Strategies to design clinical studies to identify predictive biomarkers in cancer research

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework—the DESIGN guidelines—to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field

Hydrocarbon generation and migration from Barremian – Aptian source rocks, Northern Orange Basin, offshore Western South Africa: A 3d numerical modelling study

A 3D numerical modelling workflow was applied to the Barremian—Aptian source rock interval in a shelfal to lower slope area of the northern Orange Basin, offshore western South Africa. The main objective was to investigate the timing of hydrocarbon generation and migration. Hydrocarbon migration has previously been investigated in the south of the basin by relating gas escape features with structural elements as seen on seismic sections, but migration pathways are still poorly understood. The modelling study was based on data from three exploration wells (AO-1, AE-1 and AF-1) together with 42 2D seismic sections totalling 3537 km in length, and a 3D seismic cube covering an area of 750 sq. km. Modelled formation temperatures increase from north to south in the study area and were consistent with downhole temperatures at well locations. However, there is variation between measured and modelled values of vitrinite reflectance (VR), especially in the Turonian and Cenomanian intervals. The measured VR is lower than the modelled VR within the Turonian section in the north of the study area, suggesting that erosion has affected the thermal maturity of the sediments. However, in the Cenomanian interval, the measured VR is higher than the modelled VR. Uplift, increased erosion in the hinterland and sediment transport to the coastal areas resulted in Cenomanian progradation of the Orange Basin fill

Improved Optoelectronic Properties of Rapid Thermally Annealed Dilute Nitride GaInNAs Photodetectors

We investigate the optical and electrical characteristics of GaInNAs/GaAs long-wavelength photodiodes grown under varying conditions by molecular beam epitaxy and subjected to postgrowth rapid thermal annealing (RTA) at a series of temperatures. It is found that the device performance of the nonoptimally grown GaInNAs p-i-n structures, with nominal compositions of 10% In and 3.8% N, can be improved significantly by the RTA treatment to match that of optimally grown structures. The optimally annealed devices exhibit overall improvement in optical and electrical characteristics, including increased photoluminescence brightness, reduced density of deep-level traps, reduced series resistance resulting from the GaAs/GaInNAs heterointerface, lower dark current, and significantly lower background doping density, all of which can be attributed to the reduced structural disorder in the GaInNAs alloy.© 2012 TMS

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems