Synthetic cannabinoid induced ocular self-injury.

Synthetic cannabinoids are a relatively new and increasingly popular recreational drug. While used for their hallucinogenic properties similar to natural cannabis, they have a greater and more serious side effect profile, including potentially severe neuropsychiatric toxicity. We report the cases of two patients with untreated schizophrenia who presented after ocular self-injury while intoxicated on K2. Both patients hallucinated that a bug was behind their eye, and in their attempts at removing the bug, damaged the periocular soft tissue. To our knowledge these are the first reports of ocular self-injury from synthetic cannabinoid intoxication.

UVEAL METASTASIS BASED ON PATIENT AGE IN 1,111 PATIENTS: Comparison of Clinical Features and Outcomes Per Age Category.

PURPOSE: To evaluate clinical features and survival outcomes of uveal metastasis based on patient age. METHODS: Retrospective analysis of all patients with uveal metastasis evaluated on the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA, USA between February 1, 1974 and June 1, 2017. The features and outcomes were analyzed based on patient age classified as children (0-20 years), young adults (21-40 years), middle [aged] adults (41-60 years), older adults (61-80 years) and senior adults (81-100 years). RESULTS: There were 1111 consecutive patients, including children (n = 3, <1%), young adults (n = 77, 7%), middle adults (n = 472, 42%), older adults (n = 509, 46%), and senior adults (n = 50, 4%). At uveal metastasis diagnosis, demographics included mean patient age of 60 years, Caucasian race (88%), and female gender (64%). Compared to the largest cohort (older adults), there were significant differences (age group versus [vs.] older adults) in Caucasian race (senior adult 98% vs. 89%, p = 0.042), male sex (young adults: 22% vs. 43%, p < 0.001) (middle adults: 29% vs. 43%, p < 0.001), unilateral tumor (young adult: 70% vs. 86%, p < 0.001) (middle adult: 79% vs. 86%, p = 0.003) (senior adults: 96% vs. 86%, p = 0.045), and cancer origin in breast (young adults: 51% vs. 32%, p = 0.002) (middle adults: 44% vs 32%, p < 0.001), lung (young adults: 14% vs. 30%, p = 0.004), kidney (young adults: 0% vs. 5%, p = 0.043), prostate (middle adults: 1% vs. 4%, p = 0.001), gastrointestinal tract (senior adults: 8% vs. 2%, p = 0.028), and others (children: 100% vs. 4%, p < 0.001) (young adults: 10% vs. 4%, p = 0.044). Kaplan-Meier survival (children, young, middle, older, and senior adults) at 1 year was 33%, 48%, 60%, 62%, and 76% and at 5 years was 0%, 22%, 29%, 25%, and 40%, respectively, with no difference per age category. The mean overall survival was 17.2 months and children demonstrated hazard ratio (HR) for death at 1 year of 2.1 relative to older adults. CONCLUSION: Uveal metastasis is found in all age groups. Compared to older adults, primary cancer site was more often breast and less likely lung in young and middle adults. Other rare sites were more often seen in children. Survival outcomes at 1 and 5 years were most favorable for senior adults and least favorable for children.

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature.

BACKGROUND: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. OBJECTIVE: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. METHODS: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). RESULTS: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α-coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN-γ, OASL, and TH2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17-regulated gene expression (IL17F and IL36A/IL36B/IL36G). CONCLUSION: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36-targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.

Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. OBJECTIVE: We sought to characterize age-related changes in the AD profile. METHODS: We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). RESULTS: Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b+ and FcεRI+, P < .05) decreased with age. TH2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with TH2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = -0.24 and r = -0.23, respectively; P < .05). TH22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of TH1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and TH17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with TH2 downregulation (CCL26; r = -0.32, P < .1) and TH1 upregulation (IFN-γ; r = 0.48, P < .01) with age. CONCLUSION: The adult AD profile varies with age. Although TH1/TH17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in TH2/TH22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.

Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab.

BACKGROUND: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. OBJECTIVE: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. METHODS: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. RESULTS: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10-5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10-19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22-high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. CONCLUSIONS: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.

The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.

BACKGROUND: Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD. OBJECTIVE: To analyze blood inflammatory proteins of early pediatric AD. METHODS: Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD. RESULTS: In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11). LIMITATIONS: Different baseline expression levels in healthy pediatric vs adult samples. CONCLUSIONS: Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.

Cytokine Targeted Therapeutics for Alopecia Areata: Lessons from Atopic Dermatitis and Other Inflammatory Skin Diseases.

Alopecia areata is a T-cell-mediated disease that shares phenotypic similarities with other inflammatory diseases, particularly atopic dermatitis, and lacks safe, effective, mechanism-specific treatments. Increasing data suggests that alopecia areata harbors contributions of T helper type 1, T helper type 2, T helper type 17/IL-23, and phosphodiesterase pathways. Antagonism of these axes is undergoing evaluation, and might elucidate the underlying molecular circuitry of alopecia areata, advancing the translational revolution for this disease.

Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: A randomized controlled trial.

BACKGROUND: Liver X receptors (LXRs) are involved in maintaining epidermal barrier and suppressing inflammatory responses in model systems. The LXR agonist VTP-38543 showed promising results in improving barrier function and inflammatory responses in model systems. OBJECTIVE: To assess the safety, tolerability, cellular and molecular changes, and clinical efficacy of the topical VTP-38543 in adults with mild to moderate atopic dermatitis (AD). METHODS: A total of 104 ambulatory patients with mild to moderate AD were enrolled in this randomized, double-blind, vehicle-controlled trial between December 2015 and September 2016. VTP-38543 cream in 3 concentrations (0.05%, 0.15%, and 1.0%) or placebo was applied twice daily for 28 days. Pretreatment and posttreatment skin biopsy specimens were obtained from a subset of 33 patients. Changes in SCORing of Atopic Dermatitis, Eczema Area and Severity Index, Investigator's Global Assessment, and tissue biomarkers (by real-time polymerase chain reaction and immunostaining) were evaluated. RESULTS: Topical VTP-38543 was safe and well tolerated. VTP-38543 significantly increased messenger RNA (mRNA) expression of epidermal barrier differentiation (loricrin and filaggrin, P = .02) and lipid (adenosine triphosphate-binding cassette subfamily G member 1 and sterol regulatory element binding protein 1c, P < .01) measures and reduced epidermal hyperplasia markers (thickness, keratin 16 mRNA). VTP-38543 nonsignificantly suppressed cellular infiltrates and down-regulated mRNA expression of several TH17/TH22-related (phosphatidylinositol 3, S100 calcium-binding protein A12) and innate immunity (interleukin 6) markers. CONCLUSION: Topical VTP-38543 is safe and well tolerated. Its application led to improvement in barrier differentiation and lipids. Longer-term studies are needed to clarify whether a barrier-based approach can induce meaningful suppression of immune abnormalities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02655679.

Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial.

BACKGROUND: Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. OBJECTIVE: Evaluate interleukin 22 blockade in adults with moderate-to-severe atopic dermatitis (AD). METHODS: We performed a randomized, double-blind, placebo-controlled trial with intravenous fezakinumab monotherapy every 2 weeks for 10 weeks, with follow-up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. RESULTS: At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 ± 2.7 in the fezakinumab arm and 8.0 ± 3.1 in the placebo arm (P = .134). In the severe AD patient subset (with a baseline SCORAD of ≥50), SCORAD decline was significantly stronger in the drug-treated patients than placebo-treated patients at 12 weeks (21.6 ± 3.8 vs 9.6 ± 4.2, P = .029) and 20 weeks (27.4 ± 3.9 vs 11.5 ± 5.1, P = .010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug-treated than placebo-treated patients (12.4% ± 2.4 vs 6.2% ± 2.7; P = .009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug-treated than placebo-treated patients (0.7 ± 0.2 vs 0.3 ± 0.1; P = .034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. LIMITATIONS: The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. CONCLUSION: Fezakinumab was well-tolerated, with sustained clinical improvements after last drug dosing.

Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The "plaque model" has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis. OBJECTIVE: We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics. METHODS: We enrolled 30 patients with mild-to-moderate AD in a randomized, double-blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT-PCR and immunohistochemistry) were evaluated. RESULTS: TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL-13, IL-22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers. CONCLUSION: We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.

Lynch Syndrome and Muir-Torre Syndrome: An update and review on the genetics, epidemiology, and management of two related disorders.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, is an autosomal dominant, tumor predisposing disorder usuallycaused by germline mutations in mismatch repair (MMR) genes. A subset of HNPCC, Muir-Torre Syndrome (MTS) also involves MMR gene defects and is generally accepted as a variant of HNPCC. MTS is typicallycharacterized by at least one visceral malignancy and one cutaneous neoplasm of sebaceous differentiation, with or without keratoacanthomas. In either version of the disorder, nonfunctional MMR systems lead tothe loss of genomic integrity, marked commonly by mismatches in repetitive DNA sequences, resulting in microsatellite instabilities. Deleterious nucleotide alterations ultimately drive the process of tumorigenesis in both HNPCC and MTS. The following article reviews the epidemiology, genetics, clinical presentation, and management of HNPCC and its MTS variant.

Bailout technique for entangled stent retriever and carotid stent during tandem large vessel occlusion endovascular therapy.

BACKGROUND AND IMPORTANCE: Endovascular thrombectomy for patients with tandem occlusions could be challenging. Exposure to potential technical complications and bailout rescue techniques are of utmost importance. CLINICAL PRESENTATION: A 73-year-old woman with tandem internal carotid artery and middle cerebral artery lesions underwent an unsuccessful retrograde revascularization approach in the setting of tortuous anatomy. Antegrade approach revascularization was then pursued. Following cervical internal carotid artery revascularization, a triaxial system of aspiration catheter, microcatheter and micro guidewire was navigated through the stented curved cervical ICA and intracranial stent retriever pass was performed. Upon retrieving the clot-incorporated stent retriever with the intention to retrieve the entire stent retriever into the locally placed aspiration catheter, the triaxial system collapsed into the distal common carotid artery. Large thrombus was recovered from the aspiration catheter aspirate however the proximal end of stent retriever and distal internal carotid artery stent got tangled. After unsuccessful maneuvering to disentangle stent retriever from the internal carotid artery stent, we decided to attempt safe separation of the stent retriever from its pusher wire and leave behind the patent internal carotid artery stent/stent retriever metal construct in place. Gradual pulling pressure was applied to the stent retriever wire while maintaining distal exchange-length microwire access and fully inflated extracranial balloon over the entangled portion to ensure continuous vascular access. The stent retriever wire was then safely separated from the stent retriever and fully retracted outside the body. Delayed angiographic runs continued to demonstrate full patency of the internal carotid artery lumen. No residual dissection, spasm, or thrombus was noted. CONCLUSION: This case illustrates a novel bailout endovascular salvage technique that could be considered in such cases. These techniques minimize intraoperative complication, focus on patient safety, and promote efficiency for endovascular thrombectomy in unfavorable anatomy.

Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures.

Preliminary work suggested upregulation of inflammatory pathways in patients with common forms of ichthyosis. However, a comprehensive characterization of skin from various ichthyosis subtypes is unavailable, precluding the development of targeted treatments. Thus, we sought to characterize the immune and barrier profiles of common and subtype-specific skin transcriptomes in a large group of patients with ichthyosis. We performed a global RNA-sequencing analysis in 54 patients with ichthyosis (7 with Netherton syndrome, 13 with epidermolytic ichthyosis, 16 with lamellar ichthyosis, and 18 with congenital ichthyosiform erythroderma) and 40 healthy controls. Differentially expressed genes were defined on the basis of fold changes > 2 and false discovery rate < 0.05 criteria. We found robust and significant T helper (Th) 22/Th17 skewing in all subtypes (e.g., IL-17A/C/F, S100A7/8/9/12; P < 0.001) with modest changes in Th2 pathway, primarily in Netherton syndrome, and Th1 skewing in congenital ichthyosiform erythroderma. Across all subtypes (less evident in epidermolytic ichthyosis), lipid metabolism and barrier junction markers were downregulated (e.g., FA2H, CDH10/11/12/2; P < 0.05), whereas epidermal cornification and proliferation measures were upregulated (e.g., SPRR1A/1B/2C/2G, EREG; P < 0.05). Our findings suggest that the common ichthyosis variants share aberrations in Th17/Th22 and barrier function, with minimal Th2 modulation. This may help to elucidate the pathogeneses of these subtypes and inform the development of subtype-specific treatments.

Patient education in Mohs surgery: a review and critical evaluation of techniques.

BACKGROUND: Traditional in-person discussion alone is often used for preoperative education in Mohs micrographic surgery (MMS). The appropriate use of more modern education techniques is not well defined in the MMS literature. OBJECTIVE: The authors aim to evaluate patient education techniques for MMS, address education in special populations, and highlight opportunities for improvement. METHODS AND MATERIALS: We performed a PubMed literature search with keywords "Mohs" and "education", "teaching", "understanding", "explanation", "preoperative", or "consent" with no restriction on publication time frame due to literature scarcity. RESULTS: Teledermatology consultation, MMS videos, 3D models, pamphlets/online materials, and shared medical appointments appear to be effective techniques (GRADE B). Analogies are also anecdotally helpful when integrated into traditional verbal education (GRADE C). The role of preoperative educational phone calls is more controversial (GRADE C). CONCLUSION: Regardless of the education technique utilized, no singular technique entirely replaces the traditional in-person discussion. Having access to multiple modalities can be beneficial for patients, allowing them options to choose their preferred method(s) of education. MMS is a difficult topic to conceptualize, and further research into educational techniques is needed to provide clear guidelines for Mohs surgeons.

INTRAVITREAL MELPHALAN FOR TREATMENT OF VITREOUS SEEDING FROM CHOROIDAL MELANOMA.

PURPOSE: To report treatment of vitreous seeding of choroidal melanoma with monthly injections of intravitreal melphalan. METHODS: Case report. RESULTS: A 70-year-old white woman noted floaters in her left eye, and further examination revealed visual acuity of 20/30 in both eyes. Funduscopically, there was a mushroom-shaped choroidal melanoma in her left eye, measuring 9 mm in basal dimension and 4.8 mm in thickness. Notably, there was apical retinal invasion of melanoma with mild vitreous hemorrhage, without vitreous seeding. The tumor was treated with iodine-125 plaque radiotherapy using an apex dose of 70 Gy over 99 hours, designed to include the retinal invasion. The melanoma demonstrated complete regression into a nearly flat scar of 1 mm and remained stable over 4 years. Five years after radiotherapy, there were diffuse vitreous pigmented seeds of presumed melanoma origin, emanating from the site of retinal necrosis. This progressively worsened over the following 18 months, suspicious for viable melanoma cells, as visual acuity concurrently declined to 20/100. Treatment with intravitreal melphalan (10 µg/0.05 mL) was delivered on a monthly basis for 12 cycles, resulting in vitreous seeds regression, and preservation of the eye. Final visual acuity was 20/200. There were no treatment-related complications. CONCLUSION: Intravitreal melphalan can be considered in cases of vitreous seeding from uveal melanoma.