Realistic multi-cellular dosimetry for 177Lu-labelled antibodies: model and application.

Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General-purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin®, a novel 177Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of 177Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions.

The relationship between liver stiffness measurement and outcome in patients with chronic hepatitis C and cirrhosis: a retrospective longitudinal hospital study.

BACKGROUND: There is a relationship between liver stiffness measurement (LSM) and outcome of HCV patients. AIM: To evaluate the performance of LSM to predict outcome of HCV patients at risk of liver-related complication. METHODS: We established a retrospective longitudinal cohort of 341 HCV patients with unequivocal cirrhosis. All underwent LSM and were followed from September 2006 to July 2015. Outcome measure was a composite end-point of end-stage liver disease (ESLD) and/or hepatocellular carcinoma (HCC). Cox models and areas under receiver operating characteristic (AUROC) curves were used to evaluate independent risk factors of outcome. RESULTS: Overall, LSM was below the 12.5 kPa threshold in 129 (37.8%) patients, including three-fourth and one-third of patients with or without a sustained virological response respectively. Liver disease progressed in 136 (39.9%) patients after a median observational period of 23.5 months. Older age, male gender, alcohol use disorders, metabolic syndrome and LSM were independent risk factors of liver disease progression. Age, alcohol use disorders and LSM were independently associated with ESLD. Age, gender and metabolic syndrome, but not LSM, were associated with HCC. The AUROC curves for disease progression, ESLD and HCC were 0.67, 0.70 and 0.58 respectively. Patients with a liver stiffness >12.5 kPa were at the highest risk of liver disease progression; below 12.5 kPa, liver stiffness was not discriminant. CONCLUSION: Liver stiffness measurement is not a surrogate of disease progression of HCV patients with cirrhosis. HCV patients with cirrhosis should undergo the recommended follow-up, regardless of liver stiffness measurement.

T-cell responses to hepatitis B splice-generated protein of hepatitis B virus and inflammatory cytokines/chemokines in chronic hepatitis B patients. ANRS study: HB EP 02 HBSP-FIBRO.

A new hepatitis B virus (HBV) protein, hepatitis B splice-generated protein (HBSP), has been detected in liver biopsy specimens from patients with chronic active hepatitis. The aim of this study was to characterize the phenotype and functions of peripheral HBSP-specific T cells and to determine whether these T-cell responses may be implicated in liver damage or viral control. Two groups of patients were studied: HBV-infected patients with chronic active hepatitis and HBV-infected patients who were inactive carriers of hepatitis B surface antigen. HBSP-specific T-cell responses were analysed ex vivo and after in vitro stimulation of peripheral blood mononuclear cells. Soluble cytokines and chemokines were analysed in sera and in cell culture supernatants. Few HBSP- or capsid-specific T-cell responses were detected in patients with chronic active hepatitis whereas frequency of HBV-specific T cells was significantly higher in inactive carrier patients. HBSP activated CD8+ and CD4+ T cells that recognized multiple epitopes and secreted inflammatory cytokines. The IL-12 level was significantly lower in sera from asymptomatic carrier patients compared to patients with chronic active hepatitis. IL-12 and IP-10 levels in the sera were significantly and independently correlated with both alanine amino transferase and HBV DNA levels. Our results show that the HBSP protein activates cellular immune responses in HBV-infected patients but has probably no prominent role in liver damage. The pattern of cytokines and chemokines in sera was linked to HBV viral load and was consistent with the level of inflammation during chronic hepatitis.

Saphenous vein graft interventions: strategies and devices to minimize distal embolization.

Percutaneous coronary intervention of degenerated saphenous vein grafts remains relatively high risk when compared to native vessel interventions, despite advances in pharmacotherapy and embolic protection. This article discusses the phenomenon of distal embolization that seems to plague saphenous vein graft interventions, reviews device-based strategies for embolic protection, and offers a perspective on the utility of percutaneous saphenous vein graft intervention in both elective and acute settings.

Status of the ion sources developments for the Spiral2 project at GANIL.

The SPIRAL 2 facility is now under construction and will deliver either stable or radioactive ion beams. First tests of nickel beam production have been performed at GANIL with a new version of the large capacity oven, and a calcium beam has been produced on the heavy ion low energy beam transport line of SPIRAL 2, installed at LPSC Grenoble. For the production of radioactive beams, several target∕ion-source systems (TISSs) are under development at GANIL as the 2.45 GHz electron cyclotron resonance ion source, the surface ionization source, and the oven prototype for heating the uranium carbide target up to 2000 °C. The existing test bench has been upgraded for these developments and a new one, dedicated for the validation of the TISS before mounting in the production module, is under design. Results and current status of these activities are presented.

Development of a surface ionization source for the SPIRAL 2 project.

Development of new radioactive beams, and thus of new target ion sources (TISs) for isotope-separator-on-line production systems are in progress at GANIL for the SPIRAL 2 project. The efficiency and time response measurements of each step in the production process are crucial to predict and maximize the available yields, in particular, for short lived isotopes. This paper presents a method for measuring these quantities that makes use of a stable alkali chopped beam of controlled intensity. This method was applied to surface ionization source test for high efficiency. Results of recent experiments are presented that include ionization efficiency measurements for Cs, Rb, K, Na, and Li with a graphite and rhenium ionizer and dwell time of these alkalis on graphite. The results enabled to design a first surface ionization source prototype which will be installed in the SPIRAL 2 TIS.

Direct 1+ --> N+ conversion of stable alkali ions using an electron cyclotron resonance ion source.

The production of radioactive ions using the Isotope Separation On-Line method gives rise, in most cases, to singly charged ions. In order to perform experiments with postaccelerated radioactive ion beams, these ions have to be multicharged. We describe here a new compact design for a charge breeder that will be coupled to the production target of SPIRAL1 at GANIL. We present recent results obtained offline with stable alkali ions (Na, K, Rb, and Cs) on the SIRa test bench. Particularly, 1(+) to N(+) conversion efficiencies and conversion times are presented. Several points have been identified for the improvements of the present performances.

Latest developments at GANIL for stable and radioactive ion beam production.

In the frame of the SPIRAL II (Système de Production d'Ions Radioactifs Accélérés en Ligne Partie II) project, several developments of stable and radioactive ion production systems have been started up. In parallel, GANIL has the ambition to preserve the existing stable and radioactive beams and also to increase its range by offering new ones. In order to identify the best directions for this development, a new group called GANISOL has been formed. Its preliminary conclusions and the latest developments at GANIL are presented.

GISELE: a resonant ionization laser ion source for the production of radioactive ions at GANIL.

SPIRAL2 is the new project under construction at GANIL to produce radioactive ion beams and in particular neutron rich ion beams. For the past 10 yr SPIRAL1 at GANIL has been delivering accelerated radioactive ion beams of gases. Both facilities now need to extend the range of radioactive ion beams produced to condensable elements. For that purpose, a resonant ionization laser ion source, funded by the French Research National Agency, is under development at GANIL, in collaboration with IPN Orsay, University of Mainz (Germany) and TRIUMF, Vancouver (Canada). A description of this project called GISELE (GANIL Ion Source using Electron Laser Excitation) is presented.

Emergence of the concept of platelet reactivity monitoring of response to thienopyridines.

Clinical trials have demonstrated the beneficial impact of clopidogrel in preventing major adverse cardiovascular events (MACE), particularly in patients undergoing percutaneous coronary intervention (PCI). The concept of biological clopidogrel resistance emerged with the finding of persistent platelet activation despite clopidogrel therapy in some patients. Further, a link between biological clopidogrel resistance and thrombotic recurrence after PCI was observed and a threshold of platelet reactivity (PR) for thrombotic events was suggested. Consistently, in recent trials, enhanced PR inhibition translated into a reduction in the rate of MACE after PCI. This review aims to present the emergence of the concept of PR monitoring in patients undergoing PCI following recent advances in this field.

The accuracy of the FIB-4 index for the diagnosis of mild fibrosis in chronic hepatitis B.

BACKGROUND: The Fib-4 index is a simple and inexpensive biomarker to delineate liver fibrosis in chronic hepatitis C. AIM: To assess the accuracy of the FIB-4 index in chronic hepatitis B. METHODS: We compared the FIB-4 index with 138 synchronous liver biopsies and with 372 synchronous FibroTest performed either in France or in an endemic area (Mayotte, an overseas collectivity of France). RESULTS: The FIB-4 index allowed the correct identification of patients with nil-to-moderate fibrosis with an area under the receiving operating characteristic curve of 0.81 (P < 0.001), increasing as a function of the length of the liver biopsy (up to 0.94 for liver biopsies >or=20 mm). A cut-off value

[Chronic hepatitis B: unusual situations: dialysis, renal transplantation and pre-emptive therapy in immune compromised patients]. / Hépatite chronique B : situations rares : dialyse, transplantation rénale et traitements pré-emptifs en situation d'immunosuppression.

Parenteral and community-acquired routes of contamination sanguins of hepatitis B virus (HBV) explain its frequency (9 to 20%) in dialysis patients and kidney recipients. In dialysis, HBV infection has few impact on morbidity and mortality; by contrast, in kidney recipients HBV: 1. reduces the allograft survival; 2. the patients survival in association with a frequent and rapid evolution to cirrhosis and hepatocellular carcinoma or rare cholestatic fibrosis. Finally, cirrhosis contra-indicates renal transplantation alone given its poor short-term prognosis and a combined liver-kidney transplantation has to be discussed. Thus, it is necessary to evaluate the liver severity of the liver disease. The treatement of HBV in allograft recipients and dialysis is based on nucleos(t)idic analogues like in the general population with the same advantages and questions. The variations of the immune status either in an HBV-infected patients at the induction or at the reduction of chemotherapies (solid tumors or hemopathies) or allograft transplantation may result in two, potentially severe, events in miror: a reactivation or a spontaneous discontinuation of viral replication (seronconversion). These risks evidence that any HBs Ag carrier exposed to immune suppression has to be diagnosed, evaluated for viral replication and underlying liver disease and has to be treated by a so-called pre-emptive treatment based on analogues.

The radioactive ion beam production systems for the SPIRAL2 project.

The SPIRAL2 project, currently under construction at GANIL, will include an isotope separator on line based facility for the production and acceleration of radioactive ion beams. A superconducting linear accelerator will accelerate 5 mA deuterons up to 40 MeV and 1 mA heavy ions up to 14.5 MeV/u. These primary beams will be used to bombard both thick and thin targets. We are investigating three different techniques to produce the radioactive ion beams: (1) the neutron induced fission of uranium carbide, (2) the direct interaction of deuterons in a uranium carbide target, and (3) the interaction of a heavy ion beam with a target. All these production systems will be coupled to an ion source. Four kinds of ion sources are foreseen for the ionization of the radioactive atoms: an electron cyclotron resonance ion source, a surface ionization ion source, a forced electron beam induced arc discharge ion source, and a laser ion source depending on the characteristics of the desired radioactive ion beam in terms of intensity, efficiency, purity, etc. A presentation of the SPIRAL2 project and of the different production systems is given.

[Occult hepatitis B virus infection]. / L'hépatite B occulte.

Occult hepatitis B virus (HBV) infection is a peculiar form of chronic viral infection identified since the early 80's and can be defined as the presence of HBV DNA in the serum and/or in the liver tissue of patients negative for the HBV surface antigen (HBsAg) using usual serological tests. The data about the prevalence of occult HBV infection are contrasting and the reported prevalences in various categories of individuals are highly diverse. The molecular basis of the occult HBV infection is the covalently closed-circular DNA (cccDNA) that persists in the cell nuclei and that serves as a template for gene transcription. The physiopathology of occult HBV infection is still unclear. However, the available data suggest that the host's immune response, the co-infections with other infectious agents and epigenetic factors may play important roles in indicing the occult status. The clinical relevance of occultHBVinfection remains debated but it may impact in four clinical contexts: 1) the transmission of the infection by blood transfusion or organ transplantation; 2) the acute reactivation when an immunosuppressive status occurs mainly in patients with isolated anti-HBc (chemotherapy, transplantations, immunodepression, new immunosuppressive therapy as anti-CD20 or anti TNF); 3) the potent but non proved progression of liver fibrosis in HCV infected patients or in patients with cryptogenetic liver disease; and, 4. the risk factor for hepatocellular carcinoma development.

[Antithrombotic agents in clinical practice]. / Les antithrombotiques en pratique.

The accumulation of evidence of efficacy and tolerance led to the FDA approval of bivalirudine in the United States and it has progressively replaced the use of unfractionated heparin in its traditional indication in the catheter laboratory of the Washington Hospital Center. This change has probably contributed to the reduction of bleeding complications observed in this institution. The experience acquired also showed a reduced risk of enzyme rises after the procedure. The use of bivalirudine in conditions comparable to those of the REPLACE II trial confirms that anti GPIIb/IIIa molecules should be reserved for extreme circumstances rather than be systematically associated with heparin, so significantly reducing the cost of the interventional procedures.

[The role of contrast-enhanced ultrasonography for the detection of hepatocellular carcinoma]. / La place de l'échographie de contraste dans la détection du carcinome hépatocellulaire.

The incidence of the hepatocellular carcinoma (HCC) is increasing in Occident, as well as in France. Primary prevention is the only solution for early detection. The combination of ultrasound (US) and alphaFP each 4 to 6 Months dosage has many limitations. The sensitivity of US examination is rather poor (less than 70% for lesions below 2 cm in diameter) and serum alphaFP values remain normal in almost 50% of HCC. US contrast agents (USCAs) with perfluorocarbon gases increase the backscattered signals during all phases of the liver transit, including arterial, portal and delayed phases. Hepatocellular lesions exhibit a specific kinetics with strong enhancement during arterial phase, and rapid wash-out during portal and delayed phases. USCAs increase the detection of HCCs and allow characterization of additional focal lesions found in cirrhotic livers (regenerative and dysplastic nodules, haemangiomas.). Indeed, regenerative nodules contrast uptake is synchronous to the surrounding parenchyma, and usually disappear during portal and delayed phases. However, US in cirrhosis remains a difficult examination, with limitations due to limited access to sub-diaphragmatic localization, attenuation of the ultrasound beam and shortness of the arterial phase.