EGFR gene amplification is relatively common and associates with outcome in intestinal adenocarcinoma of the stomach, gastro-oesophageal junction and distal oesophagus

BACKGROUND Approximately 50 % of gastric adenocarcinomas belong to a molecular subgroup characterised by chromosomal instability and a strong association with the intestinal histological subtype. This subgroup typically contains alterations in the receptor tyrosine kinase-RAS pathway, for example EGFR or HER2 gene amplifications leading to protein overexpression. In clinical practice, HER2 overexpressing metastatic gastric cancer is known to respond to treatment with anti-HER2 antibodies. By contrast, anti-EGFR antibodies have not been able to provide survival benefit in clinical trials, which, however, have not included patient selection based on the histological subtype or EGFR gene copy number analysis of the tumours. To examine the role of EGFR as a potential biomarker, we studied the prevalence, clinicopathological associations as well as prognostic role of EGFR and HER2 expression and gene amplification in intestinal adenocarcinomas of the stomach, gastro-oesophageal junction and distal oesophagus. METHODS Tissue samples from 220 patients were analysed with EGFR and HER2 immunohistochemistry. Those samples with moderate/strong staining intensity were further analysed with silver in situ hybridization to quantify gene copy numbers. The results were associated with clinical patient characteristics and survival. RESULTS Moderate/strong EGFR protein expression was found in 72/220 (32.7 %) and EGFR gene amplification in 31/220 (14.1 %) of the tumours, while moderate/strong HER2 protein expression was detected in 31/220 (14.1 %) and HER2 gene amplification in 29/220 (13.2 %) of the tumours. EGFR and HER2 genes were co-amplified in eight tumours (3.6 %). EGFR gene amplification was more common in tumours of distal oesophagus/gastro-oesophageal junction/cardia than in those of gastric corpus (p = 0.013). It was associated with shortened time to cancer recurrence (p = 0.026) and cancer specific survival (p = 0.033). CONCLUSIONS EGFR gene amplification is relatively common in intestinal adenocarcinomas and associates with decreased survival. It is rarely concurrent with HER2 gene amplification, suggesting that anti-EGFR therapies might be applicable to some patients not eligible for anti-HER2 treatment. Analogous to HER2 testing, determination of EGFR gene amplification status in concert with immunohistochemistry could improve the specificity of patient selection when investigating the possible benefits of anti-EGFR therapies in the treatment of gastric adenocarcinomas

Probabilistic Tsunami Hazard Assessment in Meso and Macro Tidal Areas. Application to the Cádiz Bay, Spain

ABSTRACT: Tsunami hazard can be analyzed from both deterministic and probabilistic points of view. The deterministic approach is based on a "credible" worst case tsunami, which is often selected from historical events in the region of study. Within the probabilistic approach (PTHA, Probabilistic Tsunami Hazard Analysis), statistical analysis can be carried out in particular regions where historical records of tsunami heights and runup are available. In areas where these historical records are scarce, synthetic series of events are usually generated using Monte Carlo approaches. Commonly, the sea level variation and the currents forced by the tidal motion are either disregarded or considered and treated as aleatory uncertainties in the numerical models. However, in zones with a macro and meso tidal regime, the effect of the tides on the probability distribution of tsunami hazard can be highly important. In this work, we present a PTHA methodology based on the generation of synthetic seismic catalogs and the incorporation of the sea level variation into a Monte Carlo simulation. We applied this methodology to the Bay of Cádiz area in Spain, a zone that was greatly damaged by the 1755 earthquake and tsunami. We build a database of tsunami numerical simulations for different variables: faults, earthquake magnitudes, epicenter locations and sea levels. From this database we generate a set of scenarios from the synthetic seismic catalogs and tidal conditions based on the probabilistic distribution of the involved variables. These scenarios cover the entire range of possible tsunami events in the synthetic catalog (earthquakes and sea levels). Each tsunami scenario is propagated using the tsunami numerical model C3, from the source region to the target coast (Cádiz Bay). Finally, we map the maximum values for a given probability of the selected variables (tsunami intensity measures) producing a set of thematic hazard maps. 1000 different time series of combined tsunamigenic earthquakes and tidal levels were synthetically generated using the Monte Carlo technique. Each time series had a 10000-year duration. The tsunami characteristics were statistically analyzed to derive different thematic maps for the return periods of 500, 1000, 5000, and 10000 years, including the maximum wave elevation, the maximum current speed, the maximum Froude number, and the maximum total forces