The incidence of rectal cancer in the European Union is ∼125 000 per year, i.e. ∼35% of the total colorectal cancer incidence, reflecting 15–25 cases/100 000 population per year and is predicted to increase further in both genders. The mortality is 4–10/100 000 population per year. Median age at diagnosis is ∼70 years, but predictions suggest that this figure will rise in the future.

Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.

Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein–protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more.

There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC. Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician’s choice of chemotherapy (paclitaxel 80 mg/m² on days 1, 8, and 15 or irinotecan 150 mg/m² on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9–1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4–2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm. Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy. ClinicalTrials.gov: NCT02625623.

Background Improvements in local control are required when using preoperative chemoradiation for cT4 or advanced cT3 rectal cancer. There is therefore a need to explore more effective schedules. Patients and methods Patients with fixed cT3 or cT4 cancer were randomised either to 5x5 Gy and three cycles of FOLFOX4 (group A) or to 50.4 Gy in 28 fractions combined with two 5-day cycles of bolus 5-Fu 325 mg/m²/day and leucovorin 20 mg/m²/day during the first and fifth week of irradiation along with five infusions of oxaliplatin 50 mg/m² once weekly (group B). The protocol was amended in 2012 to allow oxaliplatin to be then foregone in both groups. Results Of 541 entered patients, 515 were eligible for analysis; 261 in group A and 254 in group B. Preoperative treatment acute toxicity was lower in group A than group B, p=0.006; any toxicity being respectively 75% vs. 83%, grade III-IV 23% vs. 21% and toxic deaths 1% vs. 3%. R0 resection rates (primary endpoint) and pathological complete response rates in groups A and B were respectively 77% vs. 71%, p=0.07 and 16% vs. 12%, p=0.17. The median follow-up was 35 months. At 3 years, the rates of overall survival and disease-free survival in groups A and B were respectively 73% vs. 65%, p=0.046 and 53% vs. 52%, p=0.85, together with the cumulative incidence of local failure and distant metastases being respectively 22% vs. 21%, p=0.82 and 30% vs. 27%, p=0.26. Postoperative and late complications rates in group A and group B were respectively 29% vs. 25%, p=0.18 and 20% vs. 22%, p=0.54. Conclusions No differences were observed in local efficacy between 5x5 Gy with consolidation chemotherapy and long-course chemoradiation. Nevertheless, an improved overall survival and lower acute toxicity favours the 5x5 Gy schedule with consolidation chemotherapy.