Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study.

Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS

Methodological Challenges in Describing Medication Dosing Errors in Children

Summary: Although children are prescribed medications in 30 percent to 50 percent of clinic visits, little is known about medication errors in ambulatory pediatrics. In the process of completing a study to determine the prevalence of outpatient dosing errors, we identified a number of barriers to understanding the epidemiology of medication errors in children. These barriers include prescribing medication that is not labeled for use in children, discrepancies in published dosing recommendations for many medications, unclear guidelines on use of adult dosing recommendations for children of different ages and weights, and the lack of readily available documented weights to determine appropriate weight-based doses for children. In our study of pediatric medication errors, we found a wide range of doses prescribed to children for every medication we studied. Before we can truly understand medication errors in children and begin developing systems-based approaches to eliminating these errors, we need better national standards of medication doses that are appropriate for children and an improved ability to determine errors through databases that include children\u27s weights as well as prescription information

Early to middle Eocene history of the Arctic Ocean from Nd-Sr isotopes in fossil fish debris, Lomonosov Ridge

Strontium and neodymium radiogenic isotope ratios in early to middle Eocene fossil fish debris (ichthyoliths) from Lomonosov Ridge (Integrated Ocean Drilling Program Expedition 302) help constrain water mass compositions in the Eocene Arctic Ocean between ∼55 and ∼45 Ma. The inferred paleodepositional setting was a shallow, offshore marine to marginal marine environment with limited connections to surrounding ocean basins. The new data demonstrate that sources of Nd and Sr in fish debris were distinct from each other, consistent with a salinity-stratified water column above Lomonosov Ridge in the Eocene. The 87Sr/86Sr values of ichthyoliths (0.7079–0.7087) are more radiogenic than Eocene seawater, requiring brackish to fresh water conditions in the environment where fish metabolized Sr. The 87Sr/86Sr variations probably record changes in the overall balance of river Sr flux to the Eocene Arctic Ocean between ∼55 and ∼45 Ma and are used here to reconstruct surface water salinity values. The ɛNd values of ichthyoliths vary between −5.7 and −7.8, compatible with periodic (or intermittent) supply of Nd to Eocene Arctic intermediate water (AIW) from adjacent seas. Although the Norwegian-Greenland Sea and North Atlantic Ocean were the most likely sources of Eocene AIW Nd, input from the Tethys Sea (via the Turgay Strait in early Eocene time) and the North Pacific Ocean (via a proto-Bering Strait) also contributed

Rearrangement of bicyclo[2.2.1]heptane ring systems by titanocene alkylidene complexes to bicyclo[3.2.0]heptane enol ethers. Total synthesis of (±)-Δ^(9(12))-capnellene

A variety of ester-substituted norbornenes react with titanamethylene complex (Tebbe's reagent) to yield stable titanacyclobutanes. Endo esters do not react with the reagent in competition with the norbornene double bond. The X-ray structure of the metallacycle formed from titanacene methylene complex and 1-methylbicyclo[2.2.l]hept-5-ene-2,3-dicarboxylic acid diisopropyl ester was determined. On heating, the metallacycle rearranged to a carbene-olefin complex. The ratio of productive opening, cleavage of the bicycloheptane ring system, to nonproductive opening, regeneration of the starting materials, is controlled by a variety of steric factors that were studied and analyzed. The productive opening was detected by the formation of the product resulting from the intramolecular trapping of the intermediate titanium alkylidene by the endo ester functionality in a Wittig-like reaction to yield substituted bicyclo[3.2.0]heptenes. Rearrangement of the titanacycle formed from 4,4-dimethyltricyclo[ 5.2.1.0^(1,5)]dec-8-ene-6-carboxylic acid tert-butyl ester yielded 10,10-dimethyl-3-methoxy-7- vinyltricyclo[5.3.0.0^(2,5)]dec-2-ene, which was transformed into Δ ^(9(12))-capnellene in good yield