Developing a questionnaire for assessing clinician- and patient-reported outcomes in actinic keratosis: Results from an expert panel.

Background: Current assessments on topical treatment attributes in actinic keratosis (AK) do not evaluate safety, effectiveness, and satisfaction from both clinician and patient perspectives, creating an unmet need for more comprehensive AK-specific measures that fully capture the patient experience. Objective: To develop an actinic keratosis-specific expert panel questionnaire (AK-EPQ) of patient-reported outcomes and clinician-reported outcomes for use in research studies. Methods: Using interviews of patients with AK and targeted literature reviews, a 9-person consensus panel of dermatologists with expertise in AK treatment was convened to develop the AK-EPQ to assess AK-specific patient-reported outcomes and clinician-reported outcomes. Results: Nine expert advisers achieved consensus on 11 AK-EPQ items that encompass patient and clinician perspectives of treatment-related local skin reactions, clinical and cosmetic outcomes associated with AK, and satisfaction with treatment; the AK-EPQ will be first implemented in the Patient-Reported Outcomes for Actinic Keratosis study (NCT05260073). Limitations: The AK-EPQ does not directly measure quality of life, although it can be used with validated quality of life instruments. Conclusion: The newly developed AK-EPQ elicits insights into the patient and clinician experience with AK treatments. Comparative probing of these perspectives may help optimize precision medicine in AK treatment.

Tirbanibulin for Actinic Keratosis: Insights into the Mechanism of Action.

Actinic keratosis (AK) is a common pre-neoplastic skin lesion constituted by uncontrolled proliferation of atypical keratinocytes that may evolve to squamous cell carcinoma. With global prevalence increasing, AK is expected to be the most common carcinoma of the skin. Tirbanibulin is a reversible tubulin polymerization inhibitor with potent anti-proliferative and anti-tumoral effects. In-vivo and in-vitro studies have shown that tirbanibulin significantly inhibits cell proliferation, tumor growth and downregulates Src signaling with no overt toxicity. Early phase and Phase III trials have shown high lesion clearance, compliance, and few side effects of once daily tirbanibulin treatment. This review discusses tirbanibulin anti-cancer activity, focusing on tubulin polymerization and Src signaling inhibitory effects, highlighting relevant literature and novel preclinical results from the ATNXUS-KX01-001 study. Furthermore, we address the relevant findings obtained in recent clinical trials to evaluate the safety, efficacy, pharmacokinetics, clearance efficacy, and side effects of the 1% tirbanibulin ointment applied once daily. In summary, we highlight preclinical and clinical evidence on the use of tirbanibulin as an effective and safe treatment option for AK.

Profile of Tirbanibulin for the Treatment of Actinic Keratosis.

Actinic keratosis (AK) is a chronic disease resulting from deleterious effects of long-term, cumulative, epidermal exposure to ultraviolet (UV) light. UV-induced mutations in p53, ras, and p16 genes lead to the emergence of abnormal epidermal actinic keratosis (AKs) cells, which proliferate while avoiding apoptosis and may lead to invasive squamous cell carcinoma. There are both lesion-targeted and field-directed topical treatments. This review is of new and emerging information on tirbanibulin and tirbanibulin 1% ointment, which is approved for topical field treatment of actinic keratosis on the face and scalp. Potent antiproliferative and proapoptotic activities result from tirbanibulin's inhibition tubulin polymerization and disruption of microtubule formation and Src kinase signaling. Tirbanibulin 1% ointment is an effective treatment of facial and scalp AK after five consecutive once-daily applications, as measured by complete and partial clearance and percent reduction in the number of lesions. Localized skin reactions are usually mild to moderate, resolving within a month. The short and well-tolerated course of therapy results in very high patient adherence to the treatment regimen.

Infrequent Follow-Up for Actinic Keratosis Treatment: A National Ambulatory Medical Care Survey.

Objective: A nationally representative database was used to assess how soon patients were informed to return to clinic after cryosurgical treatment or prescription of topical 5-fluoruracil (5-FU) for actinic keratosis (AK). Methods: The National Ambulatory Medical Care Survey was used to capture diagnoses and medications associated with visits to U.S. outpatient physicians for the treatment of AKs between 2011-2016. Results: Patients treated with topical 5-FU were commonly told to return in two months or more (53%) or were not given a specific time to return at all (23%). Patients treated with cryosurgery were commonly told to return in two months or more (60%) or were not given a specific time to return at all (23%). Limitations: This study was limited by the accuracy of AK diagnosis and treatment recording. Conclusion: Adequate follow-up after cryosurgical or topical 5-FU treatment of AK allows physicians to assess response to treatment. When treatment for AKs fail due to lack of efficacy or intolerance, it is anticipated that patients may not return to clinic for long periods as return visits are scheduled months after cryosurgery or topical 5-FU is prescribed. Additionally, premature follow-up may not be adequate to ensure treatment-related inflammation has subsided. According to recently defined core outcome sets for AKs, if treatment fails due to intolerability, evaluation at 2 to 4 months could allow physicians to switch AK treatments. Follow-up 6 to 12 months post-treatment might better assess efficacy and potential reoccurrence of AKs.

Trends in Office Visits for the Five Most Common Skin Diseases in the United States.

Objective: We sought to determine the outpatient visit rates for the five most common skin conditions among dermatologists and non-dermatologists. Methods: We conducted a population-based, cross-sectional analysis using the National Ambulatory Medical Care Survey between 2007 and 2016, the most recent years available. Results: The five most common skin diagnoses among all medical specialties were contact dermatitis, acne vulgaris, actinic keratosis, benign neoplasm of the skin, and epidermoid cyst, respectively. Actinic keratosis followed by acne vulgaris and benign neoplasm of skin were the three most common visit diagnoses among dermatologists, whereas contact dermatitis, acne vulgaris, and epidermoid cyst were the most common among non-dermatologists. Overall, visits for the five most common skin conditions seen by dermatologists and non-dermatologists remained constant over the study interval. Limitations: Misclassification bias could be impacting the results of this study. Additionally, the NAMCS samples only non-hospital based outpatient clinicians, and thus cannot describe hospital-based outpatient visits or inpatient hospital care. Conclusion: Visits for contact dermatitis, acne, actinic keratosis, benign neoplasm of the skin, and epidermoid cysts have remained constant over the last ten years. These conditions represent the most common diagnoses of the skin at both dermatologists and non-dermatologists outpatient visits. Non-dermatologists continue to see almost half of visits for the five most common skin diagnoses. Patients are often referred from the primary care setting for growths of skin and skin lesions; thus, it is not surprising that actinic keratosis has remained the most common diagnosis among dermatologist and benign neoplasm the third most common dermatologic diagnosis.

Autologous Cultured Bone Marrow-Derived Mesenchymal Stem Cells in a Fibrin Spray to Treat Venous Ulcers: A Randomized Controlled Double-Blind Pilot Study.

We treated a small cohort of venous ulcers that were very unresponsive to standard and advanced therapies with autologous cultured bone marrow-derived mesenchymal stem cells (MSCs). This pilot clinical trial was randomized, controlled, and double-blinded. Subjects were treated with either normal saline (Group A), fibrin spray alone (Group B), or MSCs in fibrin (1 million cells/cm2 of wound bed surface) (Group C). The control and test materials were applied to the wound using a double-barreled syringe with thrombin and fibrinogen (with or without MSCs) in each barrel, or saline alone in both barrels. The MSCs were separated, cultured in vitro, and expanded in a dedicated Good Manufacturing Practice (GMP) facility from 30-50 ml of bone marrow aspirate obtained from the iliac crest in Group C subjects. To ensure that the study remained controlled and blinded, subjects who were randomized to one of the two control arms (saline or fibrin) underwent sham bone marrow aspiration performed by a hematologist who anesthetized the iliac crest area down to and pushing against the periosteum, but without penetrating the bone marrow. Therefore, both the clinician who evaluated wound progress and the study subjects had no knowledge of whether bone aspiration was actually performed and what treatment had been applied to the wound. The study was performed after full FDA investigational new drug (IND) approval. The primary endpoint was the rate of healing (wound closure as linear healing from the wound margins in cm/week), as measured by the Gilman equation. One-way ANOVA was used to calculate the statistical significance of differences between the mean healing rates of each of the 3 treatment groups every 4 weeks and over the 24 weeks of treatment. Overall, treatment with MSCs accelerated the healing rate by about 10-fold compared to those in the saline and fibrin control groups. Although the total number of patients in this pilot study was small (n=11), the statistical significance was surprisingly promising: p<0.01 and f-ratio of 15.9358. No serious adverse events were noted. This small but carefully performed prospective, controlled, randomized, and double-blinded pilot study in a rare population of totally unresponsive patients adds to previous reports showing the promise of MSCs in the treatment of chronic wounds and provides proof of principle for how to approach this type of very demanding clinical and translational research.

2020 IDEOM Annual Meeting: Actinic Keratosis Stakeholders Survey Identifies Gaps in Research and Care.

This is a report of the survey results from the International Dermatology Outcome Measures (IDEOM) actinic keratosis (AK) workgroup. The purpose of the survey was to compile a list of gaps within AK care and management that require refinement. The results were discussed at the IDEOM annual meeting held virtually on October 23–24, 2020. This built a framework with which the AK workgroup, which consisted of physicians, patients, and pharmaceutical scientists, discussed at length in their breakout session at the meeting. The electronic survey was distributed to patients, pharmaceutical scientists, and leading physician experts in the field via email on September 22, 2020, with a deadline of October 2, 2020. The survey consisted of three open-ended prompts concerning key gaps and/or unmet needs in (1) the care of AKs, (2) outcome measurement of AKs in clinical trials and, (3) the measurement of AKs in clinical practice. The results were qualitative, with a response rate of 47%. Responses included reform of outcome measures for clinical trials, a methodology for evaluating the efficacy of preventative measures, and a comparison of treatments to establish a treatment protocol, among other efforts. This paper will also provide a brief overview of the current state of the AK outcome measures, emphasizing the heterogeneity of the measures and detailing the AK workgroup's future efforts to create a reliable and applicable core outcome measure set. J Drugs Dermatol. 2022;21(2):128-134. doi:10.36849/JDD.6360.

Use of Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis: A Systematic Review.

BACKGROUND: Actinic Keratosis (AK) is a premalignant lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Topical 5-Fluorouracil (5-FU) and imiquimod have been used for field-directed therapy for AK; however, their use is limited by intolerable skin reactions and long treatment durations. OBJECTIVE: To assess current data on the efficacy, tolerability, and long-term effectiveness of topical calcipotriol plus 5-FU combination for the field-directed therapy of AK. The systematic review will include a critical evaluation of the available evidence. METHODS: A systematic review of the literature was performed in August 2021 using the EMBASE and MEDLINE databases. Studies that assess the use of calcipotriol and 5-FU to treat actinic keratosis (AK) and cSCC prevention were included. RESULTS: In total, four studies met the inclusion criteria. Our final analysis included three articles. One clinical trial evaluated the efficacy of calcipotriol plus 5-FU in treating AK. Another clinical trial evaluated the long-term effect of calcipotriol plus 5-FU in prevention of cSCC. A retrospective study evaluated the use of calcipotriol plus 5-FU with cryotherapy. LIMITATIONS: A limitation of this systematic review is the limited number of clinical trials that examine the combination of 5-FU plus calcipotriol in treating AK. The active control arm (Petroleum jelly plus 5-FU combination) is not equivalent to topical 5-FU monotherapy; hence, no superiority claim can be made vs topical 5-FU in terms of efficacy. CONCLUSION: Calcipotriol plus 5-FU reduced greater number of AKs in the treated area (25 cm2) when compared to 5-FU plus petroleum jelly, but only 27% of participants had complete clearance on the face at week-8. Calcipotriol plus 5-FU lowered the risk of cSCC on the face and scalp area over a 3-year period. Adequate and well-controlled studies are needed to compare the efficacy of calcipotriol plus 5-FU to 5-FU monotherapy, and other FDA-approved topical drugs such as imiquimod cream and tirbanibulin ointment. J Drugs Dermatol. 2022;21(1):60-65. doi:10.36849/JDD.6632.

1% Tirbanibulin Ointment for the Treatment of Actinic Keratoses.

OBJECTIVE: Actinic keratoses (AKs) are cutaneous lesions that arise in sun-damaged skin. AKs may transform into squamous cell carcinoma in situ. Tirbanibulin 1% ointment is a new topical treatment for AKs, recently approved by the Food and Drug Administration. DATA SOURCES: The PubMed database was searched for articles published from 1960 to March 31, 2021, using the keywords tirbanibulin and Klisyri. DATA EXTRACTION: Phase 2 and phase 3 clinical trials were reviewed. DATA SYNTHESIS: In phase 2 clinical trials, 43% of patients treated with tirbanibulin experienced complete clearance by day 57 (43% [95% CI = 32, 54]). Across two phase 3 clinical trials (pooled data), complete (100%) clearance occurred in 49% of patients in tirbanibulin groups and in only 9% of the vehicle groups (difference, 41% points; 95% CI = 35 to 47; P < 0.001). Although no comparative studies are available, tirbanibulin is applied for a shorter duration (5 days) compared with diclofenac 3% gel, fluorouracil 5% cream, and imiquimod 3.75% cream. Adverse events were mild and included pruritus, application site pain, and local skin reactions. Systemic adverse events such as necrosis and angioedema, observed with other AK treatments such as fluorouracil and imiquimod, were not observed with tirbanibulin, thus giving tirbanibulin a favorable safety profile. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Tirbanibulin effectively reduces AK burden and recurrence and has a favorable safety profile with mild adverse events. In comparison, imiquimod, 5-flourouracil, and diclofenac can result in necrosis, angioedema, and arthralgias. CONCLUSION: With a favorable safety profile and short regimen, tirbanibulin is an efficacious treatment for clinicians to utilize in their treatment toolbox when treating AKs on the face and scalp.

COVID-19 related masks increase severity of both acne (maskne) and rosacea (mask rosacea): Multi-center, real-life, telemedical, and observational prospective study.

Masks are essential for COVID-19 prevention, but recently they were suggested to modify cutaneous facial microenvironment and trigger facial dermatoses. To evaluate mask-related rosacea and acne (maskne) in untreated patients during lockdown. In this multi-center, real-life, observational prospective study, we enrolled stable, untreated acne and rosacea patients that wore masks during lockdown at least 6 h/day. They underwent two teledermatological consultations, at the baseline and after 6 weeks. Clinical, pharmacological, and psychological data were recorded. A total 66 patients, 30 (median age: 34.0 [30.25-29.75] yoa) with acne and 36 patients (median age: 48 [43-54] years) with rosacea, were enrolled in this study. After 6 weeks of mask and quarantine, patients with acne displayed an increased Global Acne Grading Scale (GAGS) score in mask-related areas (P < .0001). Likewise, after 6 weeks of mask and quarantine, patients with rosacea displayed a worsen in both physican (P < .0001) and patient (P < .0001) reported outcomes. Remarkably, patients reported also a statistically significant decrease in their quality of life (P < .0001). Masks appear to trigger both acne and rosacea flares. Additional studies are needed to generate evidence and inform clinical decision-making.

Patient-reported outcomes of topical therapies in actinic keratosis: A systematic review.

Patients' perspectives on actinic keratosis treatments may have an impact on treatment adherence and, therefore, therapeutic outcomes. We performed a systematic review to assess patients' perspectives of topical, field-directed treatments for actinic keratoses. A literature search was conducted, and 14 studies were identified encompassing 4433 patients. Only four studies were focused on face and/or scalp, which are the locations that typically impact patients' quality of life. Four studies were clinical trials. One study utilized a validated patient-reported outcomes (PRO) instrument specifically developed for actinic keratosis. In general, treatment adherence and patient satisfaction were better with shorter-duration treatment regimens such as ingenol mebutate gel. Imiquimod improved quality of life in one study but not in another. No data was available on topical piroxicam. The findings underscore the need for effective and well-tolerated, short-duration topical treatment for actinic keratosis.

The Burden of Skin and Subcutaneous Diseases in the United States From 1990 to 2017.

Importance: Skin and subcutaneous diseases affect the health of millions of individuals in the US. Data are needed that highlight the geographic trends and variations of skin disease burden across the country to guide health care decision-making. Objective: To characterize trends and variations in the burden of skin and subcutaneous tissue diseases across the US from 1990 to 2017. Design, Setting, and Participants: For this cohort study, data were obtained from the Global Burden of Disease (GBD), a study with an online database that incorporates current and previous epidemiological studies of disease burden, and from GBD 2017, which includes more than 90 000 data sources such as systematic reviews, surveys, population-based disease registries, hospital inpatient and outpatient data, cohort studies, and autopsy data. The GBD separated skin conditions into 15 subcategories according to incidence, prevalence, adequacy of data, and standardized disease definitions. GBD 2017 also estimated the burden from melanoma of the skin and keratinocyte carcinoma. Data analysis for the present study was conducted from September 9, 2019, to March 31, 2020. Main Outcomes and Measures: Primary study outcomes included age-standardized disability-adjusted life-years (DALYs), incidence, and prevalence. The data were stratified by US states with the highest and lowest age-standardized DALY rate per 100 000 people, incidence, and prevalence of each skin condition. The percentage change in DALY rates in each state was calculated from 1990 to 2017. Results: Overall, age-standardized DALY rates for skin and subcutaneous diseases increased from 1990 (821.6; 95% uncertainty interval [UI], 570.3-1124.9) to 2017 (884.2; 95% UI, 614.0-1207.9) in all 50 states and the District of Columbia. The degree of increase varied according to geographic location, with the largest percentage change of 0.12% (95% UI, 0.09%-0.15%) in New York and the smallest percentage change of 0.04% (95% UI, 0.02%-0.07%) in Colorado, 0.04% (95% UI, 0.01%-0.06%) in Nevada, 0.04% (95% UI, 0.02%-0.07%) in New Mexico, and 0.04% (95% UI, 0.02%-0.07%) in Utah. The age-standardized DALY rate, incidence, and prevalence of specific skin conditions differed among the states. New York had the highest age-standardized DALY rate for skin and subcutaneous disease in 2017 (1097.0 [95% UI, 764.9-1496.1]), whereas Wyoming had the lowest age-standardized DALY rate (672.9 [95% UI, 465.6-922.3]). In all 50 states and the District of Columbia, women had higher age-standardized DALY rates for overall skin and subcutaneous diseases than men (women: 971.20 [95% UI, 676.76-1334.59] vs men: 799.23 [95% UI, 559.62-1091.50]). However, men had higher DALY rates than women for malignant melanoma (men: 80.82 [95% UI, 51.68-123.18] vs women: 42.74 [95% UI, 34.05-70.66]) and keratinocyte carcinomas (men: 37.56 [95% UI, 29.35-49.52] vs women: 14.42 [95% UI, 10.01-20.66]). Conclusions and Relevance: Data from the GBD suggest that the burden of skin and subcutaneous disease was large and that DALY rate trends varied across the US; the age-standardized DALY rate for keratinocyte carcinoma appeared greater in men. These findings can be used by states to target interventions and meet the needs of their population.

Canadian Burden of Skin Disease From 1990 to 2017: Results From the Global Burden of Disease 2017 Study [Formula: see text].

BACKGROUND: Skin diseases can have high morbidity that can be costly to society and individuals. To date, there has been no comprehensive assessment of the burden of skin disease in Canada. OBJECTIVES: To evaluate the burden of 18 skin and subcutaneous diseases from 1990 to 2017 in Canada using the Global Burden of Disease (GBD) data. METHODS: The 2017 GBD study measures health loss from 359 diseases and injuries in 195 countries; we evaluated trends in population health in Canada from 1990 to 2017 using incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs). Data are presented as rates (per 100 000), counts, or percent change with the uncertainty interval in brackets. RESULTS: From 1990 to 2017 for all skin diseases, DALY rates increased by 8% to 971 per 100 000 (674-1319), YLD rates increased by 8% to 897 per 100 000 (616-1235), YLL rates increased by 4% to 74 per 100 000 (53-89), and death rates increased by 18% to 5 per 100 000 (3-6). DALY rates for melanoma increased by 2% to 54 per 100 000 (39-68), for keratinocyte carcinoma by 14% to 17 per 100 000 (16-19), and for skin and subcutaneous disease by 8% to 900 per 100 000 (619-1233). The observed over expected ratios were higher for skin and subcutaneous disease (1.37) and keratinocyte carcinoma (1.17) and were lower for melanoma (0.73). CONCLUSIONS: The burden of skin disease has increased in Canada since 1990. These results can be used to guide health policy regarding skin disease in Canada.

Lymphedema: Pathophysiology and clinical manifestations.

Lymphedema is a localized form of tissue swelling resulting from excessive retention of lymphatic fluid in the interstitial compartment and caused by impaired lymphatic drainage. Lymphedema is classified as primary or secondary. Primary lymphedema is caused by developmental lymphatic vascular anomalies. Secondary lymphedema is acquired and arises as a result of an underlying systemic disease, trauma, or surgery. We performed PubMed and Google Scholar searches of the English-language literature (1966-2017) using the terms lymphedema, cancer-related lymphedema, and lymphatic complications. Relevant publications were manually reviewed for additional resources. This progressive chronic disease has serious implications on patients' quality of life. It is often misdiagnosed because it mimics other conditions of extremity swelling. There is no definitive cure for lymphedema. However, with proper diagnosis and management, its progression and potential complications may be limited.

Research Techniques Made Simple: Analysis of Collective Cell Migration Using the Wound Healing Assay.

Collective cell migration is a hallmark of wound repair, cancer invasion and metastasis, immune responses, angiogenesis, and embryonic morphogenesis. Wound healing is a complex cellular and biochemical process necessary to restore structurally damaged tissue. It involves dynamic interactions and crosstalk between various cell types, interaction with extracellular matrix molecules, and regulated production of soluble mediators and cytokines. In cutaneous wound healing, skin cells migrate from the wound edges into the wound to restore skin integrity. Analysis of cell migration in vitro is a useful assay to quantify alterations in cell migratory capacity in response to experimental manipulations. Although several methods exist to study cell migration (such as Boyden chamber assay, barrier assays, and microfluidics-based assays), in this short report we will explain the wound healing assay, also known as the "in vitro scratch assay" as a simple, versatile, and cost-effective method to study collective cell migration and wound healing.

Novel Stem Cell Therapies for Applications to Wound Healing and Tissue Repair.

The number of individuals with chronic cutaneous wounds has been increasing worldwide due to an aging population, diabetes, obesity, and cardiovascular disease. In the United States, almost seven million Americans have chronic skin ulcers. Many therapeutic approaches have been used. However, the treatment outcomes are not always ideal because of failure to achieve complete wound closure in around 60% of cases, scarring, and high rate of recurrence. Therefore, there is a need for more effective therapies. Stem cells offer promising possibilities. Pre-clinical studies have shown that bone- or adipose tissue-derived mesenchymal stem cells (MSCs) have a competitive advantage over other types of stem cells due to their better defined multipotent differentiating potential, paracrine effects, immunomodulatory properties, and safety. However, large controlled clinical trials are needed to examine the capabilities of MSCs in humans and to assess their safety profile. In this review, we highlight emerging treatments in tissue regeneration and repair and provide some perspectives on how to translate current knowledge about stem cells-both multipotent and pluripotent-into viable clinical approaches for treating patients with difficult to heal wounds.