Combination of rituximab and methotrexate followed by rituximab and cytarabine in elderly patients with primary central nervous system lymphoma.

The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.

Neutrophil-lymphocyte ratio and carotid plaque burden in patients with essential thrombocythemia and polycythemia vera.

BACKGROUND AND AIMS: Chronic inflammation plays a critical role in the pathogenesis of myeloproliferative neoplasm (MPN), and inflammatory conditions are closely related to the development and exacerbation of atherosclerosis. This study aimed to compare carotid plaque burden and neutrophil-lymphocyte ratio (NLR) in the essential thrombocythemia (ET)/polycythemia vera (PV) and control groups. METHODS AND RESULTS: We retrospectively assessed carotid plaque burden and NLR in patients with ET/PV between January 2010 and September 2021 and propensity-score matched these patients to control subjects from the general population. All patients underwent carotid imaging using carotid ultrasonography for atherosclerosis screening. After 3:1 propensity-score matching, 140 patients in the control group were matched to 51 patients in ET/PV group. The mean NLR was significantly higher in the MPN group than in the control group (4.77 ± 3.96 vs. 1.93 ± 1.03, p < 0.001). The carotid plaque score was also higher in MPN group than in the control group (2.37 ± 1.47 vs. 1.94 ± 1.17, p = 0.038). CONCLUSION: Patients with PV/ET show a higher NLR and carotid plaque burden than the normal population. This reflected that PV/ET was a highly inflammatory and atherosclerotic condition expressing potentially increased cardiovascular risk.

TET2 Mutation and High miR-22 Expression as Biomarkers to Predict Clinical Outcome in Myelodysplastic Syndrome Patients Treated with Hypomethylating Therapy.

Tet methylcytosine dioxygenase 2 (TET2) is one of the most frequently mutated genes in myelodysplastic syndrome (MDS). TET2 is known to involve a demethylation process, and the loss of TET2 is thought to cause DNA hypermethylation. Loss of TET2 function is known to be caused by genetic mutations and miRNA, such as miR-22. We analyzed 41 MDS patients receiving hypomethylating therapy (HMT) to assess whether TET2 mutation status and miR-22 expression status were associated with their clinical characteristics and treatment outcomes. Responsiveness to HMT was not affected by both TET2 mutation (odds ratio (OR) 0.900, p = 0.909) and high miR-22 expression (OR 1.548, p = 0.631). There was a tendency for TET2 mutation to be associated with lower-risk disease based on IPSS (Gamma = -0.674, p = 0.073), lower leukemic transformation (OR 0.170, p = 0.040) and longer survival (Hazard ratio 0.354, p = 0.059). Although high miR-22 expression also showed a similar tendency, this tendency was weaker than that of TET2 mutation. In summary, the loss of TET2 function, including both TET2 mutation and high miR-22 expression, was not a good biomarker for predicting the response to HMT but may be associated with lower-risk disease based on IPSS, lower leukemic transformation and longer survival.

Generic Strategy to Synthesize High-Tap Density Anode and Cathode Structures with Stratified Graphene Pliable Pockets via Monomeric Polymerization and Evaporation, and Their Utilization to Enable Ultrahigh Performance in Hybrid Energy Storages.

Hybrid energy storage systems have shown great promise for many applications; however, achieving high energy and power densities with long cycle stability remains a major challenge. Here, a strategy to synthesize high-tap density anode and cathode structures that yield ultrahigh performance in hybrid energy storage is reported. First, vinyl acetate monomers are polymerized into molecular sizes via chain reactions controlled by the surface free radicals of graphene and metals. Subsequently, molecular-size polymers are thermally evaporated to construct battery-type anode structures with encapsulated tin metals for high-capacity and stratified graphene pliable pockets (GPPs) for fast charge transfer. Similarly, sulfur particles are attached to GPPs via monomeric polymerization, and capacitor-type hollow GPP (H@GPP) cathode structures are produced by evaporating sulfur, where sublimated S particles yield mesopores for rapid anion movement and micropores for high capacity. Moreover, hybrid full-cell devices with high-tap density anodes and cathodes show high gravimetric energy densities of up to 206.9 Wh kg-1 , exceeding those of capacitors by ≈16-fold, and excellent volumetric energy densities of up to 92.7 Wh L-1 . Additionally, they attain high power densities of up to 23 678 W kg-1 , outperforming conventional devices by a factor of ≈100, and long cycle stability over 10 000 cycles.

A phase II study of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) for patients with refractory or relapsed Hodgkin's lymphoma.

We assessed the efficacy and toxicity of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) combination chemotherapy in patients with refractory or relapsed Hodgkin's lymphoma (HL). This was an open-label, non-randomized, multi-center phase II study. The ESHAOx regimen consisted of intravenous (i.v.) etoposide 40 mg/m2 on days 1 to 4, i.v. methylprednisolone 500 mg on days 1 to 5, i.v. cytarabine 2 g/m2 on day 5, and i.v. oxaliplatin 130 mg/m2 on day 1. Cycles (up to six) were repeated every 3 weeks. In an effort to identify prognostic markers, the serum levels of cytokines including tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and vascular endothelial growth factor (VEGF) were measured at the time of study entry. A total of 37 patients were enrolled, and 36 were available for evaluation of tumor response. The overall response rate was 72.2% (26/36) (complete response, 33.3% [12/36]; partial response, 38.9% [14/36]). The median time to progression was 34.9 months (95% confidence interval, 23.1-46.7 months). The most common grade 3 or 4 hematological adverse events were neutropenia (16/37, 43.2%), followed by thrombocytopenia (10/37, 27.0%). Grade 3 or 4 non-hematological adverse events were nausea (3/37, 8.1%), anorexia (2/37, 5.4%), mucositis (1/37, 2.7%), and skin rash (1/37, 2.7%). There were no treatment-related deaths. High levels of TNF-α and CRP were significantly associated with poorer overall survival (p = 0.00005 for TNF-α, p = 0.0004 for CRP, respectively). The ESHAOx regimen exhibited antitumor activity and an acceptable safety profile in patients with refractory or relapsed HL. Trial Registration: ClinicalTrials.gov. Registered February 21, 2011, https://clinicaltrials.gov/ct2/show/NCT01300156.

Treatment with intravenous busulfan, melphalan, and etoposide followed by autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a multicenter study from the consortium for improving survival of lymphoma.

Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m2 /day) on days -5 and -4, and melphalan (50 mg/m2 /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.

Effect of Stem Cell Source and Dose on Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Idiopathic Aplastic Anemia: Data from the Korean Aplastic Anemia Trials.

OBJECTIVE: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA). METHODS: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA. RESULTS: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT <31 years (p = 0.010) and prior platelet transfusion <86 U (p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors. CONCLUSION: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs.

Allogeneic Stem Cell Transplantation for Patients with Natural Killer/T Cell Lymphoid Malignancy: A Multicenter Analysis Comparing Upfront and Salvage Transplantation.

Natural killer (NK)/T cell lymphoid malignancy comprises extranodal NK/T cell lymphoma (ENKTL) and aggressive NK cell leukemia (ANKL), and the outcomes for advanced or relapsed/refractory ENKTL and ANKL remain poor. Allogeneic stem cell transplantation (SCT) can be used as a frontline consolidation treatment to prevent the relapse of advanced disease or as salvage treatment after chemotherapy for relapsed sensitive disease. We retrospectively analyzed 36 patients (ENKTL, n = 26; ANKL, n = 10) who underwent upfront (n = 19) and salvage allogeneic SCT (n = 17) at 6 hospitals. Patients received myeloablative (n = 25) or reduced-intensity (n =11) conditioning regimens depending on the institute's policy. The median age at the time of allogeneic SCT was 37 years (range, 17 to 62), and more patients with ANKL (8/10) received upfront allogeneic SCT than ENKTL patients (11/26). Disease status before allogeneic SCT, conditioning regimen, and donor source did not differ between upfront and salvage allogeneic SCT groups. Febrile neutropenia (n = 20) and acute graft-versus-host disease (n = 16) were common adverse events. The median overall survival (OS) and progression-free survival (PFS) after allogeneic SCT were 11.8 months and 10.0 months, respectively. Twelve patients died from disease relapse and 12 from nondisease-related causes. Ten deaths occurred within 100 days after allogeneic SCT (10/24); these were mostly related to disease relapse (n = 8). The OS after allogeneic SCT did not differ between ENKTL and ANKL (P = .550) or between upfront and salvage SCT (P = .862). Complete chimerism was significantly associated with better PFS (P < .001). No significant differences in PFS were observed based on the conditioning regimen or source of stem cells (P > .05). Allogeneic SCT may be beneficial for patients with ENKTL and ANKL given that some patients were able to maintain their remission after allogeneic SCT. However, allogeneic SCT should only be performed in highly selected patients because the risks of disease relapse and nondisease-related mortality remain high.

Treating synchronous bilateral ocular adnexal marginal zone lymphoma: the consortium for improving survival of lymphoma study.

Both-side synchronous involvement has been reported to account for 7-24% of ocular adnexal marginal zone lymphoma (OAML). We conducted a retrospective analysis to identify the clinical features and treatment outcomes of synchronous bilateral OAML (SB-OAML) by treatment modality. We analyzed patients with a histologic diagnosis of SB-OAML, excluding metachronous bilateral involved OAML. We enrolled a total of 95 patients for this analysis, 36 males and 59 females; the median patient age was 42 years (range 16-77 years). Eleven (11.6%) patients had been treated with chemotherapy or chemo-immunotherapy (eight R-CVP, two CVP, and one R-CHOP). The median number of treatments was 6 (range 6-8); there were 9 complete responses (CRs; 81.8%) and 2 partial responses (PRs; 18.2%). Nearly all patients (88.4%) received radiotherapy in both eyes, and the median radiation dose was 27 Gy (range 20-40 Gy) to each eye; 68 CRs (80.9%) and 14 PRs (16.7%) were achieved. Ten-year progression-free survival (PFS) and overall survival (OS) rates were 79.8 and 91.1%, respectively. Radiotherapy continued to be an independent prognostic marker, with the hazard of progression (P = 0.036). Eleven patients (13.1%) had surgery for cataract treatment during follow-up, and patients who received low-dose radiation (< 30.3 Gy) experienced fewer cataract operations. SB-OAML was predominantly observed in young females, and they had good response and prognosis regardless of treatment modalities. Low-dose radiotherapy to both eyes showed a tendency of longer PFS than did chemotherapy and could decrease cataract operations.

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia.

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios <10(-5). Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.

Spectral Ripple Discrimination in Normal-Hearing Infants.

OBJECTIVES: Spectral resolution is a correlate of open-set speech understanding in postlingually deaf adults and prelingually deaf children who use cochlear implants (CIs). To apply measures of spectral resolution to assess device efficacy in younger CI users, it is necessary to understand how spectral resolution develops in normal-hearing children. In this study, spectral ripple discrimination (SRD) was used to measure listeners' sensitivity to a shift in phase of the spectral envelope of a broadband noise. Both resolution of peak to peak location (frequency resolution) and peak to trough intensity (across-channel intensity resolution) are required for SRD. DESIGN: SRD was measured as the highest ripple density (in ripples per octave) for which a listener could discriminate a 90° shift in phase of the sinusoidally-modulated amplitude spectrum. A 2 × 3 between-subjects design was used to assess the effects of age (7-month-old infants versus adults) and ripple peak/trough "depth" (10, 13, and 20 dB) on SRD in normal-hearing listeners (experiment 1). In experiment 2, SRD thresholds in the same age groups were compared using a task in which ripple starting phases were randomized across trials to obscure within-channel intensity cues. In experiment 3, the randomized starting phase method was used to measure SRD as a function of age (3-month-old infants, 7-month-old infants, and young adults) and ripple depth (10 and 20 dB in repeated measures design). RESULTS: In experiment 1, there was a significant interaction between age and ripple depth. The infant SRDs were significantly poorer than the adult SRDs at 10 and 13 dB ripple depths but adult-like at 20 dB depth. This result is consistent with immature across-channel intensity resolution. In contrast, the trajectory of SRD as a function of depth was steeper for infants than adults suggesting that frequency resolution was better in infants than adults. However, in experiment 2 infant performance was significantly poorer than adults at 20 dB depth suggesting that variability of infants' use of within-channel intensity cues, rather than better frequency resolution, explained the results of experiment 1. In experiment 3, age effects were seen with both groups of infants showing poorer SRD than adults but, unlike experiment 1, no significant interaction between age and depth was seen. CONCLUSIONS: Measurement of SRD thresholds in individual 3 to 7-month-old infants is feasible. Performance of normal-hearing infants on SRD may be limited by across-channel intensity resolution despite mature frequency resolution. These findings have significant implications for design and stimulus choice for applying SRD for testing infants with CIs. The high degree of variability in infant SRD can be somewhat reduced by obscuring within-channel cues.

Effects of age and hearing mechanism on spectral resolution in normal hearing and cochlear-implanted listeners.

Spectral resolution limits speech perception with a cochlear implant (CI) in post-lingually deaf adults. However, the development of spectral resolution in pre-lingually deaf implanted children is not well understood. Acoustic spectral resolution was measured as a function of age (school-age versus adult) in CI and normal-hearing (NH) participants using spectral ripple discrimination (SRD). A 3-alternative forced-choice task was used to obtain SRD thresholds at five ripple depths. Effects of age and hearing method on SRD and spectral modulation transfer function (SMTF) slope (reflecting frequency resolution) and x-intercept (reflecting across-channel intensity resolution) were examined. Correlations between SRD, SMTF parameters, age, and speech perception in noise were studied. Better SRD in NH than CI participants was observed at all depths. SRD thresholds and SMTF slope correlated with speech perception in CI users. When adjusted for floor performance, x-intercept did not correlate with SMTF slope or speech perception. Age and x-intercept correlations were positive and significant in NH but not CI children suggesting that across-channel intensity resolution matures during school-age in NH children. No evidence for maturation of spectral resolution beyond early school-age in pre-lingually deaf implanted CI users was found in the present study.

Influence of Tinnitus on Auditory Spectral and Temporal Resolution and Speech Perception in Tinnitus Patients.

Although cochlear damage is believed to trigger the perception of tinnitus in the central auditory system, its pathophysiological mechanism is still unclear. We aimed to investigate the pathophysiology of tinnitus using psychoacoustic assessments of auditory spectral and temporal resolution and speech perception in noise. Human subjects with tinnitus and symmetric hearing thresholds were divided into three groups: nine unilateral tinnitus subjects with normal hearing thresholds (Group 1), 12 unilateral tinnitus subjects with hearing loss (HL; Group 2), and nine bilateral tinnitus subjects with HL. Fifteen normal-hearing subjects without tinnitus were also tested as a control group. Four different tests were administered: (1) the spectral-ripple discrimination (SRD) test, (2) the temporal modulation detection (TMD) test, (3) the Schroeder-phase discrimination (SPD) test, and (4) the speech recognition threshold (SRT) in noise test. There were no significant differences in SRD, TMD, and SPD between the tinnitus-affected ears (TEs) and non-tinnitus ears (NTEs) in Groups 1 and 2 (p > 0.05). In contrast, the TEs showed poorer SRTs than the NTEs in these two subject groups (p = 0.022 and 0.049). No inferiority of spectral/temporal resolution in TEs compared with NTEs suggests that there may be no more outer hair cell (OHC) damage on the tinnitus side given that damaged OHCs are associated with broadening the auditory filters. The decoupling of the SRT results from the spectral/temporal resolution data could imply that the occurrence of tinnitus does not depend upon the degree of damage to the OHCs, but rather upon different plastic changes in the central auditory system after cochlear damage. SIGNIFICANCE STATEMENT: We can easily find unilateral tinnitus patients who have symmetric hearing thresholds. Our research question was what kind of difference would be responsible for the tinnitus in the tinnitus-affected ears but not in the non-tinnitus ears of subjects with symmetric hearing thresholds. The answer to this fundamental question could help us to understand the pathophysiology of tinnitus. We evaluated the potential influence of tinnitus upon the subjects' auditory spectral and temporal resolution and speech perception in noise by comparing these psychoacoustic performances between tinnitus-affected ears and non-tinnitus ears in the same subjects.

DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation.

The prognostic relevance of epigenetic modifying genes (DNMT3A, TET2, and IDH1/2) in patients with acute myeloid leukemia (AML) has been investigated extensively. However, the prognostic implications of these mutations after allogeneic hematopoietic cell transplantation (HCT) have not been evaluated comprehensively in patients with normal-karyotype (NK)-AML. A total of 115 patients who received allogeneic HCT for NK-AML were retrospectively evaluated for the FLT3-ITD, NPM1, CEBPA, DNMT3A, TET2, IDH1/2, WT1, NRAS, ASXL2, FAT1, DNAH11, and GATA2 mutations in diagnostic samples and analyzed for long-term outcomes after allogeneic HCT. The prevalence rates for the mutations were as follows: FLT3-ITD positivity (FLT3-ITD(pos)) (32.2%), NPM1 mutation (43.5%), CEBPA mutation (double) (24.6%), DNMT3A mutation (DNMT3A(mut)) (31.3%), DNMT3A R882(mut) (18.3%), TET2 mutation (8.7%), and IDH1/2 mutation (16.5%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57.3% and 58.1%, respectively. A multivariate analysis revealed that FLT3-ITD(pos) (hazard ratio, [HR], 2.23; P = .006) and DNMT3A R882(mut) (HR, 2.74; P = .002) were unfavorable prognostic factors for OS. In addition, both mutations were significant risk factors for EFS and relapse. People with DNMT3A R882(mut) accompanied by FLT3-ITD(pos) had worse OS and EFS, and higher relapse rates than those with the other mutations, which were confirmed in a propensity score 1:2 matching analysis. These results suggest that DNMT3A R882(mut), particularly when accompanied by FLT3-ITD(pos), is a significant prognostic factor for inferior transplantation survival outcome by increasing relapse risk, even after allogeneic HCT.

Transplant outcomes of the triple-negative NPM1/FLT3-ITD/CEBPA mutation subgroup are equivalent to those of the favourable ELN risk group, but significantly better than the intermediate-I risk group after allogeneic transplant in normal-karyotype AML.

The prognostic significance of molecular mutations (FLT3-ITD, NPM1, and CEBPA mutations) was examined in patients with normal-karyotype acute myeloid leukaemia (NK-AML) after allogeneic haematopoietic cell transplantation (HCT). In total, 115 patients received allogeneic HCT for NK-AML and were evaluated for FLT3-ITD, NPM1, and CEBPA mutations in diagnostic samples and for long-term outcomes following HCT, retrospectively. The prevalences of FLT3-ITD(pos), NPM1 (mut), and CEBPA (dm) (double mutations) were 32.2, 43.5, and 24.6 %, respectively. The triple-negative group (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) showed a similar transplant outcome to those in the favourable European LeukemiaNet (ELN) risk group for overall survival (OS) (60.9 vs. 63.7 %; p = 0.810), but a more favourable OS than others in the intermediate-I risk group (40.0 %; p = 0.034). Also, the triple-negative group showed a similar relapse rate at 5 years compared with those in the favourable risk group (9.7 vs. 15.5 %; p = 0.499), but a lower rate of relapse than the others in the intermediate-I risk group (15.5 vs. 48.6 %; p = 0.004). The 5-year relapse incidences were 4.0 % (NPM1 (mut)/FLT3-ITD(neg)), 14.7 % (CEBPA (dm)), 15.5 % (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)), 39.1 % (NPM1 (mut)/FLT3-ITD(pos)/non-CEBPA (dm)), and 66.7 % (NPM1 (wild)/FLT3-ITD(pos)/non-CEBPA (dm)). Thus, the triple-negative (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) group showed favourable long-term outcomes after allogeneic HCT in NK-AML, similar to those of the favourable risk group by the ELN risk classification.

Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant.

Normal karyotype acute myeloid leukemia (NK-AML) with CCAAT/enhancer binding protein α (CEBPA) mutations is known to have a more favorable prognosis. However, direct comparison of the clinical significance according to consolidation therapy has not been widely performed in patients with NK-AML. A total of 404 patients with NK-AML who received intensive induction chemotherapy were included in the present study. Diagnostic samples from the patients were evaluated for CEBPA mutations by direct sequencing. CEBPA single (sm) or double mutation (dm) was observed in 27 (6.7 %) and 51 (12.6 %) patients, respectively. CEBPA (dm) was associated with GATA2 (mut), and it was less frequently associated with FLT3-ITD(pos), NPM1 (mut), and DNMT3A (mut) in comparison with CEBPA (wild) or CEBPA (sm) (all p values <0.05). On multivariate analysis, CEBPA (dm) (p = 0.007, OR 39.593) was an independent risk factor for achievement of complete remission (CR). With a median follow-up of 40.1 months, CEBPA (dm) showed a favorable overall survival (OS), event-free survival (EFS), and lower relapse incidence (RI) in comparison with CEBPA (wild) (all p values <0.005). Comparison of clinical outcome analyses (consolidation chemotherapy vs. allogeneic hematopoietic cell transplantation (HCT)) demonstrated the role of consolidation treatment in patients with CEBPA (dm). Allogeneic HCT was associated with lower EFS and RI and a trend of higher non-relapse mortality. However, there was no statistically significant difference in OS. In conclusion, CEBPA (dm) was associated with other molecular mutations. Consolidation chemotherapy alone may overcome higher relapse rates by reducing the treatment mortality and increasing survival after relapse events in patients with CEBPA (dm) in NK-AML.

Assessment of Spectral and Temporal Resolution in Cochlear Implant Users Using Psychoacoustic Discrimination and Speech Cue Categorization.

OBJECTIVES: This study was conducted to measure auditory perception by cochlear implant users in the spectral and temporal domains, using tests of either categorization (using speech-based cues) or discrimination (using conventional psychoacoustic tests). The authors hypothesized that traditional nonlinguistic tests assessing spectral and temporal auditory resolution would correspond to speech-based measures assessing specific aspects of phonetic categorization assumed to depend on spectral and temporal auditory resolution. The authors further hypothesized that speech-based categorization performance would ultimately be a superior predictor of speech recognition performance, because of the fundamental nature of speech recognition as categorization. DESIGN: Nineteen cochlear implant listeners and 10 listeners with normal hearing participated in a suite of tasks that included spectral ripple discrimination, temporal modulation detection, and syllable categorization, which was split into a spectral cue-based task (targeting the /ba/-/da/ contrast) and a timing cue-based task (targeting the /b/-/p/ and /d/-/t/ contrasts). Speech sounds were manipulated to contain specific spectral or temporal modulations (formant transitions or voice onset time, respectively) that could be categorized. Categorization responses were quantified using logistic regression to assess perceptual sensitivity to acoustic phonetic cues. Word recognition testing was also conducted for cochlear implant listeners. RESULTS: Cochlear implant users were generally less successful at utilizing both spectral and temporal cues for categorization compared with listeners with normal hearing. For the cochlear implant listener group, spectral ripple discrimination was significantly correlated with the categorization of formant transitions; both were correlated with better word recognition. Temporal modulation detection using 100- and 10-Hz-modulated noise was not correlated either with the cochlear implant subjects' categorization of voice onset time or with word recognition. Word recognition was correlated more closely with categorization of the controlled speech cues than with performance on the psychophysical discrimination tasks. CONCLUSIONS: When evaluating people with cochlear implants, controlled speech-based stimuli are feasible to use in tests of auditory cue categorization, to complement traditional measures of auditory discrimination. Stimuli based on specific speech cues correspond to counterpart nonlinguistic measures of discrimination, but potentially show better correspondence with speech perception more generally. The ubiquity of the spectral (formant transition) and temporal (voice onset time) stimulus dimensions across languages highlights the potential to use this testing approach even in cases where English is not the native language.

Nonlinguistic Outcome Measures in Adult Cochlear Implant Users Over the First Year of Implantation.

OBJECTIVES: Postlingually deaf cochlear implant users' speech perception improves over several months after implantation due to a learning process which involves integration of the new acoustic information presented by the device. Basic tests of hearing acuity might evaluate sensitivity to the new acoustic information and be less sensitive to learning effects. It was hypothesized that, unlike speech perception, basic spectral and temporal discrimination abilities will not change over the first year of implant use. If there were limited change over time and the test scores were correlated with clinical outcome, the tests might be useful for acute diagnostic assessments of hearing ability and also useful for testing speakers of any language, many of which do not have validated speech tests. DESIGN: Ten newly implanted cochlear implant users were tested for speech understanding in quiet and in noise at 1 and 12 months postactivation. Spectral-ripple discrimination, temporal-modulation detection, and Schroeder-phase discrimination abilities were evaluated at 1, 3, 6, 9, and 12 months postactivation. RESULTS: Speech understanding in quiet improved between 1 and 12 months postactivation (mean 8% improvement). Speech in noise performance showed no statistically significant improvement. Mean spectral-ripple discrimination thresholds and temporal-modulation detection thresholds for modulation frequencies of 100 Hz and above also showed no significant improvement. Spectral-ripple discrimination thresholds were significantly correlated with speech understanding. Low FM detection and Schroeder-phase discrimination abilities improved over the period. Individual learning trends varied, but the majority of listeners followed the same stable pattern as group data. CONCLUSIONS: Spectral-ripple discrimination ability and temporal-modulation detection at 100-Hz modulation and above might serve as a useful diagnostic tool for early acute assessment of cochlear implant outcome for listeners speaking any native language.

The neural encoding of formant frequencies contributing to vowel identification in normal-hearing listeners.

Even though speech signals trigger coding in the cochlea to convey speech information to the central auditory structures, little is known about the neural mechanisms involved in such processes. The purpose of this study was to understand the encoding of formant cues and how it relates to vowel recognition in listeners. Neural representations of formants may differ across listeners; however, it was hypothesized that neural patterns could still predict vowel recognition. To test the hypothesis, the frequency-following response (FFR) and vowel recognition were obtained from 38 normal-hearing listeners using four different vowels, allowing direct comparisons between behavioral and neural data in the same individuals. FFR was employed because it provides an objective and physiological measure of neural activity that can reflect formant encoding. A mathematical model was used to describe vowel confusion patterns based on the neural responses to vowel formant cues. The major findings were (1) there were large variations in the accuracy of vowel formant encoding across listeners as indexed by the FFR, (2) these variations were systematically related to vowel recognition performance, and (3) the mathematical model of vowel identification was successful in predicting good vs poor vowel identification performers based exclusively on physiological data.