Painless photodynamic therapy for facial actinic keratoses: A retrospective cohort study of the post-treatment inflammatory response.

INTRODUCTION: Photodynamic therapy (PDT) is a safe, non-mutagenic, and non-scarring treatment for actinic keratoses (AK). BACKGROUND: 'Painless' photodynamic therapy (p-PDT) is a regimen for AK that employs simultaneous aminolevulinate incubation and blue light illumination. The efficacy of p-PDT resembles that of traditional PDT, but detailed mechanisms of action for p-PDT are not well understood. METHODS: To characterize the inflammatory effects of the p-PDT procedure 48 h following treatment and determine the association of inflammation with precancer burden, we performed a retrospective cohort study of 104 patients with AK of face or scalp treated with p-PDT between 2017 and 2019. Patients self-reported their side effects 48 h following p-PDT and took photographs of their face and scalp. Photographs were edited to define seven anatomic regions, and erythema was scored by four investigators. RESULTS: Ninety-eight patients provided photographs suitable for erythema evaluation. Most patients experienced 2 or more side effects and some pain 48 h post-procedure. Females experienced more pain (p = 0.01) and side effects (p = 0.002) compared to males. AK burden was positively associated with post p-PDT erythema response (p < 0.0001) at all sites, but particularly in the temples (p = 0.002) and supralabial area (p = 0.009). DISCUSSION: This study confirms a strong clinical inflammatory response after p-PDT. Severity of inflammation is positively associated with AK tumor burden, suggesting that post-treatment inflammation may be a pre-requisite for p-PDT efficacy. Interestingly, the results also identify certain gender-related differences in the severity of side effects experienced by patients post-PDT.

Significant Association of Poly-A and Fok1 Polymorphic Alleles of the Vitamin D Receptor with Vitamin D Serum Levels and Incidence of Squamous Cutaneous Neoplasia.

Vitamin D3, a prohormone, is converted to circulating calcidiol and then to calcitriol, the hormone that binds to the vitamin D receptor (VDR) (a nuclear transcription factor). Polymorphic genetic sequence variants of the VDR are associated with an increased risk of breast cancer and melanoma. However, the relationship between VDR allelic variants and the risk of squamous cell carcinoma and actinic keratosis remains unclear. We examined the associations between two VDR polymorphic sites, Fok1 and Poly-A, and serum calcidiol levels, actinic keratosis lesion incidence, and the history of cutaneous squamous cell carcinoma in 137 serially enrolled patients. By evaluating the Fok1 (F) and (f) alleles and the Poly-A long (L) and short (S) alleles together, a strong association between genotypes FFSS or FfSS and high calcidiol serum levels (50.0 ng/ml) was found; conversely, ffLL patients showed very low calcidiol levels (29.1 ng/ml). Interestingly, the FFSS and FfSS genotypes were also associated with reduced actinic keratosis incidence. For Poly-A, additive modeling showed that Poly-A (L) is a risk allele for squamous cell carcinoma, with an OR of 1.55 per copy of the L allele. We conclude that actinic keratosis and squamous cell carcinoma should be added to the list of squamous neoplasias that are differentially regulated by the VDR Poly-A allele.

Sandpaper curettage: A simple method to improve PDT outcomes for actinic keratosis.

INTRODUCTION: Photodynamic therapy (PDT) is a non-scarring, repeatable, and safe treatment for actinic keratosis (AK), but improvements in efficacy are still needed. BACKGROUND: Devices such as steel blades, needle rollers, and lasers are currently used to remove hypertrophic stratum corneum on AKs to improve PDT outcomes. However, curettage with fine sandpaper could be a gentler, effective alternative. METHODS: A retrospective study was designed to compare PDT with or without sandpaper curettage. Patients were selected from a database registry of patients with face and scalp AKs (ClinicalTrials.gov NCT03319251). Patients in Group 1 underwent PDT alone (20% ALA, 15 min; blue light 417 nm, 30 min). Patients in Group 2 were pretreated with gentle sandpaper curettage prior to ALA and illumination. The two groups were compared using multivariate matching, normalizing for age, sex, initial AK counts, and time to follow-up. RESULTS: Sixty-six patients were selected for matching analysis (n=38, PDT only; n=28, PDT+curettage). Demographics between the groups were similar (mean ± SD), including age (71.0 ± 8.3 vs. 71.0 ± 8.0 years), baseline AK count (53 ± 39 vs. 44± 32), and time to post-PDT follow-up (111 ± 28 vs. 113 ± 32 days). At follow-up, patients who received curettage showed an overall 55% improvement in scalp AK clearance compared to patients who did not receive curettage, adjusting for sex, age, time to follow-up, and baseline AK count (p = 0.0322, multivariable linear regression). DISCUSSION: Sandpaper curettage before PDT treatment is an easy and inexpensive method to significantly improve AK clearance rates.

Significant improvement of facial actinic keratoses after blue light photodynamic therapy with oral vitamin D pretreatment: An interventional cohort-controlled trial.

BACKGROUND: In mouse models of skin cancer, high-dose oral vitamin D3 (VD3; cholecalciferol) combined with photodynamic therapy (PDT) can improve the clearance of squamous precancers (actinic keratoses [AKs]). OBJECTIVE: To determine whether oral VD3 can improve the clinical efficacy of a painless PDT regimen in humans with AK. METHODS: The baseline lesion counts and serum 25-hydroxyvitamin D3 levels were determined. In group 1, 29 patients underwent gentle debridement and 15-minute aminolevulinic acid preincubation with blue light (30 minutes; 20 J/cm2). In group 2, 29 patients took oral VD3 (10,000 IU daily for 5 or 14 days) prior to debridement and PDT. Lesion clearance was assessed at 3 to 6 months. RESULTS: In group 1, the mean clearance rates of facial AK were lower in patients with VD3 deficiency (25-hydroxyvitamin D3 level < 31 ng/dL; clearance rate, 40.9% ± 42%) than in patients with normal 25-hydroxyvitamin D3 levels (62.6% ± 14.2%). High-dose VD3 supplementation (group 2) significantly improved the overall AK lesion response (72.5% ± 13.6%) compared with that in group 1 (54.4% ± 22.8%). No differences in side effects were noted. LIMITATIONS: Nonrandomized trial design (interventional cohort matched to registry-based controls). CONCLUSIONS: Oral VD3 pretreatment significantly improves AK clinical responses to PDT. The regimen appears promising and well tolerated.

Store-and-forward teledermatology impact on diagnosis, treatment and dermatology referrals: Comparison between practice settings.

INTRODUCTION: Store-and-forward (SAF) teledermatology involves non-dermatologists sending clinical images to dermatologists. This improves patient care while reducing unwarranted face-to-face (FTF) specialist office visits. Comparisons between dermatologist diagnostic concordance with referring provider, treatment change recommendations, and FTF referrals have yet to be compared by type of provider and practice setting. METHODS: This retrospective chart review examined SAF teledermatology eConsults from four practice settings: Doctor of Medicine (MD)/Doctor of Osteopathic Medicine (DO) office visits, MD/DO walk-in clinics, nurse practitioner (NP)/physician assistant (PA) office visits and NP/PA walk-in clinics. The most recent 100 MD/DO office- and 100 NP/PA walk-in-referred patient charts were reviewed. There were only 71 NP/PA office and 47 MD/DO walk-in eConsults to review. RESULTS: Teledermatologists agreed with referring provider diagnoses 50% of the time for MD/DO office visits, 29.8% for MD/DO walk-in clinics, 33.8% for NP/PA office visits and 34% for NP/PA walk-in clinics. Diagnostic concordance was significantly higher for eConsults from MD/DO office visits than MD/DO walk-in clinics (p = 0.021), NP/PA office visits (p = 0.035) or NP/PA walk-in clinics (p = 0.022). There were significantly more treatment changes recommended after walk-in eConsults than office visits (67 versus 44%, p < 0.0001). FTF visits were recommended more after office visits than walk-in clinics (46 versus 27%, p = 0.001). Overall, 21% (68/318) of patients ultimately attended FTF appointments. DISCUSSION: SAF teledermatology improves diagnosis, reducing barriers to specialty care. Overall, potential FTF visit reduction was 79%. Expanding eConsult programmes, particularly in walk-in settings, and for use by NP/PAs or early career internists, may render dermatological care more expeditiously and avoid unnecessary FTF visits.

Utility of salivary gland biopsy in diagnosing Sjogren's syndrome in a POTS patient population.

PURPOSE: POTS patients undergo labial salivary gland biopsies (LSGB) for histologic confirmation of Sjogren's syndrome (SS). Predictive features of positive results are unknown. METHODS: 161 POTS patients underwent LSGB. Their charts were reviewed for antibody and diagnostic testing results. RESULTS: Only 11% (17/161) of POTS patients were SS positive. There were more positive ANA antibodies in those with positive LSGB (65% v 28%, p = .0026). Positive skin nerve biopsy for small fiber neuropathy (SFN) was associated with positive LSGB (p = .046). CONCLUSION: A positive ANA and skin biopsy for SFN are two helpful features in selecting POTS patients for LSGB.

Cutaneous adverse effects of biologic medications.

Biologic therapies have become widely used but often cause cutaneous adverse effects. The authors discuss the cutaneous adverse effects of tumor necrosis factor (TNF) alpha inhibitors, epidermal growth factor receptor (EGFR) inhibitors, small-molecule tyrosine kinase inhibitors (TKIs), and cell surface-targeted monoclonal antibodies, including how to manage these reactions and when to refer to a dermatologist.

A regimen to minimize pain during blue light photodynamic therapy of actinic keratoses: Bilaterally controlled, randomized trial of simultaneous versus conventional illumination.

BACKGROUND: Blue light photodynamic therapy (PDT) is effective for actinic keratosis, but many patients experience stinging pain during illumination. OBJECTIVE: To compare a conventional regimen (1 hour of 5-aminolevulinic acid [ALA] preincubation, followed by blue light) versus a new modified regimen in which blue light is started immediately after ALA application. METHODS: A clinical trial with a bilaterally controlled, intrapatient study design was conducted with 23 patients. Topical 20% ALA was applied to the entire face and/or scalp. On 1 side of the body, blue light was started immediately and continued for either 30, 45, or 60 minutes (simultaneous PDT). On the contralateral side, the blue light began 1 hour after ALA application and lasted 1000 seconds (conventional PDT). Pain was evaluated on a scale from 0 to 10. Actinic keratosis lesion counts were determined by clinical examination and photography. RESULTS: All patients experienced significantly less pain during simultaneous illumination than during the conventional regimen. At 3 months after treatment, lesion clearance was nearly identical on the 2 sides, as determined by statistical testing of noninferiority ± 15% margin. LIMITATIONS: Although bilaterally controlled, the study was relatively small. Additional studies are recommended. CONCLUSION: The modified PDT regimen is essentially painless, yet it provides treatment efficacy similar to a conventional regimen.

TNF-α inhibitor-induced psoriasis: A decade of experience at the Cleveland Clinic.

BACKGROUND: Tumor necrosis factor-α (TNF-α) inhibitor (TNFI)-induced psoriasis remains poorly understood despite having been described 15 years ago. As TNFIs often provide life-changing patient benefits, understanding effective treatments for TNFI-induced psoriasis is important. OBJECTIVE: We characterized a cohort of patients with TNFI-induced psoriasis whose psoriasis was specifically diagnosed and managed or comanaged by dermatologists at a single tertiary care institution over a 10-year period. METHODS: Retrospective review of patients in whom TNFI-induced psoriasis was diagnosed between 2003 and 2013. RESULTS: A total of 102 patients with TNFI-induced psoriasis were identified. The mean age of onset was 40 years, and there was a female predominance (73.5%). Crohn's disease (in 48% of cases) and rheumatoid arthritis (in 24.5% of cases) were the most common primary conditions. Infliximab (in 52% of cases) was the most common inciting agent. The most common TNFI-induced psoriasis subtypes were plaque-type psoriasis (49.5%), scalp psoriasis (47.5%), and palmoplantar pustulosis (41%). Topical medications alone improved or resolved TNFI-induced psoriasis in 63.5% of patients, and cyclosporine and methotrexate (>10 mg weekly) were often effective if topicals failed. Discontinuation of the inciting TNFI with or without other interventions improved or resolved TNFI-induced psoriasis in 67% of refractory cases, whereas switching TNFIs resulted in persistence or recurrence in 64%. LIMITATIONS: Retrospective nature of the study and the fact that some patients may have developed typical psoriasis unresponsive to TNFIs. CONCLUSION: Our study cohort represents the largest single-institution cohort of patients with TNFI-induced psoriasis diagnosed and managed or comanaged by dermatologists to date. On the basis of our findings, we propose a treatment algorithm for TNFI-induced psoriasis.

Diagnoses of hospitalized patients with skin abnormalities prompting biopsy by consulting dermatologists: A 3-year review from a tertiary care center.

BACKGROUND: Dermatologists play an important role in diagnosing and managing hospitalized patients with cutaneous abnormalities. Skin biopsies remain an indispensable tool for aiding dermatologists in accurate diagnosis and treatment. We aimed to determine the range of conditions, and the most common conditions, prompting skin biopsy by dermatology hospital consultation (HCON) services to aid in evaluation of hospitalized patients. METHODS: All hospitalized patients seen by a single tertiary care center dermatology HCON service between 2015 and 2018 who had associated skin biopsies were identified. Histologic features and clinical diagnoses of each patient were classified into 13 histologic reaction pattern categories. RESULTS: Eight hundred and thirty one inpatients evaluated by our dermatology HCON service had 914 skin biopsies. The most frequent diagnostic categories prompting biopsy were vasculopathic (17.6%), interface dermatitis (16.5%), infectious (12.6%), and spongiotic dermatitis (10.9%). The most frequent diagnostic categories included drug reaction (13.2%), leukocytoclastic vasculitis (8.5%), skin cancer (5.4%), graft-vs-host disease (3.5%), connective tissue disease (3.3%), and calciphylaxis (3.0%). CONCLUSION: Our study suggests a variety of serious diseases affecting inpatients prompts biopsy by dermatology consultation services. Educational curricula for dermatology and pathology residents, fellows, and staff designed with these data may enhance knowledge that improves the quality of inpatient dermatology care.

Ultrastructural examination of skin biopsies may assist in diagnosing mitochondrial cytopathy when muscle biopsies yield negative results.

Ultrastructural evaluation of skin biopsies has been utilized for diagnosis of mitochondrial disease. This study investigates how frequently skin biopsies reveal mitochondrial abnormalities, correlates skin and muscle biopsy findings, and describes clinical diagnoses rendered following the evaluation. A retrospective review of surgical pathology reports from 1990 to 2015 identified skin biopsies examined by electron microscopy for suspected metabolic disease. A total of 630 biopsies were included from 615 patients. Of these patients, 178 also underwent a muscle biopsy. Of the 630 skin biopsies, 75 (12%) showed ultrastructural abnormalities and 34 (5%) specifically showed mitochondrial abnormalities including increased size (n=27), reduced or abnormal cristae (n=23), dense matrices (n=20), and increased number (n=8). Additional findings included lysosomal abnormalities (n=13), lipid accumulation (n=2) or glycogen accumulation (n=1). Of the 34 patients with mitochondrial abnormalities on skin biopsy, 20 also had muscle biopsies performed and nine showed abnormalities suggestive of a mitochondrial disorder including absent cytochrome oxidase staining (n=2), increased subsarcolemmal NADH, SDH, or cytochrome oxidase staining (n=1), or ultrastructural findings including large mitochondrial size (n=5), abnormal mitochondrial structure (n=5), and increased mitochondrial number (n=4). The most common presenting symptoms were intellectual disability (n=13), seizures (n=12), encephalopathy (n=9), and gastrointestinal disturbances (n=9). At last known follow-up, 12 patients had a definitive diagnosis of a mitochondrial disorder. One patient each had Complex I deficiency, Complex III deficiency, Charcot-Marie-Tooth disease, pyruvate dehydrogenase deficiency, and Phelan-McDermid syndrome. Our results suggest that skin biopsy sometimes yields diagnostic clues suggestive of a mitochondrial cytopathy in cases with a negative muscle biopsy.

Photodynamic therapy for dermatologic conditions in the pediatric population: a literature review.

Photodynamic therapy (PDT), using topical aminolevulinic acid (ALA), has been used for years to treat a variety of dermatologic conditions, including actinic keratosis, superficial basal cell carcinoma, and in situ squamous cell carcinoma. While there is a wide range of neoplastic and non-neoplastic skin diseases for which ALA-PDT is used in adults, there is a knowledge gap when it comes to its use in children. This review highlights what is currently known regarding the use and efficacy of this therapy in the pediatric population. A PubMed search was conducted to identify studies including pediatric patients undergoing monotherapy PDT with topical aminolevulinate (published 2005-2016). Twenty pediatric articles were identified. ALA-PDT has been used successfully in children to reduce the number and size of basal cell tumors, inflammatory acne lesions, plantar warts, and linear porokeratoses. ALA-PDT may be an attractive alternative to surgery for children with basal cell nevus syndrome, or to conventional destructive and/or topical methods used for plantar warts or linear porokeratoses. PDT can be considered for inflammatory acne when topical treatments have failed and systemic medications are not an option. Pain associated with treatment and insurance coverage may be a barrier to use.

C/EBP transcription factors in human squamous cell carcinoma: selective changes in expression of isoforms correlate with the neoplastic state.

The CCAAT/Enhancer Binding Proteins (C/EBPs) are a family of leucine-zipper transcription factors that regulate physiological processes such as energy metabolism, inflammation, cell cycle, and the development and differentiation of several tissues including skin. Recently, a role for C/EBPs in tumor cell proliferation and differentiation has been proposed, but the incomplete characterization in the literature of multiple translational isoforms of these proteins has made interpretation of these roles difficult. Therefore, we have carefully reexamined C/EBP isoform expression in human non-melanoma skin cancers. C/EBPα, C/EBPß, and C/EBPδ were analyzed histologically in squamous cell carcinomas (SCC). The individual isoforms of C/EBPα and C/EBPß were examined by immunofluorescent digital imaging, western blotting and DNA binding activity (electrophoretic mobility shift analysis). Expression of all C/EBP family proteins was decreased in SCC tumors. Suppression was greatest for C/EBPα, less for C/EBPß, and least for C/EBPδ. Western analyses confirmed that C/EBPα p42 and p30 isoforms were decreased. For C/EBPß, only the abundant full-length isoform (C/EBPß-1, LAP*, 55 kD) was reduced, whereas the smaller isoforms, C/EBPß-2 (LAP, 48 kD) and C/EBPß-3 (LIP, 20 kD), which are predominantly nuclear, were significantly increased in well- and moderately-differentiated SCC (up to 14-fold for C/EBPß-3). These elevations correlated with increases in PCNA, a marker of proliferation. Although C/EBPß displayed increased post-translational modifications in SCC, phosphorylation of C/EBPß-1 (Thr 235) was not altered. C/EBP-specific DNA binding activity in nuclear and whole-cell extracts of cultured cells and tumors was predominantly attributable to C/EBPß. In summary, two short C/EBPß isoforms, C/EBPß-2 and C/EBPß-3, represent strong candidate markers for epithelial skin malignancy, due to their preferential expression in carcinoma versus normal skin, and their strong correlation with tumor proliferation.

Noninvasive fluorescence monitoring of protoporphyrin IX production and clinical outcomes in actinic keratoses following short-contact application of 5-aminolevulinate.

Topical 5-aminolevulinic acid (ALA) is widely used in photodynamic therapy (PDT) of actinic keratoses (AK), a type of premalignant skin lesion. However, the optimal time between ALA application and exposure to light has not been carefully investigated. Our objective is to study the kinetics of protoporphyrin IX (PpIX) accumulation in AK after short contact ALA and relate this to erythemal responses. Using a noninvasive dosimeter, PpIX fluorescence measurements (5 replicates) were taken at 20-min intervals for 2 h following ALA application, in 63 AK in 20 patients. Data were analyzed for maximal fluorescent signal obtained, kinetic slope, and changes in erythema. Our results show that PpIX accumulation was linear over time, becoming statistically higher than background in 48% of all lesions by 20 min, 92% of lesions by 1 h, and 100% of lesions by 2 h. PpIX accumulation was roughly correlated with changes in lesional erythema post-PDT. We conclude that significant amounts of PpIX are produced in all AK lesions by 2 h. The linear kinetics of accumulation suggest that shorter ALA application times may be efficacious in many patients. Noninvasive fluorescence monitoring of PpIX may be useful to delineate areas of high PpIX accumulation within precancerous areas of the skin.