To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations ...in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.
This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation ...(HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, -2-30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival.
To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the ...registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/μL was significantly better in the MMF+ group (relative risk (RR), 1.55; P<0.001: RR, 1.34; P=0.003, respectively). In multivariate analyses, the risk of grade II-IV and III-IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (RR, 1.75; P<0.001: RR, 1.97; P=0.004, respectively). In disease-specific analyses of AML, the risk of relapse of high-risk disease was significantly lower in the MMF+ group (RR, 0.69; P=0.009), whereas no significant difference was observed in the risk of relapse-free and overall survival in high-risk disease. In patients with standard-risk disease, no significant differences were noted in the risk of relapse or survival between the MTX+ and MMF+ groups. Collectively, these results suggest that MMF-containing prophylaxis may be preferable in RIC-UCBT, particularly for high-risk disease.
•Eight P-gp modulating drugs were associated to ivermectin in vitro.•Cyclosporin A caused the highest reduction in IVM EC50.•The effect of P-gp modulating drugs depends of ivermectin ...concentration.•The modulator drugs increased ivermectin efficacy against Haemonchus placei.
Since its production in the 1980s, ivermectin (IVM) has been used indiscriminately and the selection pressure to which bovine gastrointestinal nematodes have been exposed has been intense, resulting in considerable economic losses due to parasitic resistance. One possibility for the control of resistant parasites is the use of P-glycoprotein (P-gp) modulators, because one of the main biochemical changes in ivermectin-resistant parasites is the increased activity of membrane proteins responsible for the efflux of drugs and xenobiotics. This study aimed to evaluate the in vitro effect of eight P-gp modulating drugs to potentiate IVM efficacy against an IVM-resistant field isolate of Haemonchus placei (Nematoda: Trichostrongylidae). The association of IVM with cyclosporin-A, ceftriaxone, dexamethasone, diminazene aceturate, quercetin, trifluoperazine, verapamil, or vinblastine resulted in increased IVM (10−4M) efficacy of 5.1%, 49.06%, 76.42%, 3.31%, 28.85%, 13.74%, 45.64% and 43.61%, respectively, and reduced the IVM half maximal effective concentration (EC50) from 4.381×10−6M to 9.877×10−8, 2.739×10−7, 1.240×10−6, 1.651×10−6, 2.710×10−7, 1.159×10−7, 1.026×10−6 and 7.136×10−7M, respectively. Only diminazene aceturate did not significantly reduce the number of migrating larvae when associated with IVM (P>0.05). The effect of P-gp modulating drugs depended on IVM concentration, with greater potentiating effect at lower IVM concentrations. The in vitro application of trifluoperazine, dexamethasone, quercetin, verapamil, cyclosporin A, vinblastine, and ceftriaxone potentiated IVM efficacy against an IVM-resistant field isolate of H. placei, resulting in higher efficacy and lower IVM EC50.
Calcineurin inhibitors are necessary as immunosuppressants during hematopoietic SCT (HSCT) to prevent alloreactivity, but have unfortunate toxicities. So, we investigated the association of gene ...polymorphisms with the initial calcineurin inhibitor concentration and the subsequent drug dose from day 1 to day 28 among patients who underwent HSCT at a single institution. We analyzed 58 serial cases of Japanese patients receiving GVHD prophylaxis with CsA (21 cases) or tacrolimus (37 cases). We investigated eight single-nucleotide polymorphisms: rs4244285 (CYP2C19), rs15524, rs4646450, rs3800959, rs776746 (CYP3A5), rs1128503, rs2032582 and rs1045642 (MDR1). The CsA concentration was significantly higher when the genotype of CYP3A5 rs15524 was T/T (P=0.044) or rs776746 was G/G (P=0.027). The CYP3A5 rs776746 and rs4646450 genotypes were also associated with tacrolimus concentration (P=0.013 and P=0.0058, respectively). The dosage of tacrolimus was remarkably reduced from day -1 to day 28 when the patient had the CYP3A5 rs4646450 C/C and/or rs776746 G/G genotype (P=0.0010 and P=0.0021, respectively). In this study, we show that genetic variation has a predictable effect on the pharmacological responses to calcineurin inhibitors in HSCT patients.
Cryptogenic organizing pneumonia (COP), previously known as bronchiolitis obliterans organizing pneumonia (BOOP), is a significant complication after allogeneic hematopoietic SCT (HCT). However, the ...pathogenesis of this complication has not yet been elucidated. Therefore, we identified the pre-transplant risk factors for the development of COP/BOOP using the Japan transplant registry database between 2005 and 2009. Among 9550 eligible recipients, 193 experienced COP/BOOP (2%). HLA disparity (odds ratio (OR) 1.51, P=0.05), female-to-male HCT (OR 1.53, P=0.023), and PBSC transplant (OR 1.84, P=0.0076) were significantly associated with an increased risk of COP/BOOP. On the other hand, BU-based myeloablative conditioning (OR 0.52, P=0.033), or fludarabine-based reduced-intensity conditioning (OR 0.50, P=0.0011) in comparison with a TBI-based regimen and in vivo T-cell depletion (OR 0.46, P=0.055) were associated with a lower risk. Of the 193 patients with COP/BOOP, 77 died, including non-relapse death in 46 (59%). Pulmonary failure and fatal infection accounted for 41% (n=19) and 26% (n=12) of the non-relapse death. Allogeneic immunity and conditioning toxicity could be associated with COP/BOOP. Prospective studies are required to elucidate the true risk factors for COP/BOOP and to develop a prophylactic approach.
Ivermectin (IVM) resistance of Cooperia spp. in cattle has become an increasing and global problem. The early detection of anthelmintic resistance (AR) is important to propose strategies to slow down ...the development of resistance and requires sensitive, reliable, economic high-throughput and practical tests. The purpose of the present study was to apply a larval migration inhibition test (LMIT) for evaluating IVM and MOX efficacy against well-characterized field isolates of Cooperia spp. infecting cattle in Brazil. Eight isolates were used for IVM and seven for MOX. The following EC50 values of IVM were observed for the isolates: susceptible, 1.16ηmol; Nova Alvorada do Sul I, 4.09ηmol (RF=3.52); Campo Grande BNA, 3.57ηmol (RF=3.07); Campo Grande TBR, 4.09ηmol (RF=3,52); Nova Alvorada do Sul II, 2.50ηmol (RF=2.15); Bandeirantes, 11.35ηmol (RF=9.78); Campo Grande II, 6.03ηmol (RF=5.20); and Porto Mortinho, 8.63ηmol (RF=7.44). For MOX, the following EC50 values were observed: susceptible, 0.75ηmol; Campo Grande BNA, 0.93ηmol (RF=1.24); Campo Grande TBR, 0.36ηmol (RF=0.48); Nova Alvorada do Sul II, 2.57ηmol (RF=3.42); Bandeirantes, 1.43ηmol (RF=1.90); Campo Grande II, 1.08ηmol (RF=1.44); and Porto Mortinho, 0.49ηmol (RF=0.65). The LMIT used in the present study can be a useful tool for in vitro evaluation of IVM, but not of MOX. However, such methodology cannot be used in large-scale studies yet. The isolates of Cooperia spp. showed various degrees of resistance to IVM, though remaining susceptible to MOX.
The aim of this report is to present the preliminary results of a Phase II study of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced ...non-small-cell lung cancer (NSCLC). Patients were treated with PBT and chemotherapy with monthly cisplatin (on Day 1) and vinorelbine (on Days 1 and 8). The treatment doses were 74 Gy RBE for the primary site and 66 Gy RBE for the lymph nodes without elective lymph nodes. Adapted planning was made during the treatment. A total of 15 patients with Stage III NSCLC (IIIA: 4, IIIB: 11) were evaluated in this study. The median follow-up period was 21.7 months. None of the patients experienced Grade 4 or 5 non-hematologic toxicities. Acute pneumonitis was observed in three patients (Grade 1 in one, and Grade 3 in two), but Grade 3 pneumonitis was considered to be non-proton-related. Grade 3 acute esophagitis and dermatitis were observed in one and two patients, respectively. Severe ( ≥ Grade 3) leukocytopenia, neutropenia and thrombocytopenia were observed in 10 patients, seven patients and one patient, respectively. Late radiation Grades 2 and 3 pneumonitis was observed in one patient each. Six patients (40%) experienced local recurrence at the primary site and were treated with 74 Gy RBE. Disease progression was observed in 11 patients. The mean survival time was 26.7 months. We concluded that high-dose PBT with concurrent chemotherapy is safe to use in the treatment of unresectable Stage III NSCLC.
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