Depression As a Potential Contributing Factor in Hidradenitis Suppurativa and Associated Racial Gaps.

The etiology of hidradenitis suppurativa (HS)-a chronic, relapsing, inflammatory disorder-is multifactorial, encompassing lifestyle, microbiota, hormonal status, and genetic and environmental factors. These factors propagate the production of deep-seated inflammatory nodules seen in HS through aberrant immune response activation and inflammation. The high prevalence of depression in individuals with HS and its association with systemic inflammation increases the likelihood that depression also may be a contributing etiology to HS. Because depression frequently has been discovered as a concomitant diagnosis in patients with HS, we hypothesize that there is a common susceptibility to depression in patients with HS, which we investigated through a literature search of articles published from 2000 to 2022 involving depression and HS.

Seborrheic Dermatitis as a Potential Trigger of Central Centrifugal Cicatricial Alopecia: A Review of Literature.

Central centrifugal cicatricial alopecia (CCCA) is a common form of scarring alopecia that affects the crown or vertex of the scalp as centrifugally spreading patches of permanent hair loss. The etiology of CCCA is uncertain. Genetic predisposition, autoimmune diseases, infections (bacterial and fungal), and other idiopathic factors have all been explored as potential risk factors for the development of CCCA. Seborrheic dermatitis (SD) has been identified in a number of studies as the most common concurrent hair disorder seen in patients with CCCA. The high prevalence of SD in African American women and its association with long-term inflammation of the scalp may increase the likelihood of a connection between SD and other inflammatory conditions of the scalp in this population. Since it has frequently been discovered as a concomitant diagnosis in patients with CCCA, we hypothesize that a history of SD may play a role in the pathogenesis of CCCA.

A Randomized Double-blind Placebo-controlled Trial of Oral Aspirin for Protection of Melanocytic Nevi Against UV-induced DNA Damage.

DNA damage plays a role in ultraviolet (UV)-induced melanoma. We previously showed that aspirin (ASA) can suppress prostaglandin-E2 (PGE2) and protect melanocytes from UV-induced DNA damage in mice, and suggested that taking ASA before acute sun exposure may reduce melanoma risk. We conducted a prospective randomized placebo-controlled trial to determine if orally administered ASA could suppress PGE2 in plasma and nevi and protect nevi from UV-induced DNA damage. After obtaining plasma and determining the minimal erythemal dose (MED) in 95 subjects at increased risk for melanoma, they were randomized to receive a daily dose of placebo, 81 mg ASA, or 325 mg ASA, in double-blind fashion for one month. After this intervention, one nevus was irradiated (dose = 1 or 2 MED) using a solar simulator. One day later, MED was re-determined, a second plasma sample was obtained, and the UV-irradiated nevus and an unirradiated nevus were removed. ASA metabolites were detected in the second plasma sample in subjects in the ASA arms. There were no significant differences in the pre- and post-intervention MED between those patients receiving ASA and placebo. Significantly reduced PGE2 levels were detected in plasma (second vs. first samples) and in nevi (both unirradiated and UV-treated) in subjects receiving ASA compared to placebo. Comparing UV-treated nevi from the ASA and placebo cohorts, however, did not reveal significant reductions in CD3-cell infiltration or 8-oxoguanine and cyclobutane pyrimidine dimers. Thus ASA did not effectively protect nevi from solar-simulated UV-induced inflammation and DNA damage under the conditions examined. PREVENTION RELEVANCE: Despite promising rationale, ASA at conventional dosing was not able to protect nevi against UV-induced DNA damage under the conditions examined.See related Spotlight, p. 71.

The dark side of immunotherapy.

Immunotherapy has broadened the therapeutic scope and response for many cancer patients with drugs that are generally of higher efficacy and less toxicity than prior therapies. Multiple classes of immunotherapies such as targeted antibodies and immune checkpoint inhibitors (ICI), cell-based immunotherapies, immunomodulators, vaccines, and oncolytic viruses have been developed to help the immune system target and destroy malignant tumors. ICI targeting programmed cell death protein-1 (PD-1) or its ligand (PD-L1) are among the most effective immunotherapy agents and are a major focus of current investigations. They have received approval for at least 16 different tumor types as well as for unresectable or metastatic tumors with microsatellite instability-high (MSI-H) or mismatch repair deficiency or with high tumor mutational burden (defined as ≥10 mutations/megabase). However, it is important to recognize that immunotherapy may be associated with significant adverse events. To summarize these events, we conducted a PubMed and Google Scholar database search through April 2020 for manuscripts evaluating treatment-related adverse events and knowledge gaps associated with the use of immunotherapy. Reviewed topics include immune-related adverse events (irAEs), toxicities on combining immunotherapy with other agents, disease reactivation such as tuberculosis (TB) and sarcoid-like granulomatosis, tumor hyperprogression (HPD), financial toxicity, challenges in special patient populations such as solid organ transplant recipients and those with auto-immune diseases. We also reviewed reports of worse or even lethal outcomes compared to other oncologic therapies in certain scenarios and summarized biomarkers predicting adverse events.

Difference in vasoconstrictors: oxymetazoline vs. brimonidine.

OBJECTIVE: Topical oxymetazoline and brimonidine are the only medications approved for treating persistent facial erythema of rosacea. This review aims to investigate the efficacy, safety, pharmacodynamics, and pharmacokinetic properties of oxymetazoline and brimonidine. METHODS AND MATERIALS: Phase II and phase III clinical studies evaluating oxymetazoline and brimonidine were assessed to compare their efficacy and safety. RESULTS: In their respective phase III trials, both oxymetazoline and brimonidine met the primary efficacy outcome of having at least a 2-grade decrease from baseline on both the Clinician Erythema Assessment (CEA) and the Subject Self-Assessment (SSA) Scales compared to the vehicle control. Treatment related adverse events of oxymetazoline and brimonidine are most often mild and localized. CONCLUSIONS: Topical oxymetazoline and brimonidine are effective for the management of persistent facial erythema associated with rosacea with a few mild and localized adverse effects. Further long-term research is imperative to further understand their long-term effects.

Is topical treatment effective for psoriasis in patients who failed topical treatment?

Objectives: To determine if resistance to topical treatments can be overcome under conditions promoting adherence.Materials and Methods: Twelve psoriasis patients treated with topical 0.25% desoximetasone spray were randomized to either twice daily phone call reminders or no phone call and were treated for 2 weeks. Pruritus Visual Analog Scale (VAS), Psoriasis Area and Severity Index (PASI), Total Lesion Severity Score (TLSS), and, Investigator Global Assessment (IGA) assessed disease severity.Results: Most subjects improved in most scoring parameters. 100%, 91.7%, 83.3%, and 58.3% had improvements in itching, PASI, TLSS, and IGA, respectively.Conclusions: While our sample size was small and treatment duration short, the effect size of topical treatment was large under conditions designed to promote adherence.

Aspirin Protects Melanocytes and Keratinocytes against UVB-Induced DNA Damage In Vivo.

UVR promotes skin cancer through multiple mechanisms, including induction of inflammation, oxidative stress, and DNA damage such as 8-oxoguanine and cyclobutane pyrimidine dimers. We investigated whether the anti-inflammatory activities of aspirin (acetylsalicylic acid [ASA]) could protect against UVB-induced DNA damage and skin carcinogenesis. ASA reduced UVB-induced 8-oxoguanine and cyclobutane pyrimidine dimers in Melan-A melanocytes and HaCaT keratinocytes. Skin from UVB-irradiated C57BL/6 mice receiving 0.4 mg ASA daily by gavage exhibited less inflammation, fewer sunburn cells, and reduced 8-oxoguanine lesions than skin from irradiated control animals. ASA similarly reduced UVB-induced sunburn cells, 8-oxoguanine, and cyclobutane pyrimidine dimer lesions in skin of melanoma-prone TN61R mice, and this was associated with decreased prostaglandin E2 in plasma and skin. These effects of ASA, however, did not delay melanoma onset in TN61R mice exposed to a single neonatal dose of UVB. In SKH1-E mice prone to squamous cell carcinoma, ASA reduced plasma and skin prostaglandin E2 levels and indices of UVB-induced DNA damage and delayed squamous cell carcinoma onset induced by chronic UVB. These results indicate that ASA can protect against UVB-induced inflammation in skin and reduce UVB-induced DNA damage in both melanocytes and keratinocytes. These effects translated into greater chemopreventive efficacy for UVB-induced squamous cell carcinoma than melanoma mouse models.

Prognostic Gene Expression Profiling in Cutaneous Melanoma: Identifying the Knowledge Gaps and Assessing the Clinical Benefit.

Importance: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care. Objective: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. Evidence Review: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed. Findings: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility. Conclusions and Relevance: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

Adherence to topical treatment can improve treatment-resistant moderate psoriasis.

Most patients with psoriasis have limited disease that should be manageable with topical treatment. However, psoriasis often is resistant to topical treatment. The aim of our study was to determine if patients using psoriasis-resistant topical treatments can be effectively treated with topicals under conditions promoting adherence. During this open-label, randomized, single-center clinical study, 12 patients with moderate psoriasis that previously failed topical treatment were selected and treated with desoximetasone spray 0.25% for 2 weeks. Six patients were randomized to receive twice-daily telephone call reminders to further encourage good adherence. Disease severity was assessed by the visual analog scale for pruritus, psoriasis area and severity index (PASI), total lesion severity score (TLSS), and investigator global assessment (IGA). At the end of the study, most patients improved in most scores. Therefore, apparent resistance to topical treatment often is due to poor adherence and can be overcome, at least over the short term.

ASA Suppresses PGE2 in Plasma and Melanocytic Nevi of Human Subjects at Increased Risk for Melanoma.

Potential anti-inflammatory and anticarcinogenic effects of aspirin (ASA) may be suitable for melanoma chemoprevention, but defining biomarkers in relevant target tissues is prerequisite to performing randomized controlled chemoprevention trials. We conducted open-label studies with ASA in 53 human subjects with melanocytic nevi at increased risk for melanoma. In a pilot study, 12 subjects received a single dose (325 mg) of ASA; metabolites salicylate, salicylurate, and gentisic acid were detected in plasma after 4-8 h, and prostaglandin E2 (PGE2) was suppressed in both plasma and nevi for up to 24 h. Subsequently, 41 subjects received either 325 or 81 mg ASA (nonrandomized) daily for one week. ASA metabolites were consistently detected in plasma and nevi, and PGE2 levels were significantly reduced in both plasma and nevi. Subchronic ASA dosing did not affect 5" adenosine monophosphate-activated protein kinase (AMPK) activation in nevi or leukocyte subsets in peripheral blood, although metabolomic and cytokine profiling of plasma revealed significant decreases in various (non-ASA-derived) metabolites and inflammatory cytokines. In summary, short courses of daily ASA reduce plasma and nevus PGE2 and some metabolites and cytokines in plasma of human subjects at increased risk for melanoma. PGE2 may be a useful biomarker in blood and nevi for prospective melanoma chemoprevention studies with ASA.

Prognostic gene expression profiling in melanoma: necessary steps to incorporate into clinical practice.

Prognostic gene expression profiling (GEP) tests for cutaneous melanoma (CM) are not recommended in current guidelines outside of a clinical trial. However, their use is becoming more prevalent and some practitioners are using GEP tests to guide patient management. Thus, there is an urgent need to bridge this gap between test usage and clinical guideline recommendations by obtaining high-quality evidence to guide us toward best practice use of GEP testing in CM patients. We focus here on the opportunities and uncertainties associated with prognostic GEP testing in CM, review how GEP testing was incorporated into clinical care guidelines for uveal melanoma and breast cancer and discuss the role of clinical trials to determine best use in patients with CM.

Topical corticosteroids for treatment-resistant atopic dermatitis.

Although topical corticosteroids are the mainstay of treatment of atopic dermatitis (AD), these medications may lose efficacy over time, a phenomenon known as tachyphylaxis. However, the underlying mechanism for tachyphylaxis may be due to lack of treatment adherence rather than loss of efficacy of topical corticosteroids. In this study, we aimed to determine if AD patients who were previously unsuccessfully treated with topical corticosteroids would respond to desoximetasone spray 0.25% under conditions designed to promote good adherence over a 7-day period. At baseline, patients were randomized to receive either twice-daily telephone calls to discuss treatment adherence (intervention group) or no telephone calls (control group) during the study period. The patients improved rapidly. In most patients, treatment-resistant AD is most likely due to poor adherence to treatment rather than loss of drug responsiveness.