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There is a persistent variation in cancer outcomes among and within European countries suggesting (among other causes) inequalities in access to or delivery of high‐quality cancer care. European policy (EU Cancer Mission and Europe’s Beating Cancer Plan) is currently moving towards a mission‐oriented approach addressing these inequalities. In this study, we used the quantitative and qualitative data of the Organisation of European Cancer Institutes’ Accreditation and Designation Programme, relating to 40 large European cancer centres, to describe their current compliance with quality standards, to identify the hallmarks common to all centres and to show the distinctive features of Comprehensive Cancer Centres. All Comprehensive Cancer Centres and Cancer Centres accredited by the Organisation of European Cancer Institutes show good compliance with quality standards related to care, multidisciplinarity and patient centredness. However, Comprehensive Cancer Centres on average showed significantly better scores on indicators related to the volume, quality and integration of translational research, such as high‐impact publications, clinical trial activity (especially in phase I and phase IIa trials) and filing more patents as early indicators of innovation. However, irrespective of their size, centres show significant variability regarding effective governance when functioning as entities within larger hospitals., This study reveals the attributes of cancer centres based on data from 40 large European cancer centres, showing that Comprehensive Cancer Centres have significantly greater output of peer‐reviewed publications and clinical trials than other centres, and that the quality of multidisciplinarity is well established in all accredited cancer centres.

We undertook a cost-effectiveness analysis (CEA) to compare an exercise and nutritional program with the usual nutritional care concomitant to adjuvant chemotherapy in localized breast cancer patients. The CEA was designed as part of the interventional, controlled, randomized, single-center, open-label PASAPAS study. Breast cancer patients receiving first-line adjuvant chemotherapy at a French Comprehensive Cancer Center were randomized 2:1 to a 6-month exercise program of supervised indoor and outdoor group sessions in addition to usual nutritional care (exercise arm) or a usual nutritional care group receiving dietary and physical activity counseling (control arm). Costs were assessed from the French national insurance perspective (in Euros, 2012). Incremental cost-effectiveness ratios (ICERs) were calculated for four criteria: body mass index, waist circumference, body fat percentage, and estimated aerobic capacity. Uncertainty around the ICERs was captured by a probabilistic analysis using a non-parametric bootstrap method. The analysis was based on 60 patients enrolled between 2011 and 2013. Average intervention costs per participant were €412 in the exercise arm (n = 41) and €117 (n = 19) in the control arm. Total mean costs were €17,344 (standard deviation 9,928) and €20,615 (standard deviation 14,904), respectively, did not differ significantly (p = 0.51). The 6-month exercise program was deemed to be cost-effective compared with usual care for the estimated aerobic capacity. Multicenter randomized studies with long-term costs and outcomes should be done to provide additional evidence. Clinical trial: The PASAPAS study is registered under ClinicalTrials.gov. Trial registration ID: NCT01331772.

A comprehensive cancer approach covering the entire research–care–prevention continuum can achieve a 10‐year cancer‐specific survival for 75% of patients diagnosed in EU member states with well‐developed health care by 2030. To ensure access to a critical mass of patient biological and technological resources, infrastructures for translational research, clinical and prevention trials, and outcomes research are needed. Here, we provide recommendations for achieving key targets and prioritize research areas., A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research–care–prevention continuum has the potential to achieve in 2030 a 10‐year cancer‐specific survival for 75% of patients diagnosed in European Union (EU) member states with a well‐developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high‐quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science‐driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC‐like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long‐term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans‐border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence‐based advice.

Pesticides have been associated with various pathologies, and there is growing evidence of pesticide presence in domestic environments. However, most available studies focused on a limited number of pesticides or households, and few have been conducted in Europe. We aimed to assess indoor pesticide contamination by screening the prevalence of 276 pesticides and ten pesticide metabolites, in French households from different agricultural and urban areas. We sampled indoor dust from 239 households in 2012, proximate to orchards (n = 69), cereals (n = 66) and vineyard (n = 68) crops, or from urban area (n = 36). we used cellulose wipes moistened with isopropanol and polypropylene dust traps to collect recent (7 and 30 days, respectively) and settled dust (6 months). Overall, 125 pesticides and piperonyl butoxide were detected at least once in households, mostly at low prevalence: 97 in recent dust, and 111 in settled dust. In recent dust, the most prevalent compounds were o-phenylphenol (168 households, 70%), pentachlorophenol (86, 36%), and piperonyl butoxide (82, 34%). In addition to agricultural pesticides, we found a high proportion of domestic and banned compounds in recent and settled house dust. Several pesticides were identified in house dust, from different pesticide groups and sources. Our results suggest that domestic usage and persistence of banned pesticides may contribute substantially to indoor pesticide contamination. Graphical abstract 97 pesticides detected in households' recent indoor dust.

Background: Studies using metabolomic data have identified metabolites from several compound classes that are associated with disease-related lifestyle factors.Objective: In this study, we identified metabolic signatures reflecting lifestyle patterns and related them to the risk of hepatocellular carcinoma (HCC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.Design: Within a nested case-control study of 147 incident HCC cases and 147 matched controls, partial least squares (PLS) analysis related 7 modified healthy lifestyle index (HLI) variables (diet, BMI, physical activity, lifetime alcohol, smoking, diabetes, and hepatitis) to 132 targeted serum-measured metabolites and a liver function score. The association between the resulting PLS scores and HCC risk was examined in multivariable conditional logistic regression models, where ORs and 95% CIs were computed.Results: The lifestyle component's PLS score was negatively associated with lifetime alcohol, BMI, smoking, and diabetes, and positively associated with physical activity. Its metabolic counterpart was positively related to the metabolites sphingomyelin (SM) (OH) C14:1, C16:1, and C22:2, and negatively related to glutamate, hexoses, and the diacyl-phosphatidylcholine PC aaC32:1. The lifestyle and metabolomics components were inversely associated with HCC risk, with the ORs for a 1-SD increase in scores equal to 0.53 (95% CI: 0.38, 0.74) and 0.28 (0.18, 0.43), and the associated AUCs equal to 0.64 (0.57, 0.70) and 0.74 (0.69, 0.80), respectively.Conclusions: This study identified a metabolic signature reflecting a healthy lifestyle pattern which was inversely associated with HCC risk. The metabolic profile displayed a stronger association with HCC than did the modified HLI derived from questionnaire data. Measuring a specific panel of metabolites may identify strata of the population at higher risk for HCC and can add substantial discrimination compared with questionnaire data. This trial was registered at clinicaltrials.gov as NCT03356535.

Background: The “meeting-in-the-middle” (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case–control study of hepatocellular carcinoma (HCC) within European Prospective Investigation into Cancer and Nutrition (EPIC), where healthy lifestyle index (HLI) variables were related to targeted serum metabolites. Methods: Lifestyle and targeted metabolomic data were available from 147 incident HCC cases and 147 matched controls. Partial least squares analysis related 7 lifestyle variables from a modified HLI to a set of 132 serum-measured metabolites and a liver function score. Mediation analysis evaluated whether metabolic profiles mediated the relationship between each lifestyle exposure and HCC risk. Results: Exposure-related metabolic signatures were identified. Particularly, the body mass index (BMI)-associated metabolic component was positively related to glutamic acid, tyrosine, PC aaC38:3, and liver function score and negatively to lysoPC aC17:0 and aC18:2. The lifetime alcohol-specific signature had negative loadings on sphingomyelins (SM C16:1, C18:1, SM(OH) C14:1, C16:1 and C22:2). Both exposures were associated with increased HCC with total effects (TE) = 1.23 (95% confidence interval = 0.93–1.62) and 1.40 (1.14–1.72), respectively, for BMI and alcohol consumption. Both metabolic signatures mediated the association between BMI and lifetime alcohol consumption and HCC with natural indirect effects, respectively, equal to 1.56 (1.24–1.96) and 1.09 (1.03–1.15), accounting for a proportion mediated of 100% and 24%. Conclusions: In a refined MITM framework, relevant metabolic signatures were identified as mediators in the relationship between lifestyle exposures and HCC risk. Impact: The understanding of the biological basis for the relationship between modifiable exposures and cancer would pave avenues for clinical and public health interventions on metabolic mediators. Cancer Epidemiol Biomarkers Prev; 27(5); 531–40. ©2018 AACR.

Introduction Dioxins are environmental and persistent pollutants mostly emitted from combustion facilities (e.g. waste incinerators, metal and cement industries). Known to be endocrine disrupting chemicals, dioxins are suspected to increase breast cancer (BC) risk. Although diet is considered the primary source of dioxin exposure, no previous study has been published on dietary dioxin exposure in relation to BC risk. We aimed to assess dietary dioxin exposure among women from the E3N cohort and estimate BC risk associated with this exposure. Methods The study included 63,830 women from the E3N cohort who completed a diet history questionnaire (DHQ) in 1993 and were followed until 2008. Dietary dioxin exposure was estimated by combining consumption data from the E3N DHQ and food dioxin contamination data from a French national monitoring program. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox models adjusted for BC risk factors. Results Mean dietary dioxin exposure was estimated at 1.3 ± 0.4 pg/kg body weight (BW)/day. A 0.4 pg/kg BW/d increase in dioxin intake was not associated with overall BC risk (HR = 1.00; 95% CI: 0.96, 1.05). A significant decrease in risk of estrogen receptor negative (ER-)/progesterone receptor negative (PR-) tumors was observed among post-menopausal women in the upper quartile of estimated dioxin intake (HR for Q4 vs. Q1: 0.65; 95% CI: 0.45, 0.96; P for trend across quartiles = 0.0463). Conclusions Overall, no association between estimated dietary dioxin exposure and BC risk was found among E3N women. Further studies should include both dietary and environmental exposures to determine whether low-dose dioxin exposure is associated with BC risk. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0536-9) contains supplementary material, which is available to authorized users.

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High-dose chemotherapy followed by autologous bone marrow transplantation is a therapeutic option for patients with chemotherapy-sensitive non-Hodgkin's lymphoma who have relapses. In this report we describe a prospective randomized study of such treatment. A total of 215 patients with relapses of non-Hodgkin's lymphoma were treated between July 1987 and June 1994. All patients received two courses of conventional chemotherapy. The 109 patients who had a response to chemotherapy were randomly assigned to receive four courses of chemotherapy plus radiotherapy (54 patients) or radiotherapy plus intensive chemotherapy and autologous bone marrow transplantation (55 patients). The overall rate of response to conventional chemotherapy was 58 percent; among patients with relapses after chemotherapy, the response rate was 64 percent, and among those with relapses during chemotherapy, the response rate was 21 percent. There were three deaths from toxic effects among the patients in the transplantation group, and none among those in the group receiving chemotherapy without transplantation. The two groups did not differ in terms of prognostic factors. The median follow-up time was 63 months. The response rate was 84 percent after bone marrow transplantation and 44 percent after chemotherapy without transplantation. At five years, the rate of event-free survival was 46 percent in the transplantation group and 12 percent in the group receiving chemotherapy without transplantation (P = 0.001), and the rate of overall survival was 53 and 32 percent, respectively (P = 0.038). As compared with conventional chemotherapy, treatment with high-dose chemotherapy and autologous bone marrow transplantation increases event-free and overall survival in patients with chemotherapy-sensitive non-Hodgkin's lymphoma in relapse

Working paper GATE 08-22; Background: The impact of compliance to clinical practice guidelines (CPG) on outcomes and/or costs of care has not been completely clarified.Objective: To estimate relationships between medical expenditures and compliance to CPG for initial sarcoma treatment.Research design: Selected cohorts of patients diagnosed with sarcoma in 2005 and 2006, and treated at the University hospital and/or the cancer centre of the Rhône-Alpes region, France (n=90). Main outcome measurements were: patient characteristics, compliance with CPG, health outcomes, and costs. Data were mainly extracted from patient records. The logarithm of treatment costs was modelled using linear and Tobit regressions.Results: Rates of compliance with CPG were 86%, 66%, 88%, 89%, and 95% for initial diagnosis, primary surgical excision, wide surgical excision, chemotherapy, and radiotherapy, respectively. Total average costs reached €24,439, with €1,784, €11,225, €10,360, and €1,016 for diagnosis, surgery (primary and wide surgical excisions), chemotherapy, and radiotherapy, respectively. Compliance of diagnosis with CPG decreased the cost of diagnosis, whereas compliance of primary surgical excision increased the cost of chemotherapy. Compliance of chemotherapy with CPG decreased the cost of radiotherapy.Conclusion: Since chemotherapy is one of the major cost drivers, these results support that compliance with guidelines increases medical care expenditures in short term.

All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, step-wise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to setting up transnational collaboration. Through its activities, CoCanCPG will make an important contribution towards better access to evidence-based cancer practices and thus contribute to reducing inequalities and improving care for patients with cancer across Europe.

In a retrospective analysis of 87 cases of Caucasian childhood non-Hodgkin malignant lymphoma (NHML) from Lyon, France, all the case were diffuse lymphomas, but 47 were diagnosed as monomorphic small non-cleaved NHML, pathologically indistinguishable from Burkitt's lymphoma (BL). BL could then be the most frequent childhood lymphoma in France. This homogeneous series allows better definition of the characteristics of BL within NHML. Age distribution is similar to that of endemic BL, with a sex ratio of 3.7/1. Abdominal masses are initially present in 68% of the cases, whereas jaw is involved in only 4%. The disease is characterized by its overwhelming evolution in the absence of therapy. However, complete remission (CR) is usually obtained after the first chemtherapy regimen. Most relapses occur at 3-8 months. Death could be related to cerebrospinal fluid (CSF) involvement, local recurrence or secondary marrow involvement. Ninety per cent of the patients alive with no evidence of disease (NED) 8 months after CR can be considered as definitely cured. Our study on Caucasian children with NHML indicates that, from histological and clinical criteria, nearly half the cases are very similar to African BL. Even though EBV rarely associated with our cases, BL could be a worldwide lymphoma.

Acute renal failure with preserved renal plasma flow induced by cancer immunotherapy. Adoptive immunotherapy in patients with advanced cancer produces significant regression of metastatic disease in selected patients, but it is complicated by severe side effects. Prevention of these complications is still limited because their precise mechanisms remain unknown. For this reason we have investigated renal function and hemodynamic parameters in 16 patients with renal cell carcinoma before and during treatment with a combination of high doses of both recombinant interleukin-2 (rIL2) and recombinant α-interferon. After patients had received three injections of combined immunotherapy, there was a decrease in mean blood pressure (-20%), glomerular filtration rate (-25%), urine output (-50%), and fractional sodium excretion (-0.8%). This was associated with an increase in heart rate (+30%), plasma creatinine level (+30%), fractional potassium excretion (+14%) and microalbuminuria (+130%). However, renal plasma flow remained constant. The increment in microalbuminuria may reflect an alteration of glomerular capillary permeability. The reduction in GFR may be accounted either for a decrease in efferent to afferent arteriolar resistance ratio, leading to a decrease in glomerular capillary pressure, or for a decrease in ultrafiltration coefficient, or both. Nonsteroidal antiinflammatory drugs, such as ketoprofen, used to minimize side effects, could considerably worsen renal function and should be avoided in patients treated by rIL2. Our results bring new insights into the pathogenesis of functional acute renal failure and provide a rational basis for the use of vasopressors in the treatment of cytokine-induced acute renal failure.

Background The incidence of testicular germ cell tumors (TGCT), the most common cancer in men aged 15 to 45 years, has doubled over the last 30 years in developed countries. Reasons remain unclear but a role of environmental factors, especially during critical periods of development, is strongly suspected. Reliable data on environmental exposure during this critical time period are sparse. Little is known on whether it could be a combined effect of early and later-life exposures. Methods/Design Our research aims to study the association between TGCT risk and pesticide exposures (domestic, occupational and environmental) during critical time periods of development and combined early and later-life exposures. The study design, developed during a 2-year pilot study, is a multicenter case–control study of 500 cases (ascertained through histology) and 1000 fertile/fecund controls recruited through 21 French ‘Centres d’Etude et de Conservation des Œufs et de Sperme humain’ (CECOS). Trained professional interviewers interview the subjects and their mothers by phone. Using a geographic information system developed and tested for application in this study design, environmental pesticides exposure assessment is based on life-time residential history. Occupational pesticides exposures are assessed by an industrial hygienist based on parents’ occupations and tasks. Exposures during the prenatal period, early childhood and puberty are focused. A blood sample is collected from each participant to assess genetic polymorphisms known to be associated with TGCT risk, as well as to explore gene-environment interactions. Discussion The results of our study will contribute to better understanding the causes of TGCT and the rapid increase of its incidence. We explore the effect of combined early and later-life pesticides exposure from multiple sources, as well as potential gene-environment interactions that have until now been rarely studied for TGCT. Our design allows future pooled studies and the bio-bank allows additional genetic or toxicological analyses.

Diet is a modifiable risk factor for many cancers. It has been estimated that about a third of cancer cases can be prevented by complying with a healthy diet and adhering to the recommendations in terms of nutrition. The nutrition-cancer relationship is a complex one, and its study is currently at a turning point with the opportunity and challenges brought by the recent technological advances in the fields of « -omics ».This thesis aims to develop new biostatistical approaches to investigate the nutrition-cancer relation within the European Prospective Investigation into Cancer and nutrition (EPIC) study. To do so, the applicability of new methodologies in the field of nutritional epidemiology has been examined.First, a new multivariate dimension reduction method, the Treelet Transform (TT) was applied to extract nutrient patterns relying on questionnaire data. The extracted patterns were more easily interpretable than those obtained with more classical methods.Then, an analytical framework was conceived for the « meeting-in-the-middle » (MITM) principle and applied to two nested case-control studies on hepatocellular carcinoma, with targeted and untargeted metabolomics data. The MITM aims to identify overlap biomarkers of certain exposures that are at the same time predictive of disease outcomes. The implementation focused on the application of partial least squares and mediation analyses. Last, the association between 60 plasma fatty acids levels assessed from biomarkers and breast cancer risk was examined in a nested case-control study in EPIC. This thesis will serve as a basis for future epidemiological applications looking into the nutrition-cancer relation, La nutrition est un facteur de risque modifiable pour le cancer puisqu'environ un tiers des cas pourraient être évités en adoptant une meilleure alimentation. La relation entre nutrition et cancer est complexe, et son étude est enrichie par de nouveaux défis apportés par les récentes avancées technologiques dans le domaine des « -omiques ». Cette thèse a pour but de développer de nouvelles approches biostatistiques afin d'étudier la relation entre nutrition et cancer au sein de la cohorte EPIC. Pour ce faire, l'applicabilité de nouvelles méthodologies multivariées dans le domaine de l'épidémiologie nutritionnelle a été étudiée.Une nouvelle méthode multivariée pour la réduction de la dimensionnalité, le Treelet Transform (TT), a été examinée afin d'extraire des patterns de nutriments issus de questionnaires. Les patterns ainsi obtenus par le TT étaient plus facilement interprétables que par les méthodes classiques. Ensuite, un cadre analytique pour implémenter le concept du « meeting-in-the-middle » (MITM) a été développé et appliqué dans 2 études cas-témoin nichées sur le cancer hépatocellulaire avec des données métabolomiques. Le MITM cherche à identifier des biomarqueurs qui soient à la fois des marqueurs de certaines expositions passées et des prédicteurs de maladies. L'implémentation s'est focalisée sur l'application de la PLS et de l'analyse de médiation.Enfin, nous avons examinés la relation entre les niveaux plasmatiques de 60 acides gras issus de biomarqueurs et le risque de cancer du sein dans une étude cas-témoin nichée dans EPIC.Cette thèse servira de base pour des applications épidémiologiques futures examinant la relation nutrition-cancer