Early high-dose treatment: SCT results from the European High Risk Neuroblastoma Study

Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dose regimens to learn about potential superiority and toxicity profiles.Patients and Methods: At interim analysis 1483 high risk neuroblastoma patients (893 males) were included since 2002 with either INSS stage 4 disease (1383 pts) above 1 year, or as infants (59 pts) and stage 2&3 of any age (145 pts) with MYCN amplification. The median age at diagnosis was 2.9 years (1 month-19.9 years) with a median follow up of 3 years. Response eligibility criteria prior randomisation after Rapid Cojec Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and at least partial response at skeletal sites with no more than 3, but improved mIBG positive spots and a PBSC harvest of at least 3x10E6 CD34/kgBW. The randomised regimens were BuMel [busulfan oral till 2006, 4x150mg/m² in 4 ED; or intravenous use according to body weight as licenced thereafter; melphalan 140mg/m²/day) and CEM [carboplatinum ctn. infusion (4x AUC 4.1mg/ml.min/day, etoposid ctn. infusion (4x 338mg/m²/day or [4x 200mg/m²/day]*, melphalan (3x70mg/m²/day; 3x60mg/m²/day*;*reduced dosis if GFR< 100ml/min/1.73m²). Supportive care followed institutional guidelines. VOD prophylaxis included ursadiol, but randomised patients were not eligible for the prophylactic defibrotide trial. Local control included surgery and radiotherapy of 21Gy.Results: Of 1483 patients, 584 were being randomised for the high dose question at data lock. A significant difference in event free survival (3-year EFS 49% vs. 33%, p<0.001) and overall survival (3-year OS 61% vs. 48%, p=0.003) favouring the BuMel regimen over the CEM regimen was demonstrated. The relapse/progression rate was significantly higher after CEM (0.60±0.03) than after BuMel (0.48±0.03)(p<0.001). Toxicity data had reached 80% completeness at last analysis. The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p= 0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute HDT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%).Conclusions: The Peto rule of P<0.001 at interim analysis on the primary endpoint, EFS was met. Hence randomization was stopped with BuMel as recommended standard treatment in the HR-NBl1/SIOPEN trial which is still accruing for the randomised immunotherapy question.

Strategic groupsin the European energy industry

Strategisten ryhmien teoria tarjoaa mahdollisuuden keskitason analyysiin yritysten ja toimialan välillä yritysten kilpailullisen aseman tarkasteluun. Strategiset ryhmät ovat samalla toimialalla toimivia yrityksiä, joilla on samanlaiset strategiset ominaisuudet, jotka kilpailevat samanlaisilla perusteilla tai jotka toteuttavat samanlaista strategiaa. Tässä tutkimuksessa strategisten ryhmien teoriaa on käytetty eurooppalaisten energiayritysten ryhmittelyyn. Tutkimuksessa oli mukana 104 energia-alan yritystä, jotka jaettiin viiteen strategiseen pääryhmään yritysten maantieteellisen toiminta-alueen ja koon mukaan. Jokainen ryhmä edustaa erilaista strategiaa. Muita strategisia ominaisuuksia, joita ovat diversifikaatioaste, tuotantoteknologia ja omistusmuoto, käytettiin muodostamaan alaryhmiä edellisistä pääryhmistä. Muodostettuja strategisia ryhmiä käytettiin seuraavaksi suoristuskykyerojen tutkimiseen ryhmien välillä. Suorituskykyä kuvaaviksi muuttujiksi valittiin liikevoitto-%, koko pääoman tuottoaste, vakavaraisuus-% ja current ratio. Tulokset osoittavat, että energiayritykset voidaan jakaa ryhmiin valittujen strategisten ominaisuuksien perusteella. Nämä yritysten strategiset valinnat eivät vaikuta merkittävästi yritysten taloudelliseen suorituskykyyn valittujen suorituskykymuuttujien osalta. Monikansalliset jättiläisyritykset ovat suorituskyvyltään heikoimpia ja eurooppalaiset suuryritykset parhaita ryhmiä, mutta erot eivät ole tilastollisesti merkittäviä. Ainut merkittävä ero suorituskykymuuttujissa oli vakavaraisuudessa monikansallisten ja eurooppalaisten suurten yritysten välillä. Muut suorituskykymuuttujat eivät eronneet ryhmien välillä tilastollisesti merkittävästi. Tilastollisesti merkittäviä eroja ei löydetty myöskään alaryhmien välillä.

Determinants of the price of allowance in the European Union emissions trading market

Teorian mukaan täydellisen kilpailun päästöoikeuskauppamarkkinoilla päästöoikeuden hinta muodostuu markkinoilla vallitsevan päästöjen vähentämisen rajakustannuksen perusteella. Euroopan päästökauppamarkkinoilla päästöjen vähentämisen kustannuksia nostavat suhteellisen lyhyet päästökauppajaksot ja epävarmuus järjestelmän jatkuvuudesta. Toisaalta päästökaupan osallistujien yhteenlaskettu päästöjen vähentämisen tarve lienee suhteellisen vähäinen ellei olematon ensimmäisellä päästökauppajaksolla. Euroopan päästökauppamarkkinoilla päästöjen vähentämisen tarve ja päästöjenvähentämisen kustannukset ovat osittain riippuvaisia muuttuvista tekijöistä. Päästöoikeuden hintaan voivat vaikuttaa päästökauppajakson aikana tapahtuva teollisuuden suhdannevaihtelu, polttoaineiden hintojen heilahtelut sekä säätilojen vaihtelu. Päästökaupan ensimmäisinä kuukausina päästöoikeuden hintakehityksellä on ollut yhteyksiä tekijöihin, joiden muutosten tulisikin vaikuttaa päästökauppamarkkinoiden tasapainoon. Näitä tekijöitä ovat esimerkiksi polttoainemarkkinoiden ja sähkömarkkinoiden hintakehitys sekä vaihtelut säätiloissa.

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months). Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 25%; P = .001), and the median duration of response was longer (17.2 v 13.4 months; P = .03). The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia. CONCLUSION VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.

Mobile Communications within the European Union: The Role of Location in the Evolution and Forecasting of the Diffusion Process

In the European Union, the importance of mobile communications was realized early on. The process of mobile communications becoming ubiquitous has taken time, as the innovation of mobile communications diffused into the society. The aim of this study is to find out how the evolution and spatial patterns of the diffusion of mobile communications within the European Union could be taken into account in forecasting the diffusion process. There is relatively lot of research of innovation diffusion on the individual (micro) andthe country (macro) level, if compared to the territorial level. Territorial orspatial diffusion refers either to the intra-country or inter-country diffusionof an innovation. In both settings, the dif- fusion of a technological innovation has gained scarce attention. This study adds knowledge of the diffusion between countries, focusing especially on the role of location in this process. The main findings of the study are the following: The penetration rates of the European Union member countries have become more even in the period of observation, from the year 1981 to 2000. The common digital GSM system seems to have hastened this process. As to the role of location in the diffusion process, neighboring countries have had similar diffusion processes. They can be grouped into three, the Nordic countries, the central and southern European countries, and the remote southern European countries. The neighborhood effect is also domi- nating in thegravity model which is used for modeling the adoption timing of the countries. The subsequent diffusion within a country, measured by the logistic model in Finland, is af- fected positively by its economic situation, and it seems to level off at some 92 %. Considering the launch of future mobile communications systemsusing a common standard should implicate an equal development between the countries. The launching time should be carefully selected as the diffusion is probably delayed in economic downturns. The location of a country, measured by distance, can be used in forecasting the adoption and diffusion. Fi- nally, the result of penetration rates becoming more even implies that in a relatively homoge- nous set of countries, such as the European Union member countries, the estimated final pene- tration of a single country can be used for approximating the penetration of the others. The estimated eventual penetration of Finland, some 92 %, should thus also be the eventual level for all the European Union countries and for the European Union as a whole.

Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey.

BACKGROUND: Predicting outcome of breast cancer (BC) patients based on sentinel lymph node (SLN) status without axillary lymph node dissection (ALND) is an area of uncertainty. It influences the decision-making for regional nodal irradiation (RNI). The aim of the NORA (NOdal RAdiotherapy) survey was to examine the patterns of RNI. METHODS: A web-questionnaire, including several clinical scenarios, was distributed to 88 EORTC-affiliated centers. Responses were received between July 2013 and January 2014. RESULTS: A total of 84 responses were analyzed. While three-dimensional (3D) radiotherapy (RT) planning is carried out in 81 (96%) centers, nodal areas are delineated in only 51 (61%) centers. Only 14 (17%) centers routinely link internal mammary chain (IMC) and supraclavicular node (SCN) RT indications. In patients undergoing total mastectomy (TM) with ALND, SCN-RT is recommend by 5 (6%), 53 (63%) and 51 (61%) centers for patients with pN0(i+), pN(mi) and pN1, respectively. Extra-capsular extension (ECE) is the main factor influencing decision-making RNI after breast conserving surgery (BCS) and TM. After primary systemic therapy (PST), 49 (58%) centers take into account nodal fibrotic changes in ypN0 patients for RNI indications. In ypN0 patients with inner/central tumors, 23 (27%) centers indicate SCN-RT and IMC-RT. In ypN1 patients, SCN-RT is delivered by less than half of the centers in patients with ypN(i+) and ypN(mi). Twenty-one (25%) of the centers recommend ALN-RT in patients with ypN(mi) or 1-2N+ after ALND. Seventy-five (90%) centers state that age is not considered a limiting factor for RNI. CONCLUSION: The NORA survey is unique in evaluating the impact of SLNB/ALND status on adjuvant RNI decision-making and volumes after BCS/TM with or without PST. ALN-RT is often indicated in pN1 patients, particularly in the case of ECE. Besides the ongoing NSABP-B51/RTOG and ALLIANCE trials, NORA could help to design future specific RNI trials in the SLNB era without ALND in patients receiving or not PST.

The international multidisciplinary consensus conference on multimodality monitoring in neurocritical care: evidentiary tables : a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine.

A variety of technologies have been developed to assist decision-making during the management of patients with acute brain injury who require intensive care. A large body of research has been generated describing these various technologies. The Neurocritical Care Society (NCS) in collaboration with the European Society of Intensive Care Medicine (ESICM), the Society for Critical Care Medicine (SCCM), and the Latin America Brain Injury Consortium (LABIC) organized an international, multidisciplinary consensus conference to perform a systematic review of the published literature to help develop evidence-based practice recommendations on bedside physiologic monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews on physiologic processes important in the care of acute brain injury. In this article we provide the evidentiary tables for select topics including systemic hemodynamics, intracranial pressure, brain and systemic oxygenation, EEG, brain metabolism, biomarkers, processes of care and monitoring in emerging economies to provide the clinician ready access to evidence that supports recommendations about neuromonitoring.

The international multidisciplinary consensus conference on multimodality monitoring in neurocritical care: a list of recommendations and additional conclusions : a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine.

Careful patient monitoring using a variety of techniques including clinical and laboratory evaluation, bedside physiological monitoring with continuous or non-continuous techniques and imaging is fundamental to the care of patients who require neurocritical care. How best to perform and use bedside monitoring is still being elucidated. To create a basic platform for care and a foundation for further research the Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to develop recommendations about physiologic bedside monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews as a background to the recommendations. In this article, we highlight the recommendations and provide additional conclusions as an aid to the reader and to facilitate bedside care.

Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet.

In 2008, a European registry of relapsed acute promyelocytic leukemia was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (P=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the 3-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90 and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in second CR (n=93), the 3-year OS was 80% compared with 59% without transplantation (n=55) (P=0.03). Multivariable analysis demonstrated the favorable prognostic impact of first remission duration ⩾1.5 years, achievement of mCR and allogeneic or autologous transplantation on OS of patients alive after induction (P=0.03, P=0.01, P=0.01) and on leukemia-free survival (P=0.006, P<0.0001, P=0.003), respectively.

Uses of cancer registries for public health and clinical research in Europe : results of the European Network of Cancer Registries survey among 161 population-based cancer registries during 2010-2012

AIM: To provide insight into cancer registration coverage, data access and use in Europe. This contributes to data and infrastructure harmonisation and will foster a more prominent role of cancer registries (CRs) within public health, clinical policy and cancer research, whether within or outside the European Research Area. METHODS: During 2010-12 an extensive survey of cancer registration practices and data use was conducted among 161 population-based CRs across Europe. Responding registries (66%) operated in 33 countries, including 23 with national coverage. RESULTS: Population-based oncological surveillance started during the 1940-50s in the northwest of Europe and from the 1970s to 1990s in other regions. The European Union (EU) protection regulations affected data access, especially in Germany and France, but less in the Netherlands or Belgium. Regular reports were produced by CRs on incidence rates (95%), survival (60%) and stage for selected tumours (80%). Evaluation of cancer control and quality of care remained modest except in a few dedicated CRs. Variables evaluated were support of clinical audits, monitoring adherence to clinical guidelines, improvement of cancer care and evaluation of mass cancer screening. Evaluation of diagnostic imaging tools was only occasional. CONCLUSION: Most population-based CRs are well equipped for strengthening cancer surveillance across Europe. Data quality and intensity of use depend on the role the cancer registry plays in the politico, oncomedical and public health setting within the country. Standard registration methodology could therefore not be translated to equivalent advances in cancer prevention and mass screening, quality of care, translational research of prognosis and survivorship across Europe. Further European collaboration remains essential to ensure access to data and comparability of the results.

The reform of the European Energy Tax Directive reform : effect on prices

[spa] Para hacer frente a los riesgos relacionados con la contaminación atmosférica, es ampliamente aceptada la necesidad de instrumentos de política encaminados a reducir las emisiones. La intervención tiene por objeto reducir las conductas contaminantes y incentivar una conducta más respetuosa y el uso de tecnologías más eficientes. La Unión Europea cuenta con dos importantes mecanismos económicos para el control de emisiones a escala europea: la directiva sobre los impuestos energéticos, un instrumento de fiscalidad ambiental aprobado en 2003 que afecta el precio de los productos energéticos, y el sistema de comercio de los derechos de emisiones, introducido en 2005, que afecta directamente a la cantidad de emisiones de CO2. En 2011, la Comisión Europea propuso una nueva versión de la directiva sobre los impuestos energéticos. El objetivo principal de la propuesta es aumentar la eficacia del instrumento a través de una mayor presión fiscal sobre los productos energéticos y de coordinar este instrumento de fiscalidad medioambiental con el sistema de comercio de los derechos de emisiones, para establecer una señal de precio de CO2 coherente para todos los sectores. Sin embargo, en mayo de 2012 el Parlamento Europeo bloqueó la propuesta de la nueva versión del impuesto, y el proceso de actualización se detuvo. La preocupación principal parecía ser el efecto de dicha propuesta en la competitividad, en particular para los sectores que serían los más afectados dado el uso intensivo de los productos energéticos, como el sector del transporte. El objetivo de este estudio es analizar el efecto que la reforma de la directiva sobre los impuestos energéticos podría tener sobre el nivel de precios, en particular en los países de la Unión Europea donde esta reforma implicaría un aumento de los impuestos energéticos. Utilizando datos del proyecto “World Input-Output Database”, la principal conclusión es que el nuevo sistema de impuestos energéticos tendría un impacto muy bajo sobre los precios. Por lo tanto, dado que los precios no serían fuertemente afectados por la reforma, no habrá inconvenientes para la competitividad y implicaciones en términos de distribución, pero, por otro lado, este resultado también implica una baja capacidad de esta reforma para provocar cambios en el consumo y la producción hacia menos presiones ambientales.

Timeframe of speciation inferred from secondary contact zones in the European tree frog radiation (Hyla arborea group).

BACKGROUND: Hybridization between incipient species is expected to become progressively limited as their genetic divergence increases and reproductive isolation proceeds. Amphibian radiations and their secondary contact zones are useful models to infer the timeframes of speciation, but empirical data from natural systems remains extremely scarce. Here we follow this approach in the European radiation of tree frogs (Hyla arborea group). We investigated a natural hybrid zone between two lineages (Hyla arborea and Hyla orientalis) of Mio-Pliocene divergence (~5 My) for comparison with other hybrid systems from this group. RESULTS: We found concordant geographic distributions of nuclear and mitochondrial gene pools, and replicated narrow transitions (~30 km) across two independent transects, indicating an advanced state of reproductive isolation and potential local barriers to dispersal. This result parallels the situation between H. arborea and H. intermedia, which share the same amount of divergence with H. orientalis. In contrast, younger lineages show much stronger admixture at secondary contacts. CONCLUSIONS: Our findings corroborate the negative relationship between hybridizability and divergence time in European tree frogs, where 5 My are necessary to achieve almost complete reproductive isolation. Speciation seems to progress homogeneously in this radiation, and might thus be driven by gradual genome-wide changes rather than single speciation genes. However, the timescale differs greatly from that of other well-studied amphibians. General assumptions on the time necessary for speciation based on evidence from unrelated taxa may thus be unreliable. In contrast, comparative hybrid zone analyses within single radiations such as our case study are useful to appreciate the advance of speciation in space and time.

The reform of the European Energy Tax Directive reform : effect on prices

[spa] Para hacer frente a los riesgos relacionados con la contaminación atmosférica, es ampliamente aceptada la necesidad de instrumentos de política encaminados a reducir las emisiones. La intervención tiene por objeto reducir las conductas contaminantes y incentivar una conducta más respetuosa y el uso de tecnologías más eficientes. La Unión Europea cuenta con dos importantes mecanismos económicos para el control de emisiones a escala europea: la directiva sobre los impuestos energéticos, un instrumento de fiscalidad ambiental aprobado en 2003 que afecta el precio de los productos energéticos, y el sistema de comercio de los derechos de emisiones, introducido en 2005, que afecta directamente a la cantidad de emisiones de CO2. En 2011, la Comisión Europea propuso una nueva versión de la directiva sobre los impuestos energéticos. El objetivo principal de la propuesta es aumentar la eficacia del instrumento a través de una mayor presión fiscal sobre los productos energéticos y de coordinar este instrumento de fiscalidad medioambiental con el sistema de comercio de los derechos de emisiones, para establecer una señal de precio de CO2 coherente para todos los sectores. Sin embargo, en mayo de 2012 el Parlamento Europeo bloqueó la propuesta de la nueva versión del impuesto, y el proceso de actualización se detuvo. La preocupación principal parecía ser el efecto de dicha propuesta en la competitividad, en particular para los sectores que serían los más afectados dado el uso intensivo de los productos energéticos, como el sector del transporte. El objetivo de este estudio es analizar el efecto que la reforma de la directiva sobre los impuestos energéticos podría tener sobre el nivel de precios, en particular en los países de la Unión Europea donde esta reforma implicaría un aumento de los impuestos energéticos. Utilizando datos del proyecto “World Input-Output Database”, la principal conclusión es que el nuevo sistema de impuestos energéticos tendría un impacto muy bajo sobre los precios. Por lo tanto, dado que los precios no serían fuertemente afectados por la reforma, no habrá inconvenientes para la competitividad y implicaciones en términos de distribución, pero, por otro lado, este resultado también implica una baja capacidad de esta reforma para provocar cambios en el consumo y la producción hacia menos presiones ambientales.