Spiny Keratoderma: Clinical and Histopathological Findings in a Series of 3 Cases.

ABSTRACT: Spiny keratoderma is a rare entity presenting with minute keratotic spines on the palms and soles. Spiny keratoderma can be inherited or acquired, and the acquired form may be associated with underlying malignancy or systemic disease. Clinically, the differential diagnosis includes other digitate keratoses on acral sites, most notably arsenical keratosis, filiform verruca, and punctate porokeratosis. Biopsy findings typically include a column of parakeratosis overlying a diminished granular cell layer. In this article, we present 3 cases of acquired spiny keratoderma in patients with various systemic diseases, but no underlying malignancy.

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

Results of a National Survey on the Definition of Surgical Site Infections After Mohs Micrographic Surgery.

BACKGROUND: There is no standardized definition of surgical site infections (SSI) after Mohs micrographic surgery (MMS) used in the clinical or research settings, which may contribute to heterogeneity in the differences in infection rates reported. OBJECTIVE: To use an electronic survey of Mohs surgeons across the country to better understand how Mohs surgeons define SSI after MMS. METHODS: A web-based survey was developed and distributed to Mohs surgeons. Respondents were asked to respond to several different scenarios that could represent SSI after MMS. RESULTS: Of potential 1,500 respondents, 79 (5.3%) responded to the survey. Presentation of a surgical site with warmth, swelling, erythema, and pain at 7 days postoperatively resulted in 79.7% consensus of SSI. Surgical sites that were cultured and found to be Staphylococcus aureus-positive resulted in 100% agreement of SSI. There was no consensus regarding timing after MMS. CONCLUSION: There is consensus on numerous aspects of SSI after MMS among Mohs surgeons, which may allow for development of standardized definition in the future.

Epigenetics and cutaneous neoplasms: from mechanism to therapy.

Epigenetics encompasses heritable, reversible gene expression patterns that do not arise from mutations in genomic DNA but, rather, are regulated by DNA methylation, histone modifications, RNA modifications and ncRNAs; and epigenetic dysregulation is increasingly recognized as a mechanism of neoplastic disease progression as well as resistance to cancer therapy. This review article focuses on epigenetic modifications implicated in the progression and therapeutic resistance of common cutaneous malignancies, including basal cell carcinoma, squamous cell carcinoma, T-cell lymphoma and malignant melanoma, with an emphasis on therapeutic strategies that may be used to target such disease-associated alterations.

Epigenetics involves the study of how genes can be turned on or off by factors that affect how these genes are packaged and regulated. In cancer, there are often epigenetic changes that contribute to the formation of tumors. Many of these epigenetic changes, some of which can be passed down through generations, increase the risk of skin cancers such as basal cell carcinoma, squamous cell carcinoma, T-cell lymphoma and malignant melanoma. Emerging therapies designed to target these epigenetic changes may be effective treatments for these types of skin cancers. Researchers are currently investigating how to best use these therapies to help the ever-increasing number of people with skin cancer.

Epigenetic Dysregulation in Autoimmune and Inflammatory Skin Diseases.

Epigenetics is the study of heritable, reversible gene expression patterns that do not originate from alterations in the DNA sequence. Epigenetic modifications influence gene expression patterns and include DNA methylation, histone modifications, and gene regulation via non-coding RNAs. While the study of epigenetics has been most broadly applied to neoplastic diseases, the role of the epigenome in a wide range of disease processes including autoimmune, allergic, and inflammatory processes is increasingly being recognized. Recent advances in the study of the epigenome have led to novel insights into the pathogenesis and potential therapeutic targets of various pathologic entities including inflammatory diseases. In this review, we examine the nature of epigenetic modifications in several well-studied autoimmune, allergic, and/or inflammatory disorders of the skin including systemic lupus erythematosus, vitiligo, systemic sclerosis, alopecia areata, pemphigus, psoriasis, atopic dermatitis, keloidal scarring, and hidradenitis suppurativa with the aim to determine how such epigenetic changes may be targeted for therapeutic benefit.

Drugging the Epigenome: Overcoming Resistance to Targeted and Immunotherapies in Melanoma.

This past decade has seen tremendous advances in understanding the molecular pathogenesis of melanoma and the development of novel effective therapies for melanoma. Targeted therapies and immunotherapies that extend survival of patients with advanced disease have been developed; however, the vast majority of patients experience relapse and therapeutic resistance over time. Moreover, cellular plasticity has been demonstrated to be a driver of therapeutic resistance mechanisms in melanoma and other cancers, largely functioning through epigenetic mechanisms, suggesting that targeting of the cancer epigenetic landscape may prove a worthwhile endeavor to ensure durable treatment responses and cures. Here, we review the epigenetic alterations that characterize melanoma development, progression, and resistance to targeted therapies as well as epigenetic therapies currently in use and under development for melanoma and other cancers. We further assess the landscape of epigenetic therapies in clinical trials for melanoma and provide a framework for future advances in epigenetic therapies to circumvent the development of therapeutic resistance in melanoma.

One Month of Cannabis Abstinence in Adolescents and Young Adults Is Associated With Improved Memory.

OBJECTIVE: Associations between adolescent cannabis use and poor neurocognitive functioning have been reported from cross-sectional studies that cannot determine causality. Prospective designs can assess whether extended cannabis abstinence has a beneficial effect on cognition. METHODS: Eighty-eight adolescents and young adults (aged 16-25 years) who used cannabis regularly were recruited from the community and a local high school between July 2015 and December 2016. Participants were randomly assigned to 4 weeks of cannabis abstinence, verified by decreasing 11-nor-9-carboxy-∆9-tetrahydrocannabinol urine concentration (MJ-Abst; n = 62), or a monitoring control condition with no abstinence requirement (MJ-Mon; n = 26). Attention and memory were assessed at baseline and weekly for 4 weeks with the Cambridge Neuropsychological Test Automated Battery. RESULTS: Among MJ-Abst participants, 55 (88.7%) met a priori criteria for biochemically confirmed 30-day continuous abstinence. There was an effect of abstinence on verbal memory (P = .002) that was consistent across 4 weeks of abstinence, with no time-by-abstinence interaction, and was driven by improved verbal learning in the first week of abstinence. MJ-Abst participants had better memory overall and at weeks 1, 2, 3 than MJ-Mon participants, and only MJ-Abst participants improved in memory from baseline to week 1. There was no effect of abstinence on attention: both groups improved similarly, consistent with a practice effect. CONCLUSIONS: This study suggests that cannabis abstinence is associated with improvements in verbal learning that appear to occur largely in the first week following last use. Future studies are needed to determine whether the improvement in cognition with abstinence is associated with improvement in academic and other functional outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03276221.

Phase IIb Trial of an α7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence.

PURPOSE/BACKGROUND: The objective of this study was to determine whether a novel α7 nicotinic acetylcholine receptor partial agonist improves cognition during nicotine withdrawal and improves abstinence rates. To do so, the effect of the α7 nicotinic acetylcholine receptor partial agonist, encenicline, on cognition and abstinence was evaluated when given as monotherapy and when combined with transdermal nicotine patch (nicotine replacement therapy [NRT]). METHODS: Adult daily smokers, n = 160, who were motivated to quit smoking completed cognitive testing at satiated baseline and after overnight abstinence and then were randomized to receive a 12-week trial of encenicline 1 mg twice daily or identical placebo the day of the overnight abstinent cognitive testing. In the first 6 weeks of the 12-week encenicline administration, participants were also randomized to 6 weeks of NRT patch or placebo patch. Primary outcomes were cognition during abstinence and 7-day point-prevalence abstinence at week 12. RESULTS: No beneficial effects of encenicline were observed on cognition or abstinence when compared with placebo or when combined with NRT compared with placebo capsule + NRT. Of the 4 conditions, abstinence rates were lowest among those assigned to encenicline alone. CONCLUSIONS: Beneficial effects of NRT were observed on cognitive and abstinence outcomes when combined with encenicline compared with encenicline plus placebo patch. Addition of NRT to encenicline improved odds of abstinence approximately 3-fold compared with encenicline plus placebo patch. We conclude that encenicline, 1 mg/d, did not improve abstinence-associated cognitive impairment or abstinence rates as monotherapy or adjunctive therapy to NRT patch.

Prolonged cannabis withdrawal in young adults with lifetime psychiatric illness.

Young adults with psychiatric illnesses are more likely to use cannabis and experience problems from use. It is not known whether those with a lifetime psychiatric illness experience a prolonged cannabis withdrawal syndrome with abstinence. Participants were fifty young adults, aged 18-25, recruited from the Boston-area in 2015-2016, who used cannabis at least weekly, completed the Structured Clinical Interview for DSM-IV to identify Axis I psychiatric diagnoses (PD+ vs PD-), and attained cannabis abstinence with a four-week contingency management protocol. Withdrawal symptom severity was assessed at baseline and at four weekly abstinent visits using the Cannabis Withdrawal Scale. Cannabis dependence, age of initiation, and rate of abstinence were similar in PD+ and PD- groups. There was a diagnostic group by abstinent week interaction, suggesting a difference in time course for resolution of withdrawal symptoms by group, F(4,46)=3.8, p=0.009, controlling for sex, baseline depressive and anxiety symptoms, and frequency of cannabis use in the prior 90days. In post hoc analyses, there was a difference in time-course of cannabis withdrawal. PD- had significantly reduced withdrawal symptom severity in abstinent week one [t(46)=-2.2, p=0.03], while PD+ did not report improved withdrawal symptoms until the second abstinent week [t(46)=-4.1, p=0.0002]. Cannabis withdrawal symptoms improved over four weeks in young people with and without a lifetime psychiatric diagnosis. However, those with a psychiatric illness reported one week delayed improvement in withdrawal symptom severity. Longer duration of cannabis withdrawal may be a risk factor for cannabis dependence and difficulty quitting.

A contingency management method for 30-days abstinence in non-treatment seeking young adult cannabis users.

BACKGROUND: Rates of young adult cannabis use are rising, perceived harm is at its historical nadir, and most users do not want to quit. Most studies evaluating effects of cannabis use in young adults are cross-sectional, limiting causal inference. A method to reliably induce abstinence periods in cannabis users would allow assessment of the effects of abstinence and resumption of use on a variety of outcomes in a within-subjects, repeated measures design. METHODS: We examined the efficacy and feasibility of a voucher-based contingency management procedure for incentivizing one month of continuous cannabis abstinence among young adults who reported at least weekly cannabis use, volunteered to participate in a laboratory study, and did not express a desire to discontinue cannabis use long-term. Continuous cannabis abstinence was reinforced with an escalating incentive schedule, and self-report of abstinence was confirmed by frequent quantitative assays of urine cannabis metabolite (THCCOOH) concentration. New cannabis use during the abstinence period was determined using an established algorithm of change in creatinine-adjusted cannabis metabolite concentrations between study visits. RESULTS: Thirty-eight young adults, aged 18-25 years, enrolled and 34 (89.5%) attained biochemically confirmed 30-day abstinence. Among those who attained abstinence, 93.9% resumed regular use within two-weeks of incentive discontinuation. CONCLUSION: Findings support the feasibility and efficacy of contingency management to elicit short-term, continuous cannabis abstinence among young adult, non-treatment seeking, regular cannabis users. Further work should test the effectiveness of this contingency management procedure for cannabis abstinence in periods longer than one month, which may be required to evaluate some effects of abstinence.