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.

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.

Status of the SPIRAL2 injector commissioning.

The SPIRAL2 injector, installed in its tunnel, is currently under commissioning at GANIL, Caen, France. The injector is composed of two low energy beam transport lines: one is dedicated to the light ion beam production, the other to the heavy ions. The first light ion beam, created by a 2.45 GHz electron cyclotron resonance ion source, has been successfully produced in December 2014. The first beam of the PHOENIX V2 18 GHz heavy ion source was analyzed on 10 July 2015. A status of the SPIRAL2 injector commissioning is given. An upgrade of the heavy ion source, named PHOENIX V3 aimed to replace the V2, is presented. The new version features a doubled plasma chamber volume and the high charge state beam intensity is expected to increase by a factor of 1.5 to 2 up to the mass ∼50. A status of its assembly is proposed.

The new ECR charge breeder for the Selective Production of Exotic Species project at INFN--Laboratori Nazionali di Legnaro.

The Selective Production of Exotic Species (SPES) project is an ISOL facility under construction at Istituto Nazionale di Fisica Nucleare-Laboratori Nationali di Legnaro (INFN-LNL). 1+ radioactive ions, produced and extracted from the target-ion-source system, will be charge bred to high charge states by an ECR charge breeder (SPES-CB): the project will adopt an upgraded version of the PHOENIX charge breeder, developed since about twenty years by the Laboratoire de Physique Subatomique et de Cosmologie (LPSC). The collaboration between LNL and LPSC started in 2010 with charge breeding experiments performed on the LPSC test bench and led, in June 2014, to the signature of a Research Collaboration Agreement for the delivery of a complete charge breeder and ancillaries, satisfying the SPES requirements. Important technological aspects were tackled during the construction phase, as, for example, beam purity issues, electrodes alignment, and vacuum sealing. This phase was completed in spring 2015, after which the qualification tests were carried out at LPSC on the 1+/q+ test stand. This paper describes the characteristics of the SPES-CB, with particular emphasis on the results obtained during the qualification tests: charge breeding of Ar, Xe, Rb, and Cs satisfied the SPES requirements for different intensities of the injected 1+ beam, showing very good performances, some of which are "best ever" for this device.

Charge breeder for the SPIRAL1 upgrade: Preliminary results.

In the framework of the SPIRAL1 upgrade under progress at the GANIL lab, the charge breeder based on a LPSC Phoenix ECRIS, first tested at ISOLDE has been modified to benefit of the last enhancements of this device from the 1+/n+ community. The modifications mainly concern the 1 + optics, vacuum techniques, and the RF-buffer gas injection into the charge breeder. Prior to its installation in the midst of the low energy beam line of the SPIRAL1 facility, it has been decided to qualify its performances and several operation modes at the test bench of LPSC lab. This contribution shall present preliminary results of experiments conducted at LPSC concerning the 1 + to n+ conversion efficiencies for noble gases as well as for alkali elements and the corresponding transformation times.

Optimizing charge breeding techniques for ISOL facilities in Europe: Conclusions from the EMILIE project.

The present paper summarizes the results obtained from the past few years in the framework of the Enhanced Multi-Ionization of short-Lived Isotopes for Eurisol (EMILIE) project. The EMILIE project aims at improving the charge breeding techniques with both Electron Cyclotron Resonance Ion Sources (ECRIS) and Electron Beam Ion Sources (EBISs) for European Radioactive Ion Beam (RIB) facilities. Within EMILIE, an original technique for debunching the beam from EBIS charge breeders is being developed, for making an optimal use of the capabilities of CW post-accelerators of the future facilities. Such a debunching technique should eventually resolve duty cycle and time structure issues which presently complicate the data-acquisition of experiments. The results of the first tests of this technique are reported here. In comparison with charge breeding with an EBIS, the ECRIS technique had lower performance in efficiency and attainable charge state for metallic ion beams and also suffered from issues related to beam contamination. In recent years, improvements have been made which significantly reduce the differences between the two techniques, making ECRIS charge breeding more attractive especially for CW machines producing intense beams. Upgraded versions of the Phoenix charge breeder, originally developed by LPSC, will be used at SPES and GANIL/SPIRAL. These two charge breeders have benefited from studies undertaken within EMILIE, which are also briefly summarized here.

Effect of immune modulation in relapsed peripheral T-cell lymphomas after post-allogeneic stem cell transplantation: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68-48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04-16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17-0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease.

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.

Results of a Prospective Study of High-Dose or Conventional Anthracycline-Cyclophosphamide Regimen Plus Radiotherapy for Localized Adult Non-Hodgkin's Primary Bone Lymphoma.

Background. Primary bone lymphoma (PBL) is a rare entity that has only been reviewed in one prospective and small retrospective studies, from which it is difficult to establish treatment guidelines. We prospectively evaluated high-dose or conventional anthracycline-cyclophosphamide dose and radiotherapy for PBL. Patients and Methods. The GOELAMS prospective multicenter study (1986-1998) enrolled adults with localized high-grade PBL according to age and performance status (PS). Patients <60 years received a high-dose CHOP regimen (VCAP) and those ≥60 years a conventional anthracycline-cyclophosphamide regimen (VCEP-bleomycin); all received intrathecal chemotherapy and local radiotherapy. Results. Among the 26 patients included (VCAP: 19; VCEP-bleomycin: 7), 39% had poor PS ≥2. With a median follow-up of 8 years, overall survival, event-free survival, and relapse-free survival were 64%, 62%, and 65%, respectively, with no significant difference between treatment groups. Poor PS was significantly associated with shorter OS and EFS. Conclusions. Our results confirm the efficacy of our age-based therapeutic strategy. High-doses anthracycline-cyclophosphamide did not improve the outcome. VCEP-bleomycin is effective and well tolerated for old patients. The intensification must be considered for patients with PS ≥2, a poor prognostic factor.

High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial.

The dosage of soluble programmed cell death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed in a prospective patient cohort. We evaluated the clinical impact of sPD-L1 level measured at the time of diagnosis for newly diagnosed diffuse large B-cell lymphoma (DLBCL). Soluble PD-L1 was measured in the plasma of 288 patients enrolled in a multicenter, randomized phase III trial that compared R-high-dose chemotherapy with R-CHOP. The median follow-up was 41.4 months. A cutoff of 1.52 ng/ml of PD-L1 level was determined and related to overall survival (OS). Patients with elevated sPD-L1 experienced a poorer prognosis with a 3-year OS of 76% versus 89% (P<0.001). Considering clinical characteristics, the multivariate analysis retained this biomarker besides bone marrow involvement and abnormal lymphocyte-monocyte score as independently related to poor outcome. sPD-L1 was detectable in the plasma and not in the serum, found elevated in patients at diagnosis compared with healthy subjects and its level dropped back to normal value after CR. The intention-to-treat analysis showed that elevated sPD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). Plasma PD-L1 protein is a potent predicting biomarker in DLBCL and may indicate usefulness of alternative therapeutic strategies using PD-1 axis inhibitors.

Future carbon beams at SPIRAL1 facility: which method is the most efficient?

Compared to in-flight facilities, Isotope Separator On-Line ones can in principle produce significantly higher radioactive ion beam intensities. On the other hand, they have to cope with delays for the release and ionization which make the production of short-lived isotopes ion beams of reactive and refractory elements particularly difficult. Many efforts are focused on extending the capabilities of ISOL facilities to those challenging beams. In this context, the development of carbon beams is triggering interest [H. Frånberg, M. Ammann, H. W. Gäggeler, and U. Köster, Rev. Sci. Instrum. 77, 03A708 (2006); M. Kronberger, A. Gottberg, T. M. Mendonca, J. P. Ramos, C. Seiffert, P. Suominen, and T. Stora, in Proceedings of the EMIS 2012 [Nucl. Instrum. Methods Phys. Res. B Production of molecular sideband radioisotope beams at CERN-ISOLDE using a Helicon-type plasma ion source (to be published)]: despite its refractory nature, radioactive carbon beams can be produced from molecules (CO or CO2), which can subsequently be broken up and multi-ionized to the required charge state in charge breeders or ECR sources. This contribution will present results of experiments conducted at LPSC with the Phoenix charge breeder and at GANIL with the Nanogan ECR ion source for the ionization of carbon beams in the frame of the ENSAR and EMILIE projects. Carbon is to date the lightest condensable element charge bred with an ECR ion source. Charge breeding efficiencies will be compared with those obtained using Nanogan ECRIS and charge breeding times will be presented as well.

Metallic beam developments for the SPIRAL 2 project.

The SPIRAL 2 facility, currently under construction, will provide either stable or radioactive beams at high intensity. In addition to the high intensity of stable beams, high charge states must be produced by the ion source to fulfill the RFQ LINAC injection requirements: Q/A = 1/3 at 60 kV ion source extraction voltage. Excepting deuterons and hydrogen, most of the stable beam requests concern metallic elements. The existing 18 GHz electron cyclotron resonance ion source (ECRIS) Phoenix V2 designed at LPSC Grenoble has been used for the tests and will be the source for the SPIRAL 2 commissioning. The tests performed at LPSC for calcium ((40)Ca(14+) and (40)Ca(16+)), nickel ((58)Ni(19+)), and sulfur ((32)S(11+)) are described and discussed. Due to the very high charge states required, the oven method has been chosen. An intensity of 1 pµA has been reached for those elements. The performance and the beam stability have been studied using different buffer gases, and some ionization efficiency preliminary results are given.

The charge breeder beam line for the selective production of exotic species project at INFN-Legnaro National Laboratories.

SPES (Selective Production of Exotic Species) is an INFN (Istituto Nazionale di Fisica Nucleare) project with the aim at producing and post-accelerating exotic beams to perform forefront research in nuclear physics. To allow post-acceleration of the radioactive ions, an ECR-based Charge Breeder (CB) developed on the basis of the Phoenix booster was chosen. The design of the complete beam line for the SPES-CB will be described: a system for stable 1+ beams production was included; special attention was paid to the medium resolution mass spectrometer after the CB to limit possible superposition of the exotic beams with the impurities present in the ECR plasma.

Ionization efficiency studies with charge breeder and conventional electron cyclotron resonance ion source.

Radioactive Ion Beams play an increasingly important role in several European research facility programs such as SPES, SPIRAL1 Upgrade, and SPIRAL2, but even more for those such as EURISOL. Although remarkable advances of ECRIS charge breeders (CBs) have been achieved, further studies are needed to gain insight on the physics of the charge breeding process. The fundamental plasma processes of charge breeders are studied in the frame of the European collaboration project, EMILIE, for optimizing the charge breeding. Important information on the charge breeding can be obtained by conducting similar experiments using the gas mixing and 2-frequency heating techniques with a conventional JYFL 14 GHz ECRIS and the LPSC-PHOENIX charge breeder. The first experiments were carried out with noble gases and they revealed, for example, that the effects of the gas mixing and 2-frequency heating on the production of high charge states appear to be additive for the conventional ECRIS. The results also indicate that at least in the case of noble gases the differences between the conventional ECRIS and the charge breeder cause only minor impact on the production efficiency of ion beams.