Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. 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 B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4—26·1) in arm A and 14·4 months (8·0—24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008—1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0—28·1) in arm A and 18·0 months (12·1—29·3) in arm C (HR 1·087, 0·986—1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80—1·15, p=0·66), versus 1·54 (1·17—2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand—foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break.

WASP-34b: a near-grazing transiting sub-Jupiter-mass exoplanet in a hierarchical triple system

We report the discovery of WASP-34b, a sub-Jupiter-mass exoplanet transiting its 10.4-magnitude solar-type host star (1SWASP J110135.89-235138.4; TYC 6636-540-1) every 4.3177 days in a slightly eccentric orbit (e = 0.038±0.012). We find a planetary mass of 0.59±0.01 MJup and radius of 1.22-0.08+0.11 RJup. There is a linear trend in the radial velocities of 55±4 m s-1 y-1 indicating the presence of a long-period third body in the system with a mass ?0.45 MJup at a distance of ?1.2 AU from the host star. This third-body is either a low-mass star, a white dwarf, or another planet. The transit depth ((RP/Rstar)2 = 0.0126) and high impact parameter (b = 0.90) suggest that this could be the first known transiting exoplanet expected to undergo grazing transits, but with a confidence of only 80%. Radial velocity and photometric data are only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/526/A130

THE IMPACT OF BURNING AND GRAZING OF HEATHLAND PLANTS AND INVERTEBRATES IN COUNTRY ANTRIM

The impact of burning and grazing on plant, ground beetle and spider species was investigated experimentally in stands of varying ages (burnt in 1982 and 1988 and unburnt plots) on an area of heather moorland in County Antrim, north-east Ireland. Burning initiated complex succession pathways which appear to have characteristic plant and invertebrate species associations. Removal of Calluna dominance initiated a period of high plant species diversity. Investigation of initial post-fire regeneration suggested that the frequency of occurrence of plant species changed over time and was affected by grazing. Grouping of species by the position of their renewal bud, i.e. their life-form, did not account for all observed interspecific variation. The dominant species after burning were Eriophorum vaginatum, E. angustifolium and Vaccinium myrtillus. Studies of vegetation canopy structure showed that, even with the exclusion of the main grazing herbivores, Calluna will not re-establish itself as the dominant species until several years after burning. The ground beetle Nebria salina was trapped more often on plots burnt in 1988 than on unburnt plots or those burnt in 1982. In comparison, Pterostichus niger and Carabus granulatus were trapped in greater numbers on plots burnt in 1982 than on unburnt plots and plots burnt in 1988. The large species Carabus problematicus and Carabus glabratus were trapped in greater numbers on unburnt plots. Similarly, more of the spiders Ceratinella brevipes and Centromerita concinna were trapped on the plots burnt in 1982. In comparison, Lepthyphantes zimmermanni and Robertus lividus were trapped more often on unburnt plots than on plots burnt in 1982 and 1988. Results are discussed with respect to the importance of the continuation of traditional heathland management practices.

THE IMPACT OF GRAZING ON COMMUNITIES OF GROUND-DWELLING SPIDERS (ARANEAE) IN UPLAND VEGETATION TYPES

Adult spider communities were sampled by pitfall trapping over a 24-month period in plots subjected to a range of grazing regimes on five vegetation types on a hill farm in County Antrim, north-east Ireland. Spider community composition was influenced by vegetation type and grazing regime. Variation in the number of individuals and species diversity was also apparent between vegetation types and grazing regime. Plots grazed by all herbivores were characterised by the predominance of species characteristic of disturbed land. Inbye land and areas where grazing had ceased had characteristic coloniser species. The spiders Erigone dentipalpis, Allomengea scopigera and Centromerita bicolor were trapped with greater success in vegetation types where grass species dominated.

Food intake, milk production, and tissue changes of Holstein-Friesian and Jersey x Holstein-Friesian dairy cows within a medium-input grazing system and a high-input total confinement system

Although interest in crossbreeding within dairy systems has increased, the role of Jersey crossbred cows within high concentrate input systems has received little attention. This experiment was designed to examine the performance of Holstein-Friesian (HF) and Jersey x Holstein-Friesian (J x HF) cows within a high concentrate input total confinement system (CON) and a medium concentrate input grazing system (GRZ). Eighty spring-calving dairy cows were used in a 2 (cow genotype) x 2 (milk production system) factorial design experiment. The experiment commenced when cows calved and encompassed a full lactation. With GRZ, cows were offered diets containing grass silage and concentrates [70:30 dry matter (DM) ratio] until turnout, grazed grass plus 1.0 kg of concentrate/day during a 199-d grazing period, and grass silage and concentrates (75:25 DM ratio) following rehousing and until drying-off. With CON, cows were confined throughout the lactation and offered diets containing grass silage and concentrates (DM ratio; 40:60, 50:50, 40:40, and 75:25 during d 1 to 100, 101 to 200, 201 to 250, and 251 until drying-off, respectively). Full-lactation concentrate DM intakes were 791 and 2,905 kg/cow for systems GRZ and CON, respectively. Although HF cows had a higher lactation milk yield than J x HF cows, the latter produced milk with a higher fat and protein content, so that solids-corrected milk yield (SCM) was unaffected by genotype. Somatic cell score was higher with the J x HF cows. Throughout lactation, HF cows were on average 37 kg heavier than J x HF cows, whereas the J x HF cows had a higher body condition score. Within each system, food intake did not differ between genotypes, whereas full-lactation yields of milk, fat plus protein, and SCM were higher with CON than with GRZ. A significant genotype x environment interaction was observed for milk yield, and a trend was found for an interaction with SCM. Crossbred cows on CON gained more body condition than HF cows, and overall pregnancy rate was unaffected by either genotype or management system. In summary, milk and SCM yields were higher with CON than with GRZ, whereas genotype had no effect on SCM. However, HF cows exhibited a greater milk yield response and a trend toward a greater SCM yield response with increasing concentrate levels compared with the crossbred cows.

Exploring Scale Effects of Best/Worst Rank Ordered Choice Data to Estimate Benefits of Tourism in Alpine Grazing Commons

In many environmental valuation applications standard sample sizes for choice modelling surveys are impractical to achieve. One can improve data quality using more in-depth surveys administered to fewer respondents. We report on a study using high quality rank-ordered data elicited with the best-worst approach. The resulting "exploded logit" choice model, estimated on 64 responses per person, was used to study the willingness to pay for external benefits by visitors for policies which maintain the cultural heritage of alpine grazing commons. We find evidence supporting this approach and reasonable estimates of mean WTP, which appear theoretically valid and policy informative. © The Author (2011).

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Grazing under experimental hypercapnia and elevated temperature does not affect the radula of a chiton (Mollusca, Polyplacophora, Lepidopleurida)

Chitons (class Polyplacophora) are benthic grazing molluscs with an eight-part aragonitic shell armature. The radula, a serial tooth ribbon that extends internally more than half the length of the body, is mineralised on the active feeding teeth with iron magnetite apparently as an adaptation to constant grazing on rocky substrates. As the anterior feeding teeth are eroded they are shed and replaced with a new row. The efficient mineralisation and function of the radula could hypothetically be affected by changing oceans in two ways: changes in seawater chemistry (pH and pCO(2)) may impact the biomineralisation pathway, potentially leading to a weaker or altered density of the feeding teeth; rising temperatures could increase activity levels in these ectothermic animals, and higher feeding rates could increase wear on the feeding teeth beyond the animals' ability to synthesise, mineralise, and replace radular rows. We therefore examined the effects of pH and temperature on growth and integrity in the radula of the chiton Leptochiton asellus. Our experiment implemented three temperature (similar to 10, 15, 20 degrees C) and two pCO(2) treatments (similar to 400 mu atm, pH 8.0; similar to 2000 mu atm, pH 7.5) for six treatment groups. Animals (n = 50) were acclimated to the treatment conditions for a period of 4 weeks. This is sufficient time for growth of ca. 7-9 new tooth rows or 20% turnover of the mineralised portion. There was no significant difference in the number of new (non-mineralised) teeth or total tooth row count in any treatment. Examination of the radulae via SEM revealed no differences in microwear or breakage on the feeding cusps correlating to treatment groups. The shell valves also showed no signs of dissolution. As a lineage, chitons have survived repeated shifts in Earth's climate through geological time, and at least their radulae may be robust to future perturbations.

Heating Mechanisms for Intermittent Loops in Active Region Cores from AIA/SDO EUV Observations

We investigate intensity variations and energy deposition in five coronal loops in active region cores. These were selected for their strong variability in the AIA/SDO 94 Å intensity channel. We isolate the hot Fe XVIII and Fe XXI components of the 94 Å and 131 Å by modeling and subtracting the "warm" contributions to the emission. HMI/SDO data allow us to focus on "inter-moss" regions in the loops. The detailed evolution of the inter-moss intensity time series reveals loops that are impulsively heated in a mode compatible with a nanoflare storm, with a spike in the hot 131 Å signals leading and the other five EUV emission channels following in progressive cooling order. A sharp increase in electron temperature tends to follow closely after the hot 131 Å signal confirming the impulsive nature of the process. A cooler process of growing emission measure follows more slowly. The Fourier power spectra of the hot 131 Å signals, when averaged over the five loops, present three scaling regimes with break frequencies near 0.1 min–1 and 0.7 min–1. The low frequency regime corresponds to 1/f noise; the intermediate indicates a persistent scaling process and the high frequencies show white noise. Very similar results are found for the energy dissipation in a 2D "hybrid" shell model of loop magneto-turbulence, based on reduced magnetohydrodynamics, that is compatible with nanoflare statistics. We suggest that such turbulent dissipation is the energy source for our loops

Intermittent and Scale-Invariant Intensity Fluctuations in Hot Coronal Loops

ABSTRACT BODY: To resolve outstanding questions on heating of coronal loops, we study intensity fluctuations in inter-moss portions of active region core loops as observed with AIA/SDO. The 94Å fluctuations (Figure 1) have structure on timescales shorter than radiative and conductive cooling times. Each of several strong 94Å brightenings is followed after ~8 min by a broader peak in the cooler 335Å emission. This indicates that we see emission from the hot component of the 94Å contribution function. No hotter contributions appear, and we conclude that the 94Å intensity can be used as a proxy for energy injection into the loop plasma. The probability density function of the observed 94Å intensity has 'heavy tails' that approach zero more slowly than the tails of a normal distribution. Hence, large fluctuations dominate the behavior of the system. The resulting 'intermittence' is associated with power-law or exponential scaling of the related variables, and these in turn are associated with turbulent phenomena. The intensity plots in Figure 1 resemble multifractal time series, which are common to various forms of turbulent energy dissipation. In these systems a single fractal dimension is insufficient to describe the dynamics and instead there is a spectrum of fractal dimensions that quantify the self-similar properties. Figure 2 shows the multifractal spectrum from our data to be invariant over timescales from 24 s to 6.4 min. We compare these results to outputs from theoretical energy dissipation models based on MHD turbulence, and in some cases we find substantial agreement, in terms of intermittence, multifractality and scale invariance. Figure 1. Time traces of 94A intensity in the inter-moss portions of four AR core loops. Figure 2. Multifractal spectra showing timescale invariance. The four cases of Figure 1 are included.