Limited Increase of Particle Entrainment in the Off-Gas System of a Cold Crucible Induction Melter Compared with a Joule-Heated Metal Melter for HLLW Vitrification -11465

ABSTRACT Fission product solutions arising from reprocessing spent fuel from the nuclear reactors used for electrical production in France are immobilized in six vitrification lines at the AREVA La Hague plant. In 2010, the conventional Joule-heated metal melter was replaced in one of these six lines with a cold crucible melter. The cold crucible melter began vitrifying radioactive effluents produced by rinsing operations in legacy facilities in April 2010. The composition of these effluents requires a containment glass synthesis temperature that exceeds the operating temperatures limits of conventional ("hot") melters. The cold crucible melter technology has three main advantages: melt temperatures well above the current limit, increased glass production capacity, extended lifetime because of the lower wall temperatures. For these reasons the cold crucible melter can subsequently be used to vitrify a wide range of High-Level Liquid Waste (HLLW). This paper describes the assessment performed to characterize the entrainment of particles or chemicals and/or radioactive species to the off-gas treatment system from a Joule-heated metal melter (JHMM) and from a cold crucible induction melter (CCIM). Vitrification is performed in a two-step process. A calciner is used in each case to dry and calcine the high-level liquid waste, supplying only the dry residue to the melter together with glass frit. The off-gas treatment is identical for both melters. The paper first describes how the CEA uses its reconfigurable vitrification prototype, a full-scale mockup of a La Hague vitrification line, in support of AREVA to anticipate cold crucible melter operation under radioactive conditions. It describes the process equipment constituting the vitrification line from the melter (using a JHMM or a CCIM) to the off-gas treatment system. All the differences that contribute to the modification of radioactive particle entrainment from the calciner/melter to the off-gas treatment system are then described. The results obtained are then discussed concerning the volatility of species produced by vitrification during weekly tests implementing either the conventional melting pot or the cold crucible melter. The distribution of volatile species in the off-gas treatment devices is discussed. The paper concludes with a discussion of how using the CCIM vitrification process on one of the La Hague vitrification units can achieve an increased vitrification throughput at a higher temperature without any impact on the resulting waste release

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only ~5% with BRAFV600E colorectal cancer (CRC) respond. Preclinical studies suggest that lack of efficacy in BRAFV600E CRC is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) \ub1 MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E CRC. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pre- and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E CRC can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism

Glass ceramic for the vitrification of high level waste with a high molybdenum content

International audienceVitrification has been selected in France as the immobilization process for high-level waste arising from spent fuel reprocessing. Several high-level waste solutions from the reprocessing of legacy UMo spent fuel, used in gas cooled reactors, have been stored in the AREVA La Hague facility in stainless steel tanks since the mid-1960s. A special glass-ceramic formulation has been developed and qualified through lab and pilot testing to meet standard waste acceptance criteria for the final disposal of the UMo waste. The Cold Crucible Induction Melter (CCIM) was selected for the vitrification of this particularly hard-to-process waste stream because it could not be reasonably processed in the standard hot induction melters currently used at the La Hague vitrification facilities the waste has a high molybdenum and phosphorous content which makes it corrosive and also requires a special high temperature glass formulation to obtain sufficiently high waste loading factors, higher than 10 wtpercent in Molybdenum oxide. Molybdenum is known to be sparingly soluble in conventional borosilicate glass. The formulated glass-ceramic matrix comprises a major vitreous phase containing secondary phase particles less than 100 et956;m in diameter. These are formed by phase separation and crystallization as the molten glass cools in the canister. The physical and microstructural properties of the UMo glass in the solid and liquid states are reported here. Evolution of microstructure as a function of the sample position in the canister was investigated, given the sensitivity of the crystallization process to the cooling profile. The chemical durability of the UMo glass-ceramic was also studied. The feasibility of this process has been demonstrated in a full-scale pilot facility with inactive surrogate solutions

UMo solutions processing in La Hague Cold Crucible Induction Melter the feedbackfrom the first years of operation

International audience250 cubic meters of high-level liquid waste from reprocessed U-Mo-Sn-Al spent fuel, used in GasCooled Reactors (GCR), were produced during the mid-1960s at La Hague facility. These UMo solutions are less radioactive than the current fission product concentrates coming from ongoingreprocessing activities, but are very rich in molybdenum and phosphorus whose contents make themolten glass quite corrosive and require a high-temperature glass formulation to obtain sufficientlyhigh waste loading factors (12 percent in molybdenum oxide). Hence the use of the Cold Crucible InductionMelter (CCIM) technology to process such solutions has been deemed a good opportunity for AREVAto meet its performance expectations.In addition to being very corrosive, the UMo waste is quite challenging to process as the molybdenumhas a strong tendency to stick in the calciner and causes clogging issues in off-gas treatmentequipment. Therefore, the process and technological qualifications were deployed in order to addressthese specific issues.UMo solutions processing in the La Hague CCIM has started in January 2013 and is currentlyongoing. During this period (from 2013 to 2015), many data have been collected to confirm theprocess parameters that were defined during the qualification of this innovating process. Even if somedifficulties occurred, operations teams experience along with engineering and RandD support allowedmanaging them.This paper presents the start-up methodology and the feedback from the first years of UMo solutionsprocessing with the CCIM technology at La Hague site. Lessons learned are presented with thedifficulties encountered and the solutions implemented, emphasizing the benefits of a close integrationbetween RandD, engineering and operations teams

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma

Background: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 subtype can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC.Patients and methods: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two pre-operative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies.Results: Significant anti-tumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a pathological complete response. An immediate and sustained decrease in peripheral natural killer (NK) cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral NK cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T-cells occurred only in the 700 mg imgatuzumab group (median 95% increase, p &lt; 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg: –34.6%; 1400 mg: –41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response.Conclusions: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune anti-tumor effects.Clinical trial registration number: NCT01046266 (ClinicalTrials.gov).</p

Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus. The Phase 2 KEYNOTE-180 Study

IMPORTANCE: Effective treatment options are limited for patients with advanced, metastatic esophageal cancer progressing after 2 or more lines of systemic therapy. OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab for patients with advanced, metastatic esophageal squamous cell carcinoma (ESCC) or advanced, metastatic adenocarcinoma of the esophagus and gastroesophageal junction that progressed after 2 or more lines of systemic therapy. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, open-label, interventional, single-arm study, KEYNOTE-180, enrolled 121 patients from January 12, 2016, to March 21, 2017, from 57 sites in 10 countries. Patients had advanced, metastatic esophageal cancer that progressed after 2 or more lines of therapy and had evaluable tumor samples for biomarkers. INTERVENTIONS: Pembrolizumab, 200 mg, was administered intravenously every 3 weeks until disease progression, unacceptable toxic effects, or study withdrawal, for up to 2 years. MAIN OUTCOMES AND MEASURES: Primary end point was objective response rate per the Response Evaluation Criteria in Solid Tumors by central imaging review for all patients. RESULTS: As of September 18, 2017, of 121 enrolled patients (100 men and 21 women; median age, 65 years [range, 33-87 years]), 18 (14.9%) had undergone 3 or more prior therapies, 63 (52.1%) had ESCC, and 58 (47.9%) had tumors positive for programmed death ligand-1 (PD-L1), defined as a combined positive score of 10 or higher assessed by immunohistochemistry. Median duration of follow-up was 5.8 months (range, 0.2-18.3 months). Objective response rate was 9.9% (95% CI, 5.2%-16.7%) among all patients (12 of 121), and median duration of response was not reached (range, 1.9-14.4 months). Objective response rate was 14.3% (95% CI, 6.7%-25.4%) among patients with ESCC (9 of 63), 5.2% (95% CI, 1.1%-14.4%) among patients with adenocarcinoma (3 of 58), 13.8% (95% CI, 6.1%-25.4%) among patients with PD-L1–positive tumors (8 of 58), and 6.3% (95% CI, 1.8%-15.5%) among patients with PD-L1–negative tumors (4 of 63). Overall, 15 patients (12.4%) had treatment-related grade 3 to 5 adverse events. Only 5 patients (4.1%) discontinued treatment because of adverse events. There was 1 treatment-related death from pneumonitis. CONCLUSIONS AND RELEVANCE: Where effective treatment options are an unmet need, pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer. Phase 3 studies evaluating pembrolizumab vs standard therapy for patients with esophageal cancer progressing after first-line therapy or in combination with chemotherapy as first-line therapy for patients with locally advanced unresectable or metastatic esophageal cancer are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT0255968

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study

Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements