In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for ...CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL.
In chronic lymphocytic leukemia (CLL), the worst prognosis is associated with TP53 defects with the affected patients being potentially directed to alternative treatment. Therapy administration was ...shown to drive the selection of new TP53 mutations in CLL. Using ultra-deep next-generation sequencing (NGS), we performed a detailed analysis of TP53 mutations' clonal evolution. We retrospectively analyzed samples that were assessed as TP53-wild-type (wt) by FASAY from 20 patients with a new TP53 mutation detected in relapse and 40 patients remaining TP53-wt in relapse. Minor TP53-mutated subclones were disclosed in 18/20 patients experiencing later mutation selection, while only one minor-clone mutation was observed in those patients remaining TP53-wt (n=40). We documented that (i) minor TP53 mutations may be present before therapy and may occur in any relapse; (ii) the majority of TP53-mutated minor clones expand to dominant clone under the selective pressure of chemotherapy, while persistence of minor-clone mutations is rare; (iii) multiple minor-clone TP53 mutations are common and may simultaneously expand. In conclusion, patients with minor-clone TP53 mutations carry a high risk of mutation selection by therapy. Deep sequencing can shift TP53 mutation identification to a period before therapy administration, which might be of particular importance for clinical trials.
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from ...Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.
The TOTEM collaboration has measured the proton-proton total cross section at √s=8 TeV using a luminosity-independent method. In LHC fills with dedicated beam optics, the Roman pots have been ...inserted very close to the beam allowing the detection of ~90% of the nuclear elastic scattering events. Simultaneously the inelastic scattering rate has been measured by the T1 and T2 telescopes. By applying the optical theorem, the total proton-proton cross section of (101.7±2.9) mb has been determined, well in agreement with the extrapolation from lower energies. This method also allows one to derive the luminosity-independent elastic and inelastic cross sections: σ(el)=(27.1±1.4) mb; σ(inel)=(74.7±1.7) mb.
The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown ...how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2-16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression.
Summary Background Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not ...suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. Methods We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m2 ) on days 1–7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov , number NCT00748189. Findings We enrolled 447 patients, median age 69 years (range 35–92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0–25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6–13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45–0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 50% patients; vs 98 43% given chlorambucil alone), with neutropenia being the most common event (56 26% vs 32 14%). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. Interpretation Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. Funding GlaxoSmithKline, Genmab A/S.
•Addition of up to 25% of C2F6 into a C3F8 refrigerant effectively decreases the evaporation temperature.•The heat transfer coefficient somewhat decreased with the progressive addition of ...C2F6.•Various flow regimes in the horizontal evaporator are clearly visible from the obtained data.
We have measured the flow boiling heat transfer coefficient (HTC) of saturated fluorocarbon blends in a horizontal copper-nickel tube with a diameter of 4mm. Direct (Joule) heating of the tube wall was used to obtain heat fluxes from 5 to 13.7kWm−2. Two different injection capillaries were used, permitting measurements at mass fluxes varying between 94 and 164kgm−2s−1. The evaporation pressure was approximately 0.2MPa for the mass fluxes close to 164kgm−2s−1 and 0.15MPa for the lower mass fluxes. The same tube dimensions and material are used in the on-detector cooling channels of the silicon micro-strip charged particle tracker (“SCT”) of the ATLAS experiment at the CERN Large Hadron Collider. The range of heat flux and mass flow studied encompasses the operating conditions of the tracker. When operating in the high radiation environment near to the proton beam collisions radiation tolerant coolants are essential. Saturated fluorocarbons (CnF(2n+2)) are radiation resistant and allow thermodynamic “tailoring” by blending saturated molecules of different orders. Measurements were made with pure C3F8 (R218) and zeotropic blends containing 5, 10, 15, 20 and 25% (molar) C2F6 (R116). This work is a continuation of a previous study which showed that the operating temperature of the ATLAS SCT could be reduced by around 10°C with the admixture of 25% (molar) C2F6, with no changes needed to the existing on-detector and circulatory pipework. The data analysis revealed multiple flow boiling regimes of the two-phase flow that varied as a function of coolant flow rate, heat flux, vapour quality and mixture composition. As expected, the HTC in pure C3F8 was higher than in blends with increasing C2F6 content. Nevertheless, the study confirmed that the ATLAS SCT could be operated at full power dissipation with cooling tube temperatures up to 10°C colder than in pure C3F8 with C3F8/C2F6 blends having relatively modest values of HTCs in the range 1500–4000Wm−2K−1.
Abstract
The TOTEM collaboration has measured the elastic proton-proton differential cross section
$$\mathrm{d}\sigma /\mathrm{d}t$$
d
σ
/
d
t
at
$$\sqrt{s}=13$$
s
=
13
TeV LHC energy using ...dedicated
$$\beta ^{*}=90$$
β
∗
=
90
m beam optics. The Roman Pot detectors were inserted to 10
$$\sigma $$
σ
distance from the LHC beam, which allowed the measurement of the range 0.04 GeV
$$^{2}$$
2
; 4 GeV
$$^{2}$$
2
$$$$
in four-momentum transfer squared |
t
|. The efficient data acquisition allowed to collect about 10
$$^{9}$$
9
elastic events to precisely measure the differential cross-section including the diffractive minimum (dip), the subsequent maximum (bump) and the large-|
t
| tail. The average nuclear slope has been found to be
$$B=(20.40 \pm 0.002^{\mathrm{stat}} \pm 0.01^{\mathrm{syst}})~$$
B
=
(
20.40
±
0
.
002
stat
±
0
.
01
syst
)
GeV
$$^{-2}$$
-
2
in the |
t
|-range 0.04–0.2 GeV
$$^{2}$$
2
. The dip position is
$$|t_{\mathrm{dip}}|=(0.47 \pm 0.004^{\mathrm{stat}} \pm 0.01^{\mathrm{syst}})~$$
|
t
dip
|
=
(
0.47
±
0
.
004
stat
±
0
.
01
syst
)
GeV
$$^{2}$$
2
. The differential cross section ratio at the bump vs. at the dip
$$R=1.77\pm 0.01^{\mathrm{stat}}$$
R
=
1.77
±
0
.
01
stat
has been measured with high precision. The series of TOTEM elastic pp measurements show that the dip is a permanent feature of the pp differential cross-section at the TeV scale.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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