Noninvasive Detection of Skin Cancer by Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging.

We report a technique for the noninvasive detection of skin cancer by imprint desorption electrospray ionization mass spectrometry imaging (DESI-MSI) using a transfer agent that is pressed against the tissue of interest. By noninvasively pressing a tape strip against human skin, metabolites, fatty acids, and lipids on the skin surface are transferred to the tape with little spatial distortion. Running DESI-MSI on the tape strip provides chemical images of the molecules on the skin surface, which are valuable for distinguishing cancer from healthy skin. Chemical components of the tissue imprint on the tape strip and the original basal cell carcinoma (BCC) section from the mass spectra show high consistency. By comparing MS images (about 150-µm resolution) of same molecules from the tape strip and from the BCC section, we confirm that chemical patterns are successfully transferred to the tape stripe. We also used the technique to distinguish cherry angiomas from normal human skin by comparing the molecular patterns from a tape strip. These results demonstrate the potential of the imprint DESI-MSI technique for the noninvasive detection of skin cancers as well as other skin diseases before and during clinical surgery.

Dupilumab significantly improves sleep in adults with atopic dermatitis: results from the 12-week placebo-controlled period of the 24-week phase IV randomized double-blinded placebo-controlled DUPISTAD study.

BACKGROUND: Sleep disturbance is a prominent symptom of atopic dermatitis (AD) and can result in insomnia, daytime fatigue, drowsiness, reduced productivity and impaired quality of life (QoL). OBJECTIVES: The Dupilumab Effect on Sleep in AD Patients (DUPISTAD) phase IV randomized double-blinded placebo-controlled study evaluated the impact of dupilumab treatment on sleep and other patient- and physician-reported outcomes. METHODS: Adults with moderate-to-severe AD were randomized 2 : 1 to dupilumab 300 mg once every 2 weeks (q2w) or placebo for 12 weeks; concomitant topical corticosteroids were permitted. Patients subsequently entered an open-label phase and received dupilumab 300 mg q2w for a further 12 weeks. The primary endpoint was the percentage change in sleep quality from baseline to week 12, assessed using a novel numeric rating scale (NRS). Secondary and exploratory endpoints included percentage change in peak pruritus NRS (PP NRS), change in SCORing Atopic Dermatitis (SCORAD), SCORAD sleep visual analogue scale (VAS), Eczema Area and Severity Index, Patient-Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment T-score and the Epworth Sleepiness Scale. Sleep diary and wrist actigraphy measurements were recorded throughout the study. RESULTS: In total, 127 patients received dupilumab and 61 patients received placebo. Demographic and baseline disease characteristics were balanced between groups. Sleep quality NRS significantly improved in patients treated with dupilumab by week 12 vs. placebo [least squares mean of the difference (LSMD) -15.5%, P < 0.001]. PP NRS (LSMD -27.9%, P < 0.001), SCORAD (LSMD -15.1, P < 0.001), SCORAD sleep VAS (LSMD -2.1, P < 0.001) and PROMIS T-score (LSMD -3.6, P < 0.001) were also significantly improved at week 12 with dupilumab vs. placebo. The overall percentage of patients reporting treatment-emergent adverse events was lower in the dupilumab group (56.7%) than in the placebo group (67.2%). CONCLUSIONS: Dupilumab significantly improved sleep quality and perception of sleep continuity, itch, metrics of AD severity and QoL in adults with moderate-to-severe AD, with an acceptable safety profile compared with placebo.

Distinguishing malignant from benign microscopic skin lesions using desorption electrospray ionization mass spectrometry imaging.

Detection of microscopic skin lesions presents a considerable challenge in diagnosing early-stage malignancies as well as in residual tumor interrogation after surgical intervention. In this study, we established the capability of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to distinguish between micrometer-sized tumor aggregates of basal cell carcinoma (BCC), a common skin cancer, and normal human skin. We analyzed 86 human specimens collected during Mohs micrographic surgery for BCC to cross-examine spatial distributions of numerous lipids and metabolites in BCC aggregates versus adjacent skin. Statistical analysis using the least absolute shrinkage and selection operation (Lasso) was employed to categorize each 200-µm-diameter picture element (pixel) of investigated skin tissue map as BCC or normal. Lasso identified 24 molecular ion signals, which are significant for pixel classification. These ion signals included lipids observed at m/z 200-1,200 and Krebs cycle metabolites observed at m/z < 200. Based on these features, Lasso yielded an overall 94.1% diagnostic accuracy pixel by pixel of the skin map compared with histopathological evaluation. We suggest that DESI-MSI/Lasso analysis can be employed as a complementary technique for delineation of microscopic skin tumors.

Phase 2 trial of a neurokinin-1 receptor antagonist for the treatment of chronic itch in patients with epidermolysis bullosa: A randomized clinical trial.

BACKGROUND: Chronic pruritus causes major morbidity in epidermolysis bullosa (EB). The substance P-neurokinin 1 receptor (SP-NK1) pathway is a promising target for treating EB-related pruritus. OBJECTIVE: To evaluate the safety and efficacy of the oral NK1 receptor antagonist serlopitant in treating moderate-severe pruritus in EB. METHODS: The study randomized 14 patients to serlopitant or placebo for 8 weeks, followed by a 4-week washout and optional open-label extension. The primary end point was change in itch as measured by the Numeric Rating Scale. Secondary end points were change in itch during dressing changes and wound size. RESULTS: We observed greater itch reduction with serlopitant, equivalent to a 0.64-point comparative reduction on the 11-point Numeric Rating Scale by week 8, although this failed to meet statistical significance (P = .11). More serlopitant patients achieved ≥3-point reduction compared with placebo (43% vs 14%, P = .35). In post hoc analysis excluding 1 patient with a concurrent seborrheic dermatitis flare, serlopitant achieved significantly greater median itch reduction from baseline by week 4 (-2 points vs 0, P = .01). We observed no statistically significant differences in secondary end points. Serlopitant was well-tolerated. LIMITATIONS: Small sample size due to disease rarity. CONCLUSION: The potential itch reduction with serlopitant observed in this trial will be pursued by a larger powered trial (NCT03836001).

A fibrous papule with abundant CD34-immunoreactive ganglion-like multinucleated giant cells: a case report and review of the literature.

Fibrous papules present clinically as benign, asymptomatic, dome-shaped, flesh colored papules on the face. Histologically, fibrous papules are characterized by fibrous stroma with fibroblasts and dilated blood vessels. Multiple variants of fibrous papules have been reported. Although scattered multinucleated cells in fibrous papules have been well described, we report a fibrous papule with abundant multinucleated ganglion-like giant cells that were immunoreactive with CD34. Recognition of such fibrous papule variants is important to avoid misdiagnosis as potentially more worrisome and/or aggressive melanocytic, soft tissue, or neural lesions that may require more aggressive treatment. Indeed, fibrous papules do not commonly appear on the differential diagnosis for lesions with multinucleated giant cells or ganglion-like cells and consideration should be given to their inclusion in the appropriate clinical setting.

Single-Lesion Skin Cancer Risk Stratification Triage Pathway.

Importance: Access to timely dermatologic care remains a challenge, especially for patients with new skin lesions. Assessing the efficiency of new triage pathways may assist in better resource allocation and shorter time to care. Objective: To evaluate whether a rule-based triage system was associated with better skin cancer risk stratification of patients and reduced wait times. Design, Setting, and Participants: This retrospective quality improvement cohort study of patients referred to Stanford University dermatology clinics was conducted between November 2017 and January 2023. A rules-based triage system based on a priori-determined high-risk lesion characteristics was implemented. Exposures: Referral reasons and risk factors of patients provided by their primary care physicians. Main Outcomes and Measures: Biopsy results of patients (diagnosis of any skin cancer and melanoma) at their visit or within 6 months after the visit. Regression models were used to assess the association between risk factors at referral and (1) biopsy outcomes and (2) time to first visit, adjusting for sociodemographic factors. Results: Among 37 478 patients (mean [SD] age, 54 (18) years; 21 292 women [57%]), the rates of aggregate biopsy, malignant biopsy specimens, and melanoma were comparable across patients seen after (n = 12 302) and before (n = 25 176) the implementation of the new triage pathway. Patients seen through the lesion pathway had a higher risk of having malignant biopsy results (adjusted risk ratio [aRR], 1.6; 95% CI, 1.4-1.9) and melanoma (aRR, 2.0; 95% CI, 1.2-3.2) than those not seen through the pathway. Lesions that were concerning to referring clinicians for skin cancer were associated with an increased risk of skin cancer (all skin cancer: aRR, 2.8; 95% CI, 2.2-3.5; melanoma: aRR, 2.02; 95% CI, 1.1-3.7). Patients in the 3 high-risk lesion groups were seen faster in the new triage pathway (mean reduction, 26 days; 95% CI, 18-34 days). Conclusions and Relevance: In this study, a new automated, rules-based referral pathway was implemented that expedited care for patients with high-risk skin cancer. This reform may have contributed to improving patient stratification, reducing the time from referral to first encounter, and maintaining accuracy in identifying malignant lesions. The findings highlight the potential to optimize clinical resource allocation by better risk stratification of referred patients.

Advanced aging skin and itch: addressing an unmet need.

Itch is the most common skin disorder in the elderly and frequently diminishes quality of life in this population. The high prevalence of pruritus in elderly patients is attributed in part to the decline in the normal physiology of the advanced aging skin, and reflects poor hydration, impaired skin barrier, and altered neural function, all ultimately contributing to inflammation and pruritus. As the elderly population continues to grow, practitioners need to be aware of how to evaluate and manage pruritus, recognizing the common conditions contributing to itch in elderly patients as well as the challenges of treatment in this group. Ultimately, management of pruritus will require an individually tailored approach that is guided by a patient's general health, severity of symptoms, and the potential adverse effects of itch therapies.

Development and Clinical Evaluation of an Artificial Intelligence Support Tool for Improving Telemedicine Photo Quality.

Importance: Telemedicine use accelerated during the COVID-19 pandemic, and skin conditions were a common use case. However, many images submitted may be of insufficient quality for making a clinical determination. Objective: To determine whether an artificial intelligence (AI) decision support tool, a machine learning algorithm, could improve the quality of images submitted for telemedicine by providing real-time feedback and explanations to patients. Design, Setting, and Participants: This quality improvement study with an AI performance component and single-arm clinical pilot study component was conducted from March 2020 to October 2021. After training, the AI decision support tool was tested on 357 retrospectively collected telemedicine images from Stanford telemedicine from March 2020 to June 2021. Subsequently, a single-arm clinical pilot study was conducted to assess feasibility with 98 patients in the Stanford Department of Dermatology across 2 clinical sites from July 2021 to October 2021. For the clinical pilot study, inclusion criteria for patients included being adults (aged ≥18 years), presenting to clinic for a skin condition, and being able to photograph their own skin with a smartphone. Interventions: During the clinical pilot study, patients were given a handheld smartphone device with a machine learning algorithm interface loaded and were asked to take images of any lesions of concern. Patients were able to review and retake photos prior to submitting, so each submitted photo met the patient's assumed standard of clinical acceptability. A machine learning algorithm then gave the patient feedback on whether the image was acceptable. If the image was rejected, the patient was provided a reason by the AI decision support tool and allowed to retake the photos. Main Outcomes and Measures: The main outcome of the retrospective image analysis was the receiver operator curve area under the curve (ROC-AUC). The main outcome of the clinical pilot study was the image quality difference between the baseline images and the images approved by AI decision support. Results: Of the 98 patients included, the mean (SD) age was 49.8 (17.6) years, and 50 (51%) of the patients were male. On retrospective telemedicine images, the machine learning algorithm effectively identified poor-quality images (ROC-AUC of 0.78) and the reason for poor quality (blurry ROC-AUC of 0.84; lighting issues ROC-AUC of 0.70). The performance was consistent across age and sex. In the clinical pilot study, patient use of the machine learning algorithm was associated with improved image quality. An AI algorithm was associated with reduction in the number of patients with a poor-quality image by 68.0%. Conclusions and Relevance: In this quality improvement study, patients use of the AI decision support with a machine learning algorithm was associated with improved quality of skin disease photographs submitted for telemedicine use.

Development of a digital tool for home-based monitoring of skin disease for older adults.

We developed a digital tool for home-based monitoring of skin disease, our digital tool. In the current observational pilot study, we found that DORA is feasible to use in practice, as it has a high patient compliance, retention and satisfaction. Clinicans rated the photos generally good quality or perfect quality. These results show that the digital health tool DORA can easily be used by patients to send photos to their dermatologist, which could reduce unnecessary clinical visits. It may also be used in other settings where digital literacy barriers and unequal access to dermatologists contribute to healthcare disparities.

Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. METHODS: Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. RESULTS: Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4-8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up. CONCLUSIONS: Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379.

A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex.

BACKGROUND: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses. Prior work has been limited by small sample sizes, and much remains unexplored about the disease burden and health-related quality of life (QOL) of patients with EBS. The aim of this study was to characterize the most common patient-reported clinical manifestations and the health-related impact of QOL in EBS, and to examine differences in disease burden by age. METHODS: Patients with a diagnosis of epidermolysis bullosa (EB) or their caregivers completed a one-time online survey administered by EBCare, an international online EB registry. Survey data from respondents self-reporting a diagnosis of EBS were analyzed for clinical and wound manifestations, medication use, and QOL (using Quality of Life in Epidermolysis Bullosa [QOLEB] scores). Differences across age groups were assessed using Kruskal-Wallis and Fisher's exact tests. RESULTS: There were 214 survey respondents with EBS. The mean age was 32.8 years (standard deviation = 19.2). Many respondents reported blisters (93%), recurrent wounds (89%), pain (74%), chronic wounds (59%), itch (55%), and difficulty walking (44%). Mean QOLEB score was 14.7 (standard deviation = 7.5) indicating a "moderate" impact on QOL, and 12% of respondents required regular use of opiates. Findings were consistent in subgroup analyses restricted to respondents with diagnostic confirmation via genetic testing or skin biopsy (n = 63 of 214). Age-stratified analyses revealed differences in disease burden: younger respondents were more likely to self-report severe disease (24% vs. 19% vs. 5% for respondents aged 0-9 vs. 10-17 vs. 18 + , p = 0.001), failure to thrive (9% vs. 15% vs. 3%, p = 0.02), and use of gastrostomy tubes (15% vs. 12% vs. 1%, p < 0.001) and topical antibiotics (67% vs. 69% vs. 34%, p < 0.001), while older respondents were more likely to be overweight or obese (6% vs. 0% vs. 51%, p < 0.001) and have difficulty walking (24% vs. 46% vs. 48%, p = 0.04). CONCLUSIONS: In the largest international cross-sectional survey of EBS patients conducted, respondents reported extensive disease burden including significant wounding, pain, itch, difficulty walking, and impact on QOL. Age stratified disease manifestations. These findings suggest significant unmet need, and treatment and counseling for EBS patients should consider age-specific differences.

Disparities in dermatology AI performance on a diverse, curated clinical image set.

An estimated 3 billion people lack access to dermatological care globally. Artificial intelligence (AI) may aid in triaging skin diseases and identifying malignancies. However, most AI models have not been assessed on images of diverse skin tones or uncommon diseases. Thus, we created the Diverse Dermatology Images (DDI) dataset-the first publicly available, expertly curated, and pathologically confirmed image dataset with diverse skin tones. We show that state-of-the-art dermatology AI models exhibit substantial limitations on the DDI dataset, particularly on dark skin tones and uncommon diseases. We find that dermatologists, who often label AI datasets, also perform worse on images of dark skin tones and uncommon diseases. Fine-tuning AI models on the DDI images closes the performance gap between light and dark skin tones. These findings identify important weaknesses and biases in dermatology AI that should be addressed for reliable application to diverse patients and diseases.

Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials.

Importance: Primary results from the Measure Up 1 and Measure Up 2 studies demonstrated upadacitinib efficacy and safety through 16 weeks in patients with atopic dermatitis. Longer-term outcomes remain unknown. Objective: To evaluate long-term (52 weeks) efficacy and safety of upadacitinib treatment in patients with atopic dermatitis. Design, Setting, and Participants: Measure Up 1 and Measure Up 2 are ongoing double-blind, placebo-controlled, replicate phase 3 randomized clinical trials that include adults and adolescents with moderate to severe atopic dermatitis at 151 and 154 centers, respectively. Cutoffs for this analysis were December 21, 2020 (Measure Up 1), and January 15, 2021 (Measure Up 2). Interventions: Patients were randomized 1:1:1 to receive once-daily oral upadacitinib 15 mg, 30 mg, or placebo. At week 16, patients randomized at baseline to receive upadacitinib 15 mg (273 and 260 patients in Measure Up 1 and Measure Up 2, respectively) and 30 mg (270 and 268 patients) continued assigned treatment; placebo-treated patients were rerandomized 1:1 to receive upadacitinib 15 mg (121 and 120 patients in Measure Up 1 and Measure Up 2, respectively) or 30 mg (123 and 121 patients) in a double-blinded manner. Main Outcomes and Measures: Safety and efficacy, including 75% improvement in the Eczema Area and Severity Index and Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement, were assessed. Results: Measure Up 1 and Measure Up 2 included a total of 1609 patients (mean [SD] age, 33.8 [15.6] years; 727 women [45.2%]; 882 men [54.8%]). Efficacy at week 16 was maintained through week 52. At week 52, 75% improvement in the Eczema Area and Severity Index was achieved by 82.0% (95% CI, 77.0%-86.9%) and 79.1% (95% CI, 73.9%-84.4%) of patients continuing the 15-mg dose and 84.9% (95% CI, 80.3%-89.5%) and 84.3% (95% CI, 79.6%-89.0%) of patients continuing the 30-mg dose (for Measure Up 1 and Measure Up 2, respectively); Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement was achieved by 59.2% (95% CI, 52.9%-65.5%) and 52.6% (95% CI, 46.2%-59.1%) and 62.5% (95% CI, 56.3%-68.7%) and 65.1% (95% CI, 58.9%-71.2%) of patients in the Measure Up 1 and Measure Up 2 studies, respectively. Treatment discontinuation due to adverse events was low overall but was slightly higher for the upadacitinib 30-mg dose. Both upadacitinib doses were well tolerated with no new safety signals. Conclusions and Relevance: In this analysis of follow-up data from 2 randomized clinical trials, longer-term treatment of adolescents and adults with moderate to severe atopic dermatitis with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 52 weeks. Trial Registration: ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2).

Parental E-Cigarette Use and Pediatric Atopic Dermatitis.

This cross-sectional study uses data from the 2014-2018 National Health Interview Survey to assess whether there is an association between parental e-cigarette use and atopic dermatitis in children.