Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

'Battling in Brussels': The DUP and the European union

Although the Democratic Unionist Party (DUP) does not conform to the model of Europeanization outlined by Ladrech (2002), there is some evidence of change along the lines identified by De Winter and Gomez-Reino (2002) with reference to other European ethnoregionalist parties. For example, the DUP has certainly adapted its behaviour and policies at both local and European levels with a view to exploiting new political opportunities offered by Europeanization. However, De Winter and Gomez-Reino's argument that participation in European institutions has made formerly-Eurosceptic ethnoregionalist parties 'moderate Eurocritics' does not fully apply to the DUP. The DUP continues to demonstrate a number of Eurosceptic characteristics, including ones grounded in extreme religious interpretations of the purpose and process of European integration. Nevertheless, the party's Eurosceptic outlook does not prevent it from being willing to 'battle in Brussels' (as put in its 2009 manifesto for the European elections) in order to serve domestic (party) interests - a tactic not dissimilar to the DUP's approach to Northern Ireland politics in general.

Using Comparative Reasoning in Human Rights Adjudication:The Court of Justice of the European Union and the European Court of Human Rights Compared

This article examines the relationship between the methods that the European Court of Human Rights (ECtHR) and the Court of Justice of the European Union (CJEU) use to decide disputes that involve ‘human’ or ‘fundamental’ rights claims, and the substantive outcomes that result from the use of these particular methods. It has a limited aim: in attempting to understand the interrelationship between human rights methodology and human rights outcomes, it considers primarily the use of ‘comparative reasoning’ in ‘human’ and ‘fundamental’ rights claims by these courts. It is not primarily concerned with examining the extent to which the use of comparative reasoning is based on an appropriate methodology or whether there is a persuasive normative theory underpinning the use of comparative reasoning. The issues considered in this chapter do some of the groundwork, however, that is necessary in order to address these methodological and normative questions.

Combining vitamin C and carotenoid biomarkers better predicts fruit and vegetable intake than individual biomarkers in dietary intervention studies

PURPOSE: The aim of this study was to determine whether combining potential biomarkers of fruit and vegetables is better at predicting FV intake within FV intervention studies than single biomarkers.

DESIGN: Data from a tightly controlled randomised FV intervention study (BIOFAV; all food provided and two meals/day on weekdays consumed under supervision) were used. A total of 30 participants were randomised to either 2, 5 or 8 portions FV/day for 4 weeks, and blood samples were collected at baseline and 4 weeks for plasma vitamin C and serum carotenoid analysis. The combined biomarker approach was also tested in three further FV intervention studies conducted by the same research team, with less strict dietary control (FV provided and no supervised meals).

RESULTS: The combined model containing all carotenoids and vitamin C was a better fit than either the vitamin C only (P < 0.001) model or the lutein only (P = 0.006) model in the BIOFAV study. The C-statistic was slightly lower in the lutein only model (0.85) and in the model based upon factor analysis (0.88), and much lower in the vitamin C model (0.68) compared with the full model (0.95). Results for the other studies were similar, although the differences between the models were less marked.

CONCLUSIONS: Although there was some variation between studies, which may relate to the level of dietary control or participant characteristics, a combined biomarker approach to assess overall FV consumption may more accurately predict FV intake within intervention studies than the use of a single biomarker. The generalisability of these findings to other populations and study designs remains to be tested. 

Contemporary Politics in the Middle East (Cambridge: Polity, 2011 – third edition)

The third edition of this dynamic book has been fully revised and updated to provide a comprehensive introduction to contemporary politics in the Middle East. Purposefully employing a clear thematic structure and including a wide range of case studies, data, visuals and further reading guidance the book explores and analyses the major issues which define the politics of this region of the globe.
Milton-Edwards begins by introducing and explaining key concepts and debates and goes on to outline the impact of colonialism and its legacy, the rise of Arab nationalism and anti-colonial politics. She then examines major political issues affecting the region, such as American foreign policy, political Islam, war and conflict, political economy, democratization, ethnicity and the role of women. The book concludes by highlighting the politics of the region in the twenty-first century and the future challenges it faces. This is a perfect introduction for undergraduates, covering key political, economic and social debates and providing updates and guidance for further reading.

"The genius of this book is that it integrates together the different themes which run through Middle Eastern politics. The coherence of the approach which the author has adopted is indicated by the manner in which she has updated the work in this second edition. Despite the substantial changes which the East has undergone since 9/11 and the 2003 Gulf War, the original line of analysis retains all its force. It remains a key reference for all those who are seeking to understand the region's politics, whether undergraduates, postgraduates or lay readers."
Tim Niblock, Exeter University
"I welcome the new edition of this comprehensive guide to the politics of such an important region of the world. It combines sensible generalizations with useful case studies of particularly important subjects. It is a must for all those who want to understand the complex politics of the modern Middle East."
Roger Owen, Harvard University
"Beverley Milton-Edwards has produced an excellent book, which is both wide-ranging in its coverage and punchy in its arguments. As such, its functions are dual. It works well as a text book, introducing the general reader to key themes in the contemporary region, from oil politics to ethnicity, to women and nationalism. But it also works as a running commentary on key debates, such as the rile of colonialism and the relationship between Islam and democracy. In short, this is a book with attitude."
Philip Robins, St Antony's College, Oxford

Beyond Criminal Justice: An anthology of abolitionist papers presented to conferences of the European Group for the Study of Deviance and Social Control over the past decade

Beyond Criminal Justice presents a vision of a future without brutal, authoritarian and repressive penal regimes. Many of the papers brought together here have been unavailable for more than two decades. Their republication indicates not only their continuing theoretical importance to abolitionist studies but also how they provide important insights into the nature and legitimacy of criminal processes in the here and now. Contributors highlight the human consequences of the harms of imprisonment, evidencing the hurt, injury and damage of penal incarceration across a number of different countries in Europe. Focusing on penal power and prisoner contestation to such power, the moral and political crises of imprisonment are laid bare. The contributors to Beyond Criminal Justice explore the urgent need for a coherent, rational and morally and politically sophisticated theoretical basis for penal abolitionism. Advocating a utopian imagination and at the same time practical solutions already implemented in countries around Europe - alongside grappling with controversial debates such as abolitionist responses to rape and sexual violence - the book steps outside of common sense assumptions regarding 'crime', punishment and 'criminal justice'. Beyond Criminal Justice will be of interest to students of criminology, zemiology, sociology, penology and critical legal studies as well as anyone interested in rethinking the problem of 'crime' and challenging the logic of the penal rationale.

WHO guidelines for a healthy diet and mortality from cardiovascular disease in European and American elderly: the CHANCES project

BACKGROUND: Cardiovascular disease (CVD) represents a leading cause of mortality worldwide, especially in the elderly. Lowering the number of CVD deaths requires preventive strategies targeted on the elderly.

OBJECTIVE: The objective was to generate evidence on the association between WHO dietary recommendations and mortality from CVD, coronary artery disease (CAD), and stroke in the elderly aged ≥60 y.

DESIGN: We analyzed data from 10 prospective cohort studies from Europe and the United States comprising a total sample of 281,874 men and women free from chronic diseases at baseline. Components of the Healthy Diet Indicator (HDI) included saturated fatty acids, polyunsaturated fatty acids, mono- and disaccharides, protein, cholesterol, dietary fiber, and fruit and vegetables. Cohort-specific HRs adjusted for sex, education, smoking, physical activity, and energy and alcohol intakes were pooled by using a random-effects model.

RESULTS: During 3,322,768 person-years of follow-up, 12,492 people died of CVD. An increase of 10 HDI points (complete adherence to an additional WHO guideline) was, on average, not associated with CVD mortality (HR: 0.94; 95% CI: 0.86, 1.03), CAD mortality (HR: 0.99; 95% CI: 0.85, 1.14), or stroke mortality (HR: 0.95; 95% CI: 0.88, 1.03). However, after stratification of the data by geographic region, adherence to the HDI was associated with reduced CVD mortality in the southern European cohorts (HR: 0.87; 95% CI: 0.79, 0.96; I(2) = 0%) and in the US cohort (HR: 0.85; 95% CI: 0.83, 0.87; I(2) = not applicable).

CONCLUSION: Overall, greater adherence to the WHO dietary guidelines was not significantly associated with CVD mortality, but the results varied across regions. Clear inverse associations were observed in elderly populations in southern Europe and the United States.

A Constitution of Social Governance for the European Union

his chapter considers the EU’s socio-economic constitution under the lens of humaneness. It argues that the EU’s unique socio-economic constitution demands equilibrium of socio-economic integration instead of widening the gap between economic integration at EU levels and social integration at national levels. While the EU lacks the legislative competences to achieve this equilibrium, the constitutional principle still prevails. Indeed, the EU competences reflect its own values as well as the socio-economic constitutions of its constituent Member States. These frequently do not allow for total state-governance of social spheres such as working life, education, care or other social services. Instead, societal actors are given scope to (co-)govern these spheres at national levels. Accordingly, the apparent tension between the EU’s socio-economic values and principles and its limited competences in the social policy field can be resolved through a dynamic interpretation of the EU Treaties towards a “constitution of social governance”. This interpretation reads the Treaties as authorising governance by societal actors. The chapter connects the idea of humanness to the ideals of social governance at EU level and proposes two options for practical application of the concept. These are rules for trans-national labour markets based on European collective labour agreements and a European higher education sector developed by agreements between universities.

Reforming civil engineering studies in recession times

The recent global economic and financial crisis has led the economies of many countries into recession, in particular at the periphery of the European Union. These countries currently face a significant contraction of both public investment in infrastructure and private investment in buildings and, as a result, the unemployment is particularly noticeable in the civil engineering and building sectors. Consequently, in all countries in recession the professional development of fresh civil engineering graduates is disproportionate to their high study effort and qualifications, since they rarely have the opportunity to gain experience in practice and their knowledge gradually becomes obsolete. Under these circumstances, it is imperative for the technical universities in countries in recession to plan and implement a substantial reform of the civil engineering studies syllabus. The objective should be to enable graduates to broaden the scope of their professional activity and increase their employability. In this paper, the widening of civil engineering studies curricula is proposed, in particular in the light of the development of the graduates’ potential on project, programme and portfolio management. In this direction, after a thorough literature review, including ASCE's Body of Knowledge for the 21st century and IPMA's Competence Baseline, it is recommended among others: to increase significantly the offered modules on project management and add new modules on strategy management, leadership behavior, delivery management, organization and environment etc; to provide adequate professional training during the university studies five year period; and to promote fresh graduates’ certification by professional bodies. The proposals are exemplified by presenting a reformed syllabus for the civil engineering studies offered currently by the National Technical University of Athens.

High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era:an analysis based on data from the European Blood and Marrow Transplantation Registry

Autologous stem cell transplantation (ASCT) consolidation remains the treatment of choice for patients with relapsed diffuse large B cell lymphoma. The impact of rituximab combined with chemotherapy in either first- or second-line therapy on the ultimate results of ASCT remains to be determined, however. This study was designed to evaluate the benefit of ASCT in patients achieving a second complete remission after salvage chemotherapy by retrospectively comparing the disease-free survival (DFS) after ASCT for each patient with the duration of the first complete remission (CR1). Between 1990 and 2005, a total of 470 patients who had undergone ASCT and reported to the European Blood and Bone Transplantation Registry with Medical Essential Data Form B information were evaluated. Of these 470 patients, 351 (74%) had not received rituximab before ASCT, and 119 (25%) had received rituximab before ASCT. The median duration of CR1 was 11 months. The median time from diagnosis to ASCT was 24 months. The BEAM protocol was the most frequently used conditioning regimen (67%). After ASCT, the 5-year overall survival was 63% (95% confidence interval, 58%-67%) and 5-year DFS was 48% (95% confidence interval, 43%-53%) for the entire patient population. Statistical analysis showed a significant increase in DFS after ASCT compared with duration of CR1 (median, 51 months versus 11 months; P < .001). This difference was also highly significant for patients with previous exposure to rituximab (median, 10 months versus not reached; P < .001) and for patients who had experienced relapse before 1 year (median, 6 months versus 47 months; P < .001). Our data indicate that ASCT can significantly increase DFS compared with the duration of CR1 in relapsed diffuse large B cell lymphoma and can alter the disease course even in patients with high-risk disease previously treated with rituximab.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.