Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma.

BACKGROUND: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. DESIGN: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. RESULTS: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. CONCLUSION: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.

Dynamic Stark spectroscopic measurements of microwave electric fields inside the plasma near a high-power antenna.

Fully dynamic Stark effect visible spectroscopy was used for the first time to directly measure the local rf electric field in the boundary plasma near a high-power antenna in high-performance, magnetically confined, fusion energy experiment. The measurement was performed in the superconducting tokamak Tore Supra, in the near field of a 1­3 MW, lower-hybrid, 3.7 GHz wave-launch antenna, and combined with modeling of neutral atom transport to estimate the local rf electric field amplitude (as low as 1­2 kV/cm) and direction in this region. The measurement was then shown to be consistent with the predicted values from a 2D full-wave propagation model. Notably the measurement confirmed that the electric field direction deviates substantially from the direction in which it is launched by the waveguides as it penetrates only a few cm radially inward into the plasma from the waveguides, consistent with the model.

Development of visible spectroscopy diagnostics for W sources assessment in WEST.

The present work concerns the development of a W sources assessment system in the framework of the tungsten-W environment in steady state tokamak project that aims at equipping the existing Tore Supra device with a tungsten divertor in order to test actively cooled tungsten Plasma Facing Components (PFCs) in view of preparing ITER operation. The goal is to assess W sources and D recycling with spectral, spatial, and temporal resolution adapted to the PFCs observed. The originality of the system is that all optical elements are installed in the vacuum vessel and compatible with steady state operation. Our system is optimized to measure radiance as low as 1016 Ph/(m2 s sr). A total of 240 optical fibers will be deployed to the detection systems such as the "Filterscope," developed by Oak Ridge National Laboratory (USA) and consisting of photomultiplier tubes and filters, or imaging spectrometers dedicated to Multiview analysis.

Stimulation and inhibition of human granulopoiesis in vitro by normal and malignant T4- or T8-lymphocyte subpopulations.

We studied the role of total peripheral blood T-lymphocytes and separated subpopulations of OKT4+ and OKT8+ cells stimulated with concanavalin A in the regulation of human granulopoiesis. Unfractionated total T cells depleted of monocytes are capable of producing colony-stimulating activity (CSA) and colony-forming unit-clone (CFU-C) suppressor activity simultaneously. After positive selection of cell subsets using a fluorescence-activated cell sorter, these two activities were produced by OKT4+ lymphocytes, whereas OKT8+ cells displayed small amounts of CSA and were incapable of releasing suppressor activity. On the other hand, total human thymocytes and subsets defined by monoclonal antibodies Leu2a/Leu3a failed to express any detectable CSA or CFU-C suppressor activity. A total of 14 cases of phenotyped lymphoid malignancies were also studied: the results showed that the production of stimulating and/or inhibiting factors is neither clearly related to a discrete stage of differentiation nor to the OKT4/OKT8 phenotype. Moreover, three monoclonal T leukemias, OKT4+OKT8-, OKT4-OKT8-, and OKT4-OKT8+ have been able in each case to produce simultaneously CSA and CFU-C suppressor activity. Finally, these studies strongly suggest that the activities of T-lymphocytes involved in the regulation of granulopoiesis are not closely linked with OKT4/OKT8 phenotype.

Limiting dilution analysis of the frequency of IL2 responsive T cells in lymph nodes involved by B-cell non-Hodgkin's lymphomas.

Total T lymphocytes separated from twelve lymph nodes involved by B-NHL were studied in limiting dilution experiments for their ability to proliferate in the presence of both R-IL2 used at a final concentration of 40 U/ml and irradiated autologous malignant B cells as feeders. The number of proliferating T-lymphocyte precursors (PTL-P) thus estimated was low in each case (mean: 1/4503; range, 1/200 to 1/11013). Once expanded, proliferation of the IL2 responsive T cells in the presence of autologous malignant B cells remained strictly dependent on the addition of exogenous IL2. Control cases consisted of T lymphocytes separated from peripheral blood of six healthy subjects and cultured in the presence of both R-IL2 (40 U/ml) and irradiated autologous total mononuclear cells as feeders; the mean frequency of PTL-P thus obtained (1/173; range, 1/49 to 1/457) was significantly higher than in malignant lymph nodes (p less than 0.01). These findings do not support the hypothesis that, in this series of patients, expansion of malignant B cells may lead to the activation and growth of T cells sensitized against the tumour.

Investigation of electron-distribution function and dynamo mechanisms in a reversed-field pinch by analysis of hydrogen-pellet deflection

In reversed-field pinches, two different mechanisms have been proposed to explain the dynamo process which drives the poloidal current needed to sustain the magnetic configuration: the kinetic dynamo theory and the magnetohydrodynamic (MHD) dynamo theory. Experimentally, they can be distinguished by the radial behavior of the electron distribution function. In this Letter the trajectory deflection of frozen hydrogen pellets has been used as a diagnostic of suprathermal electrons in the plasma. The classical Spitzer-Harm distortion of the electron distribution function consistent with the MHD dynamo electric field is found to give a better modeling of the pellet trajectory.

Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients.

Deletions of the 1p region appear as a pejorative prognostic factor in multiple myeloma patients (especially 1p22 and 1p32 deletions) but there is a lack of data on the real impact of 1p abnormalities on an important and homogeneous group of patients. To address this issue we studied by fluorescence in situ hybridization (FISH) the incidence and prognostic impact of 1p22 and 1p32 deletions in 1195 patients from the IFM (Institut Francophone du Myélome) cell collection. Chromosome 1p deletions were present in 23.3% of the patients (271): 15.1% (176) for 1p22 and 7.3% (85) for 1p32 regions. In univariate analyses, 1p22 and 1p32 appeared as negative prognostic factors for progression-free survival (PFS): 1p22: 19.8 months vs 33.6 months (P<0.001) and 1p32: 14.4 months vs 33.6 months (P<0.001); and overall survival (OS): 1p22: 44.2 months vs 96.8 months (P=0.002) and 1p32: 26.7 months vs 96.8 months (P<0.001). In multivariate analyses, 1p22 and 1p32 deletions still appear as independent negative prognostic factors for PFS and OS. In conclusion, our data show that 1p22 and 1p32 deletions are major negative prognostic factors for PFS and OS for patients with MM. We thus suggest that 1p32 deletion should be tested for all patients at diagnosis.

Probing the plasma near high power wave launchers in fusion devices for static and dynamic electric fields (invited).

An exploratory study was carried out in the long-pulse tokamak Tore Supra, to determine if electric fields in the plasma around high-power, RF wave launchers could be measured with non-intrusive, passive, optical emission spectroscopy. The focus was in particular on the use of the external electric field Stark effect. The feasibility was found to be strongly dependent on the spatial extent of the electric fields and overlap between regions of strong (>∼1 kV/cm) electric fields and regions of plasma particle recycling and plasma-induced, spectral line emission. Most amenable to the measurement was the RF electric field in edge plasma, in front of a lower hybrid heating and current drive launcher. Electric field strengths and direction, derived from fitting the acquired spectra to a model including time-dependent Stark effect and the tokamak-range magnetic field Zeeman-effect, were found to be in good agreement with full-wave modeling of the observed launcher.

Residual gas analysis for long-pulse, advanced tokamak operation.

A shielded residual gas analyzer (RGA) system on Tore Supra can function during plasma operation and is set up to monitor the composition of the neutral gas in one of the pumping ducts of the toroidal pumped limited. This "diagnostic RGA" has been used in long-pulse (up to 6 min) discharges for continuous monitoring of up to 15 masses simultaneously. Comparison of the RGA-measured evolution of the H(2)/D(2) isotopic ratio in the exhaust gas to that measured by an energetic neutral particle analyzer in the plasma core provides a way to monitor the evolution of particle balance. RGA monitoring of corrective H(2) injection to maintain proper minority heating is providing a database for improved ion cyclotron resonance heating, potentially with RGA-base feedback control. In very long pulses (>4 min) absence of significant changes in the RGA-monitored, hydrocarbon particle pressures is an indication of proper operation of the actively cooled, carbon-based plasma facing components. Also H(2) could increase due to thermodesorption of overheated plasma facing components.

Clinical and hematological improvement in a patient receiving danazol therapy for myelofibrosis with myeloid metaplasia.

We report the positive effect of danazol on clinical and hematological data in a patient with myelofibrosis and myeloid metaplasia. Severe cytopenia was corrected within 2 months and was maintained for an additional 2-month period. Myeloid metaplasia (lymph nodes and skin lesions) was greatly reduced. The patient experienced no side effects. We propose further trials to confirm the utility of this agent in this disease.

Splenectomy during chronic lymphocytic leukemia.

The combination of discontinuous high-dose chlorambucil therapy with splenectomy greatly increased the prognosis of aggressive forms of chronic lymphocytic leukemia (CLL). The median survival for 43 patients was 84 months from diagnosis and 48 months from splenectomy. For 15 stages O, according to Rai classification, obtained after splenectomy, duration ranged from 3 to 105 months. The median survival of a group of patients showing "nodular splenic infiltration" was 104 months and superior to that of a group of patients showing "diffuse splenic infiltration" (72 months). In four of 15 cases studied, the peripheral blood lymphocytic clone disappeared after splenectomy.

Investigation of current-density modification during magnetic reconnection by analysis of hydrogen-pellet deflection.

A pellet penetrating the inner region of a tokamak discharge, where the safety factor drops below unity, triggers an instability analogous to a sawtooth crash. Because of the simultaneity of the crash and pellet crossing, the latter is an appropriate probe for investigating the current distribution during reconnection. In this Letter, pellet deflection is used to characterize the associated electron distribution function. The perturbation compatible with the observed trajectory requires a negative current layer on the q=1 magnetic surface between 3 and 12 times the equilibrium current density and an expulsion of high energy electrons from the plasma core.

Production of granulopoiesis-stimulating and -inhibiting activities by T cells associated with malignant cells in lymphomas.

The possible role of T lymphocytes in the formation of granulomatous reactions seen in certain malignant lymphoid tumours was investigated by measuring the granulopoietic colony-stimulating activity (CSA) and granulopoietic-inhibiting activity (IA) produced by stimulated T-lymphocytes isolated from peripheral blood, spleen and lymph nodes of patients and normal subjects. Lymph-node T-cells from patients with benign lymphoid hyperplasia, B-cell non-Hodgkin's lymphoma (B-NHL), and non-granulomatous Hodgkin's disease (HD) showed no CSA, but the cells produced IA of 40 +/- 23%, 40 +/- 24% and 50.5 +/- 22.5% respectively. The corresponding cells from patients with HD accompanied by granulomatous reactions produced CSA of 6.85 +/- 6.5 u/microliters and IA of 23.5 +/- 21%. The presence of a granulomatous reaction in malignant lymphoma was correlated with the stimulation of granulopoiesis in vitro by T lymphocytes associated with malignant cells. A correlation was demonstrated between neutrophilic and eosinophilic colonies obtained in vitro under the influence of CSA-producing T cells isolated from malignant lymphomas and the neutrophils and eosinophils present in the granuloma. These results showed that tumour-infiltrating T cells play a role in the presence of granulomatous reactions seen in lymphomas. Peripheral-blood T cells from healthy subjects, and from patients with B-NHL, or with HD unaccompanied by granulocytic reactions produced CSAs of, respectively, 5 +/- 0.5 u/microliter, 4.8 +/- 2.2 u/microliters and 5.3 +/- 0.4 u/microliters, and IAs of 45 +/- 18%. 50 +/- 5.5% and 50.5 +/- 7% respectively. The corresponding values for HD patients with granulocytic reactions were CSA. 17 +/- 15.5 u/microliters, and IA, 9.5 +/- 9%. No correlation was demonstrated between neutrophilic colonies obtained in vitro under the influence of HD blood T cells and neutrophils present in blood. Only one correlation was found: between the percentage of eosinophilic colonies and the number of blood eosinophils. HD blood T cells did not seem to explain completely granulocytic reactions seen in blood.

[Cefmenoxime diffusion into cerebrospinal fluid during human purulent meningitis]. / Diffusion de la cefménoxime dans le liquide céphalorachidien au cours des méningites purulentes humaines.

We treated 10 patients with bacterial meningitis by 150 mg/kg/day cefmenoxime divided into six intravenous infusions. CSF samples were taken one hour after an IV on the second and fifth days. CSF cefmenoxime determined by microbiologic assay was 8.3 mg/l on days 2 and 5. Every patient recovered without sequelae. In our opinion, these results may support use of cefmenoxime in bacterial meningitis.

Non-Hodgkin's malignant lymphomas in patients older than 80. 70 cases.

In two centers (a comprehensive cancer center and a university hospital) 1300 patients with non-Hodgkin's lymphomas (NHL) were observed during the past 15 years. Seventy patients (5.4%) were diagnosed after they were 80 years old. Thirty-four patients had low-grade NHL, eight had intermediate grade, and 28 had high-grade NHL. The majority of them were classified as Stage I (n = 24) or II (n = 18), and the rest as Stage III (n = 16) or IV (n = 12). Treatment varied with grade of NHL, tumoral extension, and performance status. Forty-seven patients were given chemotherapy, 37 radiotherapy, and six patients had surgery. Overall, treatment was considered to be optimal in 12 patients, good in 34 patients, and limited in 24 patients. Toxicity was minimal in 62 patients, treatment-limiting in two patients, and lethal in six patients. Thirty-seven patients achieved a complete remission (CR), 21 a partial remission, five experienced stabilization, and seven failed to respond. For all patients, the median survival (MS) was 18 months. In contrast to younger patients, malignancy grade had no significant influence. The only significant parameter is CR (P = 0.02). In conclusion, very old patients must be treated correctly but carefully. Better tolerated treatments are needed to improve results that are neither very poor nor as good as in younger patients.

Skeletal involvement as the initial disease manifestation in Hodgkin's disease: a review of 6 cases.

Initial signs of malignant lymphoma are rarely due to bone lesions. We reviewed 6 cases with early skeletal involvement, recently observed in the rheumatology and hematology departments. In 3 patients, magnetic resonance imaging (MRI) was added to traditional investigations, including radiography, radionuclide bone scan and computerized tomography. We stress the possibility of bone involvement in the clinical onset of malignant lymphoma and the usefulness of early bone assessment using MRI.

[Bone manifestations disclosing Hodgkin's disease and non-Hodgkin's malignant lymphoma. Analysis of 11 cases]. / Manifestations osseuses révélatrices de maladies de Hodgkin et de lymphomes malins non hodgkiniens. Analyse de onze observations.

Bone localizations revealing Hodgkin's disease or non-Hodgkin's malignant lymphoma, are unusual. We are reporting 11 recent cases collected in rheumatology and haematology departments, including 4 where a comprehensive study of X-rays, scintigrams, axial tomograms and nuclear magnetic resonance imaging was performed. Review of the literature as well as our experience concerning the type of onset of the bone involvement, the clinical correlation, the imaging techniques, have led us to consider nuclear magnetic resonance as a decisive factor which should be offered at an early stage in the diagnostic approach.