Justin M. Ko

Dermatologist-level classification of skin cancer with deep neural networks

Skin cancer, the most common human malignancy, is primarily diagnosed visually, beginning with an initial clinical screening and followed potentially by dermoscopic analysis, a biopsy and histopathological examination. Automated classification of skin lesions using images is a challenging task owing to the fine-grained variability in the appearance of skin lesions. Deep convolutional neural networks (CNNs) show potential for general and highly variable tasks across many fine-grained object categories. Here we demonstrate classification of skin lesions using a single CNN, trained end-to-end from images directly, using only pixels and disease labels as inputs. We train a CNN using a dataset of 129,450 clinical images—two orders of magnitude larger than previous datasets—consisting of 2,032 different diseases. We test its performance against 21 board-certified dermatologists on biopsy-proven clinical images with two critical binary classification use cases: keratinocyte carcinomas versus benign seborrheic keratoses; and malignant melanomas versus benign nevi. The first case represents the identification of the most common cancers, the second represents the identification of the deadliest skin cancer. The CNN achieves performance on par with all tested experts across both tasks, demonstrating an artificial intelligence capable of classifying skin cancer with a level of competence comparable to dermatologists. Outfitted with deep neural networks, mobile devices can potentially extend the reach of dermatologists outside of the clinic. It is projected that 6.3 billion smartphone subscriptions will exist by the year 2021 (ref. 13) and can therefore potentially provide low-cost universal access to vital diagnostic care.

Induction and exacerbation of psoriasis with TNF-blockade therapy: A review and analysis of 127 cases

Background: There are reports of rare adverse effects of tumor necrosis factor (TNF) inhibitors, including infections, malignancies, and induction of autoimmune conditions. Intriguing, are cases of induction or exacerbation of psoriasis in conjunction with TNF inhibitor therapy, given that they are approved for treatment of the same condition. Objective: Published cases of psoriasis occurring during anti-TNF therapy were analyzed, including overviews of proposed etiologies and treatment recommendations. Methods: A literature search using Ovid MEDLINE and PubMed was performed for articles published between January 1990 and September 2007 to collect reported cases of psoriasis in patients receiving therapy with TNF blocking agents. Results: A total of 127 cases were identified: 70 in patients on infliximab (55.1%), 35 with etanercept (27.6%), and 22 with adalimumab (17.3%). Females comprised 58% of cases; mean age of reported patients was 45.8 years, and the time from initiation of treatment to onset of lesions averaged 10.5 months. These patients suffered from a number of primary conditions, with rheumatoid arthritis, ankylosing spondylitis, and Crohns disease accounting for the vast majority. Palmoplantar pustular psoriasis was observed in 40.5% of the cases, with plaque-type psoriasis in 33.1%, and other types comprising the remainder. Topical corticosteroids were the most commonly employed treatment modality but led to resolution in only 26.8% of cases in which they were employed solely. Switching to a different anti-TNF agent led to resolution in 15.4% of cases. Cessation of anti-TNF therapy with systemic therapy led to resolution in 64.3% of cases. Conclusion: More information and cases are needed. Biopsies of TNF-blockade-induced lesions may reveal what cytokines and cell types drive the development of these lesions. Additionally, there is a need to develop an algorithm to treat this paradoxical side effect of therapy with TNF-blockers.

A new era: melanoma genetics and therapeutics

We have recently witnessed an explosion in our understanding of melanoma. Knowledge of the molecular basis of melanoma and the successes of targeted therapies have pushed melanoma care to the precipice of a new era. Identification of significant pathways and oncogenes has translated to the development of targeted therapies, some of which have produced major clinical responses. In this review, we provide an overview of selected key pathways and melanoma oncogenes as well as the targeted agents and therapeutic approaches whose successes suggest the promise of a new era in melanoma and cancer therapy. Despite these advances, the conversion of transient remissions to stable cures remains a vital challenge. Continued progress towards a better understanding about the complexity and redundancy responsible for melanoma progression may provide direction for anti‐cancer drug development. Copyright

Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata

BACKGROUND Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined. METHODS This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome. RESULTS Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment. CONCLUSIONS At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease. TRIAL REGISTRATION ClinicalTrials.gov NCT02197455 and NCT02312882. FUNDING This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

Paying for Enhanced Service

Background: Concierge medical practice is a relatively new and somewhat controversial development in primary-care practice. These practices promise patients more personalized care and dedicated service, in exchange for an annual membership fee paid by patients. The experiences of patients using these practices remain largely undocumented.Objective: To assess the experiences of patients in a concierge medicine practice compared with those in a general medicine practice.Methods: Stratified random samples of patients empanelled to each of the four doctors who practice at both a general medicine and a concierge medicine practice separately situated at an academic medical center were drawn. Patients were eligible for the study if they had a visit with the physician between January and May 2006. The study questionnaire (Consumer Assessment of Healthcare Providers and Systems Clinician and Group Survey, supplemented with items from the Ambulatory Care Experiences Survey) was administered by mail to 100 general medicine patients per physician (n = 400) and all eligible concierge medicine patients (n = 201). Patients who completed the survey and affirmed the study physician as their primary-care physician formed the analytic sample (n = 344) that was used to compare the experiences of concierge medicine and general medicine patients. Models controlled for respondent characteristics and accounted for patient clustering within physicians using physician fixed effects.Results: Patients’ experiences with organizational features of care, comprising care co-ordination (p < 0.01), access to care (p < 0.001) and interactions with office staff (p < 0.001), favored concierge medicine over general medicine practice. The quality of physician-patient interactions did not differ significantly between the two groups. However, the patients of the concierge medicine practice were more likely to report that their physician spends sufficient time in clinical encounters than patients of the general medicine practice (p < 0.003).Conclusion: The results suggest patients of the concierge medicine practice experienced and reported enhanced service, greater access to care, and better care co-ordination than those of the general medicine practice. This suggests that further study to understand the etiology of these differences may be beneficial in enhancing patients’ experience in traditional primary-care practices.

Corrigendum: Dermatologist-level classification of skin cancer with deep neural networks

This corrects the article DOI: 10.1038/nature21056

Implementation and evaluation of Stanford Health Care direct-care teledermatology program

Introduction: Teledermatology has proven to be an effective means of providing dermatologic care. The existing research has primarily evaluated its usefulness in a consultative model. Few academic centers have evaluated a patient-initiated model, and direct-to-consumer services remain the subject of controversy. Stanford Health Care recently launched a direct-care, patient-initiated teledermatology pilot program. This article evaluates the viability and patient satisfaction with this service. Materials and Methods: During the pilot period, patients were able to seek remote dermatologic care using an eVisit tool in their MyHealth account. Patients initiated the consultation, answered questions regarding their complaint, and uploaded a picture if relevant. A Stanford dermatologist reviewed each eVisit and responded with an assessment and plan. The dermatologist noted whether they were able to make a diagnosis and their level of confidence in it. After the study, 10 patients participated in a focus group to provide feedback on the service. Results: In all, 38 patients sought care during the pilot period. A dermatologist was able to make a diagnosis in 36 of 38 (95%) cases, with an average confidence level of 7.9 of 10. The average time to consultation was 0.8 days. Patients indicated high levels of satisfaction with the service although they had suggestions for improvement. Discussion: Patients provided clinically useful images and information in a direct-care teledermatology model. Such services allow dermatology providers to increase access while maintaining high-quality care in an academic medical center. Further research is needed on standalone services that cannot integrate encounters with the patient’s existing medical record.

Randomized Controlled Trial of Cryotherapy With Liquid Nitrogen vs Topical Salicylic Acid vs Wait-and-See for Cutaneous Warts

Question: In outpatients who present with new cutaneous warts, what is the efficacy of treatment with cryotherapy, topical salicylic acid, and a wait-and-see approach in leading to clearance of baseline lesions at 13 weeks? Design: Unblinded, randomized-controlled trial. Setting: Multipractice, 30 family practices from the Leiden Primary Care Research Network in the Netherlands. Patients: Patients 4 years and older who presented to the general medicine clinic with one or more new cutaneous warts. Immunocompromised patients, those with genital warts, seborrheic warts, or warts larger than 1cm in diameter were excluded from the study. Intervention: Enrolled participants were randomized to 13-week treatment periods with cryotherapy (one session every two weeks until resolution of the wart), salicylic acid (daily self-application of 40% salicylic acid in petroleum jelly daily under occlusion preceded by gentle paring), or wait-and-see (advised not to undergo treatment other than over-the-counter medication). Patients were stratified according to characteristics, notably location of warts (plantar vs common [those with both common and plantar warts were grouped according to where the majority of their warts were located]) and number of warts ( 6 or 6). Outcome: The primary end point was the proportion of patients whose warts present at baseline were all cured at 13 weeks. Secondary analyses and subgroup analyses were predefined. Results: Of 250 randomized patients who received treatment, 10 were lost to follow-up at 13 weeks, and 48 patients stopped the assigned treatment protocol. The intention-to-treat analysis demonstrated cure rates of 39% (30/76) for the cryotherapy arm, 24% (20/82) for the salicylic acid arm, and 16% (13/82) for the wait-and-seen arm; two-sided 2 test, linear-by-linear association, comparing three treatment groups (P=.001). With subgroup analysis based on location of warts, cure rates of 49% (19/39) for cryotherapy, 15% (6/39) for salicylic acid, and 8% (3/38) for wait-and see were demonstrated for common warts; two-sided 2 test, linearby-linear association, comparing three treatment groups (P .001). For plantar warts, cure rates of 30% (11/37) for cryotherapy, 33% (14/43) for salicylic acid, and 23% (10/44) for wait and see two-sided 2 test, linear-bylinear association, comparing three treatment groups (P=.46) were seen. Secondary analyses including 26-week follow-up was performed (after allowing for switching after 13 weeks) and results were noted to be concordant with results at 13 weeks. Likewise, further analyses were performed: exclusion of participants with both common and plantar warts from the analysis, per-protocol analysis, and analysis based on individual warts as the unit rather than patients. All of these secondary analyses showed the same significant results as the primary analysis. Also of note, in the common wart group, patients were more satisfied after treatment with cryotherapy, 69%, compared with 24% after salicylic acid and 22% after wait-and-see (P .001). Assessment of adverse effects showed significantly greater number of adverse effects with cryotherapy than with salicylic acid, including more pain and blistering. When comparing the burden of treatment, fewer patients with common warts reported considerable treatment burden with cryotherapy, 31%, as compared with salicylic acid, 49%, two-sided 2 test, linearby-linear association, comparing two treatment groups (P=.04). No difference in patient satisfaction or treatment burden was seen in the plantar wart group. Conclusions: Use of cryotherapy was significantly more effective than use of salicylic acid treatment for common warts only. For plantar warts, there was no clinically relevant difference in effect favoring the use of cryotherapy, salicylic acid, or a wait-and-see approach.

Challenges and recommendations for epigenomics in precision health

VOLUME 35 NUMBER 12 DECEMBER 2017 NATURE BIOTECHNOLOGY 13. Di Tommaso, P. et al. Nat. Biotechnol. 35, 316–319 (2017). 14. Ioannidis, J.P.A. et al. PLoS Med. 2, 0696–0701 (2005). 15. Micheel, C.M. et al. Evolution of Translational Omics; Lessons Learned and the Path Forward. (National Academies Press, Washington, DC, 2012). 16. Ioannidis, J.P.A. et al. Nat. Genet. 41, 149–155 (2009). 17. Wilkinson, M.D. et al. Sci. Data. 3, 160018 (2016). http://www.nature.com/news/ reproducibility-1.17552; https:// f1000research.com/gateways/PRR). The newly launched International MAQC Society will strive to work with various scientific communities to develop consensus on best practices for enhanced reproducibility in generation, analysis, and interpretation of massive data from increasingly innovative biomedical fields. More information about the MAQC Society can be found at http://www.maqcsociety.org.