Safety and tolerability of topical trametinib in rosacea: Results from a phase I clinical trial.

Purpose: Overactivation of the mitogen activated kinase pathway has been associated with rosacea. We hypothesised that inhibitors of this pathway can be repurposed to alleviate rosacea symptoms. Methods: In order to test this hypothesis, we designed a double-blind, randomised, placebo-controlled phase I clinical trial to assess the safety and tolerability of a first-in-kind topical formulation of a MEK kinase inhibitor, trametinib. Subjects applied daily trametinib-containing cream (0.05 mg in 0.5 mL) to one cheek and cream without inhibitor to the other for consecutive 21 days. Skin irritation scores and blood samples were obtained during visits on days 8, 15 and 22. Results: On analysis of high-performance liquid chromatography, no systemic trametinib absorption was detected during this treatment period. Subjects demonstrated a slight but significant improvement in both cheeks, regardless of drug contents. No adverse effects were reported during this time. Conclusions: Topical trametinib was well tolerated at a dose of 0.05 mg per day without meaningful systemic absorption or local adverse events. A dose escalation trial is warranted to determine optimal dosing to treat rosacea while avoiding the adverse effects of systemic treatment.

Race and Gender in Ophthalmology: A National Analysis of Medical Students with Intention to Pursue the Field.

Purpose The field of ophthalmology must become more reflective of the increasingly diverse U.S. population. This study characterizes students intending to pursue ophthalmology and practice in an underserved area versus other surgical and nonsurgical fields. Subjects Deidentified responses from 92,080 U.S. MD students who matriculated in the academic years beginning from 2007 to 2011 were obtained from the Association of American Medical Colleges (AAMC) Graduation Questionnaires. Methods Study participants were those who fully completed the AAMC Graduation Questionnaire. Chi-squared and multivariate logistical regressions were used for analyses. Results Ophthalmology intending graduates (OIG; n = 1,177) compared with other surgical intending graduates ( n = 7,955) were more likely to be female (adjusted odds ratio [aOR]: 1.46; 95% confidence interval [CI]: 1.28-1.66), Asian (1.71 [1.46-2.01]), and have conducted a research project with a faculty member (1.58 [1.26-1.98]). OIG compared with nonsurgery intending graduates ( n = 35,865) were more likely to have completed a research project with a faculty member (4.78 [3.86-5.92]), to be Asian (1.4 [1.21-1.62]), and have received scholarships (1.18 [1.04-1.34]). OIG were less likely to be female (0.64 [0.57-0.73]) and Black/African American (0.5 [0.33-0.74]). Among OIG, Black/African American students and multiracial students were more likely than non-Hispanic (NH) White students to report intention to practice in underserved areas (IPUA; 14.29 [1.82-111.88] and 2.5 [1.06-5.92]), respectively. OIG with global health experience were more likely to report IPUA (1.64 [1.2-2.25]). Conclusion Females and underrepresented in medicine (URM), respectively, were more likely to be nonsurgery intending graduates than OIG, which, if not addressed, may lead to a persistent underrepresentation of these groups in the field. In addition, URM students, including African American students, were more likely to report IPUA, which further emphasizes the importance of more URM students entering the field to address these growing gaps in medical care. Finally, we recommend increased mentorship to help address these disparities.

Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel-resistant phenotype.

Erythropoietin (Epo), a glycoprotein hormone that is the principal regulator of erythropoiesis, is known to act also on nonhematopoietic cell types. Epo receptors have been reported on several normal and neoplastic human cells and tissues, including ovarian cancer cells. We found that long-term Epo treatment of A2780 cells resulted in the development of a phenotype exhibiting both enhanced Epo signaling, evidenced by increased peak levels of phospho-Erk1/2 and increased paclitaxel resistance. This phenotypic effect was specific for paclitaxel, since no change in cisplatin or carboplatin sensitivity was observed. In addition, the change in phenotype was stable, even after the removal of Epo. Measurement of mono- and oligonucleosome formation revealed that long-term Epo treated A2780 cells exhibited markedly less apoptosis than nonerythropoietin treated cells at essentially all concentrations of paclitaxel tested. Western blot analyses revealed that the long-term Epo treated cells had significantly reduced expression of apoptosis-related proteins Bcl-2 and Bcl-10. These findings may have implications for the clinical use of recombinant human Epo and other erythropoiesis stimulating agents to correct anemia in paclitaxel-treated cancer patients.

Optical Coherence Tomography Imaging of Presumed Sarcoid Retinal and Optic Nerve Nodules.

PURPOSE: To characterize nodular lesions of the retina and optic nerve with spectral-domain optical coherence tomography (SD-OCT) in patients with sarcoidosis. METHODS: This is a retrospective series of 6 eyes from 5 patients with an established diagnosis of sarcoidosis, with clinically detected nodules of the optic nerve or retina. All lesions were imaged with fundus photography and SD-OCT on presentation, and followed with serial imaging after treatment with corticosteroids and/or immunomodulatory therapy. RESULTS: Spectral OCT through the lesions revealed nodular hyperreflective processes obscuring the retinal layers or optic cup, with local structural changes, including subretinal and intraretinal fluid. After treatment with corticosteroids and/or immunosuppression in 4 followed patients, all lesions regressed with improvement in associated structural changes, but did not entirely disappear. CONCLUSIONS: Spectral OCT can be useful in identifying lesion morphology and location, and in tracking the response to treatment in eyes with posterior-segment nodules, presumably secondary to sarcoidosis.

Approach to the diagnosis of the uveitides.

PURPOSE: To describe an approach to diagnosing the uveitides, a collection of about 30 separate diseases characterized by intraocular inflammation. DESIGN: Perspective. METHODS: Integration of clinical approach with a more formal, informatics-derived approach to characterization and a Bayesian approach to laboratory testing. RESULTS: The patient's uveitis is characterized along several dimensions: course, laterality, anatomic location of the inflammation, morphology, presence of active infection, and the host (age, presence of a systemic disease). Posterior uveitis can be characterized further by whether it is primarily a retinitis, choroiditis, or retinal vasculitis; by whether it is paucifocal or multifocal; and by the morphology of the lesions. This characterization narrows the differential diagnosis to 1 or, at most, a few diseases. Laboratory screening (ie, testing all patients) should be reserved for those diseases that can present as any type of uveitis, whereas targeted testing (ie, testing a subset with specific features) is used selectively. Laboratory testing should be used to identify an infection (which will alter therapy) or a systemic disease that will affect the patient's health. A uveitis that is not one of the established diagnoses is designated as "undifferentiated" with the course, laterality, and anatomic location (eg, undifferentiated bilateral chronic anterior uveitis). We avoid the term "idiopathic" uveitis as most identified noninfectious uveitic diseases are idiopathic, and most systemic diseases associated with uveitis also are idiopathic (eg, juvenile idiopathic arthritis). CONCLUSION: This approach should lead to the correct diagnosis of the specific uveitic disease in the large majority of cases without overuse of laboratory testing.