A Phase I and Pharmacokinetic Study of OSI-7904L, a Liposomal Thymidylate Synthase Inhibitor in Combination with Oxaliplatin in Patients with Advanced Colorectal Cancer.

OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma. METHOD: A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity. RESULTS: Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients. CONCLUSIONS: The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

Mid to late Holocene hydrological change in continental eastern Canada: assessing regional trends from ombrotrophic peat records.

ABSTRACT High resolution records of mid-late Holocene hydro-climatic change are presented from Mer Bleue Bog, eastern Ontario. Past climatic changes in this region have previously been inferred from lake sediments, but rain-fed peatlands can offer additional insights into the spatial and temporal pattern of moisture availability. In this study, reconstructed water table depths are based on a testate amoeba-derived transfer function developed for the region and changes in bog surface wetness are compared with plant macrofossil and peat humification data.

RÉSUMÉ Nous présentons les enregistrements hautes résolutions des variations hydrologique durant la second moitié de l’Holocène pour les tourbières Mer Bleue á l’est de l'Ontario. Précédemment, les changements climatiques de cette région ont été dérivés à partir de prélèvement de sédiments de lac. Mais ils s’avèrent que les tourbières ombrotrophes offrir un éclairage supplémentaire sur les schémas de répartition spatiale et temporelle de la disponibilité de l'humidité. Dans cette étude, des profondeurs reconstruites de nappe phréatique sont basées sur un modèle de function de transfert d’amibes (Arcellinida) et des changements de l’humidité de surface de la tourbière sont comparés avec les macrofossils et au humification de tourbe dans une analyse multi-proxy.