therapeutic advantages in targeting inflammatory cells over normal keratinocytes in the treatment of T-cell-mediated skin diseases, such as cutaneous lymphomas, dermatitis, lichenoid tissue reactions and psoriasis, and it will be instructive to evaluate the role of Bcl-2 family proteins, especially Mcl-1, in the therapeutic response.

Role of photodynamic therapy in psoriasis: a brief review.

BACKGROUND AND PURPOSE: Photodynamic therapy (PDT) is a light treatment modality which involves either systemic or local application of a photosensitizing compound, which preferentially deposits in the target cells, and is then followed by selective illumination of the lesion with visible light. The purpose of this study was to review the literature to examine the success, side effects, and different protocols used thus far to treat psoriasis using PDT. METHODS: A thorough review of the literature was performed and analyzed. RESULTS AND CONCLUSIONS: After a thorough review of the literature, PDT remains a potential treatment for psoriasis. Clinical improvement has been observed in most studies. The major limiting factor seen in many of the studies was the side effect of pain and burning sensations associated with PDT. This highlights the need for other photosensitizers with better tolerability profiles.

Erythema nodosum in association with newly diagnosed hairy cell leukemia and group C streptococcus infection.

Erythema nodosum is an inflammatory reaction of the skin characterized by tender erythematous patches or nodules, usually located on the lower extremities. This report illustrates an association of erythema nodosum with a rare malignancy and an uncommon infectious agent in humans. There are many diseases associated with erythema nodosum; we propose that hairy cell leukemia and group C streptococcus be considered among this list.

Advances in photoprotection.

Major advancements in the realm of photoprotection have occurred over the last decade providing potential means to reduce the prevalence of ultraviolet radiation-related skin problems. This review elucidates current photoprotective methods and recent developments that may hold future promise.

Topical application of ST266 reduces UV-induced skin damage.

Ultraviolet radiation (UVR) has a significant impact on human skin and is the major environmental factor for skin cancer formation. It is also believed that 80% of the signs of skin aging are attributed to UVR. UVR induces inflammatory changes in the skin via the increase in oxidative stress, DNA damage vascular permeability, and fluctuation in a myriad of cytokines. Acutely, UVR causes skin inflammation and DNA damage, which manifest as sunburn (erythema). ST266 is the secretome of proprietary amnion-derived cells that have been shown to reduce inflammation and accelerate healing of various wounds by promoting migration of keratinocytes and fibroblasts in preclinical animal studies. We hypothesized that ST266 has anti-inflammatory effects that can be used to reduce ultraviolet (UV) erythema and markers of inflammation. In this study, we examined the in vivo effects of ST266 on post UV-irradiated skin by measuring erythema, level of cyclobutane pyrimidine dimer (CPD), and expression level of xeroderma pigmentosum, complementation group A (XPA). We demonstrated that ST266 has the potential to reduce the acute effects of UV-induced skin damage when applied immediately after the initial exposure. In addition, ST266 is shown to reduce erythema, increase XPA DNA repair protein, and decrease damaged DNA.