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.

The intense irradiation received by hot Jupiters suppresses convection in the outer layers of their atmospheres and lowers their cooling rates. "Inflated" hot Jupiters, i.e., those with anomalously large transit radii, require additional sources of heat or suppressed cooling. We consider the effect of forced turbulent mixing in the radiative layer, which could be driven by atmospheric circulation or by another mechanism. Due to stable stratification in the atmosphere, forced turbulence drives a downward flux of heat. Weak turbulent mixing slows the cooling rate by this process, as if the planet was irradiated more intensely. Stronger turbulent mixing buries heat into the convective interior, provided the turbulence extends to the radiative-convective boundary. This inflates the planet until a balance is reached between the heat buried into and radiated from the interior. We also include the direct injection of heat due to the dissipation of turbulence or other effects. Such heating is already known to slow planetary cooling. We find that dissipation also enhances heat burial from mixing by lowering the threshold for turbulent mixing to drive heat into the interior. Strong turbulent mixing of heavy molecular species such as TiO may be necessary to explain stratospheric thermal inversions. We show that the amount of mixing required to loft TiO may overinflate the planet by our mechanism. This possible refutation of the TiO hypothesis deserves further study. Our inflation mechanism requires a deep stratified layer that only exists when the absorbed stellar flux greatly exceeds the intrinsic emitted flux. Thus it would be less effective for more luminous brown dwarfs and for longer period gas giants, including Jupiter and Saturn.

[1] We show that by changing a single nondimensional number, the thermal Rossby number, global atmospheric simulations with only axisymmetric forcing pass from an Earth-like atmosphere to a superrotating atmosphere that more resembles the atmospheres of Venus or Titan. The transition to superrotation occurs under conditions in which equatorward propagating Rossby waves generated by baroclinic instability at intermediate and high latitudes are suppressed, which will occur when the deformation radius exceeds the planetary radius. At large thermal Rossby numbers following an initial, nearly axisymmetric phase, a global baroclinic wave of zonal wave number one generated by mixed barotropic-baroclinic instability dominates the eddy flux of zonal momentum. The global wave converges eastward zonal momentum to the equator and deposits westward momentum at intermediate latitudes during spin-up and before superrotation emerges, and the baroclinic instability ceases once superrotation is established. A global barotropic mode of zonal wave number one generated by a mix of high-and low-latitude barotropic instability is responsible for maintaining superrotation in the statistically steady state. At intermediate thermal Rossby numbers, momentum flux by the global baroclinic mode is subdominant relative to smaller baroclinic modes, and thus strong superrotation does not develop.

Although Earth's orbit is never far from circular, terrestrial planets around other stars might experience substantial changes in eccentricity. Eccentricity variations could lead to climate changes, including possible "phase transitions" such as the snowball transition (or its opposite). There is evidence that Earth has gone through at least one globally frozen, "snowball" state in the last billion years, which it is thought to have exited after several million years because global ice-cover shut off the carbonate-silicate cycle, thereby allowing greenhouse gases to build up to sufficient concentration to melt the ice. Due to the positive feedback caused by the high albedo of snow and ice, susceptibility to falling into snowball states might be a generic feature of water-rich planets with the capacity to host life. This paper has two main thrusts. First, we revisit one-dimensional energy balance climate models as tools for probing possible climates of exoplanets, investigate the dimensional scaling of such models, and introduce a simple algorithm to treat the melting of the ice layer on a globally frozen planet. We show that if a terrestrial planet undergoes Milankovitch-like oscillations of eccentricity that are of great enough magnitude, it could melt out of a snowball state. Second, we examine the kinds of variations of eccentricity that a terrestrial planet might experience due to the gravitational influence of a giant companion. We show that a giant planet on a sufficiently eccentric orbit can excite extreme eccentricity oscillations in the orbit of a habitable terrestrial planet. More generally, these two results demonstrate that the long-term habitability (and astronomical observables) of a terrestrial planet can depend on the detailed architecture of the planetary system in which it resides.

[1] We explore the effect of a finite reservoir of methane on Titan's atmospheric circulation, precipitation patterns, and surface methane content. We develop a soil model that accounts for the methane cycle in the surface-atmosphere system, and we implement this surface model in a two-dimensional model of the Titan's atmosphere. Seasonal oscillations in latitude of the large-scale circulation accomplish net drying of the lowlatitude surface by diverging methane vapor from low latitudes to higher latitudes. Simulations with an initially deep methane reservoir indicate this mechanism is able to dry $1.75 meters of liquid methane per Titan year from the low-latitude surface. The existence of low-latitude desert morphologies suggests that the system has had sufficient time to completely remove the surface methane by this mechanism. We then varied the reservoir size, focusing on initial depths of 30 meters of liquid methane or less and compared the results to available observations. The climate system has an abrupt transition to a warmer state with less precipitation and nearly global surface drying near the level at which the atmosphere can store the majority of the methane reservoir as vapor or around 6.5 meters of equivalent liquid methane for our particular choice of parameters. A comparison of our model results with Huygens' observations suggests Titan's climate mimics a state in which most of the methane inventory with direct access to the atmosphere (i.e., excluding underground sources) is stored in the atmosphere.