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High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2 ) or Id-MTX (0.5 g/m2 ). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

In this retrospective analysis using the Transplant Registry Unified Management Program, we identified 145 patients with human herpesvirus (HHV)-6 encephalitis among 6593 recipients. The cumulative incidences of HHV-6 encephalitis at 100 days after transplantation in all patients, recipients of bone marrow or PBSCs and recipients of cord blood were 2.3%, 1.6% and 5.0%, respectively. Risk factors identified in multivariate analysis were male sex, type of transplanted cells (relative risk in cord blood transplantation, 11.09, P <0.001; relative risk in transplantation from HLA-mismatched unrelated donor, 9.48, P <0.001; vs transplantation from HLA-matched related donor) and GvHD prophylaxis by calcineurin inhibitor alone. At 100 days after transplantation, the overall survival rate was 58.3% and 80.5% among patients with and without HHV-6 encephalitis, respectively ( P <0.001). Neuropsychological sequelae remained in 57% of 121 evaluated patients. With both foscarnet and ganciclovir, full-dose therapy (foscarnet ⩾180 mg/kg, ganciclovir ⩾10 mg/kg) was associated with better response rate (foscarnet, 93% vs 74%, P =0.044; ganciclovir, 84% vs 58%, P =0.047). HHV-6 encephalitis is not rare not only in cord blood transplant recipients but also in recipients of HLA-mismatched unrelated donors. In this study, development of HHV-6 encephalitis was associated with a poor survival rate, and neurological sequelae remained in many patients.

The massive tsunami generated by the 11 March 2011 Tohoku earthquake (Mw 9.0) was widely recorded by GPS buoys, wave gauges, and ocean bottom pressure sensors around the source. Numerous inversions for finite‐fault slip time histories have been performed using seismic and/or geodetic observations, yielding generally consistent patterns of large co‐seismic slip offshore near the hypocenter and/or up‐dip near the trench, where estimated peak slip is ∼60 m. Modeling the tsunami generation and near‐field wave processes using two detailed rupture models obtained from either teleseismic P waves or high‐rate GPS recordings in Japan allows evaluation of how well the finite‐fault models account for the regional tsunami data. By determining sensitivity of the tsunami calculations to rupture model features, we determine model modifications that improve the fit to the diverse tsunami data while retaining the fit to the seismic and geodetic observations. Key Points We find finite‐source rupture models that match near‐field tsunami data We iterate on inversions of seismic/tsunami and geodetic/tsunami rupture models We characterize the slip distribution responsible for large 2011 tsunami

The 27 February 2010 Chile (Mw 8.8) earthquake is the fifth largest earthquake to strike during the age of seismological instrumentation. The faulting geometry, slip distribution, seismic moment, and moment‐rate function are estimated from broadband teleseismic P, SH, and Rayleigh wave signals. We explore some of the trade‐offs in the rupture‐process estimation due to model parameterizations, limited teleseismic sampling of seismic phase velocities, and uncertainty in fault geometry. The average slip over the ∼81,500 km2 rupture area is about 5 m, with slip concentrations down‐dip, up‐dip and southwest, and up‐dip and north of the hypocenter. Relatively little slip occurred up‐dip/offshore of the hypocenter. The average rupture velocity is ∼2.0–2.5 km/s.

The effect of graft-versus-host disease (GVHD) on transplant outcomes after unrelated cord blood transplantation (UCBT) has not been fully elucidated. We analyzed the impact of acute and chronic GVHD on outcomes in adult patients with acute leukemia or myelodysplastic syndrome who underwent their first UCBT ( n= 2558). The effect of GVHD on outcomes was analyzed after adjusting for other significant variables. The occurrence of GVHD was treated as a time-dependent covariate. The occurrence of grade 1–2 or 3–4 acute GVHD was significantly associated with a lower relapse rate. Grade 3–4 acute GVHD was associated with a higher risk of non-relapse and overall mortality than no acute GVHD, whereas grade 1–2 acute GVHD was associated with a lower risk of non-relapse and overall mortality than no acute GVHD. Limited or extensive chronic GVHD was significantly associated with a lower relapse rate. Limited chronic GVHD was associated with a lower overall and non-relapse mortality than no chronic GVHD. In conclusion, mild acute or chronic GVHD was associated not only with a low risk of relapse but also with a low risk of non-relapse mortality, and provides a survival benefit in UCBT.

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 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.

To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(−)) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD(−) was significantly better than that in patients transplanted in MRD(+) (MRD(−): 67% vs MRD(+): 55% at 4 years; P =0.001). MRD(−) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD(−) was significantly lower than that in patients transplanted in MRD(+) (MRD(−): 19% vs MRD(+): 29% at 4 years; P =0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses ( P <0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph+ALL patients transplanted in CR1.

The 25 October 2010 Mentawai, Indonesia earthquake (Mw 7.8) ruptured the shallow portion of the subduction zone seaward of the Mentawai islands, off‐shore of Sumatra, generating 3 to 9 m tsunami run‐up along southwestern coasts of the Pagai Islands that took at least 431 lives. Analyses of teleseismic P, SH and Rayleigh waves for finite‐fault source rupture characteristics indicate ∼90 s rupture duration with a low rupture velocity of ∼1.5 km/s on the 10° dipping megathrust, with total slip of 2–4 m over an ∼100 km long source region. The seismic moment‐scaled energy release is 1.4 × 10−6, lower than 2.4 × 10−6 found for the 17 July 2006 Java tsunami earthquake (Mw 7.8). The Mentawai event ruptured up‐dip of the slip region of the 12 September 2007 Kepulauan earthquake (Mw 7.9), and together with the 4 January 1907 (M 7.6) tsunami earthquake located seaward of Simeulue Island to the northwest along the arc, demonstrates the significant tsunami generation potential for shallow megathrust ruptures in regions up‐dip of great underthrusting events in Indonesia and elsewhere.

Although allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor (MSD) is a potentially curative post-remission treatment for adults with acute myeloid leukemia (AML) in their first CR, transplant-related morbidity and mortality remains a major drawback. We retrospectively compared the outcomes of patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT; n =375) with those who underwent allogeneic bone marrow transplantation (allo-BMT; n =521) and allo-PBSCT ( n =380) from MSDs for adults with AML/CR1, in which propensity score models were used to adjust selection biases among patients, primary physicians and institutions to overcome ambiguity in the patients’ background information. Both the multivariate analysis and propensity score models indicated that the leukemia-free survival rate of auto-PBSCT was not significantly different from that of allo-BMT (hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.92 to 1.66; P =0.16) and allo-PBSCT (HR, 1.13; 95% CI, 0.85–1.51; P =0.40). The current results suggest that auto-PBSCT remains a promising alternative treatment for patients with AML/CR1 in the absence of an available MSD.