Despite recent advances with monoclonal antibody therapy, chronic lymphocytic leukemia (CLL) remains incurable. Natural killer (NK) cells are potent antitumoral effectors, particularly against hematological malignancies. Defective recognition of B-CLL leukemic cells by NK cells has been previously described. Here, we deciphered the mechanisms that hamper NK cell-mediated clearance of B-CLL and evaluated the potential of NK cells as therapeutic tools for treatment of CLL. First of all, leukemic B cells resemble to normal B cells with a weak expression of ligands for NK receptors. Conversely, NK cells from B-CLL patients were functionally and phenotypically competent, despite a decrease of expression of the activating receptor NKp30. Consequently, resting allogeneic NK cells were unable to kill leukemic B cells in vitro. These data suggest that patients' NK cells cannot initiate a proper immune reaction due to a lack of leukemic cell recognition. We next set up a xenotransplantation mouse model to study NK-CLL cell interactions. Together with our in vitro studies, in vivo data revealed that activation of NK cells is required in order to control B-CLL and that activated NK cells synergize to enhance rituximab effect on tumor load. This study points out the requirements for immune system manipulation for treatment of B-CLL in combination with monoclonal antibody therapy.
The online version of this article has a Supplementary Appendix. BackgroundHigh-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin's lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin's lymphoma. Design and MethodsWe report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatmentrefractory Hodgkin's lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. ResultsFive-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57-10.73 ConclusionsIn patients with relapsed/refractory Hodgkin's lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation.Key words: Hodgkin's lymphoma, PET, outcome, relapsed refractory, ASCT.Citation: Devillier R, Coso D, Castagna L, Brenot Rossi I, Anastasia A, Chiti A, Ivanov V, Schiano JM, Santoro A, Chabannon C, Balzarotti M, Blaise D, and Bouabdallah R. Positron ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n
A new sub-1-V bandgap voltage reference is presented in this paper, which has advantages over the prior arts in terms of output noise and compatibility with several fabrication processes. The topology allows the reference to operate with a supply voltage as low as 1 V by employing the reverse bandgap voltage principle (RBVP). It also has an attractive low-noise output without the use of a large external filtering capacitor. The design was fabricated with a 0.5-m BiCMOS process, but it is compatible with most CMOS and BiCMOS fabrication processes. The entire die area is approximately 0.4 mm 2 , including all test pads and dummy devices. Theoretical analysis and experimental results show that the output noise spectral density is 40 nV Hz with a bias current of 20 A. Moreover, the peak-to-peak output noise in the 0.1-10 Hz band is only 4 V. The untrimmed reference has a mean output voltage of 190.9 mV at room temperature, and it has a temperature coefficient in the 40 C to +125 C range of 11 ppm C (mean) with a standard deviation of 5 ppm C.Index Terms-BiCMOS, low noise, low voltage, noise measurement, peak-to-peak noise, sub-1-V bandgap voltage reference, temperature coefficient, 1-V supply.
Background and objectives Monoclonal gammopathies (MGs) with renal involvement can lead to ESRD caused by myeloma cast nephropathy (MCN), immunoglobulin light chain amyloidosis (ALA), or light-chain deposition disease (LCDD). Few studies have focused on the prognosis of patients with MG on chronic dialysis. We evaluated the outcomes of patients with MG incident on chronic dialysis in France.Design, setting, participants, & measurements All incident patients registered in the Renal Epidemiology and Information Network Registry between 2002 and 2011 with ESRD caused by ALA, LCDD, or MCN were included. Patient's survival, censored for renal transplantation, renal recovery, and loss to follow-up, as well as renal outcomes were analyzed and compared with a control group. Risk factors and causes of death were analyzed.Results We included 1459 patients, comprising 265 (18%) patients with ALA, 334 (23%) patients with LCDD, and 861 (59%) patients with MCN. Median age was 72 years, and 56% were men. Median follow-up was 13.1 months. Renal recovery was observed in 9.1% of patients and more frequent after 2006. Kidney transplantation was rare in this population (2.3%). Among 1272 patients who remained on dialysis, 67% died. Median survival on dialysis was 18.3 months. Main causes of death were malignancies (34.4%), cardiovascular diseases (18%), infections (13.3%), and cachexia (5.2%). Independent risk factors of death were age (hazard ratio [HR], 1.03 per year increase; 95% confidence interval [95% CI], 1.02 to 1.03), frailty (HR, 1.93; 95% CI, 1.58 to 2.36), congestive heart failure (HR, 1.54; 95% CI, 1.23 to 1.93), and dialysis initiation on a central catheter (HR, 1.40; 95% CI, 1.11 to 1.75). Factors associated with a lower risk of death were year of dialysis initiation (HR, 0.95 per year increase; 95% CI, 0.91 to 0.99) and high BP (HR, 0.80; 95% CI, 0.67 to 0.97).Conclusions Survival of patients with ALA, LCDD, or MCN on chronic dialysis is poor but has improved over time. Progressive malignancy is the main cause of death in this population. Renal recovery has increased since 2006.
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