Background Donor availability and transplantation‐related risks limit the broad use of allogeneic hematopoietic‐cell transplantation in patients with transfusion‐dependent β‐thalassemia. After previously establishing that lentiviral transfer of a marked β‐globin (βA‐T87Q) gene could substitute for long‐term red‐cell transfusions in a patient with β‐thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion‐dependent β‐thalassemia. Methods In two phase 1–2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion‐dependent β‐thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication‐competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number. Results At a median of 26 months (range, 15 to 42) after infusion of the gene‐modified cells, all but 1 of the 13 patients who had a non–β0/β0 genotype had stopped receiving red‐cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a β0/β0 genotype or two copies of the IVS1‐110 mutation, the median annualized transfusion volume was decreased by 73%, and red‐cell transfusions were discontinued in 3 patients. Treatment‐related adverse events were typical of those associated with autologous stem‐cell transplantation. No clonal dominance related to vector integration was observed. Conclusions Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long‐term red‐cell transfusions in 22 patients with severe β‐thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB‐204 and HGB‐205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526.)

β-globin gene disorders are the most prevalent inherited diseases worldwide and result from abnormal β-globin synthesis or structure. Novel therapeutic approaches are being developed in an effort to move beyond palliative management. Gene therapy, by ex vivo lentiviral transfer of a therapeutic β-globin gene derivative (βAT87Q-globin) to hematopoietic stem cells, driven by cis-regulatory elements that confer high, erythroid-specific expression, has been evaluated in human clinical trials over the past 8 years. βAT87Q-globin is used both as a strong inhibitor of HbS polymerization and as a biomarker. While long-term studies are underway in multiple centers in Europe and in the United States, proof-of-principle of efficacy and safety has already been obtained in multiple patients with β-thalassemia and sickle cell disease.

L’incidence des infections urinaires à germes producteurs de bêtalactamase à spectre étendu (BLSE) est en augmentation. Elles sont associées à une hospitalisation prolongée pour les patients (Pts) nécessitant des interventions chirurgicales urologiques. L’objectif de cette étude était de démontrer qu’une diffusion intra-prostatique significative d’ertapénème était obtenue après une seule administration intraveineuse (IV) avant chirurgie prostatique. Vingt Pts avec indication de chirurgie pour hyperplasie bénigne de prostate étaient inclus prospectivement et divisés en 2 groupes ; 19 Pts étaient analysés. Les Pts recevaient une dose d’1 gramme IV d’ertapénème 1 heure (n = 10, groupe A) ou 12 heures (n = 9, groupe B) avant prélèvements sanguins et prostatiques (copeaux de résection) (Fig. 1). Les concentrations plasmatiques et intra-prostatiques d’ertapénème étaient mesurées par chromatographie en phase liquide couplée à la spectrométrie de masse tandem (LC-MS/MS). Les concentrations intra-prostatiques étaient considérées comme satisfaisantes si elles étaient supérieures aux concentrations minimales inhibitrices90 (CMI90) des pathogènes cibles urinaires. Un test de Wilcoxon et un modèle prédictif pharmacocinétique étaient utilisés. Les concentrations plasmatiques médianes d’ertapénème étaient de 144,3 mg/L (IC95 % ; 126,5–157,9) dans le groupe A et de 30,7 mg/L (IC95 % ; 22,9–36,4) dans le groupe B (p < 0,001). Les concentrations intra-prostatiques médianes étaient de 16,6 mg/L (IC95 % ; 13,3–31,4) dans le groupe A et de 4,2 mg/L (IC95 % ; 3,1–4,9) dans le groupe B (p < 0,001), supérieures à la CMI90 des pathogènes cibles dont les bactéries productrices de BLSE, la CMI90 de l’ertapénème étant comprise entre 0,03 mg/L (contre P. vulgaris) et 1 mg/L (contre Enterobacter spp) (Fig. 2). Le rapport concentration plasmatique sur concentration intra-prostatique n’était pas significativement différent entre les groupes (p = 0,97), en faveur d’une diffusion intra-prostatique similaire indépendamment de l’intervalle de temps entre administration et chirurgie. Les analyses pharmacocinétiques retrouvaient une demi-vie de 4,8 h pour l’ertapénème comparable à la littérature. Une seule dose d’ertapénème administrée en préopératoire 1 heure avant l’intervention en IV permet d’obtenir des concentrations plasmatiques et intra-prostatiques satisfaisantes. Ces résultats suggèrent qu’il pourrait s’agit d’une stratégie prophylactique intéressante pour les Pts porteurs de BLSE nécessitant des interventions sur les voies urinaires. Ces résultats nécessitent d’être confirmés dans de futurs essais prospectifs.

La centralisation hospitaliere, sous couvert pharmaceutique, du faconnage des solutions injectables des medicaments anticancereux est devenue obligation legale en France. Nous avons etabli de longue date que les Objets Therapeutiques (OTs) ainsi fabriques devraient tous beneficier d'un Controle de Qualite Analytique [CQA] idealement Liberatoire [CQAL] pour les parametres cles d'identite, de purete et de concentration nominale en tel ou tel principe actif. Au cours de travaux recents, nous avons etabli dans plusieurs situations, la superiorite technique de la Spectroscopie Raman [SR] non intrusive sur toute autre solution analytique et notamment sur les methodes separatives chromatographiques CLHP ainsi que sur l'analyse vibrationnelle par UV/visible-IRTF. Une evaluation a la fois qualitative, economique et environnementale croisee vient enrichir ces travaux. Les 3 modeles analytiques ont ete compares en situation operationnelle au moyen: a) d'une grille de criteres qualitatifs, b) de tableaux d'amortissement des equipements, c) des couts en biens consommables, d) du poids eventuel des equipements de support et des locaux, e) de l'Unite d'Œuvre (UO) dont le cout direct composite (€) varie en fonction de l'option technique retenue, de la charge categorielle en ressources humaines (RHs) operateurs (diverses combinaisons sont possibles) et de l'eventuelle fraction de biens consommables. L'UO peut ainsi prendre 12 valeurs possibles comprises entre les bornes extremes de 1 a 5,5 €. Une grille d'evaluation qualitative et de performance positionne la technologie SR non intrusive comme constamment superieure ou equivalente aux 2 autres techniques eprouvees. Les donnees rapportees confirment le caractere prometteur de la SR pour le CQA non intrusif, y compris dans des situations inaccessibles aux autres techniques. Nos resultats confirment la place centrale que pourra dans l'avenir occuper cette solution d'exploration contextuelle d'objets de geometrie quelconque e.g. diffuseurs portables. La SR apparait comme un fort contributeur a la securisation du circuit (ou de la filiere) du medicament injectable ainsi qu'a la protection des acteurs de soins et de leur environnement de travail.

Aim: Beyond platinum-based first line chemotherapy for advanced cholangiocarcinoma (CK), second line 5FU-based treatments yield median progression-free survival (PFS) of <3 months and median overall survival (OS) of 6 months, warranting innovative treatment options. Intrahepatic CK subtypes overexpress VEGF, providing a rationale for investigating sunitinib in patients (pts) who failed platinum-based therapy.

ABSTRACT Ceftazidime is particularly efficient against Pseudomonas aeruginosa in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. Our aim was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4°C, 22°C, or 33°C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro . In model 1, we administered 12 g of ceftazidime infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Samples were collected at 0 h and then every 4 and 2 h after the shaping of portable infusion pumps in models 1 and 2, respectively. Both ceftazidime and pyridine were analyzed using an ultraviolet high-performance liquid chromatograph. Production of pyridine is highly depending on the temperature. The in situ production of pyridine per day of treatment decreases at a ratio close to 1/6 and 1/3 between 33°C and 4°C in models 1 and 2, respectively. Regardless of the conditions, the production of pyridine is significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4°C and 33°C compared to that in model 1. According to a the precautionary principle, these findings lead to three major recommendations: (i) exposing a solution of ceftazidime to over 22°C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 h instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

Objectives:In this nationwide retrospective study, we analysed early acquisition of Achromobacter spp. in Danish cystic fibrosis (CF) patients from 2000 to 2011, excluding cross-infections.Methods: Thirty-four primary isolates were identified by partial sequencing of recA, tyrB and icd, and were subjected to extended antimicrobial susceptibility testing.Achromobacter xylosoxidans accounted for 13 (38%) of the isolates, and an unnamed species, tentatively designated MLSA cluster III, accounted for 11 (32%) of the isolates.Antimicrobial susceptibility testing showed that meropenem, piperacillintazobactam and trimethoprim/sulfamethoxazole were highly active against chemotherapy-naïve Achromobacter, while ceftazidime, colistin and tobramycin were judged to have adequate activity for inhalation therapy.We assessed effectiveness of early antimicrobial treatment by a Kaplan-Meier estimation of time to recurrence of Achromobacter spp.A significant difference was observed between 25 patients treated with inhaled ceftazidime, colistin, or tobramycin, and 22 patients who did not receive inhaled antibiotics: three years after primary acquisition, 55% of treated patients remained free of Achromobacter spp., in contrast to 17% of untreated patients.Conclusion: Our findings suggest that early treatment with inhaled antibiotics may prevent or postpone chronic infection with Achromobacter species in CF patients.

In France, central IV admixture of chemotherapy (CT) treatments at the hospital is now required by law. We have previously shown that the shaping of Therapeutic Objects (TOs) could profit from an Analytical Quality Assurance (AQA), closely linked to the batch release, for the three key parameters: identity, purity, and initial concentration of the compound of interest. In the course of recent and diversified works, we showed the technical superiority of non-intrusive Raman Spectroscopy (RS) vs. any other analytical option and, especially for both HPLC and vibrational method using a UV/visible-FTIR coupling. An interconnected qualitative and economic assessment strongly helps to enrich these relevant works. The study compares in operational situation, the performance of three analytical methods used for the AQC of TOs. We used: a) a set of evaluation criteria, b) the depreciation tables of the machinery, c) the cost of disposables, d) the weight of equipment and technical installations, e) the basic accounting unit (unit of work) and its composite costs (Euros), which vary according to the technical options, the weight of both human resources and disposables; finally, different combinations are described. So, the unit of work can take 12 different values between 1 and 5.5 Euros, and we provide various recommendations. A qualitative evaluation grid constantly places the SR technology as superior or equal to the 2 other techniques currently available. Our results demonstrated: a) the major interest of the non-intrusive AQC performed by RS, especially when it is not possible to analyze a TO with existing methods e.g. elastomeric portable pumps, and b) the high potential for this technique to be a strong contributor to the security of the medication circuit, and to fight the iatrogenic effects of drugs especially in the hospital. It also contributes to the protection of all actors in healthcare and of their working environment.

The study compares the performances of three analytical methods devoted to Analytical Quality Control (AQC) of therapeutic solutions formed into care environment, we are talking about Therapeutics Objects(TN) (TOs(TN)). We explored the pharmacological model of two widely used anthracyclines i.e. adriamycin and epirubicin. We compared the performance of the HPLC versus two vibrational spectroscopic techniques: a tandem UV/Vis-FTIR on one hand and Raman Spectroscopy (RS) on the other. The three methods give good results for the key criteria of repeatability, of reproducibility and, of accuracy. A Spearman and a Kendall correlation test confirms the noninferiority of the vibrational techniques as an alternative to the reference method (HPLC). The selection of bands for characterization and quantification by RS is the results of a gradual process adjustment, at the intercept of matrix effects. From the perspective of a AQC associated to release of TOs, RS displays various advantages: (a) to decide quickly (~2min), simultaneously and without intrusion or withdrawal on both the nature of a packaging than on a solvant and this, regardless of the compound of interest; it is the founder asset of the method, (b) to explore qualitatively and quantitatively any kinds of TOs, (c) operator safety is guaranteed during production and in the laboratory, (d) the suppression of analytical releases or waste contribute to protects the environment, (e) the suppression.of consumables, (f) a negligible costs of maintenance, (g) a small budget of technicians training. These results already show that the SR technology is potentially a strong contributor to the safety of the medication cycle and fight against the iatrogenic effects of drugs.