SummaryBackgroundIn the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.MethodsIn this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.Findings1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3–29·2] in the control group vs 17·0 months [9·4–30·1] in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0–12·5] in the control group vs 8·6 months [5·1–13·8] in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5–27·4); KRAS mutant, 14·4 months (8·5–24·0); all wild-type, 20·1 months (11·5–31·7).InterpretationThis trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.FundingCancer Research UK, Cancer Research Wales, UK Medical Resear...

We combine the Cosmic Lens All-Sky Survey (CLASS) with new Sloan Digital Sky Survey (SDSS) data on the local velocity dispersion distribution function of E /S0 galaxies, ( ), to derive lens statistics constraints on à and m . Previous studies of this kind relied on a combination of the E /S0 galaxy luminosity function and the FaberJackson relation to characterize the lens galaxy population. However, ignoring dispersion in the Faber-Jackson relation leads to a biased estimate of ( ) and therefore biased and overconfident constraints on the cosmological parameters. The measured velocity dispersion function from a large sample of E/S0 galaxies provides a more reliable method for probing cosmology with strong lens statistics. Our new constraints are in good agreement with recent results from the redshift-magnitude relation of Type Ia supernovae. Adopting the traditional assumption that the E/S0 velocity function is constant in comoving units, we find a maximum likelihood estimate of à ¼ 0:74 0:78 for a spatially flat universe (where the range reflects uncertainty in the number of E/S0 lenses in the CLASS sample) and a 95% confidence upper bound of à < 0:86. If ( ) instead evolves in accord with the extended PressSchechter theory, then the maximum likelihood estimate for à becomes 0.72-0.78, with the 95% confidence upper bound à < 0:89. Even without assuming flatness, lensing provides independent confirmation of the evidence from Type Ia supernovae for a nonzero dark energy component in the universe.

We present results of an axisymmetric global circulation model of Titan with a simplified suite of atmospheric physics forced by seasonally varying insolation. The recent discovery of midlatitude tropospheric clouds on Titan has caused much excitement about the roles of surface sources of methane and the global circulation in forming clouds. Although localized surface sources, such as methane geysers or ''cryovolcanoes,'' have been invoked to explain these clouds, we find in this work that clouds appear in regions of convergence by the mean meridional circulation and over the poles during solstices, where the solar forcing reaches its seasonal maximum. Other regions are inhibited from forming clouds because of dynamical transports of methane and strong subsidence. We find that for a variety of moist regimes, i.e., with the effect of methane thermodynamics included, the observed cloud features can be explained by the large-scale dynamics of the atmosphere. Clouds at the solsticial pole are found to be a robust feature of Titan's dynamics, whereas isolated midlatitude clouds are present exclusively in a variety of moist dynamical regimes. In all cases, even without including methane thermodynamics, our model ceases to produce polar clouds Ϸ4 -6 terrestrial years after solstices.atmospheres ͉ climate ͉ planetary science M ethane clouds were first observed in Titan's troposphere as occasional brightening in disk-averaged infrared photometry (1). Clouds were observed in the southern hemisphere later during southern spring (2). In 2001, clouds were observed near the South Pole, presumably caused by strong solar heating at the pole just preceding Southern summer solstice (SSS, which occurred in October 2002) (3, 4). The first observations of midlatitude clouds after SSS were reported in 2005 (5) and confirmed by Cassini observations (6, 7) at a time when Titan was progressing toward Southern autumnal equinox. Efforts have been focused on explaining what controls the position of clouds and mechanisms that set the timing of observed shifts in their positions. Earth-based observations show midlatitude clouds preferentially form at a particular latitude and longitude, which suggests they owe their existence to localized surface sources of methane (8). But, the longitudinal distribution of clouds is more uniform if both ground-based and Cassini data are taken into account (7). It is known from ground-based observations that large outbursts in cloud activity occasionally occur (9). Ground-based observations from late 2005 revealed that Titan's south polar clouds, the most persistent cloud features, have completely dissipated, and concurrently the sporadic activity at midlatitudes first subsided and then re-established at lower latitudes (10). ¶ The position, variability, and seasonality of clouds is certainly, in some manner, influenced by the seasonally varying distribution of solar heating. However, a local radiative-convective model with no large-scale dynamics will produce convection at essentially all latitudes (see Fig...

Southwestern North America was wetter than present during the Last Glacial Maximum. The causes of increased water availability have been recently debated, and quantitative precipitation reconstructions have been underutilized in model‐data comparisons. We investigate the climatological response of North Pacific atmospheric rivers to the glacial climate using model simulations and paleoclimate reconstructions. Atmospheric moisture transport due to these features shifted toward the southeast relative to modern. Enhanced southwesterly moisture delivery between Hawaii and California increased precipitation in the southwest while decreasing it in the Pacific Northwest, in agreement with reconstructions. Coupled climate models that are best able to reproduce reconstructed precipitation changes simulate decreases in sea level pressure across the eastern North Pacific and show the strongest southeastward shifts of moisture transport relative to a modern climate. Precipitation increases of ∼1 mm d−1, due largely to atmospheric rivers, are of the right magnitude to account for reconstructed pluvial conditions in parts of southwestern North America during the Last Glacial Maximum.