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/m
) or Id-MTX (0.5 g/m
). 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.
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 study uses a neural network technique to produce maps of the partial pressure of oceanic carbon dioxide (pCO2sea ) in the North Pacific on a 0.25° latitude × 0.25° longitude grid from 2002 to ...2008. The pCO2sea distribution was computed using a self-organizing map (SOM) originally utilized to map the pCO2sea in the North Atlantic. Four proxy parameters - sea surface temperature (SST), mixed layer depth, chlorophyll a concentration, and sea surface salinity (SSS) - are used during the training phase to enable the network to resolve the nonlinear relationships between the pCO2sea distribution and biogeochemistry of the basin. The observed pCO2sea data were obtained from an extensive dataset generated by the volunteer observation ship program operated by the National Institute for Environmental Studies (NIES). The reconstructed pCO2sea values agreed well with the pCO2sea measurements, with the root-mean-square error ranging from 17.6 μatm (for the NIES dataset used in the SOM) to 20.2 μatm (for independent dataset). We confirmed that the pCO2sea estimates could be improved by including SSS as one of the training parameters and by taking into account secular increases of pCO2sea that have tracked increases in atmospheric CO2 . Estimated pCO2sea values accurately reproduced pCO2sea data at several time series locations in the North Pacific. The distributions of pCO2sea revealed by 7 yr averaged monthly pCO2sea maps were similar to Lamont-Doherty Earth Observatory pCO2sea climatology, allowing, however, for a more detailed analysis of biogeochemical conditions. The distributions of pCO2sea anomalies over the North Pacific during the winter clearly showed regional contrasts between El Niño and La Niña years related to changes of SST and vertical mixing.
To establish a simple risk stratification system for patients with congenital diaphragmatic hernia (CDH) based on postnatal information within 24 h after birth.
A multi-institutional retrospective ...cohort study was conducted including 348 neonates who had isolated CDH born between 2006 and 2010. Based on the two most powerful variables for 90-day survival selected by multivariate analyses, a risk stratification system was established.
Multiple logistic regression analysis identified two adverse prognostic factors: an Apgar score at 1 min (Ap1) of 0-4 (odds ratio (OR) 3.3, P=0.004), and a best oxygenation index (OI) ⩾8.0 (OR 11.4, P<0.001). Based on a combinations of these two factors, patients were classified into three risk categories. The 90-day survival rates in categories 1-3 were 100, 88 and 52%, respectively (P<0.001).
Our simple risk stratification system based on Ap1 and best OI was capable of predicting mortality well.
A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall ...effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49-78%) for the imatinib cohort and 44% (95% CI, 35-52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT.
Summary
Prosthodontic treatment success depends on patients' ability to adapt to an altered oral environment containing removable prostheses. We investigated adaptive chewing‐related brain activity ...changes in response to a new oral environment. Twenty‐eight fully dentate subjects (mean age: 28·6 years) wore experimental denture‐base palatal plates (3 mm thick), for 7 days. We measured food mixing ability and cycle time, and assessed brain activity by functional magnetic resonance imaging during chewing at pre‐insertion (Day 0), and immediately (Day 1), 3 days (Day 3) and 7 days (Day 7) after insertion. Food mixing ability significantly decreased and cycle time increased on Day 1 as compared to Day 0 (P < 0·001) and tended to recover to Day 0 level by Day 7. Brain activation in the right face primary sensorimotor cortex and putamen significantly decreased on Day 1 as compared to Day 0 (P < 0·001) and recovered to Day 0 level by Day 7. Brain activation in the left face primary sensorimotor cortex, putamen, anterior cingulate gyrus (ACG) and right posterior medial frontal cortex (pMFC) significantly decreased on Day 1 as compared to Day 0 (P < 0·001) and did not recover by Day 7. Thus, oral environment changes involving palate covering affected chewing and induced adaptive brain activity changes in the face primary sensorimotor cortex and putamen, possibly associated with motor learning. As ACG and pMFC activity remained unrecovered by 7 days after plate insertion, automatisation of chewing while wearing a palatal plate may require longer adaptation periods.
Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must ...continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.
Summary
It is well known that shortened dental arch decreases masticatory function. However, its potential to change brain activity during mastication is unknown. The present study investigates the ...effect of a shortened posterior dental arch with mandibular removable partial dentures (RPDs) on brain activity during gum chewing. Eleven subjects with missing mandibular molars (mean age, 66·1 years) on both sides received experimental RPDs with interchangeable artificial molars in a crossover trial design. Brain activity during gum chewing with RPDs containing (full dental arch) and lacking artificial molars (shortened dental arch) was measured using functional magnetic resonance imaging. Additionally, masticatory function was evaluated for each dental arch type. Food comminuting and mixing ability and the perceived chewing ability were significantly lower in subjects with a shortened dental arch than those with a full dental arch (P < 0·05). Brain activation during gum chewing with the full dental arch occurred in the middle frontal gyrus, primary sensorimotor cortex extending to the pre‐central gyrus, supplementary motor area, putamen, insula and cerebellum. However, middle frontal gyrus activation was not observed during gum chewing with the shortened dental arch. These results suggest that shortened dental arch affects human brain activity in the middle frontal gyrus during gum chewing, and the decreased middle frontal gyrus activation may be associated with decreased masticatory function.
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