Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Amplification of flat laser pulse train.

We present modeling and measurements of flattop amplification of a laser pulse train in a diode pumped Nd:YLF system. We establish a theoretical model, accounting for the transverse Gaussian shape of an amplified laser beam, in order to explain remaining slopes in the pulse train energy. The influence of the transverse Gaussian shape on the train's flatness has been experimentally verified. Based on the model we are able to increase the total amplification of a long train of infrared seed beam in the drive laser system at the Fermilab Accelerator Science and Technology facility. The single-pass amplifier improvements resulted in a gain of ∼7 with flat output pulse train for up to 1000 seed pulses.

Vacuum channeling radiation by relativistic electrons in a transverse field of a laser-based Bessel beam.

Relativistic electrons counterpropagating through the center of a radially polarized J_{1} optical Bessel beam in vacuum will emit radiation in a manner analogous to the channeling radiation that occurs when charged particles traverse through a crystal lattice. However, since this interaction occurs in vacuum, problems with scattering of the electrons by the lattice atoms are eliminated. Contrary to inverse Compton scattering, the emitted frequency is also determined by the amplitude of the laser field, rather than only by its frequency. Adjusting the value of the laser field permits the tuning of the emitted frequency over orders of magnitude, from terahertz to soft X rays. High flux intensities are predicted (~100 MW/cm^{2}). Extended interaction lengths are feasible due to the diffraction-free properties of the Bessel beam and its radial field, which confines the electron trajectory within the center of the Bessel beam.

Neuroprotective effect of weak static magnetic fields in primary neuronal cultures.

Low intensity static magnetic fields (SMFs) interact with various biological tissues including the CNS, thereby affecting key biological processes such as gene expression, cell proliferation and differentiation, as well as apoptosis. Previous studies describing the effect of SMFs on apoptotic cell death in several non-neuronal cell lines, emphasize the importance of such a potential modulation in the case of neurodegenerative disorders, where apoptosis constitutes a major route via which neurons degenerate and die. In this study, we examine the effect of SMFs on neuronal survival in primary cortical and hippocampal neurons that constitute a suitable experimental system for modeling the neurodegenerative state in vitro. We show that weak SMF exposure interferes with the apoptotic programing in rat primary cortical and hippocampal neurons, thereby providing protection against etoposide-induced apoptosis in a dose- and time-dependent manner. Primary cortical neurons exposed to SMF (50G) for 7days exhibited a 57.1±6.3% decrease in the percentage of cells undergoing apoptosis induced by etoposide (12µM), accompanied by a marked decrease in the expression of the pro-apoptotic markers: cleaved poly ADP ribose polymerase-1, cleaved caspase-3, active caspase-9 and the phospho-histone H2A variant (Ser139) by 41.0±5.0%, 81.2±5.0%, 72.9±6.4%, 42.75±2.9%, respectively, and by a 57.2±1.0% decrease in the extent of mitochondrial membrane potential collapse. Using the L-type voltage-gated Ca(2+) channel inhibitor nifedipine, which is selective to Ca(2+) influx through Cav1.2, we found that the anti-apoptotic effect of SMFs was mediated by Ca(2+) influx through these channels. Our findings demonstrating altered Ca(2+)-influx in response to thapsigargin stimulation in SMF-exposed cortical neurons, along with enhanced inhibition of KCl-induced Ca(2+)-influx through Cav1.2 channels and enhanced expression of Cav1.2 and Cav1.3 channels, allude to the involvement of voltage- and store-operated Ca(2+) channels in various aspects of the protective effect exerted by SMFs. These findings show the potential susceptibility of the CNS to weak SMF exposure and have implications for the design of novel strategies for the treatment and/or prevention of neurodegenerative diseases.

On the role of electron energy distribution function in double frequency heating of electron cyclotron resonance ion source plasmas.

Double frequency heating (DFH) is a tool to improve the output of highly charged ions particularly from modern electron cyclotron resonance ion source installations with very high RF-frequencies. In order to gain information on the DFH-mechanism and on the role of the lower injected frequency we have carried out a series of dedicated experiments where we have put emphasis on the creation of a discrete resonance surface also for this lower frequency. Our well-established method of inserting an emissive MD (metal-dielectric) liner into the plasma chamber of the source is used in these experiments as a tool of investigation. In this way, the electron temperature and density for both ECR zones is increased in a controlled manner, allowing conclusions on the role of the change of the electron-energy-distribution function with and without DFH.

The influence of the extraction voltage on the energetic electron population of an electron cyclotron resonance ion source plasma.

An influence of the extraction voltage on the high energy slope of bremsstrahlung radiation spectra has been reported in ECRIS experiments, which is not well understood so far. In order to provide more detailed data on this effect, we have measured bremsstrahlung radiation spectra accompanying especially the evolution of highly charge ions (i.e., by monitoring the Ar(14+) charge state) as the extraction voltage is changed from 0 to 20 kV, in dedicated experiments at the Frankfurt 14 GHz-ECRIS.

The impact of plasma-wall interaction on the gas mixing efficiency in electron cyclotron resonance ion source.

It is generally accepted that different effects are necessary to explain the gas mixing method of increasing the output of highly charged ions from an ECRIS. The two most important effects are the mass effect and the dilution effect. Their relative weights have not been determined experimentally yet, but it is generally assumed that the mass effect is dominant in standard ECRIS installations with stainless steel plasma chambers. In order to gain more insight into the physics of the gas mixing effect and in particular on the relevance of the dilution process, we have carried out a study where we have investigated the role of the plasma-wall interaction on the gas mixing effect. In this contribution, we shall discuss Charge state distributions spectra, measured at the Frankfurt ECRIS using different working gases, pure argon, a mixture of argon and oxygen, and argon mixed with neon.

Metal-dielectric structures for high power electron cyclotron resonance ion source.

Metal-dielectric (MD)-structures in electron cyclotron resonance ion source (ECRIS) devices (partially) restore the plasma ambipolarity and supply cold electrons to the plasma. Both effects lead to an enhancement of the plasma electron density and temperature and significantly increase the performance of this type of ion source. At the same time, MD-structures are well suited to reduce the heat load on cold masses by Bremsstrahlung radiation. Here, we report on experiments at high microwave powers to test the practical use of MD-structures for new, high performance ECRISs with their much higher power densities. The comparatively long conditioning times can be shortened by covering only those parts of the source with MD-structures, which are essential for the improvement.

Enhanced confinement in electron cyclotron resonance ion source plasma.

Power loss by plasma-wall interactions may become a limitation for the performance of ECR and fusion plasma devices. Based on our research to optimize the performance of electron cyclotron resonance ion source (ECRIS) devices by the use of metal-dielectric (MD) structures, the development of the method presented here, allows to significantly improve the confinement of plasma electrons and hence to reduce losses. Dedicated measurements were performed at the Frankfurt 14 GHz ECRIS using argon and helium as working gas and high temperature resistive material for the MD structures. The analyzed charge state distributions and bremsstrahlung radiation spectra (corrected for background) also clearly verify the anticipated increase in the plasma-electron density and hence demonstrate the advantage by the MD-method.

Influence of the electron cyclotron resonance plasma confinement on reducing the bremsstrahlung production of an electron cyclotron resonance ion source with metal-dielectric structures.

The influence of metal-dielectric (MD) layers (MD structures) inserted into the plasma chamber of an electron cyclotron resonance ion source (ECRIS) onto the production of electron bremsstrahlung radiation has been studied in a series of dedicated experiments at the 14 GHz ECRIS of the Institut für Kernphysik der Universität Frankfurt. The IKF-ECRIS was equipped with a MD liner, covering the inner walls of the plasma chamber, and a MD electrode, covering the plasma-facing side of the extraction electrode. On the basis of similar extracted currents of highly charged ions, significantly reduced yields of bremsstrahlung radiation for the "MD source" as compared to the standard (stainless steel) source have been measured and can be explained by the significantly better plasma confinement in a MD source as compared to an "all stainless steel" ECRIS.

A status report of the multipurpose superconducting electron cyclotron resonance ion source.

Intense heavy ion beam production with electron cyclotron resonance (ECR) ion sources is a common requirement for many of the accelerators under construction in Europe and elsewhere. An average increase of about one order of magnitude per decade in the performance of ECR ion sources was obtained up to now since the time of pioneering experiment of R. Geller at CEA, Grenoble, and this trend is not deemed to get the saturation at least in the next decade, according to the increased availability of powerful magnets and microwave generators. Electron density above 10(13) cm(-3) and very high current of multiply charged ions are expected with the use of 28 GHz microwave heating and of an adequate plasma trap, with a B-minimum shape, according to the high B mode concept [S. Gammino and G. Ciavola, Plasma Sources Sci. Technol. 5, 19 (1996)]. The MS-ECRIS ion source has been designed following this concept and its construction is underway at GSI, Darmstadt. The project is the result of the cooperation of nine European institutions with the partial funding of EU through the sixth Framework Programme. The contribution of different institutions has permitted to build in 2006-2007 each component at high level of expertise. The description of the major components will be given in the following with a view on the planning of the assembly and commissioning phase to be carried out in fall 2007. An outline of the experiments to be done with the MS-ECRIS source in the next two years will be presented.

The influence of ambipolarity on plasma confinement and on the performance of electron cyclotron resonance ion sources.

Charge diffusion in an electron cyclotron resonance ion source (ECRIS) discharge is usually characterized by nonambipolar behavior. While the ions are transported to the radial walls, electrons are lost axially from the magnetic trap. Global neutrality is maintained via compensating currents in the conducting walls of the vacuum chamber. It is assumed that this behavior reduces the ion breeding times compared to a truly ambipolar plasma. We have carried out a series of dedicated experiments in which the ambipolarity of the ECRIS plasma was influenced by inserting special metal-dielectric structures (MD layers) into the plasma chamber of the Frankfurt 14 GHz ECRIS. The measurements demonstrate the positive influence on the source performance when the ECR plasma is changed toward more ambipolar behavior.

Effect of obesity on breathlessness and airway responsiveness to methacholine in non-asthmatic subjects.

BACKGROUND: Obesity is associated with increased prevalence and incidence of asthma, but the mechanism is unknown. Obesity reduces lung volumes, which can increase airway responsiveness, and increases resistive and elastic work of breathing, which can increase dyspnea. OBJECTIVE: To determine if the intensity of dyspnea due to airway narrowing or if airway responsiveness is increased in obese, non-asthmatic subjects. SUBJECTS: Twenty-three obese (BMI (body mass index) > or =30 kg m(-2)) and 26 non-obese (BMI <30 kg m(-2)) non-asthmatic subjects, aged between 18 and 70 years. METHODS: High-dose methacholine challenge was used to determine the sensitivity and the maximal response to methacholine. Respiratory system resistance (Rrs) and reactance were measured, using the forced oscillation technique, as indicators of resistive and elastic loads during challenge. Perception of dyspnea was measured by the Borg score during challenge. Static lung volumes were measured by body plethysmography. RESULTS: Static lung volumes were reduced in the obese subjects. There were no significant differences in the sensitivity or maximal response to methacholine between obese and non-obese subjects. The magnitude of change in Rrs was similar in both groups, but obese subjects had more negative reactance after challenge (P=0.002) indicating a greater elastic load. The intensity of dyspnea was greater in obese subjects (P=0.03). CONCLUSIONS: Obesity reduces lung volumes, but does not alter the sensitivity or maximal response to methacholine. However, obese subjects have enhanced perception of dyspnea, associated with greater apparent stiffness of the respiratory system, and may therefore be at greater risk of symptoms.

Localized effects of microwave radiation on the intact eye lens in culture conditions.

A novel experimental system was used to investigate the localized effects of microwave radiation on bovine eye lenses in culture for over 2 weeks. Using this setup, we found clear evidence that this radiation has a significant impact on the eye lens. At the macroscopic level, it is demonstrated that exposure to a few mW at 1 GHz for over 36 h affects the optical function of the lens. Most importantly, self-recovery occurs if the exposure is interrupted. At the microscopic level, close examination of the lens indicates that the interaction mechanism is completely different from the mechanism-causing cataract via temperature increase. Contrary to the latter's effect, that is particularly pronounced in the vicinity of the sutures and it is assumed to be a result of local friction between the edges of the fibers consisting the lens. Even if macroscopically the lens has recovered from the irradiation, microscopically the indicators of radiation impact remain.

Polysomnography before and after weight loss in obese patients with severe sleep apnea.

OBJECTIVE: While obstructive sleep apnea (OSA) is strongly related to obesity, few studies have examined polysomnographic (PSG) changes with major weight loss. We examined the effect of weight loss following laparoscopic adjustable gastric banding (LAGB) on the PSG changes in patients with severe OSA. In addition, we studied daytime sleepiness, the metabolic syndrome and quality of life (QOL). METHODS: A prospective study was conducted of 25 severely obese patients (17 men, eight women) with paired diagnostic PSG, biochemical and questionnaire studies, the first prior to LAGB and the second at least 1 y later. Subjects with a baseline apnea-hypopnea index (AHI) >25/h were included. RESULTS: Subject baseline age was 44.7 y, weight 154 kg and body mass index 52.7 kg/m(2). The second PSG study was conducted 17.7+/-10 (range 12-42) months after surgery and mean percentage of excess loss and weight loss were 50.1+/-15% (range 24-80%) and 44.9+/-22 kg (range 18-103 kg), respectively. There was a significant fall in AHI from 61.6+/-34 to 13.4+/-13, improved sleep architecture with increased REM and stage III and IV sleep, daytime sleepiness, as measured by Epworth Sleepiness Scale, of 13+/-7.0 to 3.8+/-3.0, and fewer patients requiring nasal continuous positive airways pressure (CPAP). There were also major improvements in the metabolic syndrome, QOL, body image and fewer symptoms of depression (P<0.05 for all). CONCLUSION: Weight loss provides major improvement or resolution of OSA and CPAP requirements. It also reduces daytime sleepiness, and improves the metabolic syndrome and QOL. LAGB placement should be considered a broadly effective therapy for sleep apnea in the severely obese patient.

Asthma and atopy in overweight children.

BACKGROUND: Obesity may be associated with an increase in asthma and atopy in children. If so, the effect could be due to an effect of obesity on lung volume and thus airway hyperresponsiveness. METHODS: Data from 5993 caucasian children aged 7-12 years from seven epidemiological studies performed in NSW were analysed. Subjects were included if data were available for height, weight, age, skin prick test results to a common panel of aeroallergens, and a measure of airway responsiveness. History of doctor diagnosed asthma, wheeze, cough, and medication use was obtained by questionnaire. Recent asthma was defined as a doctor diagnosis of asthma ever and wheeze in the last 12 months. Body mass index (BMI) percentiles, divided into quintiles per year age, were used as a measure of standardised weight. Dose response ratio (DRR) was used as a measure of airway responsiveness. Airway hyperresponsiveness was defined as a DRR of >/=8.1. Adjusted odds ratios were obtained by logistic regression. RESULTS: After adjusting for atopy, sex, age, smoking and family history, BMI was a significant risk factor for wheeze ever (OR = 1.06, p = 0.007) and cough (OR = 1.08, p = 0.001), but not for recent asthma (OR = 1.02, p = 0.43) or airway hyperresponsiveness (OR = 0.97 p = 0.17). In girls a higher BMI was significantly associated with higher prevalence of atopy (chi(2) trend 7.9, p = 0.005), wheeze ever (chi(2) trend 10.4, p = 0.001), and cough (chi(2) trend 12.3, p<0.001). These were not significant in boys. CONCLUSIONS: Higher BMI is a risk factor for atopy, wheeze ever, and cough in girls only. Higher BMI is not a risk factor for asthma or airway hyperresponsiveness in either boys or girls.

Wake field in dielectric acceleration structures.

In this study we present a general approach for the analysis of the wake field of a point charge moving in a vacuum tunnel bored in dielectric material that is uniform in the direction parallel to the motion of the bunch. In the transverse direction the structure surrounding the dielectric may have arbitrary geometry. A quasianalytic expression that relates the decelerating force with the first dielectric layer, the radius of the vacuum tunnel where the charge moves, and the reflection characteristics of the structure has been developed. Simulation results for a simple structure indicate that, if the effective location where the reflection occurs in the dielectric is sufficiently apart from the edge of the vacuum tunnel, it has no effect on the point charge. In fact, the decelerating field converges exponentially as this distance increases, to the asymptotic value determined by the first dielectric layer. An estimate of the trailing wake when the structure supports a specific mode is also provided.

Wake field of an electron bunch moving parallel to a dielectric cylinder.

The wake field of an electron bunch moving parallel to the axis of a dielectric cylinder is being considered. It is shown that for a relativistic bunch (gamma>>1) the circular harmonic of order zero contributes a decelerating force inversely proportional to gamma, whereas the circular harmonics of nonzero order contribute a gamma-independent force. Moreover, the wake linked to the circular harmonic of order zero may grow in space in case the dielectric cylinder consists of an active medium; however, this growth rate does not depend on the value of gamma. On the other hand, no growth is anticipated for the case of circular harmonics of nonzero order.

Saturation of bunch-wave interaction in an active medium.

We determine the set of equations which describe the dynamics of electrons in the presence of a wave propagating in an active medium. Simulation results indicate that, even when virtually all the energy is drained from the medium, electrons remain trapped by the accelerating wave. In spite of saturation, gradients of a few GV/m may become available.

Sleep disturbance and obesity: changes following surgically induced weight loss.

BACKGROUND: Obesity causes sleep disturbance and is the most significant risk factor for sleep apnea. Only surgical methods provide substantial sustained weight loss for most severely obese subjects. OBJECTIVE: To study sleep disturbance in patients undergoing laparoscopic adjustable gastric banding with a commercially available product (Lap-Band). METHODS: In this study, 313 consecutive patients with severe obesity (body mass index [calculated as weight in kilograms divided by the square of height in meters] >35) completed a preoperative sleep questionnaire and clinical assessment. One hundred twenty-three patients completed the same assessment 12 months after surgery. The characteristics of sleep disturbance and changes in responses to weight loss have been assessed. RESULTS: There was a high prevalence of significantly disturbed sleep in men (59%) and women (45%), with women less likely to have had their sleep disturbance investigated. Observed sleep apnea was more common in men, but daytime sleepiness was not affected by sex. Waist circumference was the best clinical measure predicting observed sleep apnea (R = 0.36; P<.001). The group lost an average of 48% (SD, 16%) of excess weight by 12 months. There was a significant improvement in the responses to all questions at follow-up, with habitual snoring reduced to 14% (preoperative value, 82%), observed sleep apnea to 2% (preoperative value, 33%), abnormal daytime sleepiness to 4% (preoperative value, 39%), and poor sleep quality to 2% (preoperative value, 39%) (P<.001 for all). CONCLUSIONS: Obesity-related sleep disorders improve markedly with weight loss. Sustainable weight loss should be a primary aim in the management of severely obese patients with significant sleep disturbance, including sleep apnea. Low-risk laparoscopic obesity surgery should be considered for selected patients with this important comorbidity.