Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer.

BACKGROUND: Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. METHODS: A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. RESULTS: Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). CONCLUSIONS: Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.

The Soil Geochemistry in the Beardmore Glacier Region, Antarctica: Implications for Terrestrial Ecosystem History.

Although most models suggest continental Antarctica was covered by ice during the Last Glacial Maximum (LGM) it has been speculated that endemic species of soil invertebrates could have survived the Pleistocene at high elevation habitats protruding above the ice sheets. We analyzed a series of soil samples from different elevations at three locations along the Beardmore Glacier in the Transantarctic Mountains (in order of increasing elevation): Ebony Ridge (ER), Cloudmaker (CM), and Meyer Desert (MD). Geochemical analyses show the MD soils, which were exposed during the LGM, were the least weathered compared to lower elevations, and also had the highest total dissolved solids (TDS). MD soils are dominated by nitrate salts (NO3/Cl ratios >10) that can be observed in SEM images. High δ(17)O and δ(18)O values of the nitrate indicate that its source is solely of atmospheric origin. It is suggested that nitrate concentrations in the soil may be utilized to determine a relative "wetting age" to better assess invertebrate habitat suitability. The highest elevation sites at MD have been exposed and accumulating salts for the longest times, and because of the salt accumulations, they were not suitable as invertebrate refugia during the LGM.

Mineralogical biosignatures and the search for life on Mars.

If life ever existed, or still exists, on Mars, its record is likely to be found in minerals formed by, or in association with, microorganisms. An important concept regarding interpretation of the mineralogical record for evidence of life is that, broadly defined, life perturbs disequilibria that arise due to kinetic barriers and can impart unexpected structure to an abiotic system. Many features of minerals and mineral assemblages may serve as biosignatures even if life does not have a familiar terrestrial chemical basis. Biological impacts on minerals and mineral assemblages may be direct or indirect. Crystalline or amorphous biominerals, an important category of mineralogical biosignatures, precipitate under direct cellular control as part of the life cycle of the organism (shells, tests, phytoliths) or indirectly when cell surface layers provide sites for heterogeneous nucleation. Biominerals also form indirectly as by-products of metabolism due to changing mineral solubility. Mineralogical biosignatures include distinctive mineral surface structures or chemistry that arise when dissolution and/or crystal growth kinetics are influenced by metabolic by-products. Mineral assemblages themselves may be diagnostic of the prior activity of organisms where barriers to precipitation or dissolution of specific phases have been overcome. Critical to resolving the question of whether life exists, or existed, on Mars is knowing how to distinguish biologically induced structure and organization patterns from inorganic phenomena and inorganic self-organization. This task assumes special significance when it is acknowledged that the majority of, and perhaps the only, material to be returned from Mars will be mineralogical.

Formation of sphalerite (ZnS) deposits in natural biofilms of sulfate-reducing bacteria.

Abundant, micrometer-scale, spherical aggregates of 2- to 5-nanometer-diameter sphalerite (ZnS) particles formed within natural biofilms dominated by relatively aerotolerant sulfate-reducing bacteria of the family Desulfobacteriaceae. The biofilm zinc concentration is about 10(6) times that of associated groundwater (0.09 to 1.1 parts per million zinc). Sphalerite also concentrates arsenic (0.01 weight %) and selenium (0.004 weight %). The almost monomineralic product results from buffering of sulfide concentrations at low values by sphalerite precipitation. These results show how microbes control metal concentrations in groundwater- and wetland-based remediation systems and suggest biological routes for formation of some low-temperature ZnS deposits.

Aggregation-based crystal growth and microstructure development in natural iron oxyhydroxide biomineralization products.

Crystals are generally considered to grow by attachment of ions to inorganic surfaces or organic templates. High-resolution transmission electron microscopy of biomineralization products of iron-oxidizing bacteria revealed an alternative coarsening mechanism in which adjacent 2- to 3-nanometer particles aggregate and rotate so their structures adopt parallel orientations in three dimensions. Crystal growth is accomplished by eliminating water molecules at interfaces and forming iron-oxygen bonds. Self-assembly occurs at multiple sites, leading to a coarser, polycrystalline material. Point defects (from surface-adsorbed impurities), dislocations, and slabs of structurally distinct material are created as a consequence of this growth mechanism and can dramatically impact subsequent reactivity.

Biological impact on mineral dissolution: application of the lichen model to understanding mineral weathering in the rhizosphere.

Microorganisms modify rates and mechanisms of chemical and physical weathering and clay growth, thus playing fundamental roles in soil and sediment formation. Because processes in soils are inherently complex and difficult to study, we employ a model based on the lichen-mineral system to identify the fundamental interactions. Fixed carbon released by the photosynthetic symbiont stimulates growth of fungi and other microorganisms. These microorganisms directly or indirectly induce mineral disaggregation, hydration, dissolution, and secondary mineral formation. Model polysaccharides were used to investigate direct mediation of mineral surface reactions by extracellular polymers. Polysaccharides can suppress or enhance rates of chemical weathering by up to three orders of magnitude, depending on the pH, mineral surface structure and composition, and organic functional groups. Mg, Mn, Fe, Al, and Si are redistributed into clays that strongly adsorb ions. Microbes contribute to dissolution of insoluble secondary phosphates, possibly via release of organic acids. These reactions significantly impact soil fertility. Below fungi-mineral interfaces, mineral surfaces are exposed to dissolved metabolic byproducts. Through this indirect process, microorganisms can accelerate mineral dissolution, leading to enhanced porosity and permeability and colonization by microbial communities.

Enhanced dissolution of silicate minerals by bacteria at near-neutral pH.

Previous studies have shown that various microorganisms can enhance the dissolution of silicate minerals at low (<5) or high (>8) pH. However, it was not known if they can have an effect at near-neutral pH. Almost half of 17 isolates examined in this study stimulated bytownite dissolution at near-neutral pH while in a resting state in buffered glucose. Most of the isolates found to stimulate dissolution also oxidized glucose to gluconic acid. More detailed analysis with one of these isolates suggested that this partial oxidation was the predominant, if not sole, mechanism of enhanced dissolution. Enhanced dissolution did not require direct contact between the dissolving mineral and the bacteria. Gluconate-promoted dissolution was also observed with other silicate minerals such as albite, quartz, and kaolinite.