LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases

Purpose: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. Patients and methods: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. Results: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2–5). OS was 12.2 mos (95% CI 0.6–20.2). Grade 3–4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. Conclusion: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. Clinical Trial: (NCT01305941)

Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic Leukemia

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated

Turbulence and stratification in Priest Pot, a productive pond in a sheltered environment.

Priest Pot is an example of the abundant ponds which, collectively, contribute crucially to species diversity. Despite extensive biological study, little has been reported about the physical framework which supports its ecological richness. This paper elucidates the physical character of Priest Pot�s water column and thus that of similar waterbodies. Vertical thermal microstructure profiles were recorded during summer 2003, and analysed alongside concurrent meteorological data. During summer stratification, the thermal structure appeared to be dominated by surface heat fluxes. Surface wind stress, limited by sheltering vegetation, caused turbulent overturns once a surface mixed layer was present, but appeared to contribute little to setting up the thermal structure. Variations in full-depth mean stratification occurred pre-dominantly over seasonal and ~5-day time scales, the passage of atmospheric pressure systems being posited as the cause of the latter. In the uppermost ~0.5 m, where the stratification varied at sub-daily time scales, turbulence was active (sensu Ivey and Imberger, 1991) when this layer was mixed, with dissipation values � ~ 10-8 m2s-3 and vertical diffusivity KZ = 10-4-10-6 m2s-1. Where the water column was stratified, turbulence was strongly damped by both buoyancy and viscosity and KZ was an order of magnitude smaller. Vertical transport in the mixed layer occurred via many small overturns (Thorpe scale rms and maximum values typically 0.02m and 0.10m respectively) and seston were fully mixed through the water column

Assessment of Aquifer Storage and Recovery Feasibility Using Numerical Modeling and Geospatial Analysis: Application in Louisiana

Aquifer storage and recovery (ASR) is a solution for regions experiencing groundwater shortages, but is unexplored in wet regions such as Louisiana, which is experiencing aquifer overdrafting at alarming rates. Surface storage reservoirs are infeasible in these low-gradient environments, so ASR can provide an alternative to alleviate groundwater stress and prevent subsidence and saltwater intrusion. The purpose of this study was to assess the feasibility of ASR in the Chicot Aquifer in Southwest Louisiana. The study is based on a regional groundwater model combined with a geospatial analysis of the quantity and quality of surface water and groundwater resources and land use. A statistical distribution was used to rate each criterion and combine them into a suitability index (SI) that defines each watershed’s feasibility considering combinations of criteria determined by the user’s purpose for ASR and the availability of data. The SI was formulated as a hybrid additive-multiplicative function to provide flexibility in specifying criteria that are deemed most constraining for ASR feasibility. The analysis identified the east-central zone of the Chicot Aquifer, which is experiencing substantial groundwater stress from agricultural irrigation, as most suited for ASR operations. Besides the criteria on water availability and aquifer characteristics, the quality of the surface water and land-use considerations were key factors in constraining the feasible watersheds