Research recommendations for selected IARC-classified agents.

OBJECTIVES: There are some common occupational agents and exposure circumstances where evidence of carcinogenicity is substantial but not yet conclusive for humans. The objectives are to identify research gaps and needs for twenty agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. DATA SOURCES: A systematic review was conducted of new data published since the most recent pertinent IARC monograph meeting. DATA EXTRACTION: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. DATA SYNTHESIS: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress and immuno- and hormonal modulation. CONCLUSIONS: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.[Authors]

Need of reduced and harmonized bureaucracy in multi-centre clinical research - a case-report from a Swiss trial

Introduction: We launched an investigator-initiated study (ISRCTN31181395) to evaluate the potential benefit of pharmacokinetic-guided dosage individualization of imatinib for leukaemiapatients followed in public and private sectors. Following approval by the research ethics committee (REC) of the coordinating centre, recruitment throughout Switzerland necessitatedto submit the protocol to 11 cantonal RECs.Materials and Methods: We analysed requirements and evaluation procedures of the 12 RECs with associated costs.Results: 1-18 copies of the dossier, in total 4300 printed pages, were required (printing/posting costs: ~300 CHF) to meet initial requirements. Meeting frequencies of RECs ranged between 2 weeks and 2 months, time from submission to fi rst feedback took 2-75 days. Study approval was obtained from a chairman, a subor the full committee, the evaluation work being invoiced by0-1000 CHF (median: 750 CHF, total: 9200 CHF). While 5 RECs gave immediate approval, the other 6 rose in total 38 queries before study release, mainly related to wording in the patient information, leading to 7 different fi nal versions approved. Submission tasks employed an investigator half-time over about 6 months.Conclusion: While the necessity of clinical research evaluation by independent RECs is undisputed, there is a need of further harmonization and cooperation in evaluation procedures. Current administrative burden is indeed complex, time-consuming and costly. A harmonized electronic application form, preferably compatible with other regulatory bodies and European countries, could increase transparency, improve communication, and encourage academic multi-centre clinical research in Switzerland.

A Delphi study on National PICU nursing research priorities in Australia and New Zealand.

BACKGROUND: There is a lack of evidence to direct and support nursing practice in the specialty of paediatric intensive care (PIC). The development of national PIC nursing research priorities may facilitate the process of undertaking clinical research and translating evidence into practice. PURPOSE: To (a) identify research priorities for the care of patients and their family as well as for the professional needs of PIC nurses, (b) foster nursing research collaboration, (c) develop a research agenda for PIC nurses. METHODS: Over 13 months in 2007-2008, a three-round questionnaire, using the Delphi technique, was sent to all specialist level registered nurses working in Australian and New Zealand PICUs. This method was used to identify and prioritise nursing research topics. Content analysis was used to analyse Round I data and descriptive statistics for Round II and III data. RESULTS: In Round I, 132 research topics were identified, with 77 research priorities (mdn>6, mean MAD(median) 0.68±0.01) identified in subsequent rounds. The top nine priorities (mean>6 and median>6) included patient issues related to neurological care (n=2), pain/sedation/comfort (n=3), best practice at the end of life (n=1), and ventilation strategies (n=1), as well as two priorities related to professional issues about nurses' stress/burnout and professional development needs. CONCLUSION: The research priorities identified reflect important issues related to critically ill patients and their family as well as to the nurses caring for them. These priorities can be used for the development of a research agenda for PIC nursing in Australia and New Zealand.

An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for Human Epidermal Growth Factor Receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer.

BACKGROUND: Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1-2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial. PATIENTS AND METHODS: Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m(2)). RESULTS: Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed. CONCLUSIONS: Our recommended dose for phase II is lapatinib 1000mg/day and docetaxel 100mg/m(2) with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.

Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study.

PURPOSE: To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas. PATIENTS: AND METHODS: This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment. RESULTS: A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor-A or -B were found. CONCLUSION: In the dose range of 600 to 1,000 mg/d, single-agent imatinib is well tolerated but has limited antitumor activity in patients with recurrent gliomas.

Interdisciplinary research for the analysis and risk assesment : the case of the municipality of Uspantan Guatemala

Short description of the proposed presentation * lees than 100 words This paper describes the interdisciplinary work done in Uspantán, Guatemala, a city vulnerable to natural hazards. We investigated local responses to landslides that happened in 2007 and 2010 and had a strong impact on the local community. We show a complete example of a systemic approach that incorporates physical, social and environmental aspects in order to understand risks. The objective of this work is to present the combination of social and geological data (mapping), and describe the methodology used for identification and assessment of risk. The article discusses both the limitations and methodological challenges encountered when conducting interdisciplinary research. Describe why it is important to present this topic at the Global Platform in less than 50 words This work shows the benefits of addressing risk in an interdisciplinary perspective, in particular how integrating social sciences can help identify new phenomena and natural hazards and assess risk. It gives a practical example of how one can integrate data from different fields. What is innovative about this presentation? * The use of mapping to combine qualitative and quantitative data. By coupling approaches, we could associate a hazard map with qualitative data gathered by interviews with the population. This map is an important document for the authorities. Indeed, it allows them to be aware of the most dangerous zones, the affected families and the places where it is most urgent to intervene.

Correlative light and electron microscopy in parasite research.

The interaction of a parasite and a host cell is a complex process, which involves several steps: (1) attachment to the plasma membrane, (2) entry inside the host cell, and (3) hijacking of the metabolism of the host. In biochemical experiments, only an event averaged over the whole cell population can be analyzed. The power of microscopy, however, is to investigate individual events in individual cells. Therefore, parasitologists frequently perform experiments with fluorescence microscopy using different dyes to label structures of the parasite or the host cell. Though the resolution of light microscopy has greatly improved, it is not sufficient to reveal interactions at the ultrastructural level. Furthermore, only specifically labeled structures can be seen and related to each other. Here, we want to demonstrate the additional value of electron microscopy in this area of research. Investigation of the different steps of parasite-host cell interaction by electron microscopy, however, is often hampered by the fact that there are only a few cells infected, and therefore it is difficult to find enough cells to study. A solution is to profit from low magnification, hence large overview, and specific location of the players by fluorescence labels in a light microscope with the high power resolution and structural information provided by an electron microscope, in short by correlative light and electron microscopy.

Managing Social-Business Tensions: A Review and Research Agenda for Social Enterprise

In a world filled with poverty, environmental degradation, and moral injustice, social enterprises offer a ray of hope. These organizations seek to achieve social missions through business ventures. Yet social missions and business ventures are associated with divergent goals, values, norms, and identities. Attending to them simultaneously creates tensions, competing demands, and ethical dilemmas. Effectively understanding social enterprises therefore depends on insight into the nature and management of these tensions. While existing research recognizes tensions between social missions and business ventures, we lack any systematic analysis. Our paper addresses this issue. We first categorize the types of tensions that arise between social missions and business ventures, emphasizing their prevalence and variety. We then explore how four different organizational theories offer insight into these tensions, and we develop an agenda for future research. We end by arguing that a focus on social-business tensions not only expands insight into social enterprises, but also provides an opportunity for research on social enterprises to inform traditional organizational theories. Taken together, our analysis of tensions in social enterprises integrates and seeks to energize research on this expanding phenomenon.

Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group.

BACKGROUND: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions. METHODS: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged. RESULTS: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA. CONCLUSIONS: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA.