Search

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. ispartof: BLOOD vol:140 issue:14 pages:1635-1649 ispartof: location:United States status: published

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged 1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

STAT3 mediates inflammation and modulates immunity. We found that in addition to its role in autoimmunity, over-activated STAT3 interferes in early erythro-myeloid precursor development and reduces commitment towards the erythroid lineage by interfering with the erythropoietin-STAT5 signalling pathway.

Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT. Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient's age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis. Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT. The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn't have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn't have an influence on outcome. Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians. Disclosures Chiesa: Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak:medac: Other: travel grants; Sanofi: Other: travel grants. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynn:Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter:Medac: Other: Travel assistance.

The long held objective of directly observing atomic motions during the defining moments of chemistry has been achieved based on ultrabright electron sources that have given rise to a new field of atomically resolved structural dynamics. This class of experiments requires not only simultaneous sub-atomic spatial resolution with temporal resolution on the 100 femtosecond time scale but also has brightness requirements approaching single shot atomic resolution conditions. The brightness condition is in recognition that chemistry leads generally to irreversible changes in structure during the experimental conditions and that the nanoscale thin samples needed for electron structural probes pose upper limits to the available sample or “film” for atomic movies. Even in the case of reversible systems, the degree of excitation and thermal effects require the brightest sources possible for a given space-time resolution to observe the structural changes above background. Further progress in the field, particularly to the study of biological systems and solution reaction chemistry, requires increased brightness and spatial coherence, as well as an ability to tune the electron scattering cross-section to meet sample constraints. The electron bunch density or intensity depends directly on the magnitude of the extraction field for photoemitted electron sources and electron energy distribution in the transverse and longitudinal planes of electron propagation. This work examines the fundamental limits to optimizing these parameters based on relativistic electron sources using re-bunching cavity concepts that are now capable of achieving 10 femtosecond time scale resolution to capture the fastest nuclear motions. This analysis is given for both diffraction and real space imaging of structural dynamics in which there are several orders of magnitude higher space-time resolution with diffraction methods. The first experimental results from the Relativistic Electron Gun for Atomic Exploration (REGAE) are given that show the significantly reduced multiple electron scattering problem in this regime, which opens up micron scale systems, notably solution phase chemistry, to atomically resolved structural dynamics.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has great potential for cancer treatment since it provokes cell death in most tumor cells while leaving most normal cells unscathed. Some cancers, however, show resistance to TRAIL, indicating that TRAIL alone may be insufficient for cancer therapy. Here we studied whether the apoptotic susceptibility of A549 non-small cell lung cancer cells could be modulated by inhibiting protein kinase C (PKC). We show that an inhibitor with preference for novel PKC isozymes, NPC 15437, significantly augmented TRAIL sensitivity of A549 cells, as judged by assessing cell death and mitochondrial membrane potential. Likewise, NPC 15437 also significantly potentiated the responsiveness of DAOY medulloblastoma cells to TRAIL. In contrast, an inhibitor with preference for conventional PKC isozymes, Gö6976, did not augment TRAIL sensitivity of A549 cells. To further specify the PKC isozyme responsible for TRAIL sensitization, we used a peptide inhibitor with selectivity for the novel PKC isozyme epsilon, myr-PKC-epsilon V1-2. The inhibition of PKC-epsilon resulted in a significant amplification of the cytotoxic activity of TRAIL in A549 cells. Altogether, our study provides evidence for a considerable role of PKC-epsilon in the apoptotic responsiveness of A549 lung cancer cells, and possibly other malignancies, to TRAIL.

The master oscillator (MO) and phase reference system at FLASH must provide several RF reference frequencies to widely spread locations with low phase noise and small long term phase drifts. The phase noise requirement of the 1300 MHz reference is of the order of 0.1 deg. while the short and medium term phase stability are of of the order of 0.1 deg. and 1 deg. respectively. The frequency distribution system employs a temperature stabilized coaxial line for RF power distribution and a fiber optic system for the monitoring of phase drifts. Presented are the the concept, design and performance measured in the accelerator environment.

The UV Free-Electron Laser (UVFEL) [1], The X-Ray Free-Electron Laser (XFEL) [2] and The International Linear Accelerator (ILC) [9] projects will require phase synchronization of various RF frequency subsystems on kilometer distances with accuracy better than 1ps. To fulfill these requirements, a phase reference distribution system concept was proposed and a prototype was developed for tests in the TESLA Test Facility 2 (TTF2). An important part of the phase reference system is the fiber-optic phase stable, long distance link described in this paper. An interferometrical scheme with feedback on phase, suppressing long term phase drifts induced by temperature changes was developed and tested in laboratory and under accelerator conditions. A motorized optical delay line was used in the system to compensate for phase errors. Described are error considerations and most important project issues like the hardware development and the real time phase controller software. The presented measurement results satisfy the design requirements. Experience gained during the experiments yielded proposals for system improvements.

The UV Free-Electron Laser (UVFEL) and The TeV-Energy Superconducting Linear Accelerator (TESLA) projects will require phase synchronization of 0.1 ps short term (millisecond), 1 ps short term (minutes) and 10 ps long term (days). The stringent synchronization requirement of 10fs was given for the X-Ray Free- Electron Laser (XFEL). To fufill this requirement the XFEL may use a fiber laser as reference generator. But this requirement applies for a special location only, therefore the RF phase reference distribution system developed UVFEL and TESLA will also be used in the XFEL. The RF phase reference distribution system must deliver phase stable signals to hundreds of stations over a length of 33 km. Long, optical fiber based links are planned to be an important part of the entire distribution system. This paper describes the concept of a long optical link, with a feedback system suppressing long term drifts of the RF signal phase. Stability requirements are given and most important design issues affecting system performance are discussed. Finally, an experimental setup and measurement results demonstrating system performance is shown.