Showing papers in "JAMA Dermatology in 2019"

Association Between Surgical Skin Markings in Dermoscopic Images and Diagnostic Performance of a Deep Learning Convolutional Neural Network for Melanoma Recognition.

Abstract: Importance Deep learning convolutional neural networks (CNNs) have shown a performance at the level of dermatologists in the diagnosis of melanoma. Accordingly, further exploring the potential limitations of CNN technology before broadly applying it is of special interest. Objective To investigate the association between gentian violet surgical skin markings in dermoscopic images and the diagnostic performance of a CNN approved for use as a medical device in the European market. Design and Setting A cross-sectional analysis was conducted from August 1, 2018, to November 30, 2018, using a CNN architecture trained with more than 120 000 dermoscopic images of skin neoplasms and corresponding diagnoses. The association of gentian violet skin markings in dermoscopic images with the performance of the CNN was investigated in 3 image sets of 130 melanocytic lesions each (107 benign nevi, 23 melanomas). Exposures The same lesions were sequentially imaged with and without the application of a gentian violet surgical skin marker and then evaluated by the CNN for their probability of being a melanoma. In addition, the markings were removed by manually cropping the dermoscopic images to focus on the melanocytic lesion. Main Outcomes and Measures Sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic (ROC) curve for the CNN’s diagnostic classification in unmarked, marked, and cropped images. Results In all, 130 melanocytic lesions (107 benign nevi and 23 melanomas) were imaged. In unmarked lesions, the CNN achieved a sensitivity of 95.7% (95% CI, 79%-99.2%) and a specificity of 84.1% (95% CI, 76.0%-89.8%). The ROC AUC was 0.969. In marked lesions, an increase in melanoma probability scores was observed that resulted in a sensitivity of 100% (95% CI, 85.7%-100%) and a significantly reduced specificity of 45.8% (95% CI, 36.7%-55.2%,P Conclusions and Relevance This study’s findings suggest that skin markings significantly interfered with the CNN’s correct diagnosis of nevi by increasing the melanoma probability scores and consequently the false-positive rate. A predominance of skin markings in melanoma training images may have induced the CNN’s association of markings with a melanoma diagnosis. Accordingly, these findings suggest that skin markings should be avoided in dermoscopic images intended for analysis by a CNN. Trial Registration German Clinical Trial Register (DRKS) Identifier:DRKS00013570

Expert-Level Diagnosis of Nonpigmented Skin Cancer by Combined Convolutional Neural Networks.

Abstract: Importance Convolutional neural networks (CNNs) achieve expert-level accuracy in the diagnosis of pigmented melanocytic lesions. However, the most common types of skin cancer are nonpigmented and nonmelanocytic, and are more difficult to diagnose. Objective To compare the accuracy of a CNN-based classifier with that of physicians with different levels of experience. Design, Setting, and Participants A CNN-based classification model was trained on 7895 dermoscopic and 5829 close-up images of lesions excised at a primary skin cancer clinic between January 1, 2008, and July 13, 2017, for a combined evaluation of both imaging methods. The combined CNN (cCNN) was tested on a set of 2072 unknown cases and compared with results from 95 human raters who were medical personnel, including 62 board-certified dermatologists, with different experience in dermoscopy. Main Outcomes and Measures The proportions of correct specific diagnoses and the accuracy to differentiate between benign and malignant lesions measured as an area under the receiver operating characteristic curve served as main outcome measures. Results Among 95 human raters (51.6% female; mean age, 43.4 years; 95% CI, 41.0-45.7 years), the participants were divided into 3 groups (according to years of experience with dermoscopy): beginner raters ( 10 years). The area under the receiver operating characteristic curve of the trained cCNN was higher than human ratings (0.742; 95% CI, 0.729-0.755 vs 0.695; 95% CI, 0.676-0.713;P Conclusions and Relevance Neural networks are able to classify dermoscopic and close-up images of nonpigmented lesions as accurately as human experts in an experimental setting.

Efficacy and Safety of Oral Janus Kinase 1 Inhibitor Abrocitinib for Patients With Atopic Dermatitis: A Phase 2 Randomized Clinical Trial

Abstract: Importance Atopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis. Objective To investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis. Design, Setting, and Participants A phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site. Interventions Participants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks. Main Outcomes and Measures The primary outcome was the proportion of patients achieving an Investigator’s Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12. Results Of the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%;P Conclusions and Relevance Once-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic dermatitis. Additional trials are necessary to evaluate long-term efficacy and safety. Trial Registration ClinicalTrials.gov identifier:NCT02780167

Performance of the American Joint Committee on Cancer Staging Manual, 8th Edition vs the Brigham and Women's Hospital Tumor Classification System for Cutaneous Squamous Cell Carcinoma.

Abstract: Importance Brigham and Women’s tumor classification (BWH) better predicts poor outcomes than American Joint Committee on Cancer (AJCC) 7th edition (AJCC 7). AJCC 8th edition (AJCC 8) has not been evaluated. Objectives To compare BWH and AJCC 8 tumor classifications for head and neck cutaneous squamous cell carcinoma (HNCSCC). Design, Setting, and Participants A total of 459 patients with 680 HNCSCCs in this cohort study were staged via BWH and AJCC 8 classifications and poor outcomes (ie, local recurrence [LR], nodal metastasis [NM], disease specific death [DSD], and overall survival [OS]) were compared. The study was carried out at a single academic tertiary care center in Boston, Massachusetts. Main Outcomes and Measures Distinctiveness (outcome differences between tumor class), homogeneity (outcome similarity within tumor class), monotonicity (outcome worsening with increasing tumor class), and C statistic. Results A total of 680 HNCSCCs in 459 patients were included in this study, of which 313 (68%) were men with the mean (SD) age of 70.2 (12.7) years. The AJCC 8 (T3/T4) and BWH (T2b/T3) high tumor classes accounted for 121 (18%) vs 63 (9%), 17 (71%) vs 16 (70%), and 11 (85%) vs 12 (92%) of total cases, metastases, and deaths, respectively. The AJCC 8 T2 and T3 comprised 23% of cases and had statistically indistinguishable outcomes. The BWH had higher specificity (93%) and positive predictive value (30%) for identifying cases at risk for metastasis or death. C statistics showed BWH to be superior in predicting NM and DSD (P = .01 and P = .005, respectively), but there was no difference for LR and OS. Conclusions and Relevance Lack of distinction between AJCC T2 and T3 resulted in a 23% subset of HNCSCCs with significant risk of metastasis and death—too large of a group for routine nodal staging or consideration of adjuvant therapy. The BWH identifies the same number of poor outcomes in a 9% subset of HNCSCCs, thus minimizing inappropriate upstaging of low-risk disease.

Depression and Anxiety in Adults With Hidradenitis Suppurativa: A Systematic Review and Meta-analysis.

Abstract: Importance Previous studies suggest that depression and anxiety are common in patients with hidradenitis suppurativa (HS), more so than other dermatological conditions. Yet, to the authors’ knowledge, no previous systematic review or meta-analysis has estimated the prevalence or odds ratio (OR) for those psychiatric comorbidities in this population. Objective To assess the prevalence and odds for depression and anxiety in patients with HS. Data Sources From July 25 to September 30, 2018, observational studies investigating the prevalence and odds for depression and anxiety in adults with HS were systematically searched without language restriction from the inception of each database to July 25, 2018, in PubMed/MEDLINE, Embase, and PsycINFO databases. Searches used various configurations of the termshidradenitis suppurativa;acne inversa;depressive disorder;depression;anxiety;anxiety disorders;phobia,social;suicide; andsuicide,attempted. In addition, the reference lists of included references were screened manually. Study Selection Two investigators independently screened references that measured prevalence rates and odds for depressive and anxiety symptoms in patients with HS. Of 136 unique references, 10 ultimately met inclusion criteria. Data Extraction and Synthesis Relevant data were extracted from eligible references. Authors were contacted to provide further information when necessary. Methodological quality of included studies was assessed through a modified version of the Newcastle-Ottawa Scale. Random-effects models were used to synthesize available evidence. Main Outcomes and Measures Prevalence rates and ORs for depression and anxiety in adults with HS were the primary outcome measures. Heterogeneity across studies was assessed with theI2statistic. Sources of heterogeneity were explored through subgroup and meta-regression analyses. Results Ten studies comprising 40 307 participants with HS met inclusion criteria. The overall prevalence of depression was 16.9% (95% CI, 9.9%-27.2%). Heterogeneity was large. In the subgroup of studies that considered a clinical criteria–based diagnosis of depression, the prevalence of depression was 11.9% (95% CI, 4.9%-26.2%), compared with 26.8% (95% CI, 20.4%-34.5%) in studies that used a screening instrument. The methodological quality of included studies moderated those findings. The OR for depression in individuals with HS compared with individuals without HS was 1.84 (95% CI, 1.57-2.15). The prevalence of anxiety was 4.9% (95% CI, 1.7%-13.2%); there were insufficient data to determine an odds ratio for anxiety in persons with HS because 2 studies included a comparison group. Conclusions and Relevance This systematic review and meta-analysis indicates that depression and anxiety are common comorbid conditions in patients with HS. Results suggest that the development of strategies to recognize and treat those psychiatric comorbidities in patients with HS is warranted.

Nationwide Incidence of Metastatic Cutaneous Squamous Cell Carcinoma in England

Abstract: Senior clinical fellowship in science award (No. 205039/Z/16/Z) from the Wellcome Trust (Dr Langan) and by an informatics fellowship from the British Association of Dermatologists and Genetic Medicine (Dr Venables).

Use of Tape Strips to Detect Immune and Barrier Abnormalities in the Skin of Children With Early-Onset Atopic Dermatitis

Abstract: Importance Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always feasible in children. A reproducible minimally invasive approach that can track cutaneous disease in pediatric longitudinal studies or clinical trials is lacking. Objective To assess a minimally invasive approach using tape strips to identify skin biomarkers that may serve as a surrogate to biomarkers identified using whole-tissue biopsies. Design, Setting, and Participants This cross-sectional study of 51 children younger than 5 years recruited children with moderate to severe AD and children without AD from the dermatology outpatient clinics at a children’s hospital. Sixteen tape strips were serially collected from the nonlesional and lesional skin of 21 children who had AD and were less than 6 months from disease initiation and from the normal skin of 30 children who did not have AD between January 22, 2016, and April 20, 2018. Main Outcomes and Measures Gene and protein expression were evaluated using quantitative real-time polymerase chain reaction and immunohistochemistry. Results A total of 51 children younger than 5 years were included in the study; 21 children had moderate to severe AD with less than 6 months of disease duration, and 30 children did not have AD. Of the 21 children with AD, the mean (SD) age was 1.7 (1.7) years, and most were male (15 [71.4%] and white (15 [71.4%]). Of the 30 children without AD, the mean (SD) age was 1.8 (2.0) years, and most were female (20 [66.7%]) and white (22 [73.3%]). Seventy-seven of 79 evaluated immune and barrier gene products were detected (gene detection rate, 97%) in 70 of 71 tape strips (sample detection rate, 99%), with 53 of 79 markers differentiating between children with lesional and/or nonlesional AD from children without AD. Many cellular markers of T cells (CD3), AD-related dendritic cells (Fc e RI and OX40 ligand receptors), and key inflammatory (matrix metallopeptidase 12), innate (interleukin 8 [IL-8] and IL-6), helper T cell 2 (TH2; IL-4, IL-13, and chemokines CCL17 and CCL26), and TH17/TH22 (IL-19, IL-36G, and S100A proteins) genes were significantly increased in lesional and nonlesional AD compared with tape strips from normal skin. For example, IL-4 mean (SE) for lesional was −15.2 (0.91) and normal was −19.5 (0.48);P Conclusions and Relevance In this study, tape strips provide a minimally invasive alternative for serially evaluating AD-associated cutaneous biomarkers and may prove useful for tracking pediatric AD therapeutic response and predicting future course and comorbidities.

Association of Hidradenitis Suppurativa With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

Abstract: Importance Hidradenitis suppurativa (HS) and inflammatory bowel disease (IBD) are inflammatory diseases that share common genetic susceptibility and immunologic features. However, the link between HS and IBD has been largely unclear. Objective To conduct a meta-analysis to investigate the association between HS and IBD. Data Sources A search of the MEDLINE, Cochrane Central Register of Controlled Trials, and Embase databases yielded 397 relevant studies from inception to June 10, 2018. Two additional studies were supplied by one of the investigators. Study Selection Case-control, cross-sectional, or cohort studies that examined the odds or risk of IBD in patients with HS were included. No geographic or language limitations were imposed. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias of included studies. Crohn disease and ulcerative colitis were analyzed separately, and a random-effects model meta-analysis was conducted. Main Outcomes and Measures The odds ratios (ORs) and hazard ratios (HRs) of IBD, Crohn disease, and ulcerative colitis in association with HS. Results Five case-control studies, 2 cross-sectional studies, and 1 cohort study with a total of 93 601 unique participants were included. The meta-analysis of case-control and cross-sectional studies showed significant associations of HS with Crohn disease (pooled OR, 2.12; 95% CI, 1.46-3.08) and ulcerative colitis (pooled OR, 1.51; 95% CI, 1.25-1.82). Two case-control studies found significant association of HS with IBD (ORs, 2.16 [95% CI, 1.40-3.34] and 10.00 [95% CI, 1.94-51.50]). One cohort study found an increased risk of IBD in patients with HS (HR, 5.6; 95% CI not reported;P Conclusions and Relevance The evidence to date supports an association of HS with IBD. These results suggest that consultation with gastroenterologists should be sought when patients with HS present with recurrent abdominal pain, chronic diarrhea, bloody stool, and body weight loss.

Association of Psoriasis With the Risk of Developing or Dying of Cancer: A Systematic Review and Meta-analysis

Abstract: Importance The risk of cancer developing in people with psoriasis has raised some concern, with little clarity regarding differentiation in risk according to psoriasis severity. Objective To conduct a systematic review and meta-analysis of observational studies on the risk of cancer incidence and mortality in people with psoriasis. Data Sources Six electronic databases (MEDLINE, Embase, MEDLINE in Process, Cochrane Central Register, Web of Science, and LILACS [Literatura Latino-Americana e do Caribe em Ciencias da Saude]) were searched from inception to November 15, 2017, for eligible studies. Study Selection Cohort and case-control studies that provided estimates of the risk of cancer incidence or cancer mortality associated with psoriasis were included. Data Extraction and Synthesis Data were extracted relating to study design, study population, and risk estimates. Study-specific estimates of the relative risk (RR) were combined using a random-effects model. Heterogeneity was quantified using the I2 statistic. Data were analyzed from April 9, 2018, through February 22, 2019. Main Outcomes and Measures Pooled RR estimates for cancer incidence and cancer mortality for psoriasis cohorts compared with people without psoriasis. Results A total of 58 unique studies were included, with quality varying for the incidence and the mortality studies. Severe psoriasis (RR, 1.22; 95% CI, 1.08-1.39 [9 studies]) and all severities of psoriasis (RR, 1.18; 95% CI, 1.06-1.31 [7 studies]) were associated with an increased risk of cancer (overall), and associations were found for a range of site-specific cancers, including colon (RR, 1.18 [95% CI, 1.03-1.35]), colorectal (RR, 1.34 [95% CI, 1.06-1.70]), kidney (RR, 1.58 [95% CI, 1.11-2.24]), laryngeal (RR, 1.79 [95% CI, 1.06-3.01]), liver (RR, 1.83 [95% CI, 1.28-2.61]), lymphoma (RR, 1.40 [95% CI, 1.24-1.57]), non-Hodgkin lymphoma (RR, 1.28 [95% CI, 1.15-1.43]), keratinocyte cancers (RR, 1.71 [95% CI, 1.08-2.71]), esophageal (RR, 2.05 [95% CI, 1.04-4.07]), oral cavity (RR, 2.80 [95% CI, 1.99-3.93]), and pancreatic (RR, 1.41 [95% CI, 1.16-1.73]). Overall cancer mortality risk was higher in patients with severe psoriasis (RR, 1.22; 95% CI, 1.08-1.38 [4 studies]). Specifically, liver (RR, 1.43 [95% CI, 1.09-1.88]), esophageal (RR, 2.53 [95% CI, 1.87-3.41]), and pancreatic (RR, 1.31 [95% CI, 1.02-1.69]) cancer mortality were found to be elevated in those with severe psoriasis. The heterogeneity of estimates was often very high despite stratification. Marked attenuation of risk was found in those studies that adjusted estimates for smoking, alcohol consumption, and obesity. Conclusions and Relevance In this study, people with psoriasis appeared to have an increased risk of cancer incidence and cancer-related mortality involving a range of site-specific cancers. Future research examining specific lifestyle factors, treatments, and the inflammatory processes that contribute to psoriasis may help provide additional information on the underlying mechanisms for the apparent increased cancer risk.

Genotype-Guided Medical Treatment of an Arteriovenous Malformation in a Child

Abstract: Importance: Genetic testing results can provide guidance in developing personalized treatment plans for patients with vascular anomalies. Objective: To explore the efficacy of tramitinib in the treatment of an extracranial arteriovenous malformation with a somatic MAP2K1 mutation. Design: Case report of a child with an arteriovenousu malformation that was successfully treated with trametinib after identification of a specific somatic mutation within the malformation. Setting: Outpatient Vascular Anomalies Clinic, Stanford University, Stanford, CA. Participant: An 11-year-old girl with an arteriovenous malformation on the back who had failed treatment with systemic sirolimus. Intervention: Paired exome sequencing using tumor and saliva DNA was performed and identified a somatic mutation within the MAP2K1 gene. The patient was then transitioned to trametinib at a starting dose of 0.5 mg once daily then increased to 0.5 mg twice daily after one month. Main Outcome: Tramitinib was effective in reducing the size of and blood flow to the arteriovenous malformation. Results: After one month on tramitinib, the patient and parents noticed the malformation reduced in size and became lighter in color. After six months of treatment, quantitative analyses were performed using magnetic resonance imaging and showed significant interval decrease in the volume of the malformation and the caliber of the vasculature compared to prior examinations. To date, she has tolerated the treatment well with development of a mild acneiform eruption responding well to over the counter adapalene and benzoyl peroxide. Conclusion and Relevance: Management of arteriovenous malformations is very challenging due to almost inevitable disease progression and high recurrence rates after surgical resection. The discovery of a somatic mutation associated with this arteriovenous malformation provided guidance for targeted therapy. Trametinib may be a promising targeted therapeutic option for sporadic extracranial arteriovenous malformations harboring MAP2K1 mutations.

Association of Dipeptidyl Peptidase 4 Inhibitor Use With Risk of Bullous Pemphigoid in Patients With Diabetes

Abstract: Importance Recent studies suggest that dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with an increased risk of developing bullous pemphigoid (BP). Population-based studies on the association between DPP-4 inhibitors and BP are limited. Objective To characterize the potential association between the use of DPP-4 inhibitors and an increased risk of developing BP. Design, Setting, and Participants This retrospective, nationwide, population-based, case-control study using Korean insurance claims data from January 1, 2012, to December 31, 2016, included patients with newly diagnosed BP and diabetes. Control patients with diabetes (and without BP) were randomly obtained after matching for age, sex, and year of diagnosis within the same period. Main Outcomes and Measures The number of patients with newly diagnosed BP and diabetes per year and annual changes in the proportion of patients with diabetes among all patients with BP were measured. The association between use of DPP-4 inhibitors and risk of developing BP was analyzed using univariate and multivariate logistic regression analyses. Results The study included 670 case patients (with diabetes and BP) and 670 control patients (with only diabetes) (mean [SD] age, 75.3 [10.0] years in each group; 342 [51.0%] male in each group). The number of patients with diabetes and BP more than doubled during the study period (from 77 in 2012 to 206 in 2016). The proportion of patients with diabetes among all patients with BP also increased (from 0.18 in 2012 to 0.33 in 2016). The use of DPP-4 inhibitors was associated with a significant increase in the risk of developing BP (adjusted odds ratio [aOR], 1.58; 95% CI, 1.25-2.00; P < .001); among all DPP-4 inhibitors used in Korea, the highest aOR was associated with the use of vildagliptin (aOR, 1.81; 95% CI, 1.31-2.50; P < .001). Subgroup analyses revealed a significant association in male patients (aOR, 1.91; 95% CI, 1.39-2.63; P < .001) and that vildagliptin was the most high-risk DPP-4 inhibitor (aOR, 2.70; 95% CI, 1.73-4.34; P < .001). Conclusions and Relevance The findings suggest that DPP-4 inhibitors are associated with a significantly increased risk of the development of BP in patients with diabetes. Of the DPP-4 inhibitors available in Korea, vildagliptin was associated with the highest risk, particularly in male patients. Practitioners should consider that DPP-4 inhibitors, particularly vildagliptin, may be associated with the development of BP in patients with diabetes. These nationwide, population-based results may serve as a foundation for further studies seeking to understand how DPP-4 inhibitors contribute to the development of BP.

Assessment of Clinical Response to Janus Kinase Inhibition in Patients With Familial Chilblain Lupus and TREX1 Mutation

Abstract: Importance Familial chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). Familial chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available. Objectives To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial chilblain lupus and assess the effect of cold on patient fibroblasts. Design, Setting, and Participants In this case series, 3 patients with familial chilblain lupus due toTREX1mutation underwent treatment with baricitinib for 3 months. Interventions Doses of baricitinib, 4 mg, were administered daily for 3 months. Main Outcomes and Measures Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed. Results All 3 patients (2 women and 1 man; mean [SD] age, 51 [24] years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro. Conclusions and Relevance These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold inTREX1-deficient cells. This finding may be relevant to other type I IFN–mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.

Imatinib Treatment for Locally Advanced or Metastatic Dermatofibrosarcoma Protuberans: A Systematic Review

Abstract: Importance Dermatofibrosarcoma protuberans (DFSP) has the potential for local destruction and recurrence, although it carries a low risk of metastasis. Complete surgical resection with negative margins is considered the gold standard for treatment; however, there are cases that are unresectable owing to tumor extension or size or owing to risk of cosmetic and/or functional impairment. Imatinib treatment has been used for locally advanced or metastatic DFSP. Objective To evaluate the usefulness of imatinib for treating DFSP. Evidence Review We conducted a systematic review on the PubMed and Embase databases for articles published from September 2002 through October 2017 using the key words “dermatofibrosarcoma” or “dermatofibrosarcoma protuberans” AND “therapy” AND “imatinib.” References within retrieved articles were also reviewed to identify additional studies. Studies of adults with histologically proven DFSP treated with imatinib as monotherapy or as an adjuvant or neoadjuvant therapy to surgery were included. Extracted data were analyzed using descriptive statistics. PRISMA guidelines were followed. All analysis took place October through December 2017. Findings Nine studies met inclusion criteria; 152 patients were included. The calculated mean patient age was 49.3 years (range, 20-73 years). Calculated mean tumor diameter was 9.9 cm (range, 1.2-49.0 cm). When COL1A1-PDGFβ protein translocation (collagen, type 1, alpha 1–platelet-derived growth factor β) was reported, it was present in 90.9% of patients (111 of 122). Complete response was seen in 5.2% of patients (8 of 152), partial response in 55.2% (84 of 152), stable disease in 27.6% (42 of 152), and progression in 9.2% (14 of 152). Four of the 152 patients (2.6%) were excluded from the analysis owing to unknown or unevaluable response. There were no differences in response rate using 400-mg or 800-mg daily doses (67.5% or 27 of 40 patients for 400-mg dose vs 67.1% or 49 of 73 patients for 800-mg dose complete or partial response;P > .99). Adverse events were present in at least 73.5% of cases (78 of 106); severe adverse events were present in 15.1% of cases (20 of 132). Conclusions and Relevance Imatinib is a useful directed therapy in patients with DFSP who are not surgical candidates owing to disease extension or significant cosmetic or functional impairment. There seems to be no difference between 400- or 800-mg daily doses.

Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria: A Meta-analysis of “Real-world” Evidence

Abstract: Importance Omalizumab is indicated for the management of chronic idiopathic urticaria (CIU) (also known as chronic spontaneous urticaria) in adolescents and adults with persistent hives not controlled with antihistamines. The effectiveness of omalizumab in the real-world management of CIU is largely unknown. Objective To quantitatively synthesize what is known about the benefits and harms of omalizumab in the real-world clinical management of CIU regarding urticaria activity, treatment response, and adverse events. Data Sources Published observational studies (January 1, 2006, to January 1, 2018) and scientific abstracts on the effectiveness of omalizumab in CIU were identified using PubMed, Embase, Web of Science, and Cochrane search engines; references were searched to identify additional studies. Study Selection Included studies were observational in design and included at least 1 outcome in common with other studies and at a concurrent time point of exposure to omalizumab. A total of 67 articles (35.2% of those screened) were included in the analysis. Data Extraction and Synthesis PRISMA and MOOSE guidelines were followed; independent selection and data extraction were completed by 2 observers. Random-effects meta-analyses were performed. Main Outcomes and Measures Main outcomes were change in weekly Urticaria Activity Score (UAS7; range, 0-42), change in Urticaria Activity Score (UAS; range 0-6) (higher score indicating worse outcome in both scales), complete and partial response rates (percentages), and adverse event rate (percentage). Results Omalizumab therapy was associated with an improvement in UAS7 scores (−25.6 points, 95% CI, −28.2 to −23.0;P Conclusions and Relevance Benefits and safety of omalizumab in the real-world treatment of CIU meet or exceed results gleaned from clinical trials. These real-world data on omalizumab in CIU may help inform both clinical treatment expectations and policy decision making.

Association Between Atopic Dermatitis and Suicidality: A Systematic Review and Meta-analysis

Abstract: Importance Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with numerous psychiatric comorbidities. However, the association between AD and suicidality has not been well established. Objective To synthesize the available literature to evaluate the association between AD and suicidality. Data Source The protocol was prospectively registered in the PROSPERO database (CRD42018105291). Study Selection Per PRISMA guidelines, PubMed, Embase, PsycINFO, and Cochrane databases were systematically searched for relevant articles published from 1946 to May 25, 2018. The search criteria for PubMed were as follows: (dermatitis, atopic[MeSH] OReczema[MeSH]) AND (suicidal ideation[MeSH] ORsuicide, attempted[MeSH] ORsuicide[MeSH] ORsuicidalityORsuicidal behavior). The search criteria for Embase, PsycINFO, and Cochrane were as follows: (atopic dermatitisOReczema) AND (suicidal ideationORsuicide attemptORsuicideORsuicidalityORsuicidal behavior). Data Extraction and Synthesis This systematic review and meta-analysis performed in an academic medical setting included observational studies that evaluated suicidal ideation, suicide attempts, and completed suicide among patients with AD. Main Outcome and Measure The quality of included studies was assessed using the Newcastle-Ottawa Scale for observational studies. Results The analysis identified 15 studies with a total of 4 770 767 participants, of whom 310 681 were patients with AD (52.7% female) and 4 460 086 served as controls (50.9% female). In the meta-analyses, patients with AD were 44% more likely to exhibit suicidal ideation (pooled odds ratio, 1.44; 95% CI, 1.25-1.65) and 36% more likely to attempt suicide (pooled odds ratio, 1.36; 95% CI, 1.09-1.70) compared with patients without AD. Studies investigating completed suicides in patients with AD had inconsistent results. Conclusions and Relevance Results of this study suggest that patients with AD are at significantly increased risk of suicidal ideation and suicide attempts. It is important for dermatology providers to be aware of this risk, screen for suicidality in patients with AD, and make mental health referrals when necessary.

Development and Validation of a Risk Prediction Model for In-Hospital Mortality Among Patients With Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis—ABCD-10

Abstract: Importance Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a spectrum of severe mucocutaneous drug reaction associated with significant morbidity and mortality. A previously developed SJS/TEN-specific severity-of-illness model (Score of Toxic Epidermal Necrolysis [SCORTEN]) has been reported to overestimate and underestimate SJS/TEN-related in-hospital mortality in various populations. Objective To derive a risk prediction model for in-hospital mortality among patients with SJS/TEN and to compare prognostic accuracy with the SCORTEN model in a multi-institutional cohort of patients in the United States. Design, Setting, and Participants Data from a multicenter cohort of patients 18 years and older treated for SJS/TEN between January 1, 2000, and June 1, 2015, were obtained from inpatient consult databases and electronic medical record systems at 18 medical centers in the United States as part of the Society for Dermatology Hospitalists. A risk model was derived based on data from 370 of these patients. Model discrimination (calculated as area under the receiver operating characteristic curve [AUC]) and calibration (calculated as predicted vs observed mortality, and examined using the Hosmer-Lemeshow goodness-of-fit statistic) were assessed, and the predictive accuracy was compared with that of SCORTEN. All analysis took place between December 2016 and April 2018. Main Outcomes and Measures In-hospital mortality. Results Among 370 patients (mean [SD] age 49.0 [19.1] years; 195 [52.7%] women), 54 (15.14%) did not survive to hospital discharge. Five covariates, measured at the time of admission, were independent predictors of in-hospital mortality: age in years (odds ratio [OR], 1.05; 95% CI, 1.02-1.07), body surface area (BSA) in percentage of epidermal detachment (OR, 1.02; 95% CI, 1.01-1.04), serum bicarbonate level below 20 mmol/L (OR, 2.90; 95% CI, 1.43-5.88), active cancer (OR, 4.40; 95% CI, 1.82-10.61), and dialysis prior to admission (OR, 15.94; 95% CI, 3.38-66.30). A severity-of-illness score was calculated by taking the sum of 1 point each for age 50 years or older, epidermal detachment greater than 10% of BSA, and serum bicarbonate level below 20 mmol/L; 2 points for the presence of active cancer; and 3 points for dialysis prior to admission. The score was named ABCD-10 (age, bicarbonate, cancer, dialysis, 10% BSA). The ABCD-10 model showed good discrimination (AUC, 0.816; 95% CI, 0.759-0.872) and calibration (Hosmer-Lemeshow goodness of fit test, P = .30). For SCORTEN, on admission, the AUC was 0.827 (95% CI, 0.774-0.879) and was not significantly different from that of the ABCD-10 model (P = .72). Conclusions and Relevance In this cohort of patients with SJS/TEN, ABCD-10 accurately predicted in-hospital mortality, with discrimination that was not significantly different from SCORTEN. Additional research is needed to validate ABCD-10 in other populations. Future use of a new mortality prediction model may provide improved prognostic information for contemporary patients, including those enrolled in observational studies and therapeutic trials.

Trends in Private Equity Acquisition of Dermatology Practices in the United States.

Abstract: Importance Private equity (PE) firms invest in dermatology management groups (DMGs), which are physician practice management firms that operate multiple clinics and often acquire smaller, physician-owned practices. Consolidation of dermatology practices as a result of PE investment may be associated with changes in practice management in the United States. Objective To describe the scope of PE-backed dermatology practice acquisitions geographically over time. Design, Setting, and Participants This cross-sectional study examined acquisitions of dermatology practices by PE-backed DMGs in the United States. Acquisition and investment data through May 31, 2018, were compiled using information from 5 financial databases. Transaction data were supplemented with publicly available information from 2 additional financial databases, 2 financial news outlets, and press releases from DMGs. All dermatology practices acquired by PE-backed DMGs were included. Acquisitions were verified to be dermatology practices that provided medical, surgical, and/or cosmetic clinical care. Private equity financing data were included when available. The addresses of clinics associated with acquired practices were mapped using spatial analytics software. Main Outcomes and Measures The number and location of PE practice acquisitions over time were measured based on the date of deal closure, the geographic footprint of each DMG’s acquisition, and the financing of each DMG. Results Seventeen PE-backed DMGs acquired 184 practices between May 1, 2012, and May 22, 2018. These acquired practices accounted for an estimated 381 dermatology clinics as of mid-2018 (assessment period from May 1 to August 31). The total number of PE-owned dermatology clinics in the United States was substantially larger because these data did not reflect DMGs that opened new clinics (organic growth); acquisitions data represented only the ownership transfer of existing practices from physician to PE-backed DMG. Practice acquisitions increased each year, from 5 in 2012 to 59 in 2017. An additional 34 acquisitions took place from January 1 to May 31, 2018. The number of financing rounds to sustain transactions mirrored the aforementioned trends in practice acquisitions. Clinics associated with acquired practices spanned at least 30 states, with 138 of 381 clinics (36%) located in Texas and Florida. Conclusion and Relevance The study findings suggest that PE firms have a financial stake in an increasing number of dermatology practices throughout the United States. Further research is needed to assess whether and how PE-backed ownership influences clinical decision-making, health care expenditures, and patient outcomes.

Risk of Melanoma Recurrence After Diagnosis of a High-Risk Primary Tumor.

Abstract: Importance: With emerging new systemic treatments for metastatic melanoma, early detection of disease recurrence is increasingly important. Objective: To investigate the risk of melanoma recurrence in patients with a localized melanoma at a high risk of metastasis. Design, Setting, and Participants: A total of 1254 patients with newly diagnosed, histologically confirmed tumor category T1b to T4b melanoma in Queensland, Australia, were recruited prospectively between October 1, 2010, and October 1, 2014, for participation in a cohort study. Data analysis was conducted from February 8, 2018, to February 20, 2019. We used Cox proportional hazards regression analysis to examine associations between patient and tumor factors and melanoma recurrence. Exposures Disease-free survival: (DFS) by melanoma tumor category defined by the 7th vs 8th editions of the AJCC Cancer Staging Manual (AJCC 7 vs AJCC 8). Main Outcomes and Measures: Melanoma recurrences were self-reported through follow-up questionnaires administered every 6 months and confirmed by histologic or imaging findings. Results: Of 1254 patients recruited, 825 individuals (65.8%) agreed to participate. Thirty-six were found to be ineligible after providing consent and a further 89 patients were excluded after reclassifying tumors using AJCC 8, leaving 700 participants with high-risk primary melanoma (mean [SD] age, 62.2 [13.5] years; 410 [58.6%] men). Independent predictors of recurrence were head or neck site of primary tumor, ulceration, thickness, and mitotic rate greater than 3/mm2 (hazard ratio, 2.36; 95% CI, 1.19-4.71). Ninety-four patients (13.4%) developed a recurrence within 2 years of diagnosis: 66 tumors (70.2%) were locoregional, and 28 tumors (29.8%) developed at distant sites. After surgery for locoregional disease, 37 of 64 patients (57.8%) remained disease free at 2 years, 7 patients (10.9%) developed new locoregional recurrence, and 20 patients (31.3%), developed distant disease. Two-year DFS was similar when comparing AJCC 7 and AJCC 8, for T1b (AJCC 7, 253 [93.3% DFS]; AJCC 8, 242 [93.0% DFS]) and T4b (AJCC 7 and AJCC 8, 50 [68.0% DFS] category tumors in both editions. Patients with T2a to T4a tumors who did not have a sentinel lymph node biopsy (SLNB) at diagnosis had lower DFS than patients with the same tumor category and a negative SLNB (T2a: 136 [91.1%; 95% CI, 86.4-95.9] vs 96 [96.9%; 95 % CI, 93.4-100.0]; T4a: 33 [78.8%; 95% CI, 64.8-92.7] vs 6 [83.3; 95% CI, 53.5-100.0]). Conclusions and Relevance: These findings suggest that 13.4% of patients with a high-risk primary melanoma will experience disease recurrence within 2 years. Head or neck location of initial tumor, SLNB positivity, and signs of rapid tumor growth may be associated with primary melanoma recurrence.

Accuracy of Computer-Aided Diagnosis of Melanoma: A Meta-analysis

Abstract: Importance The recent advances in the field of machine learning have raised expectations that computer-aided diagnosis will become the standard for the diagnosis of melanoma. Objective To critically review the current literature and compare the diagnostic accuracy of computer-aided diagnosis with that of human experts. Data Sources The MEDLINE, arXiv, and PubMed Central databases were searched to identify eligible studies published between January 1, 2002, and December 31, 2018. Study Selection Studies that reported on the accuracy of automated systems for melanoma were selected. Search terms includedmelanoma,diagnosis,detection,computer aided, andartificial intelligence. Data Extraction and Synthesis Evaluation of the risk of bias was performed using the QUADAS-2 tool, and quality assessment was based on predefined criteria. Data were analyzed from February 1 to March 10, 2019. Main Outcomes and Measures Summary estimates of sensitivity and specificity and summary receiver operating characteristic curves were the primary outcomes. Results The literature search yielded 1694 potentially eligible studies, of which 132 were included and 70 offered sufficient information for a quantitative analysis. Most studies came from the field of computer science. Prospective clinical studies were rare. Combining the results for automated systems gave a melanoma sensitivity of 0.74 (95% CI, 0.66-0.80) and a specificity of 0.84 (95% CI, 0.79-0.88). Sensitivity was lower in studies that used independent test sets than in those that did not (0.51; 95% CI, 0.34-0.69 vs 0.82; 95% CI, 0.77-0.86;P Conclusions and Relevance Although the accuracy of computer-aided diagnosis for melanoma detection is comparable to that of experts, the real-world applicability of these systems is unknown and potentially limited owing to overfitting and the risk of bias of the studies at hand.

Trends in Oral Antibiotic Prescription in Dermatology, 2008 to 2016.

Abstract: Importance Dermatologists prescribe more oral antibiotic courses per clinician than any other specialty, and this use puts patients at risk of antibiotic-resistant infections and antibiotic-associated adverse events. Objective To characterize the temporal trends in the diagnoses most commonly associated with oral antibiotic prescription by dermatologists, as well as the duration of this use. Design, Setting, and Participants Repeated cross-sectional analysis of antibiotic prescribing by dermatologists from January 1, 2008, to December 31, 2016. The setting was Optum Clinformatics Data Mart (Eden Prairie, Minnesota) deidentified commercial claims data. Participants were dermatology clinicians identified by their National Uniform Claim Committee taxonomy codes, and courses of oral antibiotics prescribed by these clinicians were identified by their National Drug Codes. Exposures Claims for oral antibiotic prescriptions were consolidated into courses of therapy and associated with the primary diagnosis from the most recent visit. Courses were stratified into those of extended duration (>28 days) and those of short duration (≤28 days). Main Outcomes and Measures Frequency of antibiotic prescribing and associated diagnoses. Poisson regression models were used to assess for changes in the frequency of antibiotic prescribing over time. Results Between 2008 and 2016 among 985 866 courses of oral antibiotics prescribed by 11 986 unique dermatologists, overall antibiotic prescribing among dermatologists decreased 36.6% (1.23 courses per 100 visits) from 3.36 (95% CI, 3.34-3.38) to 2.13 (95% CI, 2.12-2.14) courses per 100 visits with a dermatologist (prevalence rate ratio for annual change, 0.931; 95% CI, 0.930-0.932), with much of this decrease occurring among extended courses for acne and rosacea. Oral antibiotic use associated with surgical visits increased 69.6% (2.73 courses per 100 visits) from 3.92 (95% CI, 3.83-4.01) to 6.65 (95% CI, 6.57-6.74) courses per 100 visits associated with a surgical visit (prevalence rate ratio, 1.061; 95% CI, 1.059-1.063). Conclusions and Relevance Continuing to develop alternatives to oral antibiotics for noninfectious conditions, such as acne, can improve antibiotic stewardship and decrease complications from antibiotic use. In addition, the rising use of postoperative antibiotics after surgical visits is concerning and may put patients at unnecessary risk of adverse events. Future studies are needed to identify the value of this practice and the risk of adverse events.

Association of Systemic Antibiotic Treatment of Acne With Skin Microbiota Characteristics.

Abstract: Importance Given the widespread use of systemic antibiotics for treatment of moderate to severe acne, it is important to understand the associations of such antibiotic use with changes not only inCutibacterium acnes(formerlyPropionibacterium acnes) but also in the complete bacterial community of the skin. Objective To examine the composition, diversity, and resilience of skin microbiota associated with systemic antibiotic perturbation in individuals with acne. Design, Setting, and Participants This longitudinal cohort study conducted at an academic referral center in Maryland from February 11 to September 23, 2014, included 4 female participants who had received a recent diagnosis of acne vulgaris, showed comedonal and inflammatory acne on the face, were at least 18 years old, and had no recent use of systemic or topical treatments for acne, including antibiotics and retinoids. Data analysis was performed between July 5, 2017, and November 7, 2018. Interventions Participants were prescribed oral minocycline, 100 mg, twice daily for 4 weeks. Skin areas on the forehead, cheek, and chin were sampled for 16S ribosomal RNA gene sequencing at baseline, 4 weeks after starting minocycline treatment, and then 1 week and 8 weeks after discontinuation of treatment. Main Outcomes and Measures Skin microbiota examined with respect to relative abundance of bacterial taxa, α diversity (represents within-sample microbial diversity), and β diversity (represents between-sample microbial diversity). Acne status evaluated with photography and lesion count. Results Of the 4 patients included in this study, 2 were 25 years old, 1 was 29 years old, and 1 was 35 years old; 2 were white women, 1 was an African American woman, and 1 was an Asian woman. Across all 4 patients, antibiotic treatment was associated with a 1.4-fold reduction in the level ofC acnes(difference, −10.3%; 95% CI, −19.9% to −0.7%;P = .04) with recovery following cessation of treatment. Distinct patterns of change were identified in multiple bacterial genera, including a transient 5.6-fold increase in the relative abundance ofPseudomonasspecies (difference, 2.2%; 95% CI, 0.9%-3.4%;P Conclusions and Relevance In this study, systemic antibiotic treatment of acne was associated with changes in the composition and diversity of skin microbiota, with variable rates of recovery across individual patients and parallel changes in specific bacterial populations. Understanding the association between systemic antibiotic use and skin microbiota may help clinicians decrease the likelihood of skin comorbidities related to microbial dysbiosis.

Comparative Overall Comorbidity Burden Among Patients With Hidradenitis Suppurativa.

Abstract: Importance The overall comorbidity burden among patients with hidradenitis suppurativa (HS) has not been systematically evaluated. Objectives To investigate the standardized overall comorbidity burden among patients with HS and to compare it with the comorbidity burden in patients with psoriasis and a control group. Design, Setting, and Participants A cross-sectional analysis was conducted of 5306 patients with HS, 14 037 patients with psoriasis, and 1 733 810 controls identified using electronic health records data from October 1, 2013, through October 1, 2018. Main Outcome and Measure The primary outcome was the mean Charlson Comorbidity Index (CCI) score. Results Each matched cohort had 3818 patients (2789 women and 1029 men; mean [SD] age, 45.7 [15.0]). Before matching, the overall mean (SD) CCI score was highest among the psoriasis cohort (2.33 [3.13]), followed by the HS cohort (1.80 [2.79]) and control cohort (1.26 [2.35]). In matched analyses, the overall mean (SD) CCI score was highest among the HS cohort (1.95 [2.96]), followed by the psoriasis cohort (1.47 [2.43]; P < .001) and control cohort (0.95 [1.99]; P < .001) patients. A total of 516 patients with HS (13.5%) had an overall mean CCI score of 5 or greater. Mean CCI score was highest for patients with HS across all sex, race, and age groups. The most common comorbidities among patients with HS were chronic pulmonary disease (1540 [40.3%]), diabetes with chronic complications (365 [9.6%]), diabetes without chronic complications (927 [24.3%]), and mild liver disease (455 [11.9%]). Patients with HS with a CCI score of 5 or greater had 4.97 (95% CI, 1.49-16.63) times the adjusted risk of 5-year mortality compared with patients with HS with a CCI score of zero. Conclusions and Relevance Patients with HS have a higher overall comorbidity burden compared with patients with psoriasis and a control group. A significant proportion of patients with HS have CCI scores of 5 or greater, which are associated with increased mortality. This degree of comorbidity burden may warrant multidisciplinary implementation of routine screening measures

Efficacy and Safety of Guselkumab in Japanese Patients With Palmoplantar Pustulosis: A Phase 3 Randomized Clinical Trial.

Abstract: Importance Palmoplantar pustulosis (PPP) causes erythematous, scaly plaques with recurrent sterile pustules refractory to treatment and with few randomized clinical trials conducted. Evidence points to involvement of interleukin 23 in the pathogenesis of PPP. Objective To determine the efficacy and safety of guselkumab, an anti–IL-23 monoclonal antibody, in Japanese patients with PPP. Design, Setting, and Participants A phase 3 randomized clinical trial was conducted from December 15, 2015, to December 12, 2017. A total of 159 enrolled patients (aged ≥20 years) had an inadequate response to conventional therapies, with a diagnosis of PPP for 24 or more weeks before screening. Intention-to-treat analysis was performed. Interventions Subcutaneous injections of guselkumab, 100 or 200 mg, at weeks 0, 4, and 12, and every 8 weeks thereafter were administered; placebo was given at weeks 0, 4, and 12. Main Outcomes and Measures Changes from baseline in PPP Area and Severity Index (PPPASI) score (possible score range, 0-72, with higher scores indicating greater area and severity), PPP severity index (PPSI) score (possible score range, 0-12, with higher scores indicating greater severity), and proportion of PPPASI-50 (≥50% reduction) responders at weeks 16 and 52 were assessed. Safety was monitored through week 52. Results A total of 159 patients (mean [SD] age at diagnosis, 46.8 [11.9] years; 126 women [79.2%]) were enrolled. Treatment groups comprised guselkumab, 100 mg (n = 54), guselkumab, 200 mg (n = 52), or placebo (n = 53). Both guselkumab groups demonstrated significant improvement in least-squares mean changes in PPPASI score compared with placebo: −15.3 and −11.7 in the guselkumab 100-mg and 200-mg groups, respectively, and −7.6 in the placebo group (difference [SE] vs placebo: −7.7 [1.7] in the 100-mg group,P Conclusions and Relevance Targeting interleukin 23 with guselkumab may be an effective and safe treatment option for a recalcitrant disease such as PPP. Trial Registration ClinicalTrials.gov identifier:NCT02641730

Assessment of Black Patients' Perception of Their Dermatology Care.

Abstract: Importance The availability and quality of skin and hair care for black patients in the United States has been a subject of growing interest in dermatology. There is limited understanding of the perceptions of black patients about the care they receive from dermatologists and the factors affecting their care satisfaction. Objective To elucidate black patients’ perceptions of their dermatology experience in and outside of a skin of color clinic (SOCC). Design, Setting, and Participants A cross-sectional study involving a survey and focus groups was conducted including adult black patients treated in an SOCC. Recruitment was conducted April through June 2015 through clinic-posted flyers. Participants engaged in 1 of 4 focus groups on July 14, 15, 29, or 30, 2015, and completed a survey. Data were analyzed March 2016 through June 2017. Main Outcomes and Measures Planned outcomes of the focus groups were black patients’ inductively generated themes on their perspectives and experiences in dermatology clinics. Planned outcomes of the survey were patients’ ratings of SOCC and non-SOCC dermatologists in terms of interaction style, cultural awareness, and treatment satisfaction. Importance of patient-dermatologist racial concordance was a planned outcome in both measures. Given lack of existing prior research, no specific hypotheses were generated. Results Of the 19 adult black patients who participated in the study, 18 (95%) were women, and the mean (SD) age was 50.0 (14.2) years. All patients reported positive experiences in the SOCC. Compared with non-SOCC dermatology treatment experiences, patients reported higher levels of overall satisfaction with SOCC dermatologists (t13 = 2.85;P = .01). Patients perceived that SOCC dermatologists were better trained to care for black patients (t13 = 4.42;P = .001); showed patients greater respect and dignity (t13 = 3.37;P = .005), as well as understanding (t13 = 2.56,P = .02); and were more trustworthy (t13 = 3.47;P = .004). The majority of the comments in the focus groups (n = 207) described 2 themes: dermatologists’ interaction style (62/207; 30.0%) and knowledge about black skin and hair (42/207; 20.3%). Other themes were partnering with patients on outcomes (17/207; 8.2%), shared life experiences (14/207; 6.8%), and economic sensitivity (7/207; 3.4%). These themes accounted for a large part of the participants’ discussion. Of all respondents, 71% (12/17) stated that they would prefer a black (or race concordant) dermatologist; this included 91% (10/11) of the race-concordant group and 33% (2/6) of the race-discordant group. Conclusions and Relevance Participants reported that the SOCC dermatologists provided unique and uniformly beneficial care to black patients. Care satisfaction appeared most related to dermatologists’ interpersonal style and specialized knowledge in care of black skin and hair. Findings suggest that black patients’ dermatologic care satisfaction would increase if dermatologists underwent enhanced residency training in skin of color, cultural competency, cost-conscious care, and empathic communication skills, and if there were greater dermatology workforce diversity.

Evidence-Based Clinical Practice Guidelines for Microcystic Adnexal Carcinoma: Informed by a Systematic Review

Abstract: Importance Microcystic adnexal carcinoma (MAC) occurs primarily in older adults of white race/ethnicity on sun-exposed skin of the head and neck. There are no formal guiding principles based on expert review of the evidence to assist clinicians in providing the highest-quality care for patients. Objective To develop recommendations for the care of adults with MAC. Evidence review A systematic review of the literature (1990 to June 2018) was performed using MEDLINE, Embase, Web of Science, and the Cochrane Library. The keywords searched were microcystic adnexal carcinoma, sclerosing sweat gland carcinoma, sclerosing sweat duct carcinoma, syringomatous carcinoma, malignant syringoma, sweat gland carcinoma with syringomatous features, locally aggressive adnexal carcinoma, and combined adnexal tumor. A multidisciplinary expert committee critically evaluated the literature to create recommendations for clinical practice. Statistical analysis was used to estimate optimal surgical margins. Findings In total, 55 studies met our inclusion criteria. The mean age of 1968 patients across the studies was 61.8 years; 54.1% were women. Recommendations were generated for diagnosis, treatment, and follow-up of MAC. There are 5 key findings of the expert committee based on the available evidence: (1) A suspect skin lesion requires a deep biopsy that includes subcutis. (2) MAC confined to the skin is best treated by surgery that examines the surrounding and deep edges of the tissue removed (Mohs micrographic surgery or complete circumferential peripheral and deep margin assessment). (3) Radiotherapy can be considered as an adjuvant for MAC at high risk for recurrence, surgically unresectable tumors, or patients who cannot have surgery for medical reasons. (4) Patients should be seen by a physician familiar with MAC every 6 to 12 months for the first 5 years after treatment. Patient education on photoprotection, periodic skin self-examination, postoperative healing, and the possible normal changes in local sensation (eg, initial hyperalgesia) should be considered. (5) There is limited evidence to guide the treatment of metastasis in MAC due to its rarity. Limitations of our findings are that the medical literature on MAC comprises only retrospective reviews and descriptions of individual patients and there are no controlled studies to guide management. Conclusions and relevance The presented clinical practice guidelines provide an outline for the diagnosis and management of MAC. Future efforts using multi-institutional registries may improve our understanding of the natural history of the disease in patients with lymph node or nerve involvement, the role of radiotherapy, and the treatment of metastatic MAC with drug therapy.

Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis.

Abstract: Importance Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. Objective To identify genetic mutations associated with linear porokeratosis. Design, Setting, and Participants Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. Interventions or Exposures Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. Main Outcomes and Measures Germline and somatic genomic characteristics of participants with linear porokeratosis. Results Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygousPMVKc.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygousPMVKc.79G>T mutation and an additionalPMVKc.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation inMVD(c.70 + 5G>A) and a somatic deletion inMVDcausing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). Conclusions and Relevance Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.

Association of Phenotypic Characteristics and UV Radiation Exposure With Risk of Melanoma on Different Body Sites.

Abstract: Importance Two pathways have been hypothesized for the development of cutaneous melanoma: one typically affects the head and neck, a site with chronic sun damage, and the other affects the trunk, which is less exposed to the sun. However, the possible cause of limb melanomas is less studied under this hypothesis. Objective To investigate the association between phenotypic characteristics, pattern of UV radiation exposure, and risk of melanoma on different body sites. Design, Setting, and Participants This study used data on 161 540 women with information on phenotypic characteristics and UV radiation exposure who were part of the Norwegian Women and Cancer study, a population-based prospective study established in 1991 with exposure information collected by questionnaires at baseline and every 4 to 6 years during follow-up through 2015. Data analysis was performed from October 2017 through May 2018. Exposures Participants reported hair color, eye color, untanned skin color, number of small symmetric and large asymmetric nevi, and freckling, as well as histories of sunburns, sunbathing vacations, and indoor tanning in childhood, adolescence, and adulthood. Main Outcomes and Measures The Norwegian Women and Cancer study was linked to the Cancer Registry of Norway for data on cancer diagnosis and date of death or emigration. Primary melanoma site was categorized as head and neck, trunk, upper limbs, and lower limbs. Results During follow-up of the 161 540 women in the study (mean age at study entry, 50 years [range, 34-70 years]; mean age at diagnosis, 60 years [range, 34-87 years]), 1374 incident cases of melanoma were diagnosed. Having large asymmetric nevi was a significant risk factor for all sites and was strongest for the lower limbs (relative risk [RR], 3.38; 95% CI, 2.62-4.38) and weakest for the upper limbs (RR, 1.96; 95% CI, 1.22-3.17; P = .02 for heterogeneity). Mean lifetime number of sunbathing vacations was significantly associated with risk of trunk melanomas (RR, 1.14; 95% CI, 1.07-1.22) and lower limb melanomas (RR, 1.12; 95% CI, 1.05-1.19) but not upper limb melanomas (RR, 0.98; 95% CI, 0.88-1.09) and head and neck melanomas (RR, 0.87; 95% CI, 0.73-1.04; P = .006 for heterogeneity). Indoor tanning was associated only with trunk melanomas (RR for the highest tertile, 1.49; 95% CI, 1.16-1.92) and lower limb melanomas (RR for the highest tertile, 1.33; 95% CI, 1.00-1.76; P = .002 for heterogeneity). Skin color, hair color, small symmetric nevi, and history of sunburns were associated with risk of melanoma on all sites. Conclusions and Relevance These results appear to support the hypothesis of divergent pathways to melanoma and that recreational sun exposure and indoor tanning are associated with melanoma on the lower limbs, the most common site of melanoma in women. These findings appear to have important preventive implications.

US Food and Drug Administration Reports of Pregnancy and Pregnancy-Related Adverse Events Associated With Isotretinoin.

Abstract: Importance iPLEDGE is a rigorous program initiated in 2006 to reduce fetal exposure to isotretinoin, a disease-modifying medication for acne that carries a risk of teratogenesis. Despite the imposition of iPLEDGE requirements on patients and clinicians, the scope of isotretinoin-related adverse events is unknown. Objective To determine the frequency and rate of pregnancy and pregnancy-related adverse events among women taking isotretinoin reported to the US Food and Drug Administration (FDA). Design, Setting, and Participants Pregnancy reports from the FDA Adverse Event Reporting System, a public database of medication adverse event reports filed by prescribers, consumers, and manufacturers, were used to perform a retrospective analysis of pregnancy-related adverse events associated with isotretinoin from January 1, 1997, to December 31, 2017. Each individual reporting any pregnancy-related adverse event signified 1 pregnancy. Abortions, pregnancies that occurred while contraception was used, and fetal defects were counted as subgroups of total pregnancy events. Main Outcomes and Measures The frequency of pregnancy and of pregnancy-related events (abortions, pregnancies that occurred while using contraception, and fetal defects) were stratified by year that the FDA was notified of the event and by age. The rates of adverse events were calculated using isotretinoin prescribing data. Results There was a total of 6740 pregnancies among women taking isotretinoin reported to the FDA from 1997 to 2017, peaking in 2006 (768 pregnancies) before settling into a range of 218 to 310 annual reports of pregnancy after 2011. The mean (SD) age of the women was 24.6 (7.1) years. The rate of pregnancy for females of childbearing potential was between 0.33% (388 of 115 925) and 0.65% (768 of 117 784), with a peak in 2006. Although pregnancies, abortions, and fetal defects among women taking isotretinoin have decreased since the initiation of iPLEDGE in 2006, all 3 persist. Conclusions and Relevance The number of reports of pregnancies, abortions, and fetal defects among women taking isotretinoin has decreased since peaking around the initiation of iPLEDGE in 2006. Explanations for this trend include a broader national decrease in teenage pregnancies and abortion rates, improvements in access to effective long-term and emergency contraception, stringent iPLEDGE requirements, and reporting fatigue over time. Despite the decrease, persistent reporting of pregnancy-related events in the last decade warrants investigation into the efficacy of iPLEDGE and exploration of new approaches for lowering fetal exposure to isotretinoin.