Atypical Fibroxanthoma Treated with a Topical Combination of Imiquimod, Tazarotene, and 5-Fluorouracil.

This case report describes an 80-year-old man who presented with a growing erythematous nodule with erosion, measuring 0.6 cm × 0.6 cm, on his right temple. This lesion was later diagnosed as atypical fibroxanthoma (AFX). Instead of undergoing Mohs surgery, the gold standard treatment, the patient opted to pursue a topical treatment regimen because of financial costs associated with surgical removal and repair. This topical regimen consisted of tazarotene cream, imiquimod cream, and 5-fluorouracil solution, applied for 30 days. The patient was directed to use this combination 5 days per week for 6 weeks. The specified dosage for each medication was a fifth of a packet of imiquimod 5% cream, an equivalent amount of tazarotene 0.1% cream, and a single drop of 5-fluorouracil 2% solution. These were combined on a bandage and placed on the lesion overnight. Following the treatment, a 3-week post-application examination revealed an erosion, 1.0 cm × 0.9 cm, amidst erythema. A subsequent incisional biopsy with histopathology and stains for CD10 and CD99, 3 weeks after treatment, and three punch biopsies with histopathology and stains for CD10 and CD99, 1-year post-treatment, confirmed the absence of AFX. AFX is a superficial variant of pleomorphic dermal sarcoma (PDS), which shares histologic similarities, yet the exact relationship between AFX/PDS and undifferentiated pleomorphic sarcoma is still not well understood. Previous studies have indicated a genomic similarity between AFX/PDS and cutaneous squamous cell carcinoma (cSCC), which suggests the potential efficacy of cSCC-targeted treatments for AFX/PDS. This case marks the first recorded instance of successful topical medical treatment of AFX, offering an alternative for patients who may opt out of surgical intervention. Continued research to assess the broader efficacy of this approach is encouraged.

Keratinocyte Carcinoma Chemoprevention With a Combination of Imiquimod, 5-Fluorouracil, and Tretinoin.

BACKGROUND: The incidence of keratinocyte carcinomas (KCs), comprising basal and squamous cell carcinomas, is rising in the United States. Chemoprevention is one modality by which patients can reduce the incidence of KCs. METHODS: We performed a retrospective review of 327 patients who employed a combination of imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream in a field therapy regimen over the face/ears or scalp for chemoprevention. RESULTS: Patients had dramatically lower odds of having KCs in the treatment location (face/ears or scalp) in the one-year period after field treatment than in the one-year period preceding field treatment (OR=0.06, 95% CI: [0.02, 0.15]). Patients were also at lower odds of having KCs in non-treated areas the year after field treatment than in the year preceding it (OR=0.25, 95% CI: [0.14, 0.42]). Additionally, fewer cryotherapy sessions were performed for actinic keratoses in the treatment areas in the year after treatment (mean=1.5, SD=1.21) than the year preceding treatment (mean=2.3, SD=0.99; t=11.68, P<0.001). CONCLUSIONS: A combination of imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream were effective at reducing the incidence of new KCs for at least one year. Individualized treatment application frequency allowed for increased patient adherence. Prospective studies evaluating combination topical treatments for chemoprevention of KCs are needed to further assess the treatment effects found in this study. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7334.

Model to Inhibit Contraction in Third-Degree Burns Employing Split-Thickness Skin Graft and Administered Bone Marrow-Derived Stem Cells.

Third-degree burns typically result in pronounced scarring and contraction in superficial and deep tissues. Established techniques such as debridement and grafting provide benefit in the acute phase of burn therapy, nevertheless, scar and contraction remain a challenge in deep burns management. Our ambition is to evaluate the effectiveness of novel cell-based therapies, which can be implemented into the standard of care debridement and grafting procedures. Twenty-seven third-degree burn wounds were created on the dorsal area of Red Duroc pig. After 72 h, burns are surgically debrided using a Weck knife. Split-thickness skin grafts (STSGs) were then taken after debridement and placed on burn scars combined with bone marrow stem cells (BM-MSCs). Biopsy samples were taken on days 17, 21, and 45 posttreatment for evaluation. Histological analysis revealed that untreated control scars at 17 days are more raised than burns treated with STSGs alone and/or STSGs with BM-MSCs. Wounds treated with skin grafts plus BM-MSCs appeared thinner and longer, indicative of reduced contraction. qPCR revealed some elevation of α-SMA expression at day 21 and Collagen Iα2 in cells derived from wounds treated with skin grafts alone compared to wounds treated with STSGs + BM-MSCs. We observed a reduction level of TGFß-1 expression at days 17, 21, and 45 in cells derived from wounds treated compared to controls. These results, where the combined use of stem cells and skin grafts stimulate healing and reduce contraction following third-degree burn injury, have a potential as a novel therapy in the clinic.

The effect of mesenchymal stem cells improves the healing of burn wounds: a phase 1 dose-escalation clinical trial.

Background: Stem cell therapy holds promise to improve healing and stimulate tissue regeneration after burn injury. Preclinical evidence has supported this; however, clinical studies are lacking. We examined the application of bone marrow-derived mesenchymal stem cells (BM-MSC) to deep second-degree burn injuries using a two-dose escalation protocol. Methods: Ten individuals aged 18 years or older with deep second-degree burn wounds were enrolled. The first five patients were administered 2.5 × 10³ BM-MSC/cm2 to their wounds. After safety of the initial dose level was assessed, a second group of five patients was treated with a higher concentration of 5 × 10³ allogeneic BM-MSC/cm2. Safety was assessed clinically and by evaluating cytokine levels in mixed recipient lymphocyte/donor BM-MSC reactions (INFγ, IL-10 and TNFα). At each visit, we performed wound measurements and assessed wounds using a Patient and Observer Scar Assessment Scale (POSAS). Results: All patients responded well to treatment, with 100% closure of wounds and minimal clinical evidence of fibrosis. No adverse reactions or evidence of rejection were observed for both dose levels. Patients receiving the first dose concentration had a wound closure rate of 3.64 cm2/day. Patients receiving the second dose concentration demonstrated a wound closure rate of 10.47 cm2/day. The difference in healing rates between the two groups was not found to be statistically significant (P = 0.17). Conclusion: BM-MSC appear beneficial in optimising wound healing in patients with deep second-degree burn wounds. Adverse outcomes were not observed when administering multiple doses of allogeneic BM-MSC. Lay Summary: Thermal injuries are a significant source of morbidity and mortality, constituting 5%-20% of all injuries and 4% of all deaths. Despite overall improvements in the management of acutely burned patients, morbidities associated with deeper burn injuries remain commonplace. Burn patients are too often left with significant tissue loss, scarring and contractions leading to physical loss of function and long-lasting psychological and emotional impacts.In previous studies, we have demonstrated the safety and efficacy of administering bone marrow-derived mesenchymal stem cells (BM-MSC) to chronic wounds with substantial improvement in healing and evidence of tissue regeneration. In this report, we have examined the application of BM-MSC to deep second-degree burn injuries in patients.The aim of the present phase I/II clinical trial was to examine the safety and efficacy of administering allogeneic BM-MSC to deep second-degree burns. We utilised two different dose levels at concentrations 2.5 × 103 and 5 × 103 cells/cm2. Patients with deep second-degree burn wounds up to 20% of the total body surface area were eligible for treatment. Allogeneic BM-MSC were applied to burn wounds topically or by injection under transparent film dressing <7 days after injury. Patients were followed for at least six months after treatment.Using two dose levels allowed us to gain preliminary information as to whether different amounts of BM-MSC administered to burn wounds will result in significant differences in safety/ clinical response. Once the safety and dose-response analysis were completed, we evaluated the efficacy of allogeneic stem cell therapy in the treatment of deep second-degree burn wounds.In this study, we examined the role of allogeneic BM-MSC treatment in patients with deep second-degree burn injuries, in a dose-dependent manner. No significant related adverse events were reported. Safety was evaluated both clinically and by laboratory-based methods. Efficacy was assessed clinically through evidence of re-pigmentation, hair follicle restoration and regenerative change. While these findings are encouraging, more studies will be needed to better establish the benefit of BM-MSC in the treatment of burn injuries.

Role of Extracellular Vesicles in Stem Cell Therapy

Burn wounds are a major source of morbidity and mortality in both the military and civilian settings. Research about the pathophysiology of thermal injury has revealed possible interventions that can aid this process to reduce scarring and wound contracture. Bone Marrow derived Mesenchymal Stem Cells (BM-MSCs) have been an exciting topic in research for many years. They have been shown to facilitate wound healing and tissue regeneration, two areas that are vital in the healing process, especially in burn wounds. More recently the discovery of Extracellular Vesicles (EVs) has allowed us to further characterize the immunomodulatory roles and understand the cellular pathways implicated in wound healing. The purpose of this review is to discuss the role of EVs in wound healing, and to propose that EVs are the main mechanism that deliver cellular materials to target cells to coordinate wound healing following tissue injury.

Mesenchymal Stem Cell-Derived Extracellular Vesicles as an Advanced Therapy for Chronic Wounds.

Chronic wounds are a significant challenge for patients, healthcare providers, and healthcare systems. Chronic wounds develop due to a complex interplay between chronic inflammation, tissue hypoxia, and oxidative stress, often occurring in the setting of advancing age. Ideally, new therapeutics should address all the components of chronic wound pathophysiology. Mesenchymal stem cell (MSC) therapies show significant promise to promote healing of chronic wounds. Extracellular vesicles (EVs) secreted by MSCs mediate many of their beneficial effects. We review the evidence demonstrating that MSC-EVs target the processes leading to chronic wounds. Additionally, we discuss how MSCs can be influenced to generate more potent wound healing EVs. Finally, we highlight the current state of EV clinical trials for wound healing and important preclinical studies that will lead to optimal use of MSC-EVs for patient care.

Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds.

Chronic wounds develop when the orderly process of cutaneous wound healing is delayed or disrupted. Development of a chronic wound is associated with significant morbidity and financial burden to the individual and health-care system. Therefore, new therapeutic modalities are needed to address this serious condition. Mesenchymal stem cells (MSCs) promote skin repair, but their clinical use has been limited due to technical challenges. Extracellular vesicles (EVs) are particles released by cells that carry bioactive molecules (lipids, proteins, and nucleic acids) and regulate intercellular communication. EVs (exosomes, microvesicles, and apoptotic bodies) mediate key therapeutic effects of MSCs. In this review we examine the experimental data establishing a role for EVs in wound healing. Then, we explore techniques for designing EVs to function as a targeted drug delivery system and how EVs can be incorporated into biomaterials to produce a personalized wound dressing. Finally, we discuss the status of clinically deploying EVs as a therapeutic agent in wound care.

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown therapeutic potential in various in vitro and in vivo studies in cutaneous wound healing. Furthermore, there are ubiquitous studies highlighting the pro-regenerative effects of BM-MSC extracellular vesicles (BM-MSC EVs). The similarities and differences in BM-MSC EV cargo among potential healthy donors are not well understood. Variation in EV protein cargo is important to understand, as it may be useful in identifying potential therapeutic applications in clinical trials. We hypothesized that the donors would share both important similarities and differences in cargo relating to cell proliferation, angiogenesis, Wnt signaling, and basement membrane formation-processes shown to be critical for effective cutaneous wound healing. METHODS: We harvested BM-MSC EVs from four healthy human donors who underwent strict screening for whole bone marrow donation and further Good Manufacturing Practices-grade cell culture expansion for candidate usage in clinical trials. BM-MSC EV protein cargo was determined via mass spectrometry and Proteome Discoverer software. Corresponding proteomic networks were analyzed via the UniProt Consortium and STRING consortium databases. RESULTS: More than 3000 proteins were identified in each of the donors, sharing > 600 proteins among all donors. Despite inter-donor variation in protein identities, there were striking similarities in numbers of proteins per biological functional category. In terms of biologic function, the proteins were most associated with transport of ions and proteins, transcription, and the cell cycle, relating to cell proliferation. The donors shared essential cargo relating to angiogenesis, Wnt signaling, and basement membrane formation-essential processes in modulating cutaneous wound repair. CONCLUSIONS: Healthy donors of BM-MSC EVs contain important similarities and differences among protein cargo that may play important roles in their pro-regenerative functions. Further studies are needed to correlate proteomic signatures to functional outcomes in cutaneous repair.

A Non-Surgical and Cost-Effective Treatment Approach Employing Topical Imiquimod, 5-Fluorouracil, and Tretinoin for Primary Non-Melanoma Skin Cancers.

BACKGROUND: Minimally invasive alternative approaches to treat non-melanoma skin cancers remain limited and unproven. OBJECTIVE: We aim to assess the efficacy of varying combinations of anti-tumor agents—imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream—with brief cryotherapy in treating non-melanoma skin cancers. METHODS: This retrospective study included 690 cases of non-melanoma skin cancers in 480 patients who received a diagnosis of a basal cell carcinoma or squamous cell carcinoma during a ten-year period. During treatment period, patients applied 30 applications of one of three combinations (imiquimod/tretinoin, 5-fluorouracil/tretinoin, or imiquimod/5-fluorouracil/tretinoin) and had cryotherapy every 2 weeks. Each patient had a clinical examination at least three years post-treatment or documented treatment failure. Clearance was defined by a lack of persistence or recurrence for 3 years following the completion of treatment. The likelihood of lesion clearance was evaluated using multivariable logistic regression analysis. RESULTS: A total of 186 cases (97; basal cell carcinoma and 89; squamous cell carcinoma) in 133 patients [37% women and 63% men; median (interquartile range) age, 77 (69, 83) years] met the inclusion criteria. Multivariable logistic regression analysis adjusting for clinical and lesion variables demonstrated that, relative to the imiquimod/5-fluorouracil/tretinoin treatment approach, imiquimod/ tretinoin (odds ratio, 0.05; 95% confidence interval, 0.00-0.99) and 5-fluorouracil/tretinoin (0.02; 0.00–0.45) were associated with lower likelihoods of lesion clearance. Likewise, morpheaform basal cell carcinoma had a lower probability of clearance (0.05; 0.00–0.72). CONCLUSIONS: The combination of imiquimod/5-fluorouracil/tretinoin with cryotherapy had high clearance rates and was the most effective treatment regimen. J Drugs Dermatol. 2021;20(3):260-267. doi:10.36849/JDD.5427.

Treating Melanoma in Situ During a Pandemic with Telemedicine and a Combination of Imiquimod, 5-Fluorouracil, and Tretinoin.

The recent coronavirus disease 2019 (COVID-19) pandemic has created a quandary for the physician in terms of evaluating and treating cutaneous skin cancers, particularly melanomas. At the onset of the pandemic, many planned medical and surgical visits for skin cancers were postponed. Physicians and patients have had to balance the risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with that of worsening morbidity and mortality due to delays in skin cancer treatments. We present a male patient who had two melanoma-in-situs (MISs) that were treated during the COVID-19 pandemic with a combination of topical imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream. The successful treatments occurred without in-person visits and with the aid of telemedicine. Although surgery is the standard for the treatment of melanoma in situ, this case demonstrates an effective viable treatment modality for MIS during a pandemic situation.

Laser and light therapies for the treatment of necrobiosis lipoidica.

Necrobiosis lipoidica (NL) is a rare, inflammatory granulomatous skin disorder involving collagen degeneration. In recent years, several light and laser therapies have been proposed and used in the treatment of NL with variable outcomes. The aim of the study was to investigate the efficacy and safety of lasers and light therapies for the treatment of NL. A review of PubMed was conducted to search for studies using laser and light therapies for the treatment of NL. Articles that employed a combination of treatment modalities were excluded. Twenty-four studies were reviewed. Light and laser therapies used in these studies included CO2 laser, pulsed dye laser, methyl aminolevulinate (MAL)-photodynamic therapy (PDT), aminolevulinic acid (ALA)-PDT, ultraviolet A1 (UVA1) phototherapy, and psoralen plus ultraviolet-A (PUVA). PUVA was identified as the modality with the most available evidence (7 studies), followed by MAL-PDT and ALA-PDT (5 studies each), pulsed dye laser and UVA1 (3 studies each), and lastly CO2 laser (2 studies). Most modalities demonstrated variable efficacies and side effects with the exception of PDL, which consistently showed successful outcomes. Multiple dermatologic light and laser therapies have been investigated for the treatment of NL, including PUVA, ALA-PDT, MAL-PDT, pulsed dye laser, UVA1, and CO2 laser. However, a clear consensus on the preferred treatment is yet to be addressed. Each treatment option demonstrates both advantages and disadvantages that should be discussed with patients when selecting the treatment modality.

Treatment of Hypertrophic Burn and Traumatic Scars With a 2,940-nm Fractional Ablative Erbium-doped Yttrium Aluminium Garnet Laser: A Pilot Study.

BACKGROUND: In recent years, fractional ablative lasers at low density have proven to be the centerpiece in a multimodality approach to treating hypertrophic burn scars. OBJECTIVE: To determine the safety and efficacy of fractional ablative erbium-doped yttrium aluminium garnet (Er:YAG) laser in the treatment of hypertrophic burn scars. METHODS: Eleven patients received 3 fractional ablative Er:YAG laser to hypertrophic burn scars at 400 to 800 µm, density 11%, no coagulation, and single pass at 4-week intervals. RESULTS: Overall, average improvement was noted to be 2.27 of 3 as determined by blinded observers. A significant improvement was noted in all measured parameters including dyschromia, atrophy hypertrophy, vascularity, and texture. CONCLUSION: This is a pilot study showing the safety and efficacy of fractional ablative Er:YAG laser treatment is a safe and effective treatment modality in the treatment of hypertrophic scars.

A bioengineered living cell construct activates metallothionein/zinc/MMP8 and inhibits TGFß to stimulate remodeling of fibrotic venous leg ulcers.

Venous leg ulcers (VLU) represent a major clinical unmet need, impairing quality of life for millions worldwide. The bioengineered bilayered living cell construct (BLCC) is the only FDA-approved therapy demonstrating efficacy in healing chronic VLU, yet its in vivo mechanisms of action are not well understood. Previously, we reported a BLCC-mediated acute wounding response at the ulcer edge; in this study we elucidated the BLCC-specific effects on the epidermis-free ulcer bed. We conducted a randomized controlled clinical trial (ClinicalTrials.gov NCT01327937) enrolling 30 subjects with nonhealing VLUs, and performed genotyping, genomic profiling, and functional analysis on wound bed biopsies obtained at baseline and 1 week after treatment with BLCC plus compression or compression therapy (control). The VLU bed transcriptome featured processes of chronic inflammation and was strikingly enriched for fibrotic/fibrogenic pathways and gene networks. BLCC application decreased expression of profibrotic TGFß1 gene targets and increased levels of TGFß inhibitor decorin. Surprisingly, BLCC upregulated metallothioneins and fibroblast-derived MMP8 collagenase, and promoted endogenous release of MMP-activating zinc to stimulate antifibrotic remodeling, a novel mechanism of cutaneous wound healing. By activating a remodeling program in the quiescent VLU bed, BLCC application shifts nonhealing to healing phenotype. As VLU bed fibrosis correlates with poor clinical healing, findings from this study identify the chronic VLU as a fibrotic skin disease and are first to support the development and application of antifibrotic therapies as a successful treatment approach.

Research Techniques Made Simple: Molecular Docking in Dermatology - A Foray into In Silico Drug Discovery.

Drug discovery is a complex process with many potential pitfalls. To go to market, a drug must undergo extensive preclinical optimization followed by clinical trials to establish its efficacy and minimize toxicity and adverse events. The process can take 10-15 years and command vast research and development resources costing over $1 billion. The success rates for new drug approvals in the United States are < 15%, and investment costs often cannot be recouped. With the increasing availability of large public datasets (big data) and computational capabilities, data science is quickly becoming a key component of the drug discovery pipeline. One such computational method, large-scale molecular modeling, is critical in the preclinical hit and lead identification process. Molecular modeling involves the study of the chemical structure of a drug and how it interacts with a potential disease-relevant target, as well as predicting its ADMET properties. The scope of molecular modeling is wide and complex. Here we specifically discuss docking, a tool commonly employed for studying drug-target interactions. Docking allows for the systematic exploration of how a drug interacts at a protein binding site and allows for the rank-ordering of drug libraries for prioritization in subsequent studies. This process can be efficiently used to virtually screen libraries containing over millions of compounds.

Combined Systemic and Intratumoral Administration of Human Papillomavirus Vaccine to Treat Multiple Cutaneous Basaloid Squamous Cell Carcinomas.

Importance: Squamous cell carcinoma (SCC) is the second most common form of skin cancer, and its incidence is increasing. When surgical management is not an option, finding a safe and efficacious treatment is a challenge. Mounting evidence suggests that the human papillomavirus (HPV) is involved in the pathogenesis of some SCCs. Objective: To assess whether the 9-valent HPV vaccine could be an effective treatment strategy for cutaneous SCC. Design, Setting, and Participants: A woman in her 90s with multiple, inoperable cutaneous basaloid SCCs was successfully treated at a university-based outpatient dermatology clinic with a combination of systemic and intratumoral delivery of the 9-valent HPV vaccine from March 17, 2016, through February 27, 2017, and then followed up through May 21, 2018. Main Outcomes and Measures: Reduction in tumor size and number after a combination of systemic and intratumoral administration of the HPV vaccine. Results: All tumors resolved 11 months after the first intratumoral injection of the vaccine. The patient remained free of tumors at the end of follow-up. Conclusions and Relevance: This is the first report, to our knowledge, of complete regression of a cutaneous malignant tumor after combined systemic and direct intratumoral injection of the 9-valent HPV vaccine. This report suggests that the HPV vaccine may have therapeutic utility for SCCs in patients who are poor surgical candidates, have multiple lesions, or defer surgery.

Systematic review of the therapeutic roles of adipose tissue in dermatology.

BACKGROUND: Adipose tissue has classically functioned as a filler in restoring facial volume. Adipose tissue is also rich in stem cells, which may have a role in regenerative medicine. OBJECTIVE: To summarize the literature on the clinical uses of adipose tissue in scarring, wound healing, and hair growth and determine whether evidence exists for changes in clinical practice in dermatology. METHODS: We utilized the Preferred Reporting Items for Systemic Reviews and Meta-Analyses to conduct the review. The PubMed search engine was used to assess the available literature on adipose tissue in scarring, wound healing, and hair growth. RESULTS: A total of 13 studies matched our inclusion criteria; 6 of the 7 studies on scar treatment, all 3 studies on wound healing, and all 3 studies on hair growth demonstrated improved outcomes with adipose tissue treatments. LIMITATIONS: The literature supporting the use of adipose tissue is limited to case series, cohort studies, and small randomized controlled trials, which have an overall low level of evidence. CONCLUSION: The existing evidence for adipose tissue as a treatment option in scarring, wound healing, and hair growth is not strong enough to justify changes to current clinical practice. The literature does provide evidence for future large randomized clinical trials.