Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).CONCLUSIONS:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active

Evaluation de la surveillance staturo-pondérale par les médecins au cours de la deuxième enfance

La prévalence de l'obésité n'a cessé de croître depuis quelques années, elle atteignait 16% en 2000 selon l'ANAES. Un dépistage précoce basé sur l'indice de masse corporelle et la courbe de croissance, présents dans tous les carnets de santé depuis 1995, est préconisé pour tenter d'enrayer cette augmentation. Mais sont-ils utilisés dans la pratique médicale quotidienne ? A partir d'une étude rétrospective de 101 carnets de santé d'enfants de 5 à 7 ans recueillis aux urgences pédiatriques de Nantes, nous avons déterminé que la courbe de corpulence n'était pas tracée dans 67,33% des cas, et l'indice de masse corporelle n'était pas calculé au niveau des examens obligatoires dans plus de 75% des cas. A l'inverse 2/3 des parents connaissent l'IMC, mais pas sa courbe. Il reste donc un long chemin à parcourir pour une prévention efficace, qui devra peut être passer par une formation sérieuse des professionnels de santé, une valorisation de l'acte médical préventif, une réorganisation du carnet de santé et une implication parentale.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

OPTIMIZATION OF 226RA URINE EXTRACTION FOR INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS) ANALYSIS

International audienceRadium 226 has been identified as a highly radiotoxic radionuclide with a high potential of malevolence uses. In radiological emergency situations and for medical monitoring of nuclear workers, urine analysis is the more convenient to estimate the effective dose. A lot of methods for radium analysis in urine have been described in the literature, differing from the time of preparation and analysis and detection limit. Based on the protocol defined by Cozzella and al. in 2011(1) who used the Dowex® 50W-X8 resin, the urine extraction procedure of 226Ra was optimized for ICP-MS analysis in order to realize the extraction as fast as possible with a detection limit adapted to highlight an effective dose of 1 mSv. Besides this optimization, the contribution of polyatomic interferences as 88Sr138Ba, very common interference for 226Ra measurement by ICP-MS, was determined and taken into account in our results. First results showed that the radium extraction on Dowex® 50W-X8 resin was not complete in our experimental conditions. Two hypothesis could explain these results: the saturation of the resin or the acid conditions that are not optimal for the radium extraction on Dowex® 50W-X8 resin. To improve these results, some experiments were performed:-Determination of the distribution coefficient of 226Ra on Dowex® 50W-X8 to adapt the preconditionement of the resin and optimize the radium elution step,-Determination of the maximal capacity of Dowex® 50W-X8 resin for radium extraction,-Optimization of the procedure with a mineralization step after the co-precipitation of radium in order to eliminate the organic matter which prevent the radium extraction on the resin.Besides that, two other resins were also tested: -The Analig® Ra-01, a specific resin for radium, that has been applied by Verlinde et al. for water analysis (2),-The calix-[6]-arene based column that has been developed for actinides in urine by Bouvier-Capely et al.(1)Cozzella M.L. et al. Determination of 226Ra in urine samples by Q-ICP-MS : a method for routine analyses. Radiat Meas. 2011 ; 46 : 109-111.(2)Verlinde M. and al. A new protocol for 226Ra separation and preconcentration in natural water sample using molecular recognition technology for ICP-MS analysis. J Environ Radioact. 2019 ; 202 : 1-7.(3)Bouvier-Capely et al. Operational protocol for detection of contamination by actinides U, Pu and Am in urine using Calixarene columns : from mineralization to ICP-MS measurement. Am J Anal Chem. 2017 ; 8 : 317-333

OPTIMIZATION OF 226RA URINE EXTRACTION FOR INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS) ANALYSIS

International audienceRadium 226 has been identified as a highly radiotoxic radionuclide with a high potential of malevolence uses. In radiological emergency situations and for medical monitoring of nuclear workers, urine analysis is the more convenient to estimate the effective dose. A lot of methods for radium analysis in urine have been described in the literature, differing from the time of preparation and analysis and detection limit. Based on the protocol defined by Cozzella and al. in 2011(1) who used the Dowex® 50W-X8 resin, the urine extraction procedure of 226Ra was optimized for ICP-MS analysis in order to realize the extraction as fast as possible with a detection limit adapted to highlight an effective dose of 1 mSv. Besides this optimization, the contribution of polyatomic interferences as 88Sr138Ba, very common interference for 226Ra measurement by ICP-MS, was determined and taken into account in our results. First results showed that the radium extraction on Dowex® 50W-X8 resin was not complete in our experimental conditions. Two hypothesis could explain these results: the saturation of the resin or the acid conditions that are not optimal for the radium extraction on Dowex® 50W-X8 resin. To improve these results, some experiments were performed:-Determination of the distribution coefficient of 226Ra on Dowex® 50W-X8 to adapt the preconditionement of the resin and optimize the radium elution step,-Determination of the maximal capacity of Dowex® 50W-X8 resin for radium extraction,-Optimization of the procedure with a mineralization step after the co-precipitation of radium in order to eliminate the organic matter which prevent the radium extraction on the resin.Besides that, two other resins were also tested: -The Analig® Ra-01, a specific resin for radium, that has been applied by Verlinde et al. for water analysis (2),-The calix-[6]-arene based column that has been developed for actinides in urine by Bouvier-Capely et al.(1)Cozzella M.L. et al. Determination of 226Ra in urine samples by Q-ICP-MS : a method for routine analyses. Radiat Meas. 2011 ; 46 : 109-111.(2)Verlinde M. and al. A new protocol for 226Ra separation and preconcentration in natural water sample using molecular recognition technology for ICP-MS analysis. J Environ Radioact. 2019 ; 202 : 1-7.(3)Bouvier-Capely et al. Operational protocol for detection of contamination by actinides U, Pu and Am in urine using Calixarene columns : from mineralization to ICP-MS measurement. Am J Anal Chem. 2017 ; 8 : 317-333

OPTIMIZATION OF 226RA URINE EXTRACTION FOR INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS) ANALYSIS

International audienceRadium 226 has been identified as a highly radiotoxic radionuclide with a high potential of malevolence uses. In radiological emergency situations and for medical monitoring of nuclear workers, urine analysis is the more convenient to estimate the effective dose. A lot of methods for radium analysis in urine have been described in the literature, differing from the time of preparation and analysis and detection limit. Based on the protocol defined by Cozzella and al. in 2011(1) who used the Dowex® 50W-X8 resin, the urine extraction procedure of 226Ra was optimized for ICP-MS analysis in order to realize the extraction as fast as possible with a detection limit adapted to highlight an effective dose of 1 mSv. Besides this optimization, the contribution of polyatomic interferences as 88Sr138Ba, very common interference for 226Ra measurement by ICP-MS, was determined and taken into account in our results. First results showed that the radium extraction on Dowex® 50W-X8 resin was not complete in our experimental conditions. Two hypothesis could explain these results: the saturation of the resin or the acid conditions that are not optimal for the radium extraction on Dowex® 50W-X8 resin. To improve these results, some experiments were performed:-Determination of the distribution coefficient of 226Ra on Dowex® 50W-X8 to adapt the preconditionement of the resin and optimize the radium elution step,-Determination of the maximal capacity of Dowex® 50W-X8 resin for radium extraction,-Optimization of the procedure with a mineralization step after the co-precipitation of radium in order to eliminate the organic matter which prevent the radium extraction on the resin.Besides that, two other resins were also tested: -The Analig® Ra-01, a specific resin for radium, that has been applied by Verlinde et al. for water analysis (2),-The calix-[6]-arene based column that has been developed for actinides in urine by Bouvier-Capely et al.(1)Cozzella M.L. et al. Determination of 226Ra in urine samples by Q-ICP-MS : a method for routine analyses. Radiat Meas. 2011 ; 46 : 109-111.(2)Verlinde M. and al. A new protocol for 226Ra separation and preconcentration in natural water sample using molecular recognition technology for ICP-MS analysis. J Environ Radioact. 2019 ; 202 : 1-7.(3)Bouvier-Capely et al. Operational protocol for detection of contamination by actinides U, Pu and Am in urine using Calixarene columns : from mineralization to ICP-MS measurement. Am J Anal Chem. 2017 ; 8 : 317-333

Human CYP2B6: expression, inducibility and catalytic activities

Human cytochrome (CYP)2B6 cDNA was cloned and expressed in bacteria and in yeast. Its expression in Saccharomyces cerevisiae enabled us to obtain, at a high level, an active yeast-expressed CYP2B6 protein, so as to assess its role in the metabolism of ethoxyresorufin, pentoxyresorufin, benzyloxyresorufin, ethoxycoumarin, testosterone and cyclophosphamide. Kinetic analysis showed that human CYP2B6 preferentially metabolized benzyloxyresorufin and pentoxyresorufin, although other CYPs also metabolized these substrates in human liver microsomes. CYP2B6 also manifested a strong 4-hydroxycyclophosphamide activity. Its expression in Escherichia coli enabled us to produce a very specific anti-human CYP2B6 antibody. No cross reactivity of this antibody was observed with CYPs1A1, 1A2, 3A4, 3A5, 2C8, 2C9, 2C18, 2C19, 2D6 or 2E1. This antibody enabled us to study the hepatic and extrahepatic expression of CYP2B6 in man, as well as its expression and inducibility in primary cultured human hepatocytes and in different human cell lines. Immunoblot analysis revealed that the CYP2B6 protein was expressed in 43 of the 48 human liver samples tested, with levels ranging from 0.4 to 8 pmol/mg of microsomal protein with a mean of 1.7 pmol/mg protein. CYP2B was also expressed in human brain, intestine and kidney, and at a lower level in the lung. CYP2B mRNA was detected in human liver, kidney, lung, trachea and intestine. We also found that CYP2B6 is induced at protein and mRNA levels by phenobarbital (2 mM) and cyclophosphamide (1 mM), an anticancer drug known to be metabolized by CYP2B6. No expression or inducibility of CYP2B6 was observed in any of the human cell lines tested