Overcoming minimal residual disease using intensified conditioning with medium-dose etoposide, cyclophosphamide and total body irradiation in allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults

BACKGROUND AIMS: An intensified conditioning regimen incorporating medium-dose etoposide (VP16) is an option for patients with acute lymphoblastic leukemia (ALL). However, the prognostic impacts of the addition of VP16 to cyclophosphamide (CY) and total body irradiation (TBI) in patients with Philadelphia chromosome-positive (Ph+) ALL with regard to minimal residual disease (MRD) status have not been elucidated. METHODS: The authors retrospectively compared the outcomes of patients with Ph+ ALL who underwent allogeneic transplantation following VP16/CY/TBI (n = 101) and CY/TBI (n = 563). RESULTS: At 4 years, the VP16/CY/TBI group exhibited significantly better disease-free survival (DFS) (72.6% versus 61.7%, P = 0.027) and relapse rate (11.5% versus 21.1%, P = 0.020) and similar non-relapse mortality (16.0% versus 17.2%, P = 0.70). In subgroup analyses, the beneficial effects of the addition of VP16 on DFS were more evident in patients with positive MRD status (71.2% versus 48.4% at 4 years, P = 0.022) than those with negative MRD status (72.8% versus 66.7% at 4 years, P = 0.24). Although MRD positivity was significantly associated with worse DFS in patients who received CY/TBI (48.4% versus 66.7%, P < 0.001), this was not the case in those who received VP16/CY/TBI (71.2% versus 72.8%, P = 0.86). CONCLUSIONS: This study demonstrated the benefits of the addition of VP16 in Ph+ ALL patients, especially those with positive MRD status. VP16/CY/TBI could be a potential strategy to overcome the survival risk of MRD positivity

Angular correlation of the two gamma rays produced in the thermal neutron capture on gadolinium-155 and gadolinium-157

The ANNRI-Gd collaboration studied in detail the single $\gamma$-ray spectrum produced from the thermal neutron capture on $^{155}$Gd and $^{157}$Gd in our previous publications. Gadolinium targets were exposed to a neutron beam provided by the Japan Spallation Neutron Source (JSNS) in J-PARC, Japan. In the present analysis, one new additional coaxial germanium crystal was used in the analysis in combination with the fourteen germanium crystals in the cluster detectors to study the angular correlation of the two $\gamma$ rays emitted in the same neutron capture. We present for the first time angular correlation functions for two $\gamma$ rays produced during the electromagnetic cascade transitions in the (n, $\gamma$) reactions on $^{\rm 155}$Gd and $^{\rm 157}$Gd. As expected, we observe the mild angular correlations for the strong, but rare transitions from the resonance state to the two energy levels of known spin-parities. Contrariwise, we observe negligibly small angular correlations for arbitrary pairs of two $\gamma$ rays produced in the majority of cascade transitions from the resonance state to the dense continuum states.Comment: 21 pages, 13 figure

Adult patients with Ph+ ALL benefit from conditioning regimen of medium‐dose VP16 plus CY/TBI

The medium-dose etoposide (VP16) added on cyclophosphamide (CY)/total body irradiation (TBI) is one of the intensified myeloablative conditioning regimens used in allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL). However, the patient subgroups who can actually benefit from VP16/CY/TBI compared to CY/TBI have not been precisely defined. Therefore, we conducted a multi-center retrospective study using the Japanese nationwide registry database to elucidate the efficacy of VP16/CY/TBI on post-transplant prognosis. Biological and clinical distinct subtypes (i.e., Philadelphia chromosome-positive (Ph+) and -negative (Ph−) ALL) were evaluated separately, which included 820 Ph+ and 1463 patients with Ph− ALL, respectively. Compared with the CY/TBI group, the VP16/CY/TBI group showed superior progression-free survival (PFS) in patients with Ph+ ALL (65% vs. 57% at 3 years after HSCT; adjusted hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.55–0.98; p = 0.03), along with significantly reduced incidence of relapse (adjusted HR, 0.58; 95% CI, 0.37–0.90; p = 0.02) without the increase of non-relapse mortality (NRM). By contrast, in patients with Ph− ALL, VP16/CY/TBI did not improve PFS nor incidence of relapse; addition of VP16 reduced relapse (HR, 0.65; p = 0.06) in patients with Ph− ALL transplanted at CR1, while improved PFS was not observed (HR, 0.90; p = 0.52) due to increased NRM. This study demonstrated that VP16/CY/TBI is a more effective and well-tolerated regimen in comparison with CY/TBI in patients with myeloablative allo-HSCT for adult Ph+ ALL. Our findings can provide a novel algorithm for conditioning regimen selection in patients with adult ALL

Prognostic impact of complex and/or monosomal karyotypes in post‐transplant poor cytogenetic acute myeloid leukaemia: A quantitative approach

To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT-CI score ≥3 (HR, 1.23), non-remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post-HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post-HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics

Gamma Ray Spectra from Thermal Neutron Capture on Gadolinium-155 and Natural Gadolinium

Abstract Natural gadolinium is widely used for its excellent thermal neutron capture cross section, because of its two major isotopes: $^{\rm 155}$Gd and $^{\rm 157}$Gd. We measured the $\gamma$-ray spectra produced from the thermal neutron capture on targets comprising a natural gadolinium film and enriched $^{\rm 155}$Gd (in Gd$_{2}$O$_{3}$ powder) in the energy range from 0.11 MeV to 8.0 MeV, using the ANNRI germanium spectrometer at MLF, J-PARC. The freshly analyzed data of the $^{\rm 155}$Gd($n, \gamma$) reaction are used to improve our previously developed model (ANNRI-Gd model) for the $^{\rm 157}$Gd($n, \gamma$) reaction [K. Hagiwara et al. [ANNRI-Gd Collaboration], Prog. Theor. Exp. Phys. 2019, 023D01 (2019)], and its performance confirmed with the independent data from the $^{\rm nat}$Gd($n, \gamma$) reaction. This article completes the development of an efficient Monte Carlo model required to simulate and analyze particle interactions involving the thermal neutron captures on gadolinium in any relevant future experiments

High-temperature and starvation tolerances of juvenile Japanese Spanish mackerel Scomberomorus niphonius

Japanese Spanish mackerel Scomberomorus niphonius is a target species for stocking, but its biological characteristics at the juvenile stage are not well understood. Here, we investigated the high-temperature and starvation tolerances of hatchery-reared juveniles in captivity. We used juveniles of approximately 40 mm standard length, the size of juveniles released into the field. The upper incipient lethal temperature (50% lethal water temperature) was estimated to be 31.8 °C, higher than the maximum sea surface temperature in the field (approximately 29 °C). The critical thermal maximum was 34.8 °C, whereas it was 36.1 °C when juveniles were preliminarily acclimated to 31 °C for 24 h. Juveniles died from 3 to 11 days under nonfeeding conditions at 20 °C, but from 2 to 7 days at 27 °C. This information is expected to contribute to the development of the production of juvenile Japanese Spanish mackerel.This study was partly supported by JSPS KAKENHI Grant Number 19K06207

Carbon Monoxide Reduction Reaction to Produce Multicarbon Products in Acidic Electrolytes Using Gas Diffusion Electrode Loaded with Copper Nanoparticles

Abstract The synthesis of multi‐carbon products (C2+) by electrochemical CO2 reduction reaction (CO2RR) is a promising technology that will contribute to the realization of a carbon‐neutral society. In particular, efficient CO2RR to produce C2+ in acidic electrolytes is desirable because the conversion of CO2 to inert (bi)carbonate can be suppressed under acidic conditions, thereby increasing the efficiency of substrate CO2 utilization. Herein, since C2+ products are produced via the dimerization of carbon monoxide, an intermediate in CO2RR, the focus is on the carbon monoxide reduction reaction (CORR). A gas diffusion electrode loaded with copper nanoparticles is used in acidic electrolytes to investigate the conditions necessary for efficient C2+ production. The faradaic efficiency and partial current density for C2+ production attained 75% and 280 mA cm−2 in a pH 2.0 solution, and they reached up to 66% and 260 mA cm−2 even in a pH 1.0 solution. Numerical simulations showed that increasing the alkalinity of the electrode surface to greater than pH 7 by consuming protons is necessary to facilitate the production of C2+ during the CORR. When the desired level of alkalinity is achieved, the concentration and type of alkali cations present at the electrode surface have an impact on the selectivity for C2+ production

Residue-selective C−H sulfenylation enabled by acid-activated S-acetamidomethyl cysteine sulfoxide with application to one-pot stapling and lipidation sequence

A tyrosine (Tyr)- or tryptophan (Trp)-selective metal-free C−H sulfenylation reaction using an acid-activated Sacetamidomethyl cysteine (Cys) sulfoxide, Cys(Acm)(O), has been achieved. The dually protonated intermediate produced from the Cys(Acm)(O) under acidic conditions allows the sulfenylation of Tyr. Significantly, the reaction in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) mainly affords a Cys-Tyr-linked peptide even in the presence of Trp residues. In contrast, a Cys-Trplinked peptide was selectively obtained from the reaction in the presence of guanidine hydrochloride (Gn·HCl) under acidic conditions. Established Tyr- and Trp-selective sulfenylation methods were used in the Cys-Tyr stapling and Trp-lipidation of glucagon-like peptides 1 in a one-pot/stepwise manner. Investigation of the mechanism showed that orbital- and charge-controlled reactions are responsible for the Trp and Tyr selectivity, respectively