The addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for advanced colorectal cancer: results of the MRC COIN trial.

Background: In 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.
Methods: In 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.
Findings: 1630 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).
Interpretation: This 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.

The 'Unified airway': The RCPCH care pathway for asthma/or rhinitis

Abstract Aims The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies: the asthma/rhinitis care pathway is the third such pathway. Asthma and rhinitis have been considered together. These conditions co-exist commonly, have remarkably similar immuno-pathology and an integrated management approach benefits symptom control. Method The asthma/rhinitis pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including the public and was approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. Results The pathway entry points are defined by symptom type and severity at presentation. Acute severe rhinitis and life-threatening asthma are presented as distinct entry routes to the pathway, recognising that initial care of these conditions requires presentation-specific treatments. However, the pathway emphasises that ideal long term care should take account of both conditions in order to achieve maximal improvements in disease control and quality of life. Conclusions The pathway recommends that acute presentations of asthma and/or rhinitis should be treated separately. Where both conditions exist, ongoing management should address the upper and lower airways. The authors recommend that this pathway is implemented locally by a multidisciplinary team (MDT) with a focus on creating networks. The MDT within these networks should work with patients to develop and agree on care plans that are age and culturally appropriate.

The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC + ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with > 10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML. Leukemia (2011) 25, 1122-1127; doi:10.1038/leu.2011.59; published online 8 April 2011

A Unified Scheduler for Recursive and Task Dataflow Parallelism

Task dataflow languages simplify the specification of parallel programs by dynamically detecting and enforcing dependencies between tasks. These languages are, however, often restricted to a single level of parallelism. This language design is reflected in the runtime system, where a master thread explicitly generates a task graph and worker threads execute ready tasks and wake-up their dependents. Such an approach is incompatible with state-of-the-art schedulers such as the Cilk scheduler, that minimize the creation of idle tasks (work-first principle) and place all task creation and scheduling off the critical path. This paper proposes an extension to the Cilk scheduler in order to reconcile task dependencies with the work-first principle. We discuss the impact of task dependencies on the properties of the Cilk scheduler. Furthermore, we propose a low-overhead ticket-based technique for dependency tracking and enforcement at the object level. Our scheduler also supports renaming of objects in order to increase task-level parallelism. Renaming is implemented using versioned objects, a new type of hyper object. Experimental evaluation shows that the unified scheduler is as efficient as the Cilk scheduler when tasks have no dependencies. Moreover, the unified scheduler is more efficient than SMPSS, a particular implementation of a task dataflow language.

An allelic series reveals essential roles for FY in plant development in addition to flowering-time control.

The autonomous pathway functions to promote flowering in Arabidopsis by limiting the accumulation of the floral repressor FLOWERING LOCUS C (FLC). Within this pathway FCA is a plant-specific, nuclear RNA-binding protein, which interacts with FY, a highly conserved eukaryotic polyadenylation factor. FCA and FY function to control polyadenylation site choice during processing of the FCA transcript. Null mutations in the yeast FY homologue Pfs2p are lethal. This raises the question as to whether these essential RNA processing functions are conserved in plants. Characterisation of an allelic series of fy mutations reveals that null alleles are embryo lethal. Furthermore, silencing of FY, but not FCA, is deleterious to growth in Nicotiana. The late-flowering fy alleles are hypomorphic and indicate a requirement for both intact FY WD repeats and the C-terminal domain in repression of FLC. The FY C-terminal domain binds FCA and in vitro assays demonstrate a requirement for both C-terminal FY-PPLPP repeats during this interaction. The expression domain of FY supports its roles in essential and flowering-time functions. Hence, FY may mediate both regulated and constitutive RNA 3'-end processing.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes:results of the MRC AML15 trial

Two hundred eighty-five patients, median age 42, with PML-RARa-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia:results from the LRF AML14 and NCRI AML16 pick-a-winner comparison

The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.

Aqueous phase reforming of xylitol over Pt-Re bimetallic catalyst: Effect of the Re addition

The aqueous phase reforming (APR) of xylitol was studied in a continuous fixed bed reactor over three catalysts: Pt/Al2O3, Pt/TiO2 and Pt-Re/TiO2. The data obtained in the case of the monometallic Pt catalysts was compared to the bimetallic Pt-Re sample. The effect of Re addition on the catalyst stability, activity, product formation and selectivity toward hydrogen and alkanes was studied. The bimetallic catalyst demonstrated a higher selectivity to alkanes compared to the monometallic samples. The monometallic catalyst was more selective toward hydrogen formation. A plausible reaction scheme explaining differences in selectivity toward hydrogen and alkanes was proposed and discussed.

Arsenic biogeochemistry as affected by phosphorus fertilizer addition, redox potential and pH in a west Bengal (India) soil

This laboratory experiment systematically examines arsenic, iron, and phosphorus solubilities in soil suspensions as affected by addition of phosphorus fertilizer under different redox potential (Eh) and pH conditions. Under aerobic conditions, As solubility was low, however, under moderately reducing conditions (0, -150 mV), As solubility significantly increased due to dissolution of iron oxy-hydroxides. Upon reduction to -250 mV, As solubility was controlled by the formation of insoluble sulfides, and as a result soluble As contents significantly decreased. Soluble Fe concentration increased from moderate to highly anaerobic conditions; however, it decreased under aerobic conditions likely due to formation of insoluble oxy-hydroxides. A low pH, 5.5, led to increased soluble concentrations of As, Fe, and P. Finally, addition of P-fertilizers resulted in higher soluble P and As, even though the concentration of As did not increased after an addition rate of 600 mg P kg(-1) soil. (c) 2006 Elsevier B.V. All rights reserved.