Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial

Background: Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Methods: In this multicentre, randomised, open-label phase 2–3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. Findings: Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5–54·9) in the chemotherapy alone group and 48·1% (43·2–52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91–1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). Interpretation: The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. Funding: Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited

Temporal evolution of solar energetic particle spectra

During solar flares and coronal mass ejections, solar energetic par- ticles (SEPs) may be released into the interplanetary medium and near-Earth locations. The energy spectra of SEP events at 1 AU are typically averaged over the entire event or studied in a few snapshots. In this paper we analyze the time evolution of the energy spectra of four large selected SEP events using a large number of snapshots. We use a multi-spacecraft and multi-instrument approach for the observations, obtained over a wide SEP energy range. We find large differences in the spectra at the beginning of the events as measured by different instruments. We show that over time, a wave-like structure is observed traveling through the spectra from the highest energies to the lowest energies, creating an “arch” shape which then straightens into a power law later in the event, after times of the order of 10 hours. We discuss the processes that determine SEP intensities and their role in shaping the spectral time evolution

The role of urocanic acid in UVB-induced suppression of immunity to Trichinella spiralis infection in the rat

The naturally occurring trans-isomer of urocanic acid (trans-UCA), found in the stratum corneum, absorbs ultraviolet light (UV) and isomerizes to the cis-form. Cis-UCA has been shown to impair some cellular immune responses, and has been proposed as an initiator of the suppression that follows UV irradiation. UVB exposure leads to an increase in cis-UCA in the skin of rats from about 10% to 40% of the total UCA. Previously it has been demonstrated that UVB lowers immune responses to Trichinella spiralis after oral infection of rats with the parasitic worm. In the present study we investigated the role of cis-UCA in the control of this parasitic infection. Rats were infected orally with T. spiralis and injected with different doses of cis- or trans-UCA subcutaneously. Mitogenic responses and the mixed lymphocyte reaction were not affected by either isomer. In contrast, the number of T. spiralis larvae in muscle tissue of infected rats was increased significantly in the cis-UCA-treated animals compared with the trans-UCA-treated animals. In addition, delayed-type hypersensitivity (DTH) to T. antigen in infected rats was significantly impaired by cis-UCA but not by trans-UCA. If rats were injected with a monoclonal antibody with specificity for cis-UCA 2 hr prior to UVB exposure, the UVB-induced suppression in DTH to T. spiralis and the increase in larvae counts were significantly inhibited compared with rats that were similarly injected with a control antibody. Thus cis-UCA can inhibit the specific resistance to parasitic infections and acts as an important mediator of UVB-induced suppression of immunity to T. spiralis in the rat

A blockchain‐enabled framework for sharing logistics resources during emergency operations

This study presents conceptual research designed to assess how the sharing economy concept can be leveraged to increase the participation of commercial organisations, such as retailers and transporters, in disaster relief operations. Drawing on social exchange theory, the academic literature on the sharing economy and blockchain, as well as existing resource-sharing practices in commercial and humanitarian logistics, the study develops a theoretical framework for analysing the structure, benefits, and prerequisites of a logistics-sharing system in emergency response. In addition, it proposes to utilise the blockchain distributed ledger technology-a shared data platform that enables authenticated communication and the widespread sharing of real-time information-to facilitate interactions and enhance trust between emergency responders and commercial organisations. It is argued that using commercial logistics resources, including emergency supplies, transport capacity, and storage space, has the potential to improve the mobilisation and deployment of urgently needed relief items and augment the flexibility of emergency response