Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Predicting the performance of passenger ships using computer simulation

When designing a new passenger ship or naval vessel or modifying an existing design, how do we ensure that the proposed design is safe from an evacuation point of view? In the wake of major maritime disasters such as the Herald of Free Enterprise and the Estonia and in light of the growth in the numbers of high density, high-speed ferries and large capacity cruise ships, issues concerned with the evacuation of passengers and crew at sea are receiving renewed interest. In the maritime industry, ship evacuation models are now recognised by IMO through the publication of the Interim Guidelines for Evacuation Analysis of New and Existing Passenger Ships including Ro-Ro. This approach offers the promise to quickly and efficiently bring evacuation considerations into the design phase, while the ship is "on the drawing board" as well as reviewing and optimising the evacuation provision of the existing fleet. Other applications of this technology include the optimisation of operating procedures for civil and naval vessels such as determining the optimal location of a feature such as a casino, organising major passenger movement events such as boarding/disembarkation or restaurant/theatre changes, determining lean manning requirements, location and number of damage control parties, etc. This paper describes the development of the maritimeEXODUS evacuation model which is fully compliant with IMO requirements and briefly presents an example application to a large passenger ferry.

Appalachian Trail /

"March 1981."

Statue of Liberty and Ellis Island /

Statue of Liberty view is from ground level and Ellis Island views are aerial views.

Statue of Liberty and Ellis Island /

Statue of Liberty view is from ground level and Ellis Island views are aerial views.

Statue of Liberty and Ellis Island /

Statue of Liberty view is from ground level and Ellis Island views are oblique aerial views.

Modelling and analysing cargo screening processes: a project outline

The efficiency of current cargo screening processes at sea and air ports is unknown as no benchmarks exists against which they could be measured. Some manufacturer benchmarks exist for individual sensors but we have not found any benchmarks that take a holistic view of the screening procedures assessing a combination of sensors and also taking operator variability into account. Just adding up resources and manpower used is not an effective way for assessing systems where human decision-making and operator compliance to rules play a vital role. For such systems more advanced assessment methods need to be used, taking into account that the cargo screening process is of a dynamic and stochastic nature. Our project aim is to develop a decision support tool (cargo-screening system simulator) that will map the right technology and manpower to the right commodity-threat combination in order to maximize detection rates. In this paper we present a project outline and highlight the research challenges we have identified so far. In addition we introduce our first case study, where we investigate the cargo screening process at the ferry port in Calais.

Work, class and conflict: a comparative study of three Cork factories, incorporating oral testimony

This dissertation presents a comparative study of three factories in Cork Harbour area, Sunbeam Wolsey (1927-90), Irish Steel (1939-2001) and the Ford Marina Plant (1917-84). All three factories were significant industrial employers in both a domestic (Irish) and a local (Cork) context and are broadly representative of the Irish manufacturing industry that was developed under the policies of tariff protection introduced in the 1930s and gradually phased out between the late 1950s and the mid-1980s. Sunbeam Wolsey was a textile and clothing concern located on the north side of Cork City that possessed a borderline monopoly within its economic sector and was among the largest private employers of female labour in twentieth century Ireland. Irish Steel was the country’s only steel mill, located on Haulbowline island, a brief ferry-ride from the seaside town of Cobh, and was unusual in being one of the few manufacturing concerns operated as a nationalised industry under the auspices of the state. The Ford Marina plant predated the introduction of protectionism by more than a decade and began as the centre of the Ford empire’s tractor manufacturing business, before switching to the production of private motor vehicles for the Irish market in 1932. All three industries were closed or sold off when the state withdrew support, either in the form of tariff protection (Ford, Sunbeam) or direct funding (Irish Steel). While devoting much attention to the three firms, the central concern of this dissertation is not the companies themselves (though the economic history portion of the dissertation is substantial), but the workers they employed, examining the lives of these individuals both as members of the Irish working class, and, more specifically, as employees of the three factories under consideration. The project can be best described as a comparative factory study, comparing and contrasting the three workforces, focusing primarily on industrial relation and the experience of work. This dissertation utilises both documentary evidence and a significant quantity of oral testimony, breaking new ground by making the workplace the central focus of its investigation. The principal aims of the study are: 1. To document the lives of those who worked in these factories, capturing through oral testimony their subjective experiences of social class and factory life, as well as differences among narrators in terms of gender and status. In achieving this aim, the study will provide a broader social context for its detailed analysis of work and industrial relations in each firm. 2. To analyse the three workplaces and determine how and why each developed such distinct systems of industrial relations at the factory level, as well as to compare and contrast these systems. 3. To examine the nature of work in each factory and to determine how work and industrial relations in each firm developed over time, relating these changes both to internal and external factors. Additionally, the project will provide a comparative analysis of these changes.

“Afinal de que se fala quando se fala de amor? Uma perspectiva filosófica”

O amor é um conceito polissémico ligado a um fenómeno complexo, que une aspectos fisiológicos, psicológicos e culturais, se orienta para diferentes objectos e cumpre diversas funções. Ao longo da história, são muitos os filósofos que prestaram atenção a este fenómeno e lhe deram um lugar de relevo nas suas concepções, desde Platão até aos nossos dias. O presente trabalho pretende introduzir alguns aspectos dessa atenção histórica, privilegiando concepções não redutoras nem simplistas, desde a sua compreensão grega como força cósmica até à mais actual duma mudança de paradigma social, nele assente.