Systematic review of randomized controlled trials of topicals for actinic keratosis field therapy.

Cutaneous field cancerization in dermatology describes the anatomic region of photodamaged skin with actinic keratoses (AKs) or cutaneous squamous cell carcinoma (cSCC) that is surrounded by cellular atypia, forming a dysplastic field. The concept of field cancerization is especially relevant in dermatology, as actinic keratoses and the surrounding dysplastic region can progress to carcinomas, necessitating the treatment of the field. Recent research has focused on field-directed therapy using topical agents. This study aims to systematically review randomized controlled trials on topical treatments for actinic keratosis field cancerization, following the PRISMA guidelines. Clinical recommendations were based on the Oxford Centre for Evidence-Based Medicine. We identified 20 original randomized controlled trials for topical cutaneous field therapy. 0.5% 5-Fluorouracil/salicylic acid and 0.5% 5-fluorouracil received a clinical recommendation grade of A, while diclofenac sodium received a clinical recommendation grade of B. Calcipotriol/5-fluorouracil, Imiquimod, sunscreen combination therapies, and tirbanibulin received a recommendation grade of C. This review provides a framework for clinicians when considering topical treatments for patients with field cancerization.

Blue light aminolevulinic acid photodynamic therapy downregulates cell division and proliferation pathways in cutaneous squamous cell carcinoma.

5-Aminolevulinic acid (5-ALA) photodynamic therapy (PDT) is a treatment for actinic keratosis (AK) and has been studied as a treatment for noninvasive cutaneous squamous cell carcinoma (cSCC). PDT induces apoptosis and necrosis in AKs and cSCC. 5-ALA blue light PDT may modulate gene expression and pathways in surviving cells. In this study, differential gene expression and pathway analysis of cSCC and human dermal fibroblasts were compared before and after 5-ALA blue light PDT using RNA sequencing. No genes were differentially expressed after correcting for multiple testing (false discovery rate < 0.05). As a result, transcription factor, gene enrichment, and pathway analysis were performed with genes identified before multiple testing (p < 0.05). Pathways associated with proliferation and carcinogenesis were downregulated. These findings using 5-ALA blue light PDT are similar to previously published studies using methyl-aminolevulinic and red light protocols, indicating that surviving residual cells may undergo changes consistent with a less aggressive cancerous phenotype.

Near-infrared light does not induce DNA damage in human dermal fibroblasts.

Photobiomodulation (PBM) can be used to treat a range of conditions in dermatology. PBM refers to the changes induced by red (RL, 620-700 nm) and near-infrared (NIR, 700-1440 nm) light. Light radiation-induced DNA damage is a major contributor to aging and skin cancer. It is crucial to study the effects of PBM on DNA to ensure safety. Our lab previously demonstrated that RL (633 ± 6 nm) did not result in human dermal fibroblasts (HDFs) DNA damage. This study employed similar methods to investigate NIR effects. Commercially available LED-NIR (830 ± 5 nm) panels (66, 132, and 264 J/cm2 ) did not result in DNA damage measured by cyclobutane pyrimidine dimers and pyrimidine-6,4-pyrimidone photoproducts in HDFs compared to temperature-matched controls immediately, 3 h, and 24 h following irradiation and compared to positive and negative controls. This demonstrates that LED-NIR does not damage DNA in HDFs in vitro.

The Association Between Herpes Simplex Virus and Alzheimer's Disease: A Systematic Review.

Alzheimer's disease (AD) is a significant public health concern, affecting more than 6 million Americans; and currently, there are no cure or effective treatment options. The underlying etiology and pathogenesis are not fully understood, presenting a barrier to therapy. A substantial amount of data exists associating infection with Herpes simplex virus 1 (HSV-1) and AD. This review of published studies highlights the epidemiological associations between HSV-1 and AD. A systematic search of PubMed, Embase, and Web of Science was conducted on January 6, 2022, using PRISMA guidelines. Articles that presented epidemiological data correlating HSV-1 with AD were included. Bibliographies were screened for additional relevant articles as well. After review, 21 studies were included: 2 review articles and 19 population-based studies including case control, cohort, and cross-sectional studies.  The quantitative data derived from the studies in this report substantiate a relationship between infection with HSV-1 and AD. Based on these results, it may be of reasonable benefit to more consistently treat latent or active HSV-1 infection with anti-viral medications to potentially reduce the risk of AD. Furthermore, a prospective randomized controlled clinical trial could elucidate the benefit of anti-viral therapy to prevent or limit AD.J Drugs Dermatol. 2023;22(10):1046-1052     doi:10.36849/JDD.6785.

Male facial rejuvenation using a combination 633, 830, and 1072 nm LED face mask.

Home-based photobiomodulation is a popular treatment modality for patients seeking non-invasive aesthetic treatment. Studies demonstrate that photobiomodulation is effective for skin rejuvenation, which is aimed at improving the overall appearance of the skin by reducing fine lines and wrinkles and improving skin texture, skin tone, and dyspigmentation. Most current skin rejuvenation research focuses on treatments in women. However, men's aesthetics remains an underserved market. A combined red light (RL) and near-infrared (NIR) light-emitting diode (LED) has been designed specifically to target male skin, which may have different physiological and biophysical properties compared to female skin. Herein, the safety and efficacy of a commercially available RL and NIR (633, 830, and 1072 nm) LED array designed to be worn as a face mask was assessed. Primary outcomes included adverse events and facial rejuvenation as determined by participant-reported satisfaction scales and quantitative digital skin photography and computer analysis after 6 weeks of treatment. The participants reported overall favorable results and improvements in all individual categories, were satisfied with the treatment, and would recommend the product to others. The participants perceived the greatest improvement in fine lines and wrinkles, skin texture, and youthful appearance. Photographic digital analysis demonstrated favorable improvements in wrinkles, UV spots, brown spots, pores, and porphyrins. These results support the use of RL and NIR to treat male skin. Advantages of the LED facemask include its safety, efficacy, convenient home-based use, minimal associated downtime, simple operation, non-invasiveness, and appreciable results in as few as 6 weeks.

Cutaneous effects of photobiomodulation with 1072 nm light.

Photobiomodulation, also known as low-level light therapy, has gained popularity in treating a variety of dermatologic and non-dermatologic conditions. The near-infrared (NIR) portion ranging from 700 to 1440 nm has a broad spectrum but most current research focuses on relatively shorter wavelengths. To date, clinical research regarding the application of 1072 NIR is limited to treatments for infections and photorejuvenation treatment in females. However, 1072 NIR light therapy may benefit male patients. This theoretical application is based on the biological properties of this subgroup having increased cutaneous density and thickness and the physical properties of 1072 NIR allowing it to penetrate increased depth. 1072 NIR can reach more cells throughout the epidermis and dermis compared to other parts of the electromagnetic spectrum traditionally used in phototherapy to provide unique and targeted benefits. 1072 NIR light-emitting diodes are commercially available and therefore hold tremendous potential to become accessible, affordable treatment options. Given the increased demand and market size for aesthetics for men that remains untapped, there is opportunity for future research to elucidate the potential for this wavelength as a safe and effective treatment.

Red Light Phototherapy Using Light-Emitting Diodes Inhibits Melanoma Proliferation and Alters Tumor Microenvironments.

Background: Total annual cancer rates have decreased due to improved treatment and prevention. However, the incidence of melanoma is rising, and not all patients respond to immune and targeted approaches. Therefore, we sought to determine the efficacy of red light (RL) phototherapy in preclinical models of melanoma. Methods: Melanoma cells (A375, B16F10, MNT-1) were irradiated with RL. Melanoma proliferation, apoptosis, oxidative stress, and p53 phosphorylation were measured in vitro. In C57BL/6 mice, phototherapy safety, B16F10 tumor growth, and immunocyte infiltration were assessed following RL. Results: In vitro, 640 J/cm2 RL decreased cellular proliferation without increasing apoptosis, while 1280 J/cm2 increased apoptosis. RL increased intracellular reactive oxygen species generation and p53 phosphorylation. In animal models, 2560 J/cm2 RL significantly prevented melanoma growth and increased the expression of CD103+ dendritic cells. 1280 and 1920 J/cm2 RL decreased tumor volume, but not significantly. RL did not cause skin inflammation or erythema in normal skin. Conclusion: RL represents a potentially safe and effective melanoma therapeutic. RL prevented tumor growth and increased the expression of immune markers, such as CD103, that are associated with favorable melanoma outcomes. Further research is needed to determine the optimal clinical treatment regimen for melanoma using RL.

Visible red light does not induce DNA damage in human dermal fibroblasts.

Visible red light (RL) therapy is a rapidly expanding treatment option for dermatological conditions, including acne, psoriasis and chronic wounds. It is currently unknown if high fluences of RL induce DNA damage via reactive oxygen species (ROS) stress or other pathways. Our lab previously demonstrated that RL generates ROS in human dermal fibroblasts (HDFs). Other studies show that UV and blue light generate ROS and DNA damage in fibroblasts. This study aims to determine if RL induces DNA damage in HDFs. We found that 320 J/cm2 , 640 J/cm2 and 1280 J/cm2 RL (633 ± 6 nm) did not measurably increase DNA damage in the form of cyclobutane pyrimidine dimers (CPD) or 6-4 photoproducts (6-4PP) immediately, 3 hours and 24 hours following irradiation. Our study further supports that RL therapy is safe in human skin fibroblasts.

Home-based devices in dermatology: a systematic review of safety and efficacy.

There is increasing demand for home-based devices for the treatment of dermatologic conditions and cosmesis. Commercially available devices include intense pulsed light, laser diodes, radiofrequency, light-emitting diodes, and ultraviolet B phototherapy. The objective of this report is to evaluate the current evidence regarding the efficacy and safety of home-based devices for the treatment of skin conditions. A systematic search of PubMed, Embase, and Cinahl was conducted on November 9, 2020 using PRISMA guidelines. Original research articles that investigated the efficacy and safety of home-based devices for dermatologic use were included. Bibliographies were screened for additional relevant articles. Strength of evidence was graded using the Oxford Centre for Evidence-Based Medicine guidelines. Clinical recommendations were then made based on the quality of the existing literature. After review, 37 clinical trials were included-19 were randomized controlled trials, 16 were case series, and 2 were non-randomized controlled trials. Ultimately, from our analysis, we recommend the home-based use of intense pulsed light for hair removal, laser diodes for androgenic alopecia, low power radiofrequency for rhytides and wrinkles, and light-emitting diodes for acne vulgaris. Trials investigating ultraviolet B phototherapy for psoriasis revealed mixed evidence for home treatments compared to clinic treatments. All devices had favorable safety profiles with few significant adverse events. Limitations to our review include a limited number of randomized controlled trials as well as a lack of data on the long-term efficacy and safety of each device.

Symptom Resolution and Recurrent Urinary Incontinence Following Removal of Painful Midurethral Slings.

OBJECTIVE: To evaluate pain improvement and recurrent stress incontinence (SUI) following painful synthetic midurethral sling (MUS) removal. METHODS: We conducted a retrospective review of patients who underwent synthetic MUS removal at our institution from 2009-2016 for the indication of pain. We recorded sling type (transobturator vs retropubic), complete vs partial removal, and presenting symptoms. Postoperative pain improvement was categorized as resolved (pain resolved, requiring no further therapy), improved (pain less bothersome, may require further therapy), or unresolved (no/minimal improvement, requiring further management). Recurrent incontinence and further reconstructive procedures were assessed. RESULTS: 87 patients (49 complete and 38 partial removal) with pain as the primary indication for removal were included. Median age at intervention was 54 years with median follow-up of 8 months. Overall, pain improved or resolved in 78.1% of cases. Complete removal was associated with significantly greater percentage of pain resolution (63.3%) compared to partial removal (26.3%) (P = 0.002) regardless of sling type. No significant differences in recurrent SUI were noted in complete vs partial removal. Additional reconstructive procedures were performed in 28 patients, most commonly sling placement, with no significant difference in complete (20.4%) vs partial (28.9%) removal groups (P = 0.36). The overall complication rate was low (5.7%), a majority of which were transfusions (4.6%). CONCLUSION: Following MUS removal, most patients experienced resolution or improvement of pain. Complete sling removal was associated with significantly greater percentage of pain resolution compared to partial removal in both retropubic and transobturator slings. Rates of recurrent SUI and reintervention for SUI were not related to the extent of sling removal.

Transcriptome analysis of human dermal fibroblasts following red light phototherapy.

Fibrosis occurs when collagen deposition and fibroblast proliferation replace healthy tissue. Red light (RL) may improve skin fibrosis via photobiomodulation, the process by which photosensitive chromophores in cells absorb visible or near-infrared light and undergo photophysical reactions. Our previous research demonstrated that high fluence RL reduces fibroblast proliferation, collagen deposition, and migration. Despite the identification of several cellular mechanisms underpinning RL phototherapy, little is known about the transcriptional changes that lead to anti-fibrotic cellular responses. Herein, RNA sequencing was performed on human dermal fibroblasts treated with RL phototherapy. Pathway enrichment and transcription factor analysis revealed regulation of extracellular matrices, proliferation, and cellular responses to oxygen-containing compounds following RL phototherapy. Specifically, RL phototherapy increased the expression of MMP1, which codes for matrix metalloproteinase-1 (MMP-1) and is responsible for remodeling extracellular collagen. Differential regulation of MMP1 was confirmed with RT-qPCR and ELISA. Additionally, RL upregulated PRSS35, which has not been previously associated with skin activity, but has known anti-fibrotic functions. Our results suggest that RL may benefit patients by altering fibrotic gene expression.

The history of medical education: a commentary on race.

The institution of medicine was built on a foundation of racism and segregation, the consequences of which still permeate the experiences of Black physicians and patients. To predict the future direction of medical inclusivity, we must first understand the history of medicine as it pertains to race, diversity, and equity. In this Commentary, we review material from publicly available books, articles, and media outlets in a variety of areas, including undergraduate medical education and professional medical societies, where we found an abundance of policies and practices that created a foundation of systemic racism in medical training that carried through the career paths of Black physicians. The objective of this Commentary is to present the history of race in the medical education system and medical society membership, acknowledge the present state of both, and offer concrete solutions to increase diversity in our medical community.

Visible light. Part I: Properties and cutaneous effects of visible light.

Approximately 50% of the sunlight reaching the Earth's surface is visible light (400-700 nm). Other sources of visible light include lasers, light-emitting diodes, and flash lamps. Photons from visible light are absorbed by photoreceptive chromophores (e.g., melanin, heme, and opsins), altering skin function by activating and imparting energy to chromophores. Additionally, visible light can penetrate the full thickness of the skin and induce pigmentation and erythema. Clinically, lasers and light devices are used to treat skin conditions by utilizing specific wavelengths and treatment parameters. Red and blue light from light-emitting diodes and intense pulsed light have been studied as antimicrobial and anti-inflammatory treatments for acne. Pulsed dye lasers are used to treat vascular lesions in adults and infants. Further research is necessary to determine the functional significance of visible light on skin health without confounding the influence of ultraviolet and infrared wavelengths.

Visible light. Part II: Photoprotection against visible and ultraviolet light.

Cutaneous photobiology studies have focused primarily on the ultraviolet portion of the solar spectrum. Visible light (VL), which comprises 50% of the electromagnetic radiation that reaches the Earth's surface and, as discussed in Part I of this CME, has cutaneous biologic effects, such as pigment darkening and erythema. Photoprotection against VL includes avoiding the sun, seeking shade, and using photoprotective clothing. The organic and inorganic ultraviolet filters used in sunscreens do not protect against VL, only tinted sunscreens do. In the United States, these filters are regulated by the Food and Drug Administration as an over-the-counter drug and are subject to more stringent regulations than in Europe, Asia, and Australia. There are no established guidelines regarding VL photoprotection. Alternative measures to confer VL photoprotection are being explored. These novel methods include topical, oral, and subcutaneous agents. Further development should focus on better protection in the ultraviolet A1 (340-400 nm) and VL ranges while enhancing the cosmesis of the final products.

High-fluence light emitting diode-red light inhibits cell cycle progression in human dermal fibroblasts.

Skin fibrosis is a debilitating feature of several systemic and dermatologic diseases. While current treatment options carry significant risk of side effects and recurrence, high-fluence light emitting diode-generated red light (LED-RL) is an alternative therapeutic that is safe, non-invasive, and accessible. We previously demonstrated LED-RL decreases fibroblast proliferation, a key pathogenic component of fibrosis. However, the cellular mechanism by which high fluence LED-RL modulates fibroblast proliferation is unclear. Herein, we explored the effects of high fluence LED-RL on human dermal fibroblast cell cycle progression. We demonstrate that LED-RL at 640 J/cm2 induced significant arrest of cells in G0 /G1 compared to temperature-matched control. This was accompanied by a corresponding increase in expression of checkpoint regulator p53 in irradiated cells. These data demonstrate high fluence LED-RL may exert its anti-proliferative effect on fibroblasts by inducing G0 /G1 arrest. Further, this study provides insight into the molecular mechanism underlying LED-RL as an anti-fibrotic therapeutic.

Pain Resolution and Recurrent Prolapse Rates Following Vaginal Mesh Removal.

OBJECTIVE: To evaluate pain resolution and recurrent prolapse following removal of painful pelvic organ prolapse (POP) mesh. METHODS: This was an IRB-approved retrospective review of patients who underwent POP mesh removal from 2009 to 2018 for the primary indication of pain and/or dyspareunia. Factors of interest included mesh type, complete versus partial removal, presenting symptom(s), and recurrent prolapse. Complete removal was defined as complete excision of all possible mesh, including arms, and partial removal was anything less. Postoperative symptom improvement was categorized as resolved, improved, or unresolved. RESULTS: Ninety-two mesh removal patients were identified, 78 of whom underwent mesh removal for pain or dyspareunia, with mean follow-up of 17.25 months (range: 0.46-60.25). Overall, presenting symptoms resolved or improved in 85.9%. In the 45 complete removal patients, 46.7% resolved, 40.0% improved, and 11.1% unresolved compared to 51.5% resolved, 33.3% improved, and 12.1% unresolved in the 33 partial removal patients (P = .82). Recurrent symptomatic POP developed in 31.1% of patients after complete removal compared to 15.2% after partial removal (P = .12). Overall, 23 (30.3%) patients required additional reconstructive procedures. CONCLUSION: Most patients experienced resolution or improvement in painful symptoms after any degree of mesh removal. Complete removal was not significantly associated with greater symptom improvement compared to partial removal. Complete removal was associated with a higher percentage of recurrent POP, but this association was not statistically significant. Less than one-third of patients required additional surgery.

The Vascular Component of Melasma: A Systematic Review of Laboratory, Diagnostic, and Therapeutic Evidence.

BACKGROUND: Melasma is a common acquired disorder of hyperpigmentation, classically manifesting as symmetric brown patches on the face. Although the exact pathogenesis is not fully understood, vascular abnormalities have been implicated in melasma. OBJECTIVE: To evaluate the laboratory and clinical evidence regarding the safety and efficacy of antivascular agents for the treatment of melasma. METHODS: A systematic review of PubMed, EMBASE, and Cochrane was conducted on May 13, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Original research articles investigating the role of vascularity and/or evaluating the use of antivascular therapeutics in melasma were included. Clinical recommendations were based on the American College of Physicians guidelines. RESULTS: A total of 34 original research articles as follows were identified: 4 laboratory studies, 15 diagnostic studies, and 15 therapeutic studies. CONCLUSION: There is promising evidence supporting the use of tranexamic acid and laser/light therapies to treat the vascular component of melasma, and more rigorous clinical trials are needed to validate their efficacy. Clinicians may consider treatment with one or more antivascular therapeutics in patients with melasma. Further research is warranted to characterize the role of cutaneous vascularization in melasma and may provide insights for novel therapies.

Facial rejuvenation using photodynamic therapy with a novel preparation of ALA and hyaluronic acid in young adults.

Photodynamic therapy (PDT) is a well-established, non-invasive treatment modality that has shown desirable effects such as improvement of fine lines, dyspigmentation, and other signs of photodamage. Many patients seek to decrease, or reverse, effects of sun damage on the skin. Hyaluronic acid (HA), a naturally occurring glycosaminoglycan found in the body, has enormous potential to bind water which allows the skin to retain moisture and maintain elasticity. Topical application of HA has been found to produce anti-wrinkle effects. We conducted a pilot case series evaluating the safety and efficacy of a commercially available 2% 5-aminolevulinic acid (ALA) gel with hyaluronic acid (ALA-HA) and light-emitting diode-red light (LED-RL) for facial rejuvenation as determined by clinical assessments and digital skin analysis of rhytides, pore size, and erythema. All patients noted improvement of their skin and experienced minimal pain during PDT. Evaluation by dermatologists demonstrated significant improvement in overall skin appearance. Digital analysis of photographs revealed improvement of skin spots, wrinkles, pores, texture, UV spots, brown spots, red areas, and porphyrins. Our findings demonstrated safety and efficacy of this novel preparation of photodynamic gel with HA and subsequent activation with LED-RL.

The IL-4/IL-13 axis in skin fibrosis and scarring: mechanistic concepts and therapeutic targets.

Skin fibrosis, characterized by excessive fibroblast proliferation and extracellular matrix deposition in the dermis, is the histopathologic hallmark of dermatologic diseases such as systemic sclerosis, hypertrophic scars, and keloids. Effective anti-scarring therapeutics remain an unmet need, underscoring the complex pathophysiologic mechanisms of skin fibrosis. The Th2 cytokines interleukin (IL)-4 and IL-13 have been implicated as key mediators in the pathogenesis of fibroproliferative disorders. The goal of this article is to summarize the current understanding of the role of the IL-4/IL-13 axis in wound healing and skin fibrosis. We conducted a literature search to identify research studies investigating the roles of IL-4 and IL-13 in fibrotic skin diseases. While transforming growth factor-beta has long been regarded as the main driver of fibrotic processes, research into the cellular and molecular biology of wound healing has revealed other pathways that promote scar tissue formation. IL-4 and IL-13 are important mediators of skin fibrosis, supported by evidence from in vitro data, animal models of fibrosis, and clinical studies. Overactive signaling of the IL-4/IL-13 axis contributes to the initiation and perpetuation of fibrotic skin diseases. Further insights into the IL-4/IL-13 axis may reveal potential targets for the development of novel therapies that prevent or treat fibrotic skin diseases.