The health effects of internal contamination by radionuclides, and notably by uranium, are poorly characterised. New cohorts of uranium workers are needed to better examine these effects. This paper analyses for the first time the mortality profile of the French cohort of uranium cycle workers. It considers mortality from cancer and non-cancer causes.
The cohort includes workers employed at least 6 months between 1958 and 2006 in French companies involved in the production of nuclear fuel. Vital status and causes of death were collected from French national registries. Workers were followed-up from 1 January 1968 to 31 December 2008. Standardised mortality ratios (SMRs) were computed based on mortality rates for the French general population.
The cohort includes 12 649 workers (88% men). The average length of follow-up is 27 years and the mean age at the end of the study is 60 years. Large mortality deficits are observed for non-cancer causes of death such as non-cancer respiratory diseases (SMR=0.51 (0.41 to 0.63)) and circulatory diseases (SMR=0.68 (0.62 to 0.74)). A mortality deficit of lower magnitude is also observed for all cancers combined (SMR (95% CI): 0.76 (0.71 to 0.81)). Pleural mesothelioma is elevated (SMR=2.04 (1.19 to 3.27)).
A healthy worker effect is observed in this new cohort of workers involved in the uranium cycle. Collection of individual information on internal uranium exposure as well as other risk factors is underway, to allow for the investigation of uranium-related risks.
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Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of biosimilarity is to conduct a pharmacokinetics similarity study in which the potential biosimilar is compared with the reference product. In the context of biosimilar development, a pharmacokinetics similarity study is not necessarily designed for a comparative assessment of safety. Development of PF-05280014, a potential biosimilar to trastuzumab, illustrates how a numerical imbalance in an adverse event in a small pharmacokinetics study can raise questions on safety that may require additional clinical trials.

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Protein phosphorylation plays a central role in creating a highly dynamic network of interacting proteins that reads and responds to signals from growth factors in the cellular microenvironment. Cells of the neural crest employ multiple signaling mechanisms to control migration and differentiation during development. It is known that defects in these mechanisms cause neuroblastoma, but how multiple signaling pathways interact to govern cell behavior is unknown. In a phosphoproteomic study of neuroblastoma cell lines and cell fractions, including endosomes and detergent-resistant membranes, 1622 phosphorylated proteins were detected, including more than half of the receptor tyrosine kinases in the human genome. Data were analyzed using a combination of graph theory and pattern recognition techniques that resolve data structure into networks that incorporate statistical relationships and protein-protein interaction data. Clusters of proteins in these networks are indicative of functional signaling pathways. The analysis indicates that receptor tyrosine kinases are functionally compartmentalized into distinct collaborative groups distinguished by activation and intracellular localization of SRC-family kinases, especially FYN and LYN. Changes in intracellular localization of activated FYN and LYN were observed in response to stimulation of the receptor tyrosine kinases, ALK and KIT. The results suggest a mechanism to distinguish signaling responses to activation of different receptors, or combinations of receptors, that govern the behavior of the neural crest, which gives rise to neuroblastoma.

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The objective was to obtain a standardized evaluation of available specific and generic breast cancer health-related quality-of-life instruments.
We carried out systematic literature reviews in the PubMed and EMBASE databases to identify manuscripts which contained information regarding either the development process or metric properties of health-related quality-of-life instruments used among breast cancer patients. Each instrument was evaluated independently by two researchers, and occasionally a third one, using the Evaluating Measures of Patient-Reported Outcomes (EMPRO) tool. An overall score and seven attribute-specific EMPRO scores were calculated (range 0-100, worst to best): concept and measurement model, reliability, validity, responsiveness, interpretability, burden, and alternative forms.
FACT-B was the instrument with the best global performance, obtaining an overall EMPRO score of 79.27. It was also the most accurate instrument on the Concept and Measurement Model, Reliability, and Interpretability attributes. Four more instruments scored over 50 points on the overall score, which summarizes the five attribute-specific scores: EORTC BR-23, IBCSG, WHO-QOL BREF, and SF-36. An overall score of at least 50 points implies that the use of these instruments could be recommended for assessing health-related quality of life in breast cancer patients.
The FACT-B scored the highest on overall on our EMPRO evaluation of instruments measuring health-related quality of life among breast cancer patients. However, depending on the purpose of the study, several instruments (EORTC BR-23, IBCSG, SF-36, and WHO-QOL BREF) have shown good performance in some of the specific individual dimensions included in the EMPRO.

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Background Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results. Methods We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy. Results A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival. Conclusions In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375 .).

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