o 013safety and efficacy of trifluridine tipiracil in previously treated metastatic colorectal cancer mcrc preliminary results from the phase iiib international open label early access preconnect study

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Prediction of survival with second-line therapy in biliary tract cancer: Actualisation of the AGEO CT2BIL cohort and European multicentre validations

BACKGROUND: The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. METHODS: We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. RESULTS: The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p < 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N = 392). CONCLUSION: We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design

Pre-conceptual design of ASTRID fuel sub-assemblies

International audienceThe French 600 MWe Advanced Sodium Technological Reactor for Industrial Demonstration (ASTRID) project is currently reaching the end of its conceptual design phase (AVP2). The core design studies are being conducted by the CEA with support from AREVA and EDF. Innovative design choices for the core have been made to comply with the GEN IV reactor objectives, marking a break with the former Phenix and SuperPhenix Sodium Fast Reactors.The main objective to improve safety compared with current GEN II or III reactors led to a core design that demonstrates intrinsically safe behaviour. A negative sodium void worth is achieved thanks to a new fuel sub-assembly design including (U,Pu)O$_2$ and UO$_2$ axially heterogeneous fuel pins, a large cladding/small spacer wire bundle, a sodium plenum above the fuel pins, and upper neutron shielding with both enriched and natural boron carbide (B$_4$C) which also maintain a low secondary sodium activity level. As Na-bonded B$_4$C pins can lead to the retention of unacceptable amounts of sodium, the whole upper neutron shielding has been made removable on-line through the sub-assembly head just before the washing operations. To prevent unsafe reactivity insertions due to hypothetical radial core compaction, the stiffness of the embossed spacer pads has been improved significantly by optimising its geometry using finite elementcalculations. More generally, all design choices for ASTRID have been made with the permanent objective of minimising the sub-assembly height 4.50 m to decrease the overall costs of the boiler reactor and the fuel cycle.This paper describes the fuel sub-assembly design for the ASTRID CFV v4 core at the end of the conceptual design phase. Focus is placed on innovations and specificities in the design compared with former French SFRs. The paper also mentions some open options that will be studied during the next basic design phase

Incidence and management of malignant digestive endocrine tumours in a well defined French population

Background and aims: Little is known about the epidemiology of malignant digestive endocrine tumours. The aim of this study was to report on their incidence and management in a well defined population. Methods: Data were obtained from the population based Digestive Cancer Registry of Burgundy (France) over a 24 year period. Incidence rates were calculated by sex, age groups, and period of diagnosis. Treatment and stage at diagnosis were also investigated. Prognosis was determined using crude and relative survival rates. A multivariate relative survival analysis was performed. Results: Between 1976 and 1999, 229 cases were recorded. Age standardised incidence rates were 0.76/100 000 for men and 0.50/100 000 for women. They increased over time in both sexes. The resectability rate was 74.1%. Among recorded cases, 26.6% did not extend beyond the organ, 20% had lymph node metastases, and 53.3% had visceral metastases or were unresectable. There was no improvement in the resection rate or in the stage at diagnosis over the study period. The overall relative survival rate was 66.9% at one year, 50.4% at five years, and 40.6% at 10 years. Stage at diagnosis, age at diagnosis, and subsite were independent significant prognostic factors. Conclusions: Although their incidence is increasing, malignant digestive endocrine tumours remain a rare cancer, representing 1% of digestive cancers. Stage at diagnosis and prognosis at a population level are worse than those reported in hospital series. In the short term, new therapeutic possibilities represent the best way to improve their prognosis

The screening and consensus based on practices and evidence (Scope) program–results of a survey on daily practice patterns for patients with mcrc

The SCOPE project aimed to better understand practice patterns, identify drivers for treatment goals, and determine third-and fourth-line treatment choices for patients with metastatic colorectal cancer (mCRC). The survey was developed by an expert panel of gastrointestinal oncolo-gists. Questions concerned general practice patterns, and treatment decisions for three hypothetical patient case scenarios. Participants had to routinely manage patients with mCRC. We present results from 629 participants who provided input on patient treatment scenarios (data cutoff: 17/01/2020). Prolonging overall survival (OS; 51%) was the main aim in first line. In third line, quality of life (QOL) was the primary goal (34%). Forty-three percent also cited efficacy-focused goals; 18% and 13% noted prolonging OS and improving progression-free survival as main aims, respectively. For fit and active patients, 89% of respondents considered trifluridine-tipiracil an appropriate third-line treatment; regorafenib (31%) or clinical trial enrollment (29%) were the fourth-line options. For patients with comorbidities and limited caregiver support, trifluridine-tipiracil was the preferred third-line treatment (70%). For KRAS-mutated patients with comorbidities and adverse events who received prior oxaliplatin, 90% considered oxaliplatin rechallenge an unsuitable third-line treatment, mainly due to the risk of cumulative toxicity (75%). In the third/fourth-line settings, trifluridine-tipiracil followed by regorafenib was the most common option (54%); 17% chose regorafenib followed by trifluridine-tipiracil. Efficacy coupled with QOL are important goals in third-line treatment. Daily practice patterns reflect the guideline recommendations in third-and fourth-line settings, with a trend toward using trifluridine-tipiracil versus regorafenib in KRAS-wildtype and KRAS-mutant tumors

Analytical developments for high precision isotope measurements on transmutation target in the phenix fast neutron reactor

International audienceThe objective of the PROFIL-R (fast spectrum) and PROFIL-M (moderated spectrum) experiments, performed between 2003and 2008 in the French fast neutron reactor Phénix, was to collect accurate information on the total capture integral crosssections of the principal heavy isotopes and some important fission products in the spectral range of fast reactor. The methodconsists of the irradiation of pure isotope samples and the determination of the composition change induced by irradiation.The elements present in powder form are representative of actinides and fission products present in irradiated fuels and coverall the applications for which accurate capture integral cross section are necessary. Then, accurate measurements of isotopiccompositions and concentrations of the elements (actinides and fission products) before and after irradiation are required. Themajor difficulty for the analyses of products is the low quantity of the initial powder enclosed in steel container (3 to 5 mg)and the very low quantities of products formed (several $\mu$g) after irradiation. During several years developments have beenperformed in different laboratories of the CEA for the conception of a system implanted in shielded cell installations to openthe steel container, collect the integrality of the powder and quantitatively dissolve each product. For several powders, likemetallic ruthenium, metallic silver or metallic rhodium, this last step was a challenge due to the very high resistance of thesemetals to acid solutions. After recuperation and dissolution the second stage consists of mass spectrometric measurements inorder to obtain isotope and elemental ratio at uncertainty of few per mil level. As very low measurement uncertainties arerequired for these applications, elemental and isotopic measurements are usually performed with state of the art massspectrometric techniques such as thermal ionization mass spectrometry (TIMS) and multiple collector inductively coupledplasma mass spectrometry (MC-ICPMS) associated with the isotope dilution technique (ID). Furthermore it requirespreliminary chemical separation to eliminate the elements which could prevent ionization and/or generate isobaricinterferences in the mass spectrum of the analytes during measurements, thus leading to non-accurate isotopic analysis. Wepresent the axes of analytical developments performed in the Nuclear, isotope and elemental analytical developmentlaboratory (LANIE) to acquire accurate isotope ratios. Innovative method of separation like the hyphenation of liquidchromatography with ICPMS and MC-ICPMS or the use of collision reaction cell present in recent generation of ICPMS,have been developed. Several examples of analyses of irradiated transmutation targets will be presented. These variousanalytical developments demonstrate the considerable gains that can be expected in the near future in terms of sampleamounts, handling time, and waste production associated to the high precision elemental and isotopic characterization ofirradiated samples

Colon cancer in France: Evidence for improvement in management and survival

Background: Cancer registries recording all cases diagnosed in a well defined population represent the only way to assess real changes in the management of colon cancer at the population level. Aims: To determine trends over a 23 year period in treatment, stage at diagnosis, and prognosis of colon cancer in the Côte-d'Or region, France. Patients: A total of 3389 patients with colon cancer diagnosed between 1976 and 1998. Methods: Time trends in clinical presentation, surgical treatment, chemotherapy treatment, stage at diagnosis, postoperative mortality, and survival were studied. A non-conditional logistic regression was performed to obtain an odds ratio for each period adjusted for the other variables. To estimate the independent effect of the period on prognosis, a relative survival analysis was performed. Results: Between 1976 and 1991, the resection rate increased from 69.3% to 91.9% and then remained stable. This increase was particularly marked in the older age group (56.4% to 90.5%). The proportion of stage III patients treated with adjuvant chemotherapy rose from 4.1% for the 1989–1990 period to 45.7% for the 1997–1998 period. Over the 23 years of the study the proportion of stage I and II patients increased from 39.6% to 56.6%, associated with a corresponding decrease in the proportion of patients with advanced stages. Postoperative mortality decreased from 19.5% to 7.3%. This led to an improvement in five year relative survival (from 33.0% for the 1976–1979 period to 55.3% for the 1992–1995 period). Conclusions: Advances in the management of colon cancer have resulted in improving the prognosis of this disease. However, progress is still possible, particularly in the older age group

Development of an Algorithm Incorporating Pharmacokinetics of Adalimumab in Inflammatory Bowel Diseases

International audienceOBJECTIVES:Several decision algorithms based on the measurement of infliximab (IFX) trough levels and antibodies to IFX have been proposed. Whether such algorithms can be extrapolated to the pharmacokinetics of adalimumab (ADA) has yet to be determined.METHODS:A prospective study included all consecutive patients with inflammatory bowel disease (IBD) having a disease flare while being on ADA 40 mg every 2 weeks were included. All patients were primary responders to ADA therapy and were anti-tumor necrosis factor (TNF) naive. ADA trough levels and antibodies against ADA (AAA) were measured blinded to clinical data (Elisa LISA-Tracker, Theradiag). All patients were optimized with ADA 40 mg weekly. Four months later, in the absence of clinical remission (CR; Crohn's disease activity index 4.9 μg/ml; group B, ADA10 ng/ml.RESULTS:A total of 82 patients were included (55% CD; mean age=43 years, disease duration=7.4 years, duration of ADA therapy=17 months). After optimization of ADA treatment, 29.2% of patients achieved CR in group A (N=41), 67% in group B (N=24), and 12% in group C (N=17; P4.9 μg/ml are associated with failure of two anti-TNF agents (ADA and IFX) in 90% of cases, and switching to another drug class should be considered

Conceptual design of astrid radial shielding sub-assemblies

International audienceThe French 600 MWe Advanced Sodium Technological Reactor for Industrial Demonstration (ASTRID) project reached in 2015 the end of its conceptual design phase. The core design studies are being conducted by the CEA with support from AREVA and EDF. Innovative design choices for the core have been made to comply with the GEN IV reactor objectives, marking a break with the former Phénix and SuperPhénix Sodium Fast Reactors. One of the biggest challenges of the last five years was to propose a consistent design for the reflectors and neutron shielding sub-assemblies surrounding the fuel core in order to fulfill ASTRID requirements of minimising the secondary sodium activity level. Heavy iterative studies on both core and sub-assemblies were necessary to propose and evaluate different solutions following a strict value analysis process considering neutron shielding performances, life duration, maturity levels, washing and manufacturing capability, and qualification needs. Evaluated options were reflectors sub-assemblies made of steel or MgO rods, and radial neutron shielding sub-assemblies made of B 4 C or borated steel, with different configurations in the design and in the core layout. This paper presents the iterative engineering studies, conducted by CEA and performed by AREVA-NP, concerning the radial shielding sub-assemblies for ASTRID core, from the selection of possible solutions to a final consistent conceptual design