The palliative role of lasers in the treatment of melanoma.

Melanoma, accounting for a significant proportion of skin cancer-related deaths, has variable survival outcomes based on the stage at diagnosis and treatment efficacy. Traditional treatments, while effective, pose risks of scarring and systemic side effects. Laser therapy offers an emerging non-surgical alternative, with CO2 lasers particularly showing promise in palliative care.A comprehensive search was conducted using PubMed, focusing on laser therapy for melanoma treatment. The search included studies on both stand-alone and adjunct laser therapies, with inclusion criteria requiring peer-reviewed articles detailing treatment outcomes for primary, recurrent, or metastatic melanoma.The literature shows that laser therapy for melanoma falls into four major types when categorized by laser medium: solid-state, diode, pulse-dye, and gas (CO2). Data on solid-state lasers for melanoma are limited and their use remains controversial. However, one study with high-energy pulsed neodymium lasers reported a 5-year survival of 82.9% with minimal adverse effects for primary melanoma. CO2 laser therapy has been effective for palliative treatment, with one study showing 54.8% of patients with recurrent melanoma surviving 5.4 years post-ablation. For metastatic melanoma, numerous studies have shown that CO2 laser therapy can provide symptomatic relief and disease control. Combination therapies using lasers and immune-based therapies have demonstrated enhanced outcomes and immune activation, highlighting the potential of laser therapies in melanoma management.While traditional treatments remain the standard for primary melanoma, laser therapies, particularly CO2 laser ablation, show substantial promise in palliative care for metastatic melanoma. Careful patient selection and assessment are crucial for achieving positive outcomes.

Neoadjuvant PD-1 Inhibitors: A Tale of Two Cases.

Treatment responses for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC) are often short lived and are marred with recurrences. The introduction of adjuvant PD-1 inhibitors has demonstrated significant improvement in both, response rates, and duration of response. For patients with high-risk resectable disease, adjuvant treatments have not demonstrated an ability to reduce recurrence risk. However, there is an opportunity in the neoadjuvant setting to alter recurrence risk. Here we dem-onstrate two cases of neoadjuvant treatment of cSCC and MCC with impressive results.  J Drugs Dermatol. 2024;23(2):     doi:10.36849/JDD.7043e.

Identifying critical quality metrics in Mohs Surgery: A national expert consensus process.

BACKGROUND: Amid a movement toward value-based healthcare, increasing emphasis has been placed on outcomes and cost of medical services. To define and demonstrate the quality of services provided by Mohs surgeons, it is important to identify and understand the key aspects of Mohs micrographic surgery (MMS) that contribute to excellence in patient care. OBJECTIVE: The purpose of this study is to develop and identify a comprehensive list of metrics in an initial effort to define excellence in MMS. METHODS: Mohs surgeons participated in a modified Delphi process to reach a consensus on a list of metrics. Patients were administered surveys to gather patient perspectives. RESULTS: Twenty-four of the original 66 metrics met final inclusion criteria. Broad support for the initiative was obtained through physician feedback. LIMITATIONS: Limitations of this study include attrition bias across survey rounds and participation at the consensus meeting. Furthermore, the list of metrics is based on expert consensus instead of quality evidence-based outcomes. CONCLUSION: With the goal of identifying metrics that demonstrate excellence in performance of MMS, this initial effort has shown that Mohs surgeons and patients have unique perspectives and can be engaged in a data-driven approach to help define excellence in the field of MMS.

Biosafety and biohazard considerations of HSV-1-based oncolytic viral immunotherapy.

Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with genetic modifications for tumor selectivity, safety, and immunogenicity. Despite these modifications, HSV-1 OV immunotherapies are often treated with the same biosafety guidelines as the wild-type virus, potentially leading to reduced patient access and logistical hurdles for treatment centers, including community treatment centers and small group or private practices, and healthcare workers. Despite the lack of real-world evidence documenting possible transmission to close contacts, and in the setting of shedding and biodistribution analyses for T-VEC demonstrating limited infectivity and low risk of spread to healthcare workers, barriers to treatment with OV immunotherapies remain. With comprehensive information and educational programs, our hope is that updated biosafety guidance on OV immunotherapies will reduce logistical hurdles to ensure that patients have access to these innovative and potentially life-saving medicines across treatment settings. This work reviews a comprehensive collection of data in conjunction with the opinions of the authors based on their clinical experience to provide the suggested framework and key considerations for implementing biosafety protocols for OV immunotherapies, namely T-VEC, the only approved agent to date.

Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei.

Nosocomial infections caused by multidrug-resistant (MDR) Enterobacter cloacae complex (ECC) pathogens are on the rise. However, the virulence strategies employed by these pathogens remain elusive. Here, we study the interaction of ECC clinical isolates with human serum to define how this pathogen evades the antimicrobial action of complement, one of the first lines of host-mediated immune defense. We identified a small number of serum-sensitive strains, including Enterobacter hormaechei strain NR3055, which we exploited for the in vitro selection of serum-resistant clones. Comparative genomics between the serum-sensitive NR3055 strain and the isolated serum-resistant clones revealed a premature stop codon in the wzy gene of the capsular polysaccharide biosynthesis locus of NR3055. The complementation of wzy conferred serum resistance to NR3055, prevented the deposition of complement proteins on the bacterial surface, inhibited phagocytosis by human neutrophils, and rendered the bacteria virulent in a mouse model of peritonitis. Mice exposed to a nonlethal dose of encapsulated NR3055 were protected from subsequent lethal infections by encapsulated NR3055, whereas mice that were previously exposed to unencapsulated NR3055 succumbed to infection. Thus, capsule is a key immune evasion determinant for E. hormaechei, and it is a potential target for prophylactics and therapeutics to combat these increasingly MDR human pathogens. IMPORTANCE Infections caused by antimicrobial resistant bacteria are of increasing concern, especially those due to carbapenem-resistant Enterobacteriaceae pathogens. Included in this group are species of the Enterobacter cloacae complex, regarding which there is a paucity of knowledge on the infection biology of the pathogens, despite their clinical relevance. In this study, we combine techniques in comparative genomics, bacterial genetics, and diverse models of infection to establish capsule as an important mechanism of Enterobacter pathogens to resist the antibacterial activity of serum, a first line of host defense against bacterial infections. We also show that immune memory targeting the Enterobacter capsule protects against lethal infection. The further characterization of Enterobacter infection biology and the immune response to infection are needed for the development of therapies and preventative interventions targeting these highly antibiotic resistant pathogens.

Long-term follow up of ALA 10% gel and red-light photodynamic therapy for the treatment of squamous cell carcinoma in situ.

Photodynamic Therapy (PDT) with 10% aminolevulinic acid (ALA) gel and narrow-band red light has been previously shown to be safe and effective for the treatment of squamous cell carcinoma in situ (SCCis) on the trunk and extremities. However, there is a paucity of data in the literature evaluating long-term disease recurrence after PDT. Hence, we performed a follow-up study in which nine of the original twelve patients from our pilot study returned 29-40 months after their last PDT treatment. All patients were clinically clear of disease and only one of seven patients biopsied had residual disease, indicating a long-term clearance rate of 88%. Cosmetic outcomes and patient satisfaction were favorable. Our data supports that red-light PDT with 10% ALA gel can achieve long-term clinical and histopathologic disease clearance and is a viable alternative to surgery for select SCCis.

Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

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.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Photodynamic therapy utilizing 10% ALA nano-emulsion gel and red-light for the treatment of squamous cell carcinoma in-situ on the trunk and extremities: Pilot study and literature update.

BACKGROUND: Data evaluating the effectiveness of photodynamic therapy (PDT) with aminolevulinic acid (ALA) 10% nanoemulsion gel and red-light LED lamp for the treatment of squamous cell carcinoma in situ (SCCis) on the trunk and extremities is limited. Our study sought to investigate the safety and efficacy of utilizing ALA 10% gel with red-light lamp for the treatment of SCCis on the trunk and extremities. METHODS: A single center prospective study of 12 patients with biopsy proven SCCis underwent one or two cycles of red-light PDT with ALA 10 % gel and 3 hours incubation period. Each cycle consisted of two treatments approximately 10 days apart. All participants had a biopsy for histologic evaluation 4 weeks following the last treatment. RESULTS: All patients achieved clinical and histologic clearance following either one or two cycles at the 4-week post treatment follow up period. The majority of lesions were located on the extremities (n=10) with the remainder located on the trunk (n=2). The mean diameter of the lesions was 1.83 cm. Mild pain was noted in patients, with no interruption of treatment. CONCLUSIONS: Our study indicates that ALA 10% gel with a red-light lamp is a safe and effective treatment option for SCCis on the trunk and extremities.

SARS-CoV-2 is rapidly inactivated at high temperature.

In the absence of a vaccine, preventing the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the primary means to reduce the impact of the 2019 coronavirus disease (COVID-19). Multiple studies have reported the presence of SARS-CoV-2 genetic material on surfaces suggesting that fomite transmission of SARS-CoV-2 is feasible. High temperature inactivation of virus has been previously suggested, but not shown. In the present study, we investigated the environmental stability of SARS-CoV-2 in a clinically relevant matrix dried onto stainless steel at a high temperature. The results show that at 54.5 °C, the virus half-life was 10.8 ± 3.0 min and the time for a 90% decrease in infectivity was 35.4 ± 9.0 min. These findings suggest that in instances where the environment can reach temperatures of at least 54.5 °C, such as in vehicle interior cabins when parked in warmer ambient air, that the potential for exposure to infectious virus on surfaces could be decreased substantially in under an hour.

Talimogene Laherparepvec in Non-Melanoma Cancers.

BACKGROUND: Talimogene laherparepvec (T-VEC) is the first oncolytic virus therapy approved by the United States Food and Drug Administration (in 2015) for the treatment of advanced-stage melanoma. Despite a paucity of Phase III trials for T-VEC as a therapy for non-melanoma cancers, successful off-label use of T-VEC for this purpose has been reported in the literature. OBJECTIVE: We sought to review the literature describing T-VEC as a treatment for non-melanoma cancer. METHODS: Systematic searches of the PubMed literature database and ClinicalTrials.gov website were performed in July 2020, focusing on T-VEC in combination with non-melanoma cancer, including squamous cell carcinoma, Merkel cell carcinoma, sarcoma, cutaneous B-cell lymphoma, and cutaneous T-cell lymphoma. Articles were screened based on their title and abstract. RESULTS: Nine articles with 87 patients were included. Relevant articles included case reports, case series, and Phase I and Phase II trials. The majority of patients in the studies had refractory cancers or had been heavily pretreated. Overall, T-VEC demonstrated efficacy for non-melanoma cancer, both independently and in combination with biologics. CONCLUSION: T-VEC has demonstrated efficacy for non-melanoma cancers. Phase III trials of T-VEC for this indication are warranted to expand its clinical utility.

Photodynamic Therapy with 5-aminolevulinic Acid 10% Gel and Red Light for the Treatment of Actinic Keratosis, Nonmelanoma Skin Cancers, and Acne: Current Evidence and Best Practices.

Photodynamic therapy (PDT) can be an effective treatment for actinic keratosis (AK) as well as selected non-melanoma skin cancers (NMSCs), such as Bowen's disease and superficial basal cell carcinoma. PDT has also demonstrated effectiveness in the management of acne vulgaris. Results from controlled clinical trials have shown the safety and efficacy of PDT for these conditions with the use of different photosensitizers and a wide range of light sources. PDT has been employed effectively as monotherapy and in combination with other topicals and alternate light or laser energy therapies. This article provides expert practical guidance for the use of the newest 5-aminolevulinic acid (ALA) product (ALA 10% gel) plus red light as monotherapy for AKs, NMSC, and acne. Here, information from clinical guidelines and a summary of supporting evidence is provided for each cutaneous condition. The authors also provide detailed guidance for employing ALA 10% gel, a photosensitizer precursor, for each of these applications.

Photodynamic therapy for extramammary Paget's disease: A systematic review of the literature.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma that arises in areas rich in apocrine sweat glands. Photodynamic therapy (PDT) is a non-invasive technique demonstrating clinical efficacy in various case reports and case series for the treatment of EMPD. METHODS: A review of the current literature of patients with EMPD treated with PDT. RESULTS: 177 patients with 211 lesions were included in this review with an overall complete response rate of 59.7 %. Lesion size was correlated with the efficacy of 5-aminolevulinic acid (ALA) PDT. Topical methyl-ALA had lower complete response rates compared to ALA. Systemic PDT with intravenous sodium porfimer had high response rates but can be associated with more adverse reactions. The efficacy of PDT was enhanced with the combination of other treatments such as surgery, imiquimod, or laser ablation. PDT was also shown to be effective for previously treated lesions, recurrent lesions, and select invasive lesions. CONCLUSION: PDT can be a therapeutic option for EMPD patients. Given the lack of PDT guidelines, general recommendations for treatment are offered.