No abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss, the treatment of which may require monthly intravitreal injections. This is a burden on patients and health services, and new delivery modalities that reduce injection frequency are required. To that end, we investigated the suitability of a novel reverse thermoresponsive polymer (RTP) as an ocular drug-delivery vehicle. In this work, we detail the structure and synthesis of a novel RTP, and determine drug release curves for two drugs commonly used in the treatment of AMD, bevacizumab and aflibercept. Biocompatibility of the RTP was assessed in vitro in human and rat cell lines and in vivo following intravitreal injection in rats. Bevacizumab demonstrated a more appropriate release profile than aflibercept, with 67% released within 14 days and 78% released in total over a 183-day period. No toxic effects of RTP were seen in human or rat cells in up to 14 days of co-culture with RTP. Following intravitreal injection, intraocular pressure was unaffected by the presence of RTP and no changes in retinal function or structure were observed at 1 week or 1 month post-injection. RTP injection did not cause inflammation, gliosis or apoptosis in the retina. This work demonstrates the potential suitability of the novel RTP as a sustained-release vehicle for ocular drug delivery for anti-neovascular therapies. Optimization of polymer chemistry for optimal drug loading and release is needed.

BACKGROUND: Despite established guidelines for bladder cancer (BC) management, significant treatment variability remains across the United States. OBJECTIVE: To report the impact of a tertiary center, bladder cancer multidisciplinary clinic (BCMC) on diagnostic evaluation and treatment recommendations in externally referred patients with BC. METHODS: Our BCMC clinic format includes simultaneous consultation with urologic, medical and radiation oncology, with real-time expert genitourinary pathology and radiology review. We retrospectively assessed all external referrals for concordance between outside radiology/pathology records and BCMC interpretation after central review and explored potential differences between outside treatment plan and BCMC recommendations. RESULTS: 233 patients with BC were referred to BCMC between the years 2014-2017. Complete radiographic and pathology data were available for 201 patients. Median age was 69 (Interquartile Range: 60-75) and 83% were performance status ECOG 0-1. After BCMC review of outside records, imaging interpretation was changed in 53 (26%) patients; pathology was changed in 59 (29%). Further diagnostic work-up was recommended in 85 (42%) patients. Overall, 56 (28%) patients had a change in their clinical staging. BCMC recommended treatment modification in 117 (58%) patients. Subsequent treatment plan was concordant with BCMC recommendations 91.5% of the time.

Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.