Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus-Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders

Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T- and/or NK-cell (EBV+ T/NK-cell) lymphoproliferative disorders. Most subtypes of these are lethal. We established a unified treatment strategy composed of step 1 (immunochemotherapy: steroids, cyclosporine A, and etoposide), step 2 (multi-drug block chemotherapy), and step 3 (allogeneic hematopoietic stem cell transplantation; HSCT) for CAEBV and its related diseases. Allogeneic HSCT is the only cure for CAEBV with few exceptions. Primary-EBV infection-associated hemophagocytic lymphohistiocytosis (primary-EBV HLH) is also an EBV+ T/NK-cell lymphoproliferation. The nature of EBV+ T/NK cells in CAEBV and those in primary-EBV HLH differ. In primary-EBV HLH, most patients need step 1 only and some require step 2 for the successful induction of apoptosis in EBV-infected T cells; however, some exceptional patients require HSCT. We herein present our single institutional experience of CAEBV and primary-EBV HLH, together with that of post-transplant EBV+ T/NK-cell lymphoproliferative disease. We also discuss some practical points on HCST with a review of the literature

小児急性リンパ性白血病のL-アスパラギナーゼを含む寛解導入療法ではトロンピン・プラスミン生成試験において著明な線溶抑制を主体とする凝固障害を示す。

Background: L-asparaginase (L-Asp)-associated thromboembolisms are serious complications in pediatrics patients with acute lymphoblastic leukemia (ALL), especially at ≥10.0 years old, but the pathogenesis remains to be clarified. Procedure: We conducted a multicenter, prospective study of 72 patients with ALL aged 1.0 to 15.2 years treated with either a Berlin-Frankfurt-Münster (BFM) 95-ALL oriented regimen or Japan Association of Childhood Leukemia Study ALL-02 protocol. We divided patients into each treatment protocol and investigated the dynamic changes in coagulation and fibrinolysis using simultaneous thrombin and plasmin generation assay. Patients' plasma samples were collected at the prephase (T0), intermittent phase (T1), and postphase of L-Asp therapy (T2), and postinduction phase (T3). Measurements of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) were compared to normal plasma. Results: None of the cases developed thromboembolisms. Median ratios of T-EP and P-Peak for the controls in the JACLS group were 1.06 and 0.87 (T0), 1.04 and 0.71 (T1), 1.02 and 0.69 (T2), and 1.20 and 0.92 (T3), respectively, while those in the BFM group were 1.06 and 1.00 (T0), 1.04 and 0.64 (T1), 1.16 and 0.58 (T2), and 1.16 and 0.85 (T3), respectively. In particular, P-Peak ratios were depressed at T1 and T2 compared to T0 in the BFM group (P < .01). Moreover, P-Peak ratios in patients ≥10.0 years old were lower at T1 in the BFM group (P = .02). Conclusions: The results demonstrated that hemostatic dynamics appeared to shift to a hypercoagulable state with marked hypofibrinolysis associated with L-Asp therapy, especially in patients ≥10.0 years old following the BFM regimen.博士（医学）・甲第722号・令和元年12月5日© 2019 Wiley Periodicals, Inc.This is the pre-peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28016], which has been published in final form at [https://doi.org/10.1002/pbc.28016]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

Stomach and colonic microbiome of wild Japanese macaques

Within the gastrointestinal tract, the physiochemical microenvironments are highly diversified among the different stages of food digestion. Accordingly, gut microbiome composition and function vary at different gut sites. In this study, we examine and compare the compositional and functional potential between the stomach and colonic microbiome of wild Japanese macaques (Macaca fuscata yakui) living in the evergreen forest of Yakushima Island. We find a significantly lower microbial diversity in the stomach than in the colon, possibly due to the stomach's acidic and aerobic environment, which is suboptimal for microbial survival. According to past studies, the microbial taxa enriched in the stomach are aero- and acid-tolerant. By functional prediction through PICRUSt2, we reveal that the stomach microbiome is more enriched in pathways relating to the metabolism of simple sugars. On the contrary, the colonic microbiota is more enriched with fiber-degrading microbes, such as those from Lachnospiracea, Ruminococcaceae, and Prevotella. Our study shows a clear difference in the microbiome between the stomach and colon of Japanese macaques in both composition and function. This study provides a preliminary look at the alpha diversity and taxonomic composition within the stomach microbiome of Japanese macaques, a hindgut-fermenting nonhuman primate

Umbilical Cord Blood as an Alternative Source of Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Epstein-Barr Virus–Associated T or Natural Killer Cell Lymphoproliferative Diseases

AbstractChronic Epstein-Barr virus–associated T/natural killer cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently, we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9% ± 6.9% and 93.3% ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and 1 patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor

Clinical outcome of patients with recurrent or refractory localized Ewing's sarcoma family of tumors: A retrospective report from the Japan Ewing Sarcoma Study Group

[Background] Patients with Ewing's sarcoma family of tumors (ESFT) who experience relapse or progression have a poor prognosis. [Aim] This study aimed to identify the prognostic and therapeutic factors affecting overall survival (OS) of patients with recurrent or refractory localized ESFT. [Methods and results] Thirty-eight patients with localized ESFT who experienced first relapse or progression between 2000 and 2018 were retrospectively reviewed. The 5-year OS rate of the entire cohort was 48.3% (95% confidence interval, 29.9%-64.5%). Multivariate analysis of OS identified time to relapse or progression, but not stem cell transplantation (SCT), as the sole independent risk factor (hazard ratio, 35.8; P = .002). Among 31 patients who received salvage chemotherapy before local treatment, 21 received chemotherapy regimens that are not conventionally used for newly diagnosed ESFT. The objective response rate to first-line salvage chemotherapy was 55.2% in the 29 evaluable patients. Time to relapse or progression was significantly associated with response to first-line salvage chemotherapy (P = .006). [Conclusions] The present study fails to demonstrate significant clinical benefit of SCT for recurrent or refractory localized ESFT. Recently established chemotherapy regimens may increase the survival rate of patients with recurrent or refractory localized ESFT while attenuating the beneficial effect of SCT

Evaluation of a Rapid Immunochromatographic ODK-0901 Test for Detection of Pneumococcal Antigen in Middle Ear Fluids and Nasopharyngeal Secretions

Since the incidence of penicillin-resistant Streptococcus pneumoniae has been increasing at an astonishing rate throughout the world, the need for accurate and rapid identification of pneumococci has become increasingly important to determine the appropriate antimicrobial treatment. We have evaluated an immunochromatographic test (ODK-0901) that detects pneumococcal antigens using 264 middle ear fluids (MEFs) and 268 nasopharyngeal secretions (NPSs). A sample was defined to contain S. pneumoniae when optochin and bile sensitive alpha hemolytic streptococcal colonies were isolated by culture. The sensitivity and specificity of the ODK-0901 test were 81.4% and 80.5%, respectively, for MEFs from patients with acute otitis media (AOM). In addition, the sensitivity and specificity were 75.2% and 88.8%, respectively, for NPSs from patients with acute rhinosinusitis. The ODK-0901 test may provide a rapid and highly sensitive evaluation of the presence of S. pneumoniae and thus may be a promising method of identifying pneumococci in MEFs and NPSs

A pristine record of outer Solar System materials from asteroid Ryugu’s returned sample

Volatile and organic-rich C-type asteroids may have been one of the main sources of Earth’s water. Our best insight into their chemistry is currently provided by carbonaceous chondritic meteorites, but the meteorite record is biased: only the strongest types survive atmospheric entry and are then modified by interaction with the terrestrial environment. Here we present the results of a detailed bulk and microanalytical study of pristine Ryugu particles, brought to Earth by the Hayabusa2 spacecraft. Ryugu particles display a close compositional match with the chemically unfractionated, but aqueously altered, CI (Ivuna-type) chondrites, which are widely used as a proxy for the bulk Solar System composition. The sample shows an intricate spatial relationship between aliphatic-rich organics and phyllosilicates and indicates maximum temperatures of ~30 °C during aqueous alteration. We find that heavy hydrogen and nitrogen abundances are consistent with an outer Solar System origin. Ryugu particles are the most uncontaminated and unfractionated extraterrestrial materials studied so far, and provide the best available match to the bulk Solar System composition