Objective
To assess the safety and efficacy of 2 repeated intrathecal injections of autologous bone marrow–derived mesenchymal stem cells (BM‐MSCs) in amyotrophic lateral sclerosis (ALS).
Methods
In ...a phase 2 randomized controlled trial (NCT01363401), 64 participants with ALS were randomly assigned treatments (1:1) of riluzole alone (control group, n = 31) or combined with 2 BM‐MSC injections (MSC group, n = 33). Safety was assessed based on the occurrence of adverse events. The primary efficacy outcome was changes in Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R) score from baseline to 4 and 6 months postinjection. Post hoc analysis includes investigation of cerebrospinal fluid biomarkers and long‐term survival analysis.
Results
Safety rating showed no groupwise difference with absence of serious treatment‐related adverse events. Mean changes in ALSFRS‐R scores from baseline to 4 and 6 months postinjection were reduced in the MSC group compared with the control group (4 months: 2.98, 95% confidence interval CI = 1.48–4.47, p < 0.001; 6 months: 3.38, 95% CI = 1.23–5.54, p = 0.003). The MSC group showed decreased proinflammatory and increased anti‐inflammatory cytokines. In good responders, transforming growth factor β1 significantly showed inverse correlation with monocyte chemoattractant protein‐1. There was no significant difference in long‐term survival between groups.
Interpretation
Repeated intrathecal injections of BM‐MSCs demonstrated a possible clinical benefit lasting at least 6 months, with safety, in ALS patients. A plausible action mechanism is that BM‐MSCs mediate switching from pro‐ to anti‐inflammatory conditions. A future randomized, double‐blind, large‐scale phase 3 clinical trial with additional BM‐MSC treatments is required to evaluate long‐term efficacy and safety. Ann Neurol 2018;84:361–373
Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, ...open-label study compared the efficacy of isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed multiple myeloma.
This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib–dexamethasone (isatuximab group) or carfilzomib–dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285.
Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77–not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32–0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients.
The addition of isatuximab to carfilzomib–dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population.
Sanofi.
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Summary Background In 2015, a large outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection occurred following a single patient exposure in an emergency room at the Samsung ...Medical Center, a tertiary-care hospital in Seoul, South Korea. We aimed to investigate the epidemiology of MERS-CoV outbreak in our hospital. Methods We identified all patients and health-care workers who had been in the emergency room with the index case between May 27 and May 29, 2015. Patients were categorised on the basis of their exposure in the emergency room: in the same zone as the index case (group A), in different zones except for overlap at the registration area or the radiology suite (group B), and in different zones (group C). We documented cases of MERS-CoV infection, confirmed by real-time PCR testing of sputum samples. We analysed attack rates, incubation periods of the virus, and risk factors for transmission. Findings 675 patients and 218 health-care workers were identified as contacts. MERS-CoV infection was confirmed in 82 individuals (33 patients, eight health-care workers, and 41 visitors). The attack rate was highest in group A (20% 23/117 vs 5% 3/58 in group B vs 1% 4/500 in group C; p<0·0001), and was 2% (5/218) in health-care workers. After excluding nine cases (because of inability to determine the date of symptom onset in six cases and lack of data from three visitors), the median incubation period was 7 days (range 2–17, IQR 5–10). The median incubation period was significantly shorter in group A than in group C (5 days IQR 4–8 vs 11 days 6–12; p<0·0001). There were no confirmed cases in patients and visitors who visited the emergency room on May 29 and who were exposed only to potentially contaminated environment without direct contact with the index case. The main risk factor for transmission of MERS-CoV was the location of exposure. Interpretation Our results showed increased transmission potential of MERS-CoV from a single patient in an overcrowded emergency room and provide compelling evidence that health-care facilities worldwide need to be prepared for emerging infectious diseases. Funding None.
Background
The sensitivity of Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) to reduced‐intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) ...versus myeloablative conditioning (MAC) allogeneic HCT by minimal residual disease (MRD) kinetics is not well established.
Methods
This study compared long‐term outcomes based on MRD kinetics for 79 patients with RIC transplants and 116 patients with MAC transplants in first complete remission (CR1) after tyrosine kinase inhibitor–based chemotherapy (median follow‐up, 67.1 months). MRD monitoring was centrally evaluated by real‐time quantitative polymerase chain reaction for all patients.
Results
RIC showed a cumulative incidence of relapse (CIR; 30.6% vs 31.7%), nonrelapse mortality (17.5% vs 14.9%), disease‐free survival (DFS; 51.9% vs 53.4%), and overall survival (61.1% vs 61.4%) comparable to those associated with MAC. In all MRD kinetics–based subgroups, no differences in CIR (early complete molecular response CMR, 19.3% vs 4.8%; early major molecular response MMR, 17.0% vs 26.8%; late CMR, 20.0% vs 14.3%; late MMR, 28.3% vs 31.0%; poor molecular response PMR, 57.9% vs 62.4%) or DFS (early CMR, 71.6% vs 76.2%; early MMR, 66.9% vs 52.1%; late CMR, 50.0% vs 64.3%; late MMR, 50.7% vs 53.7%; PMR, 31.6% vs 34.1%) were observed between RIC and MAC. In a multivariate analysis, the conditioning intensity had no significant impact on transplantation outcomes.
Conclusions
RIC is a valid alternative choice for long‐term disease control and is worthy of further investigation in prospective trials for adult Ph‐positive ALL in CR1.
Reduced‐intensity conditioning shows long‐term outcomes comparable to those with myeloablative conditioning in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia who undergo hematopoietic cell transplantation during their first complete remission after tyrosine kinase inhibitor–based chemotherapy. The sensitivity of Philadelphia chromosome–positive acute lymphoblastic leukemia to reduced‐intensity conditioning versus myeloablative conditioning is not different in all minimal residual disease kinetics–based patient subgroups.
A self-seeded X-ray free-electron laser (XFEL) is a promising approach to realize bright, fully coherent free-electron laser (FEL) sources in the hard X-ray domain that have been a long-standing ...issue with longitudinal coherence remaining challenging. At the Pohang Accelerator Laboratory XFEL, we have demonstrated a hard X-ray self-seeded XFEL with a peak brightness of 3.2 × 1035 photons s–1 mm–2 mrad–2 0.1% bandwidth (BW)–1 at 9.7 keV. The bandwidth (0.19 eV) is about 1/70 times as wide (close to the Fourier transform limit) and the peak spectral brightness is 40 times higher than in self-amplified spontaneous emission (SASE), with substantial improvements in the stability of self-seeding and noticeably suppressed pedestal effects. We could reach an excellent self-seeding performance at a photon energy of 3.5 keV (lowest) and 14.6 keV (highest) with the same stability as the 9.7 keV self-seeding. The bandwidth of the 14.6 keV seeded FEL was 0.32 eV, and the peak brightness was 1.3 × 1035 photons s–1 mm–2 mrad–2 0.1%BW–1. We show that the use of seeded FEL pulses with higher reproducibility and a cleaner spectrum results in serial femtosecond crystallography data of superior quality compared with data collected using SASE mode.A hard X-ray self-seeded X-ray free-electron laser at the Pohang Accelerator Laboratory provides X-ray pulses with peak brightness of 3.2 × 1035 photons s–1 mm–2 mrad–2 0.1%BW–1 at 9.7 keV and a very small shot-to-shot electron energy jitter of 0.012%.
Summary
Real‐world outcomes of daratumumab monotherapy (DM) for relapsed/refractory multiple myeloma (RRMM) have remained unclear. We conducted a multicentre retrospective study of 107 patients ...receiving DM for RRMM. The cohort included 64 trial‐unfit patients whose characteristics could not meet inclusion criteria in two previous clinical trials (GEN501 and SIRIUS). The overall response rate (ORR), and median first and second progression‐free survival (PFS1 and PFS2) and overall survival were 42·1%, and 3·6, 8·1 and 11·9 months, respectively. Refractoriness to carfilzomib and/or lenalidomide, and neutropenia (<1.0 × 109/l) resulted in poorer ORRs. An Eastern Cooperative Oncology Group Performance Status of ≥3, neutropenia (<1.0 × 109/l), thrombocytopenia (<75 × 109/l), and renal failure (glomerular filtration rate of <20 ml/min/1·73 m2) were associated with poor PFS1 and PFS2 in respective univariate analysis. The modified trial‐unfit group, based on the above factors, showed significantly negative impacts on PFS1 and PFS2 (hazard ratio 2·823 and 3·677, all P < 0·001) in multivariate analysis despite having a 34% ORR. Fatal infections occurred more often in the modified trial‐unfit group than in the others (16·1% vs. 4·3%; P = 0·099). Despite failure of DM, subsequent therapy with pomalidomide‐based therapy or carfilzomib‐dexamethasone provided a 66·6% ORR. Real‐world DM showed favourable efficacies for RRMM and, potentially, additional benefits with subsequent therapies. However, characteristics corresponding with trial‐unfitness might offset the efficacy of DM.
Acute myelogenous leukemia (AML) is a heterogeneous disorder characterized by clonal proliferation of stem cell-like blasts in bone marrow (BM); however, their unique cellular interaction within the ...BM microenvironment and its functional significance remain unclear. Here, we assessed the BM microenvironment of AML patients and demonstrate that the leukemia stem cells induce a change in the transcriptional programming of the normal mesenchymal stromal cells (MSC). The modified leukemic niche alters the expressions of cross-talk molecules (i.e., CXCL12 and JAG1) in MSCs to provide a distinct cross-talk between normal and leukemia cells, selectively suppressing normal primitive hematopoietic cells while supporting leukemogenesis and chemoresistance. Of note, AML patients exhibited distinct heterogeneity in the alteration of mesenchymal stroma in BM. The distinct pattern of stromal changes in leukemic BM at initial diagnosis was associated with a heterogeneous posttreatment clinical course with respect to the maintenance of complete remission for 5 to 8 years and early or late relapse. Thus, remodeling of mesenchymal niche by leukemia cells is an intrinsic self-reinforcing process of leukemogenesis that can be a parameter for the heterogeneity in the clinical course of leukemia and hence serve as a potential prognostic factor.
The effect of the clinical phenotype of
complex (MAC) lung disease on treatment outcome and redevelopment of nontuberculous mycobacterial (NTM) lung disease after treatment completion has not been ...studied systematically.We evaluated 481 treatment-naïve patients with MAC lung disease who underwent antibiotic treatment for ≥12 months between January 2002 and December 2013.Out of 481 patients, 278 (58%) had noncavitary nodular bronchiectatic (NB) disease, 80 (17%) had cavitary NB disease and 123 (25%) had fibrocavitary disease. Favourable outcome was higher in patients with noncavitary disease (88%) than in patients with cavitary disease (76% for fibrocavitary and 78% for cavitary NB disease; p<0.05). Cavitary disease was independently associated with unfavourable outcomes (p<0.05). Out of 402 patients with favourable outcomes, 118 (29%) experienced redevelopment of NTM lung disease, with the same MAC species recurring in 65 (55%) patients. The NB form was an independent risk factor for redevelopment of NTM lung disease (p<0.05). In patients with recurrent MAC lung disease due to the same species, bacterial genotyping revealed that 74% of cases were attributable to reinfection and 26% to relapse.Treatment outcomes and redevelopment of NTM lung disease after treatment completion differed by clinical phenotype of MAC lung disease.
Excited charge-transfer complexes, or exciplexes, have attracted significant attention due to their potential applications to improving the performance of organic light-emitting diodes (OLEDs) and ...organic photovoltaic cells (OPVs). In solid states, exciplexes exhibit extraordinary characteristics, including broad emission spectra, multiexponential photoluminescence (PL) decay curves, and spectral red shifts as time delays in transient PL. Here, we present experimental and theoretical evidence that all of the emission characteristics of solid-state exciplexes originate from differences in their dimer configurations, which have different charge transfer rates, emission energies, singlet–triplet energy gaps, kinetic rate constants, and emitting dipole orientations. This conclusion is based on experimental observations, quantum chemical calculations, and molecular dynamics simulations. These results enabled us to develop a model of the electronic structure of an exciplex in a solid-state medium. This comprehensive model accommodates all of the characteristics of the exciplex and can be used to further our understanding of OLEDs and OPVs.
Optical laser systems for ultrafast X‐ray sciences have been established at the Pohang Accelerator Laboratory X‐ray Free‐Electron Laser (PAL‐XFEL) beamlines. Three Ti:sapphire regenerative amplifier ...systems are synchronized to the XFEL with femtosecond precision, and the low temporal jitter of the PAL‐XFEL results in an experimental time resolution below 150 fs (full width at half‐maximum). A fundamental wave and its harmonics are currently provided for all beamlines, and tunable sources from ultraviolet to near‐infrared are available for one beamline. The position stability of the optical laser extracted from the intensity‐based center of mass at the sample position is less than 3% (r.m.s.) of the spot size.
The experimental lasers at the PAL‐XFEL beamlines, from the source to the sample position, are described.
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