International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

Chronic natural killer lymphoproliferative disorders: characteristics of an international cohort of 70 patients.

BACKGROUND: The 2008 World Health Organization (WHO) classification distinguishes three entities among the large granular lymphocytic leukemia (LGL leukemia): T-cell LGL leukemia (T-LGL leukemia), aggressive natural killer (NK) cell leukemia, and chronic NK lymphoproliferative disorders (LPD), the later considered as a provisional entity. Only a few and small cohorts of chronic NK LPD have been published. PATIENTS AND METHODS: We report here clinicobiological features collected retrospectively from 70 cases of chronic NK LPD, and compared with those of T-LGL leukemia. RESULTS: There were no statistical differences between chronic NK LPD and T-LGL leukemia concerning median age [61 years (range 23-82 years)], organomegaly (26%), associated autoimmune diseases (24%), and associated hematological malignancies (11%). Patients with chronic NK LPD were significantly less symptomatic (49% versus 18%, P < 0.001) and the association with rheumatoid arthritis was more rarely observed (7% versus 17%, P = 0.03). The neutropenia (<0.5 × 10(9)/l) was less severe in chronic NK LPD (33% versus 61%, P < 0.001) without difference in the rate of recurrent infections. STAT3 mutation was detected in 12% of the cohort, which is lower than the frequency observed in T-LGL leukemia. Thirty-seven percent of the patients required specific therapy. Good results were obtained with cyclophosphamide. Overall and complete response rates were, respectively, 69% and 56%. Overall survival was 94% at 5 years. CONCLUSION: This study suggests very high similarities between chronic NK LPD and T-LGL leukemias. Since chronic NK LPD is still a provisional entity, our findings should be helpful when considering further revisions of the WHO classification.

Evaluating the contributions of change in investment and change in efficiency to age-related declines in male and female reproduction.

It is commonly observed that reproduction decreases with age, often at a different rate in males and females. This phenomenon is generally interpreted as senescence. Such reproductive declines may stem from at least two sources: a change in resource allocation and a decline in the ability to convert resources into offspring. This distinction is important because a shift in resource allocation may be favoured by selection, while reduced efficiency is purely deleterious. We propose a way to distinguish whether a decline in reproduction is purely deleterious based on estimating reproductive investment, output, and their ratio, efficiency. We apply this approach to the hermaphroditic snail Physa acuta and demonstrate that both male and female functions decline with age. The male decline largely stems from reduced investment into male activity while female decline is due to increased reproductive inefficiency. This shows that age-related declines in reproduction can occur for a number of different reasons, a distinction that is usually masked by the general term 'senescence'. This approach could be applied to any species to evaluate age-related reproductive decline. We advocate that future studies measure age trajectories of reproductive investment and output to explore the potential processes hidden behind the observation that reproduction declines with age.

Lymphoma occurring in patients over 90 years of age: characteristics, outcomes, and prognostic factors. A retrospective analysis of 234 cases from the LYSA.

BACKGROUND: Lymphoma occurring in patients aged 90 or older is not uncommon, and its incidence is expected to increase over time. Management of these patients is difficult given their underlying fragility and the lack of information regarding this population. PATIENTS AND METHODS: We retrospectively analyzed 234 patients diagnosed with lymphoma at the age of 90 years or older (90+) between 1990 and 2012 to describe their characteristics, management, outcomes and prognostic factors. RESULTS: The median age was 92 years; 88% were B-cell lymphomas consisting mainly in diffuse large B-cell lymphoma. The median overall survival (OS) was 7.2 months (range, 0-92 months) for the 227 patients with non-Hodgkin Lymphoma (NHL), with a significant difference between aggressive and indolent NHL (5.2 months versus 19.4 months, respectively). We further analyzed 166 NHL patients for whom detailed characteristics were available. Among these patients, 63.5% received a treatment, either local (7.5%) or systemic (56%). Lymphoma was reported as the main cause of death (40%). Treatment administration was associated with improved OS in patients with aggressive (P < 0.001) but not indolent NHL (P = 0.96). In patients with aggressive NHL, hypoalbuminemia appeared as a strong and independent negative prognostic factor. CONCLUSIONS: The median OS is short in 90+ patients diagnosed with lymphoma but some patients experience prolonged survival. Lymphoma represents the main cause of death in these patients. Treatment may improve survival of selected patients with aggressive but not indolent NHL. Management of these patients may be guided by prognostic factors identified in this study, notably serum albumin.

Variation in habitat connectivity generates positive correlations between species and genetic diversity in a metacommunity.

An increasing number of studies are simultaneously investigating species diversity (SD) and genetic diversity (GD) in the same systems, looking for 'species- genetic diversity correlations' (SGDCs). From negative to positive SGDCs have been reported, but studies have generally not quantified the processes underlying these correlations. They were also mostly conducted at large biogeographical scales or in recently degraded habitats. Such correlations have not been looked for in natural networks of connected habitat fragments (metacommunities), and the underlying processes remain elusive in most systems. We investigated these issues by studying freshwater snails in a pond network in Guadeloupe (Lesser Antilles). We recorded SD and habitat characteristics in 232 ponds and assessed GD in 75 populations of two species. Strongly significant and positive SGDCs were detected in both species. Based on a decomposition of SGDC as a function of variance-covariance of habitat characteristics, we showed that connectivity (opportunity of water flow between a site and the nearest watershed during the rainy season) has the strongest contribution on SGDCs. More connective sites received both more alleles and more species through immigration resulting in both higher GD and higher SD. Other habitat characteristics did not contribute, or contributed negatively, to SGDCs. This is true of the desiccation frequency of ponds during the dry season, presumably because species markedly differ in their ability to tolerate desiccation. Our study shows that variation in environmental characteristics of habitat patches can promote SGDCs at metacommunity scale when the studied species respond homogeneously to these environmental characteristics.

Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria.

BACKGROUND: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, clonal haemopoietic stem cell disorder that causes chronic intravascular haemolysis, increases the risk of thrombosis and results in significant patient morbidity and mortality. The symptoms of PNH may have a major impact on patient quality of life. AIMS: To assess patient fatigue and health-related quality of life in 29 patients with PNH using the Functional Assessment of Chronic Illness Therapy Fatigue subscale version 4 (FACIT-Fatigue) and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30, version 3 (EORTC QLQ-C30). METHODS: Following completion of the questionnaires, patients were interviewed to assess the validity, clarity, relevance and comprehensiveness of the assessments. RESULTS: Overall, patients considered both the FACIT-Fatigue and EORTC QLQ-C30 instruments to be relevant and adequate in assessing the level of PNH-associated fatigue and other quality-of-life measures. The FACIT-Fatigue questionnaire was considered to be clear and to comprehensively cover PNH-related fatigue. The EORTC QLQ-C30 instrument was considered to be easy to understand, but of an overall lower relevance, although some differences between countries were observed. Patients suggested additional questions that could be incorporated into future EORTC QLQ-C30 versions to make it more relevant to PNH. CONCLUSIONS: This study confirms the validity of the FACIT-Fatigue and the EORTC QLQ-C30 questionnaires in this patient population and their routine use should be considered in the management of patients with PNH.

Large granular lymphocyte leukemia: An indolent clonal proliferative disease associated with an array of various immunologic disorders.

Large granular lymphocyte leukemia (LGLL) is a chronic lymphoproliferative disorder characterized by the proliferation of T or NK cytotoxic cells in the peripheral blood, the spleen and the bone marrow. Neutropenia leading to recurrent infections represents the main manifestation of LGLL. One specificity of LGLL is its frequent association with auto-immune disorders, among them first and foremost rheumatoid arthritis, and other hematologic diseases, including pure red cell aplasia and bone marrow failure. The large spectrum of manifestations and the classical indolent course contribute to the diagnosis difficulties and the frequency of underdiagnosed cases. Of importance, the dysimmune manifestations disappear with the treatment of LGLL as the blood cell counts normalize, giving a strong argument for a pathological link between the two entities. The therapeutic challenge results from the high rate of relapses following the first line of immunosuppressive drugs. New targeted agents, some of which are currently approved in autoimmune diseases, appear to be relevant therapeutic strategies to treat LGLL, by targeting key activated pathways involved in the pathogenesis of the disease, including JAK-STAT signaling.

Testing metapopulation dynamics using genetic, demographic and ecological data.

The metapopulation concept is a cornerstone in the recent history of ecology and evolution. However, determining whether a natural system fits a metapopulation model is a complex issue. Extinction-colonization dynamics are indeed often difficult to quantify because species detectability is not always 100%, resulting in an imperfect record of extinctions. Here, we explore whether combining population genetics with demographic and ecological surveys can yield more realistic estimates of metapopulation dynamics. We apply this approach to the freshwater snail Drepanotrema depressissimum in a fragmented landscape of tropical ponds. In addition to studying correlations between genetic diversity and demographical or ecological characteristics, we undertake, for the first time, a detailed search for genetic signatures of extinction-recolonization events using temporal changes in allele frequencies within sites. Surprisingly, genetic data indicate that extinction is much rarer than suggested by demographic surveys. Consequently, this system is better described as a set of populations with different sizes and immigration rates than as a true metapopulation. We identify several cases of apparent extinction owing to nondetection of low-density populations, and of aestivating individuals in desiccated ponds. More generally, we observed a frequent mismatch between genetic and demographical/ecological information at small spatial and temporal scales. We discuss the causes of these discrepancies and show how these two types of data provide complementary information on population dynamics and history, especially when temporal genetic samples are available.

18F-fluorodeoxyglucose-positron emission tomography before, during and after treatment in mature T/NK lymphomas: a study from the GOELAMS group.

BACKGROUND: In non-cutaneous T-cell/natural killer (T/NK) lymphomas, the prognostic value of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) during or after therapy is unknown. PATIENTS AND METHODS: In this retrospective study, 54 T/NK lymphoma patients were assessed using FDG-PET before (n = 40), during (n = 44) and/or after therapy (n = 31). RESULTS: FDG-PET showed an abnormal FDG uptake in all cases. Interim FDG-PET was negative in 25 of 44 cases. After completion of therapy, 19 of 31 patients reached complete remission with negative FDG-PET. In ALK+ anaplastic large cell lymphomas, the 4-year progression-free survival (PFS) was 80% and the negative predictive value of post-therapy FDG-PET was 83% (n = 9). In ALK- T/NK lymphomas, the 4-year PFS was 59% for patients with a negative interim FDG-PET versus 46% for patients with a positive interim FDG-PET (P = 0.28, n = 35). Similarly, there was no statistical difference in 4-year PFS between negative and positive post-therapy FDG-PET in these lymphomas (51% and 67%, respectively, P = 0.96). The 4-year cumulative incidence of relapse from a negative post-therapy FDG-PET was 53% in ALK- T/NK lymphomas. CONCLUSIONS: Although T/NK lymphomas are FDG-avid at diagnosis, a negative interim or post-therapy FDG-PET does not translate into an improved PFS in ALK- T/NK lymphomas.

[Gaucher's disease in Rennes University hospital: a 10-year retrospective study]. / Etude rétrospective sur dix ans des patients atteints de maladie de Gaucher au CHU de Rennes.

INTRODUCTION: Gaucher's disease (GD) remains rare and cohort studies are essential to improve our knowledge of this disease. METHODS: We performed a 10-year retrospective study of patients with GD followed-up in the Rennes University teaching hospital. RESULTS: Among a population of 1,500,000 inhabitants, 12 patients with GD were identified. Eight were men, and four were women. Mean age at diagnosis was 32.3 years and the first symptoms appeared around 31 years old. Main symptoms were: splenomegaly (82%), hepatomegaly (64%), thrombocytopenia (73%), anemia (64%), deterioration of general status (45%), bone pain (27%). Parkinsonism was noted in two patients, polyclonal gammopathy in two others, and monoclonal gammopathy was evidenced in four patients, with chronic lymphocytic lymphoma in one of them. Enzymatic activity dosage confirmed the diagnosis of GD for eight patients. For the remaining four patients, diagnosis was obtained by identification of Gaucher's cells on tissue examination. Substitutive enzymotherapy (SE) was performed for seven patients, with great improvement of initial symptoms. For two of these seven patients, SE is changed for miglustat with persistent improvement of clinical status. CONCLUSION: Association between GD and Parkinsonism or between GD and gammopathy was confirmed in our study. Other cohort studies are needed to improve the knowledge of GD.

Clinical spectrum of gammadelta+ T cell LGL leukemia: analysis of 20 cases.

We report on the clinico-biological characteristics of 20 cases of gammadelta T cell large granular lymphocyte (LGL) leukemia. All the data were compared to that of 196 cases with alphabeta T cell subtype, which represents the majority of T cell LGL leukemias. Clinical findings were quite similar in the two groups regarding age, sex ratio, recurrent infections, and association with auto-immune diseases especially rheumatoid arthritis. Gammadelta LGL predominantly expressed a CD3+/CD4-/CD8+/CD16+/CD57+ phenotype, in 50% of cases. Clinical outcome was favorable for these patients with overall survival of 85% at 3 years. Fifty percent of gammadelta patients required treatment and the response to therapy was estimated at 55%. gammadelta and alphabeta T cell LGL leukemia harbor a very similar clinico-biological behavior and represent part of an antigen-driven T cell lymphoproliferation.

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.

One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10(-7)). We identified a subgroup of patients presenting at diagnosis with both low beta(2)-microglobulin <4 mg/l and high hemoglobin (Hb) >/=10 g/l (46% of the cases) with a median OS of 54.6 months and a median EFS of 26 months, respectively, which benefits from high-dose therapy (HDT); conversely patients with one or both adverse prognostic factor (high beta(2)-microglobulin and/or low Hb) had a poor outcome. The achievement of either complete response or very good partial response after HDT was also a powerful independent prognostic factor for both OS and EFS.

European research activities on charge state breeding related to radioactive ion beam facilities.

European effort on charge breeders is mainly dedicated to present and future Radioactive Ion Beam facilities. The main projects are High Intensity and Energy-ISOLDE at CERN, SPIRAL2 at GANIL, and EURISOL. Most of the experimental developments are funded by the European programs EURONS (European Nuclear Structure) and EURISOL (European Isotope Separation On-Line Radioactive Ion Beam Facility). Two ion source types (electron beam ion source and electron cyclotron resonance ion source) have been adapted to accept the injection and the capture of an ion beam, in order to increase its charge with the highest efficiency within the shortest time. Both charge breeders have advantages and disadvantages with regard to their use in a Radioactive Ion Beam facility. The most important parameters studied are acceptance (in emittance and intensity) of the charge breeder, efficiency, and charge breeding time of a specific n+ charge state, emittance of the extracted n+ beam. The charge breeder parameters are studied with different 1+ ion sources dedicated to 1+ radioactive ion beam production, and the tuning procedure of the charge breeder as a beam line section of a specific accelerator is established and measured too.

First plasma of the A-PHOENIX electron cyclotron resonance ion source.

A-PHOENIX is a new compact hybrid electron cyclotron resonance ion source using a large permanent magnet hexapole (1.92 T at the magnet surface) and high temperature superconducting Solenoids (3 T) to make min- B structure suitable for 28 GHz cw operation. The final assembly of the source was achieved at the end of June 2007. The first plasma of A-PHOENIX at 18 GHz was done on the 16th of August, 2007. The technological specificities of A-PHOENIX are presented. The large hexapole built is presented and experimental magnetic measurements show that it is nominal with respect to simulation. A fake plasma chamber prototype including thin iron inserts showed that the predicted radial magnetic confinement can be fulfilled up to 2.15 T at the plasma chamber wall. Scheduled planning of experiments until the end of 2008 is presented.

The influence of ambipolarity on plasma confinement and on the performance of electron cyclotron resonance ion sources.

Charge diffusion in an electron cyclotron resonance ion source (ECRIS) discharge is usually characterized by nonambipolar behavior. While the ions are transported to the radial walls, electrons are lost axially from the magnetic trap. Global neutrality is maintained via compensating currents in the conducting walls of the vacuum chamber. It is assumed that this behavior reduces the ion breeding times compared to a truly ambipolar plasma. We have carried out a series of dedicated experiments in which the ambipolarity of the ECRIS plasma was influenced by inserting special metal-dielectric structures (MD layers) into the plasma chamber of the Frankfurt 14 GHz ECRIS. The measurements demonstrate the positive influence on the source performance when the ECR plasma is changed toward more ambipolar behavior.

Study of pulsed electron cyclotron resonance ion source plasma near breakdown: the preglow.

A careful study of pulsed mode operation of the PHOENIX electron cyclotron resonance (ECR) ion source has clearly demonstrated the reality of an unexpected transient current peak, occurring at the very beginning of the plasma breakdown. This regime was named the preglow, as an explicit reference to the afterglow occurring at the microwave pulse end. After the transient preglow peak, the plasma regime relaxes to the classical steady state one. Argon preglow experiments performed at LPSC are presented. A theoretical model of ECR gas breakdown in a magnetic trap, developed at IAP, showing satisfactory agreement with the experimental results is suggested.

The ECRIS charge state breeding project at TRIUMF.

The performance of charge state breeding with an electron cyclotron resonance (ECR) ion source intended to increase the charge state of online produced radioactive ions at the ISAC facility at TRIUMF has been investigated. A 14 GHz PHOENIX from PANTECHNIK has been setup on a test bench. Singly charged ions have been produced with several ion sources typical for the on-line operation and were injected into the charge breeder. The main purpose of the tests has been the optimization of the efficiency for the charge breeding into the desired charge state. Maximum efficiencies reached so far with the standard one step deceleration of the ions in front of the plasma are up to about 6% for noble gas ions and about 3.5% for alkalines. As ion optics simulations show, the acceptance can be increased by a two step deceleration. In order to meet the velocity acceptance of the accelerator at different A/q values a similar two gap acceleration system for the highly charged ions has been installed to allow the source to run at different voltages. For the further beam transport to the accelerator, cross sections for charge exchange of the highly charged ions with the residual gas have been determined.

[Thymic tumours, autoimmune neutropaenia and autoimmune haemolytic anaemia]. / Tumeurs épithéliales thymiques, neutropénie et anémie hémolytique auto-immunes.

INTRODUCTION: Although an association between thymic tumour and autoimmune disease (including autoimmune cytopenia) has been established, the association between thymic tumour and autoimmune neutropenia has rarely been reported, with only 13 cases described in the literature. OBSERVATION: We report on a 30 year old man diagnosed with autoimmune neutropenia who had been treated for invasive thymic tumour one year previously. He successfully responded to cyclosporin and steroids therapy. A few months later, the patient presented with autoimmune haemolytic anaemia after prematurely halting his own immunosuppressive treatment. CONCLUSION: This observation brings additional insights about the clinical features, biology and treatment of autoimmune neutropenia associated with thymic tumours and underlines the potential severity of such an association. Furthermore, the association of a thymic tumour with both autoimmune neutropaenia and autoimmune haemolytic anaemia has not been reported previously.

Prospect for a 60 GHz multicharged ECR ion source.

The conceptual design of a fourth generation hybrid electron cyclotron resonance (ECR) ion source operated at 60 GHz is proposed. The axial magnetic mirror is generated with a set of three Nb3Sn coils, while the hexapole is made with room temperature (RT) copper coils. The motivations for such a hybrid development are to study further the ECR plasma physics and the intense multicharged ion beams' production and transport at a time when a superconducting (SC) hexapole appears unrealistic at 60 GHz. The RT hexapole coil designed is an evolution of the polyhelix technology developed at the French High Magnetic Field Facility. The axial magnetic field is generated by means of 3 Nb3Sn SC coils operated with a maximum current density of 350 A/mm2 and a maximum coil load line factor of 81%. The ECR plasma chamber resulting from the design features an inner radius of 94 mm and a length of 500 mm. The radial magnetic intensity is 4.1 T at the wall. Characteristic axial mirror peaks are 8 and 4.5 T, with 1.45 T minimum in between.