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BACKGROUND: Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. METHODS: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS: The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3%vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. INTERPRETATION: Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. FUNDING: F Hoffmann-La Roche, Michelangelo Foundation. [ABSTRACT FROM AUTHOR]

Purpose: The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies., Methods: The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments., Results: Ibrutinib significantly delayed progression to symptomatic disease ( P < .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases ( P = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group., Conclusion: Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.

The Particle Time of Flight (PTOF) diagnostic is a chemical vapor deposition diamond-based detector and is the only diagnostic for measuring nuclear bang times of low yield (<1013) shots on the National Ignition Facility. Recently, a comprehensive study of detector impulse responses revealed certain detectors with very fast and consistent impulse responses with a rise time of <50 ps, enabling low yield burn history measurements. At the current standoff of 50 cm, this measurement is possible with fast 14 MeV neutrons from deuterium-tritium (DT) fusion plasmas. PTOF-inferred DT burn width numbers compare well with widths inferred from the gamma reaction history diagnostic on mid-yield (1013-1015) shots, where both systems are capable of making this measurement. These new capabilities could be extended to 2.5 MeV deuterium-deuterium neutrons from D plasmas and to even lower yield by reducing the detector standoff distance to 10 cm; a design for this is also presented., (© 2025 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

As neutron yields increase at fusion facilities, a universal symptom the community must deal with is MeV neutron-induced backgrounds in cables running to diagnostics. On the first Gain >1 plasmas in the world, the National Ignition Facility (NIF) neutron time-of-flight (nToF) diagnostic registered significant cable backgrounds that compromised key performance measurements. The South Pole nToF is uniquely located inside the NIF Target Bay shield walls, ∼18 m from the fusion source, and consequently has long coaxial cable runs (>20 m) that see significant neutron fluence. The resulting neutron-driven current in the cable is comparable to the downscattered neutron signal, compromising the downscattered ratio (DSR) measurement. We have characterized this background with a series of on-shot tests and developed a background subtraction technique to mitigate these effects. The background subtracted DSR results are validated against zirconium activation measurements, indicating that we have successfully reclaimed high-quality data output. The ion temperature measurement is found to not be affected by this background. Alternative approaches to addressing neutron-induced cable backgrounds are presented for potential future hardware upgrades., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

On pulsed fusion experiments, the neutron time of flight (nToF) diagnostic provides critical information on the fusion neutron energy spectrum. This work presents an analysis technique that uses two collinear nToF detectors, potentially to measure nuclear bang time and directional flow velocities. Two collinear detectors may be sufficient to disambiguate the contributions of nuclear bang time and directional flow velocities to the first moment of the neutron energy spectrum, providing an independent measurement of nuclear bang time. Preliminary results from measured nToF traces on the National Ignition Facility and additional applications of this technique are presented., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Neutrons generated in Inertial Confinement Fusion (ICF) experiments provide valuable information to interpret the conditions reached in the plasma. The neutron time-of-flight (nToF) technique is well suited for measuring the neutron energy spectrum due to the short time (100 ps) over which neutrons are typically emitted in ICF experiments. By locating detectors 10s of meters from the source, the neutron energy spectrum can be measured to high precision. We present a contextual review of the current state of the art in nToF detectors at ICF facilities in the United States, outlining the physics that can be measured, the detector technologies currently deployed and analysis techniques used., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

In the dynamic environment of burning, thermonuclear deuterium-tritium plasmas, diagnosing the time-resolved neutron energy spectrum is of critical importance. Strategies exist for this diagnosis in magnetic confinement fusion plasmas, which presently have a lifetime of ∼10 12 longer than inertial confinement fusion (ICF) plasmas. Here, we present a novel concept for a simple, precise, and scale-able diagnostic to measure time-resolved neutron spectra in ICF plasmas. The concept leverages general tomographic reconstruction techniques adapted to time-of-flight parameter space, and then employs an updated Monte Carlo algorithm and National Ignition Facility-relevant constraints to reconstruct the time-evolving neutron energy spectrum. Reconstructed spectra of the primary 14.028 MeV n DT peak are in good agreement with the exact synthetic spectra. The technique is also used to reconstruct the time-evolving downscattered spectrum, although the present implementation shows significantly more error.

The analysis of the National Ignition Facility (NIF) neutron time-of-flight (nToF) detectors uses a forward-fit routine that depends critically on the instrument response functions (IRFs) of the diagnostics. The details of the IRFs used can have large impacts on measurements such as ion temperature and down-scattered ratio (DSR). Here, we report on the recent steps taken to construct and validate nToF IRFs at the NIF to an increased degree of accuracy, as well as remove the need for fixed DSR baseline offsets. The IRF is treated in two parts: a "core," measured experimentally with an x-ray impulse source, and a "tail" that occurs later in time and has limited experimental data. The tail region is calibrated with the data from indirect drive exploding pusher shots, which have little neutron scattering and are traditionally assumed to have zero DSR. Using analytic modeling estimates, the non-zero DSR for these shots is estimated. The impact of varying IRF tail components on DSR is investigated with a systematic parameter study, and good agreement is found with the non-zero DSR estimates. These approaches will be used to improve the precision and uncertainty of NIF nToF DSR measurements.

A concept for using an intermediate distance (0.3-3.0 m) neutron time-of-flight (nToF) to provide a constraint on the measurement of the time-dependence of ion temperature in inertial confinement fusion implosions is presented. Simulated nToF signals at different distances are generated and, with a priori knowledge of the burn-averaged quantities and burn history, analyzed to determine requirements for a future detector. Results indicate a signal-to-noise ratio >50 and time resolution <20 ps to constrain the ion temperature gradient to ∼±25% (0.5 keV/100 ps).

Observation is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early-stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. At a median follow-up of 31 months, the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs 47.8 months; hazard ratio = 0.25; 95% confidence interval = 0.14-0.43, P < .0001). Compared with placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events (AEs). The most common serious AEs were atrial fibrillation, pneumonia, and rash in the ibrutinib group, and basal cell carcinoma, pneumonia, and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting the use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Ibrutinib confirms efficacy in CLL patients at an early stage with an increased risk of progression. However, the results do not justify changing the current standard of "watch and wait." This trial was registered at www.clinicaltrials.gov as #NCT02863718., (© 2022 by The American Society of Hematology.)

Inertial confinement fusion implosions designed to have minimal fluid motion at peak compression often show significant linear flows in the laboratory, attributable per simulations to percent-level imbalances in the laser drive illumination symmetry. We present experimental results which intentionally varied the mode 1 drive imbalance by up to 4% to test hydrodynamic predictions of flows and the resultant imploded core asymmetries and performance, as measured by a combination of DT neutron spectroscopy and high-resolution x-ray core imaging. Neutron yields decrease by up to 50%, and anisotropic neutron Doppler broadening increases by 20%, in agreement with simulations. Furthermore, a tracer jet from the capsule fill-tube perturbation that is entrained by the hot-spot flow confirms the average flow speeds deduced from neutron spectroscopy.

Purpose: Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking., Methods: Patients were eligible for the randomized, multicenter AMBORA study, if they were newly started on any of the oral anticancer drugs approved in 2001 or later without restriction to certain tumor entities. Patients were randomly assigned to receive either standard of care (control group) or an additional, intensified clinical pharmacological/pharmaceutical care, which included medication management and structured patient counseling, over a period of 12 weeks (intervention group). Primary end points were the number of antitumor drug-related problems (ie, side effects and unresolved medication errors) and patient treatment satisfaction with the oral anticancer therapy after 12 weeks measured with the Treatment Satisfaction Questionnaire for Medication, category convenience., Results: Two hundred two patients were included. Antitumor drug-related problems were significantly lower in the intervention compared with the control group (3.85 v 5.81 [mean], P < .001). Patient treatment satisfaction was higher in the intervention group (Treatment Satisfaction Questionnaire for Medication, convenience; 91.6 v 74.4 [mean], P < .001). The hazard ratio for the combined end point of severe side effects (Common Terminology Criteria for Adverse Events ≥ 3), treatment discontinuation, unscheduled hospital admission, and death was 0.48 (95% CI, 0.32 to 0.71, P < .001) in favor of the intervention group., Conclusion: Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. An intensified clinical pharmacological/pharmaceutical care has considerable, positive effects on the number of medication errors, patient treatment perception, and severe side effects., Competing Interests: Katja SchlichtigHonoraria: Roche Pharma AG Carolin KelzEmployment: Heumann Pharma GmbH & Co, Generica KG Renke MaasConsulting or Advisory Role: Pfizer Michael EckartConsulting or Advisory Role: AbbVie, AstraZeneca Caroline Ines PreußEmployment: Merck KGaAHonoraria: AMOENA Valeska BruecklHonoraria: AstraZeneca, BMS, MSD, Lilly, Novartis, Pfizer, Roche, Takeda, Roche, Novartis, BMS, AmgenConsulting or Advisory Role: AstraZeneca, BMS, MSD, Lilly, Novartis, Pfizer, Roche, Takeda, NovartisExpert Testimony: AstraZeneca, BMS, MSD, Lilly, Novartis, Pfizer, Roche, TakedaTravel, Accommodations, Expenses: Astra Zeneca, Boehringer, Roche, Novartis, Amgen Norbert MeidenbauerTravel, Accommodations, Expenses: Janssen Oncology Rainer FietkauHonoraria: Merck Sharp & Dohme, AstraZeneca, Novocure, Merck Serono, Sennewald GmbHConsulting or Advisory Role: MSD Oncology, Merck, AstraZeneca, Novocure, Bristol-Myers SquibbSpeakers' Bureau: Sennewald GmbH, Novocure, AstraZeneca, MSDResearch Funding: Merck, MSD Oncology, AstraZeneca, Novocure, Siemens Healthineers, Abbvie, DebiosTravel, Accommodations, Expenses: Sennewald GmbH, AstraZeneca, MSD Oncology, Merck, Novocure Peter-Juergen GoebellHonoraria: Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Novartis, Pfizer, Roche, SanofiTravel, Accommodations, Expenses: Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Novartis, Pfizer, Roche, Sanofi Andreas MackensenConsulting or Advisory Role: Bristol-Myers SquibbResearch Funding: Amgen Markus NeurathHonoraria: Takeda Pharma Vertrieb GmbH, PENTAX Europe GmbH, Boehringer Ingelheim Pharma GmbH & Co, Progenity, Janssen-Cilag, BMJ, BMA HouseConsulting or Advisory Role: Takeda Pharma Vertrieb GmbH, Pentax Europe GmbH, Boehringer Ingelheim Pharma GmbH & Co, Progenity, Janssen-Cilag, BMJ, BMA HouseResearch Funding: Amgen, Immunic AGTravel, Accommodations, Expenses: Janssen-Cilag, Takeda Pharma Vertrieb GmbH, Zealand Pharma, Vienna Medical Academy, Celgene, Falk Foundation e.V, United Arab Emirates University (UAEU), F. Hoffmann-La Rouche Ltd Marianne PavelHonoraria: IPSEN, Hutchison MediPharma, Advanced Accelerator Applications, Riemser, Boehringer IngelheimConsulting or Advisory Role: Advanced Accelerator Applications, IPSENTravel, Accommodations, Expenses: IPSEN, Hutchison Frank DörjeHonoraria: B. Braun Melsungen, Sanofi Aventis GmbHConsulting or Advisory Role: Lilly Martin F. FrommHonoraria: Janssen-CilagConsulting or Advisory Role: Boehringer IngelheimResearch Funding: Boehringer Ingelheim, Heidelberg PharmaNo other potential conflicts of interest were reported

Recent inertial confinement fusion measurements have highlighted the importance of 3D asymmetry effects on implosion performance. One prominent example is the bulk drift velocity of the deuterium-tritium plasma undergoing fusion ("hotspot"), v HS . Upgrades to the National Ignition Facility neutron time-of-flight diagnostics now provide v HS to better than 1 part in 10 4 and enable cross correlations with other measurements. This work presents the impact of v HS on the neutron yield, downscatter ratio, apparent ion temperature, electron temperature, and 2D x-ray emission. The necessary improvements to diagnostic suites to take these measurements are also detailed. The benefits of using cross-diagnostic analysis to test hotspot models and theory are discussed, and cross-shot trends are shown.

Nuclear diagnostics provide measurements of inertial confinement fusion implosions used as metrics of performance for the shot. The interpretation of these measurements for shots with low mode asymmetries requires a way of combining the data to produce a "sky map" where the individual line-of-sight values are used to interpolate to other positions in the sky. These interpolations can provide information regarding the orientation of the low mode asymmetries. We describe the interpolation method, associated uncertainties, and correlations between different metrics, e.g., T ion , down scatter ratio, and hot-spot velocity direction. This work is also related to recently reported studies [H. G. Rinderknecht et al., Phys. Rev. Lett. 124, 145002 (2020) and K. M. Woo et al., Phys. Plasmas 27, 062702 (2020)] of low mode asymmetries. We report an analysis that makes use of a newly commissioned line of sight, a scheme for incorporating multiple neutron spectrum measurement types, and recent work on the sources of implosion asymmetry to provide a more complete picture of implosion performance.

The measurement of plasma hotspot velocity provides an important diagnostic of implosion performance for inertial confinement fusion experiments at the National Ignition Facility. The shift of the fusion product neutron mean kinetic energy as measured along multiple line-of-sight time-of-flight spectrometers provides velocity vector components from which the hotspot velocity is inferred. Multiple measurements improve the hotspot velocity inference; however, practical considerations of available space, operational overhead, and instrumentation costs limit the number of possible line-of-sight measurements. We propose a solution to this classical "experiment design" problem that optimizes the precision of the velocity inference for a limited number of measurements.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin >3.5 mg/dL, lymphocyte doubling time (LDT) <12 months, and age >60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P < 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.

Neutron spectra from secondary ^{3}H(d,n)α reactions produced by an implosion of a deuterium-gas capsule at the National Ignition Facility have been measured with order-of-magnitude improvements in statistics and resolution over past experiments. These new data and their sensitivity to the energy loss of fast tritons emitted from thermal ^{2}H(d,p)^{3}H reactions enable the first statistically significant investigation of charged-particle stopping via the emitted neutron spectrum. Radiation-hydrodynamic simulations, constrained to match a number of observables from the implosion, were used to predict the neutron spectra while employing two different energy loss models. This analysis represents the first test of stopping models under inertial confinement fusion conditions, covering plasma temperatures of k&#95;{B}T≈1-4  keV and particle densities of n≈(12-2)×10^{24}  cm^{-3}. Under these conditions, we find significant deviations of our data from a theory employing classical collisions whereas the theory including quantum diffraction agrees with our data.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874 ., (Copyright© 2019 Ferrata Storti Foundation.)

An important diagnostic value of a shot at the National Ignition Facility is the resultant center-of-mass motion of the imploding capsule. This residual velocity reduces the efficiency of converting laser energy into plasma temperature. A new analysis method extracts the effective hot spot motion by using information from multiple neutron time-of-flight (nToF) lines-of-sight (LoSs). This technique fits a near Gaussian spectrum to the nToF scope traces and overcomes reliance on models to relate the plasma temperature to the mean energy of the emitted neutrons. This method requires having at least four nToF LoSs. The results of this analysis will be compared to an approach where each LoS is analyzed separately and a model is used to infer the mean energy of the emitted neutrons.

A Cherenkov neutron time-of-flight (nTOF) detector developed and constructed at Lawrence Livermore National Laboratory was tested at 13 m from the target in a collimated line of sight (LOS) and at 5.3 m from the target in the open space inside the OMEGA Target Bay. Neutrons interacting with the quartz rod generate gammas, which through Compton scattering produce relativistic electrons that give rise to Cherenkov light. A photomultiplier tube (PMT) transferred the Cherenkov light into an amplified electrical signal. The Cherenkov nTOF detector consists of an 8-mm-diam, 25-cm quartz hexagonal prism coupled with a Hamamatsu gated PMT R5916U-52. The tests were performed with DT direct-drive implosions with cryogenic and room-temperature targets, producing a wide range of neutron yields and ion temperatures. The results of the tests and comparison with other nTOF detectors on OMEGA are presented. In the collimated LOS at 13 m from the target, the Cherenkov nTOF detector demonstrated good precision measurement in both the yield and ion temperature for DT yields above 3 × 10 13 .

Neutron time-of-flight diagnostics at the NIF were recently outfitted with Cherenkov detectors. A fused silica radiator delivers sub-nanosecond response time and is optically coupled to a microchannel plate photomultiplier tube with gain from ∼1 to 10 4 . Capitalizing on fast time response and gamma-ray sensitivity, these systems can provide better than 30 ps precision for measuring first moments of neutron distributions. Generation of ab initio instrument response functions (IRFs) is critical to meet the <1% uncertainty needed. A combination of Monte Carlo modeling, benchtop characterization, and in situ comparison is employed. Close agreement is shown between the modeled IRFs and in situ measurements using the NIF's short-pulse advanced radiographic capability beams. First and second moments of neutron spectra calculated using ab initio IRFs agree well with established scintillator measurements. Next-step designs offer increased sensitivity and time-response.

A fused silica Cherenkov radiator has been implemented at the National Ignition Facility to provide a new high precision measurement of the time-of-flight spectrum of 14.1 MeV DT fusion neutrons. This detector enables a high precision (<30 ps) co-registered measurement of both a thresholded γ -ray and a neutron spectrum on a single record. Other methods typically require γ and neutron signals to be co-registered via other diagnostics and/or dedicated timing experiments. Analysis of the co-registered γ and neutron signals allows precise extraction of the mean neutron energy and bulk hot-spot velocity, both of which were not possible with prior scintillator technologies. Initial measurements demonstrate the feasibility of this measurement and indicate that combined detection of neutrons and γ -rays on multiple lines-of-sight should enable the bulk vector velocity of the implosion hot-spot to be determined to ≈5 km/s and reduced uncertainty in the spectral width ≈0.1 keV.

The temporal response of a microchannel plate photomultiplier tube used in the suite of neutron time of flight (nToF) diagnostics at the National Ignition Facility has been characterized to reduce uncertainty in, and understanding of, shot parameters obtained from nTOF data. A short pulse laser, neutral density glass filters, and electrical attenuators were used to gather statistically significant samples of photodetector impulse response functions (IRF) in rapid succession. Individual components have been absolutely calibrated to minimize systematic uncertainties. The zeroth (collected charge), first (transit time), and second central moments (transit time spread) of the IRF were calculated as either the bias voltage or the amount of light incident on the detector was varied. Timing reference was provided by a monitor photodiode viewing a pickoff of the incident laser pulse. The primary sources of uncertainty are jitter in the monitor photodiode and the statistical variation across our measurement period. The spreads in the first moment, with respect to the timing photodiode, and the square root of the second central moment were found to be less than 50 ps and 150 ps, respectively.

Cherenkov radiators deployed to measure the neutron time-of-flight spectrum have response times associated with the neutron transit across the detector and are free from long time response tails characteristic of scintillation detectors. The Cherenkov radiation results from simple physical processes which makes them amenable to high fidelity Monte Carlo simulation. The instrument response function of neutron time-of-flight systems is a major contributor to both the systematic and statistical uncertainties of the parameters used to describe these spectra; in particular, the first and second moments of these distributions are associated with arrival time, t 0 , and ion temperature, T ion . We present the results of uncertainty analysis showing the significant reduction of the uncertainty in determining these quantities in the Cherenkov detector system recently deployed at NIF. The increased sensitivity to gamma radiation requires additional consideration of the effect of this background to the uncertainties in both t 0 and T ion .

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

A common analysis procedure minimizes the ln-likelihood that a set of experimental observables matches a parameterized model of the observation. The model includes a description of the underlying physical process as well as the instrument response function (IRF). In the case investigated here, the National Ignition Facility (NIF) neutron time-of-flight (nTOF) spectrometers, the IRF is constructed from measurements and models. IRF measurements have a finite precision that can make significant contributions to determine the uncertainty estimate of the physical model's parameters. We apply a Bayesian analysis to properly account for IRF uncertainties in calculating the ln-likelihood function used to find the optimum physical parameters.

The Magnetic Recoil neutron Spectrometer (MRS) on the National Ignition Facility measures the DT neutron spectrum from cryogenically layered inertial confinement fusion implosions. Yield, areal density, apparent ion temperature, and directional fluid flow are inferred from the MRS data. This paper describes recent advances in MRS measurements of the primary peak using new, thinner, reduced-area deuterated plastic (CD) conversion foils. The new foils allow operation of MRS at yields 2 orders of magnitude higher than previously possible, at a resolution down to ∼200 keV FWHM.

Sixty-four neutral density filters constructed of metal plates with 88 apertures of varying diameter have been radiographed with a soft x-ray source and CCD camera at National Security Technologies, Livermore. An analysis of the radiographs fits the radial dependence of the apertures' image intensities to sigmoid functions, which can describe the rapidly decreasing intensity towards the apertures' edges. The fitted image intensities determine the relative attenuation value of each filter. Absolute attenuation values of several imaged filters, measured in situ during calibration experiments, normalize the relative quantities which are now used in analyses of neutron spectrometer data at the National Ignition Facility.

An accurate understanding of burn dynamics in implosions of cryogenically layered deuterium (D) and tritium (T) filled capsules, obtained partly through precision diagnosis of these experiments, is essential for assessing the impediments to achieving ignition at the National Ignition Facility. We present measurements of neutrons from such implosions. The apparent ion temperatures T&#95;{ion} are inferred from the variance of the primary neutron spectrum. Consistently higher DT than DD T&#95;{ion} are observed and the difference is seen to increase with increasing apparent DT T&#95;{ion}. The line-of-sight rms variations of both DD and DT T&#95;{ion} are small, ∼150eV, indicating an isotropic source. The DD neutron yields are consistently high relative to the DT neutron yields given the observed T&#95;{ion}. Spatial and temporal variations of the DT temperature and density, DD-DT differential attenuation in the surrounding DT fuel, and fluid motion variations contribute to a DT T&#95;{ion} greater than the DD T&#95;{ion}, but are in a one-dimensional model insufficient to explain the data. We hypothesize that in a three-dimensional interpretation, these effects combined could explain the results.

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874., (© 2015 by The American Society of Hematology.)

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population that shares certain characteristics including an aberrant myeloid phenotype and the ability to suppress T cells. MDSCs have been predominantly studied in malignant diseases and findings suggest involvement in tumor-associated immune suppression. Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence among adults. Immune defects occur already at early disease stages and impact the clinical course. We assessed presence, frequency, association to other immune parameters, and functional properties of circulating CD14(+) cells lacking HLA-DR expression (HLA-DR(lo)) in patients with untreated CLL. These monocytic cells represent one of the best-defined human MDSC subsets. Frequency of CD14(+)HLA-DR(lo) cells was significantly increased in CLL patients. Furthermore, MDSCs suppressed in vitro T-cell activation and induced suppressive regulatory T cells (TRegs). The MDSC-mediated modulation of T cells could be attributed to their increased indoleamine 2,3-dioxygenase (IDO) activity. CLL cells induced IDO(hi) MDSCs from healthy donor monocytes suggesting bidirectional crosstalk between CLL-cells, MDSCs, and TRegs. Overall, we identified a MDSC population that expands in CLL. The exact mechanisms responsible for such accumulation remain to be elucidated and it will be of interest to test whether antagonizing suppressive functions of CLL MDSCs could represent a mean for enhancing immune responses., (© 2014 by The American Society of Hematology.)

In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified 8 independent predictors of OS: sex, age, ECOG status, del(17p), del(11q), IGHV mutation status, serum β2-microglobulin, and serum thymidine kinase. Using a weighted grading system, a prognostic index was derived that separated 4 risk categories with 5-year OS ranging from 18.7% to 95.2% and having a C-statistic of 0.75. The index stratified OS within all analyzed subgroups, including all Rai/Binet stages. The validity of the index was externally confirmed in a series of 676 newly diagnosed CLL patients from Mayo Clinic. Using this multistep process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. The studies were registered as follows: CLL1 trial (NCT00262782, http://clinicaltrials.gov), CLL4 trial (ISRCTN 75653261, http://www.controlled-trials.com), and CLL8 trial (NCT00281918, http://clinicaltrials.gov)., (© 2014 by The American Society of Hematology.)

Alterations of cellular metabolism represent a hallmark of cancer. Numerous metabolic changes are required for malignant transformation, and they render malignant cells more prone to disturbances in the metabolic framework. Despite the high incidence of chronic lymphocytic leukemia (CLL), metabolism of CLL cells remains a relatively unexplored area. The examined untreated CLL patients displayed a metabolic condition known as oxidative stress, which was linked to alterations in their lymphoid compartment. Our studies identified mitochondrial metabolism as the key source for abundant reactive oxygen species (ROS). Unlike in other malignant cells, we found increased oxidative phosphorylation in CLL cells but not increased aerobic glycolysis. Furthermore, CLL cells adapted to intrinsic oxidative stress by upregulating the stress-responsive heme-oxygenase-1 (HO-1). Our data implicate that HO-1 was, beyond its function as an antioxidant, involved in promoting mitochondrial biogenesis. Thus ROS, adaptation to ROS, and mitochondrial biogenesis appear to form a self-amplifying feedback loop in CLL cells. Taking advantage of the altered metabolic profile, we were able to selectively target CLL cells by PK11195. This benzodiazepine derivate blocks the mitochondrial F1F0-ATPase, leads to a surplus production of mitochondrial superoxide, and thereby induces cell death in CLL cells. Taken together, our findings depict how bioenergetics and redox characteristics could be therapeutically exploited in CLL.

Neutron time-of-flight spectra from inertial confinement fusion experiments with tritium-filled targets have been measured at the National Ignition Facility. These spectra represent a significant improvement in energy resolution and statistics over previous measurements, and afford the first definitive observation of a peak resulting from sequential decay through the ground state of (5)He at low reaction energies E(c.m.) 100

The south pole bang-time diagnostic views National Ignition Facility (NIF) implosions through the lower Hohlraum laser entrance hole to measure the time of peak x-ray emission (peak compression) in indirect-drive implosions. Five chemical-vapor-deposition diamond photoconductive detectors with different filtrations and sensitivities record the time-varying x rays emitted by the target. Wavelength selecting highly oriented pyrolytic graphite crystal mirror monochromators increase the x-ray signal-to-background ratio by filtering for 11-keV emission. Diagnostic timing and the in situ temporal instrument response function are determined from laser impulse shots on the NIF. After signal deconvolution and background removal, the bang time is determined to 45-ps accuracy. The x-ray "yield" (mJ∕sr∕keV at 11 keV) is determined from the time integral of the corrected peak signal.

The first several campaigns of laser fusion experiments at the National Ignition Facility (NIF) included a family of high-sensitivity scintillator∕photodetector neutron-time-of-flight (nTOF) detectors for measuring deuterium-deuterium (DD) and DT neutron yields. The detectors provided consistent neutron yield (Y(n)) measurements from below 10(9) (DD) to nearly 10(15) (DT). The detectors initially demonstrated detector-to-detector Y(n) precisions better than 5%, but lacked in situ absolute calibrations. Recent experiments at NIF now have provided in situ DT yield calibration data that establish the absolute sensitivity of the 4.5 m differential tissue harmonic imaging (DTHI) detector with an accuracy of ± 10% and precision of ± 1%. The 4.5 m nTOF calibration measurements also have helped to establish improved detector impulse response functions and data analysis methods, which have contributed to improving the accuracy of the Y(n) measurements. These advances have also helped to extend the usefulness of nTOF measurements of ion temperature and downscattered neutron ratio (neutron yield 10-12 MeV divided by yield 13-15 MeV) with other nTOF detectors.

DT neutron yield (Y(n)), ion temperature (T(i)), and down-scatter ratio (dsr) determined from measured neutron spectra are essential metrics for diagnosing the performance of inertial confinement fusion (ICF) implosions at the National Ignition Facility (NIF). A suite of neutron-time-of-flight (nTOF) spectrometers and a magnetic recoil spectrometer (MRS) have been implemented in different locations around the NIF target chamber, providing good implosion coverage and the complementarity required for reliable measurements of Y(n), T(i), and dsr. From the measured dsr value, an areal density (ρR) is determined through the relationship ρR(tot) (g∕cm(2)) = (20.4 ± 0.6) × dsr(10-12 MeV). The proportionality constant is determined considering implosion geometry, neutron attenuation, and energy range used for the dsr measurement. To ensure high accuracy in the measurements, a series of commissioning experiments using exploding pushers have been used for in situ calibration of the as-built spectrometers, which are now performing to the required accuracy. Recent data obtained with the MRS and nTOFs indicate that the implosion performance of cryogenically layered DT implosions, characterized by the experimental ignition threshold factor (ITFx), which is a function of dsr (or fuel ρR) and Y(n), has improved almost two orders of magnitude since the first shot in September, 2010.

The National Ignition Facility has been used to compress deuterium-tritium to an average areal density of ~1.0±0.1 g cm(-2), which is 67% of the ignition requirement. These conditions were obtained using 192 laser beams with total energy of 1-1.6 MJ and peak power up to 420 TW to create a hohlraum drive with a shaped power profile, peaking at a soft x-ray radiation temperature of 275-300 eV. This pulse delivered a series of shocks that compressed a capsule containing cryogenic deuterium-tritium to a radius of 25-35 μm. Neutron images of the implosion were used to estimate a fuel density of 500-800 g cm(-3).

Purpose: The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL)., Patients and Methods: Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m(2) on days 1 and 2 combined with rituximab 375 mg/m(2) on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses., Results: On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively., Conclusion: Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

We demonstrate the hohlraum radiation temperature and symmetry required for ignition-scale inertial confinement fusion capsule implosions. Cryogenic gas-filled hohlraums with 2.2 mm-diameter capsules are heated with unprecedented laser energies of 1.2 MJ delivered by 192 ultraviolet laser beams on the National Ignition Facility. Laser backscatter measurements show that these hohlraums absorb 87% to 91% of the incident laser power resulting in peak radiation temperatures of T(RAD)=300 eV and a symmetric implosion to a 100 μm diameter hot core., (© 2011 American Physical Society)

The National Ignition Facility will soon be producing x-ray flux and neutron yields higher than any produced in laser driven implosion experiments in the past. Even a non-igniting capsule will require x-ray imaging of near burning plasmas at 10(17) neutrons, requiring x-ray recording systems to work in more hostile conditions than we have encountered in past laser facilities. We will present modeling, experimental data and design concepts for x-ray imaging with electronic recording systems for this environment (ARIANE). A novel instrument, active readout in a nuclear environment, is described which uses the time-of-flight difference between the gated x-ray signal and the neutron which induces a background signal to increase the yield at which gated cameras can be used.

The first 3 of 18 neutron time-of-flight (nTOF) channels have been installed at the National Ignition Facility (NIF). The role of these detectors includes yield, temperature, and bang time measurements. This article focuses on nTOF data analysis and quality of results obtained for the first set of experiments to use all 192 NIF beams. Targets produced up to 2×10(10) 2.45 MeV neutrons for initial testing of the nTOF detectors. Differences in neutron scattering at the OMEGA laser facility where the detectors were calibrated and at NIF result in different response functions at the two facilities. Monte Carlo modeling shows this difference. The nTOF performance on these early experiments indicates that the nTOF system with its full complement of detectors should perform well in future measurements of yield, temperature, and bang time.

The National Ignition Facility (NIF) successfully completed its first inertial confinement fusion (ICF) campaign in 2009. A neutron time-of-flight (nTOF) system was part of the nuclear diagnostics used in this campaign. The nTOF technique has been used for decades on ICF facilities to infer the ion temperature of hot deuterium (D(2)) and deuterium-tritium (DT) plasmas based on the temporal Doppler broadening of the primary neutron peak. Once calibrated for absolute neutron sensitivity, the nTOF detectors can be used to measure the yield with high accuracy. The NIF nTOF system is designed to measure neutron yield and ion temperature over 11 orders of magnitude (from 10(8) to 10(19)), neutron bang time in DT implosions between 10(12) and 10(16), and to infer areal density for DT yields above 10(12). During the 2009 campaign, the three most sensitive neutron time-of-flight detectors were installed and used to measure the primary neutron yield and ion temperature from 25 high-convergence implosions using D(2) fuel. The OMEGA yield calibration of these detectors was successfully transferred to the NIF.