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Leukemia accepted article preview online, 01 August 2016. doi:10.1038/leu.2016.212.

Background/purpose Perceived age may be a better predictor of mortality rate than chronological age. We have demonstrated that perceived age was a significant biomarker for carotid atherosclerosis in Japanese. However, it remains to be determined which skin parameter is associated with atherosclerosis. The purpose of this study is to analyze the relationship between 10 facial skin-aging parameters and atherosclerosis in 169 middle-aged to elderly Japanese women who participated. Methods Facial photographs were taken under a shadowless lamp from three directions using a high-resolution digital camera. The digital images of each subject were analyzed using computer software and various parameters of skin aging such as pigmentation, wrinkles, and skin color were quantified. Carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were measured as indices for atherosclerosis. Results Facial pigmentation showed a significant correlation with carotid IMT, even after correction for age (r = 0.13, P = 0.03), and with visceral fat area. Stepwise regression analysis indicated that facial pigmentation was associated with carotid IMT via visceral fat area. Conclusion Facial pigmentation may be a useful biomarker for carotid atherosclerosis in Japanese women.

Background and aims To investigate relationship between cystatin C (Cys)/creatinine ratio and disease activity of systemic lupus erythematosus (SLE). Methods Clinical and laboratory data were collected from 52 patients with SLE who had been examined their Cys at least once. Female rate was 96.2% and the average age±standard deviation was 47.9±13.2 years old. Estimated GFR (eGFR) was calculated based on Cys (eGFRcys) and creatinine (eGFRcre). Shrunken pore syndrome (SPS) was defined as eGFRcys/eGFRcre Results Comparing 20 patients with Cys Conclusions SLE patients with increased ratio of Cys to creatinine had high disease activity, and organ involvements were found with high frequency in patients with SPS.

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.

The aim of this retrospective study was to evaluate the toxicity profiles of dasatinib in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) or acute lymphatic leukemia (ALL) who were intolerant to imatinib, and who had been enrolled in our previous clinical trials to evaluate efficacy of dasatinib in patients resistant or tolerant to imatinib therapy. Twenty-four patients with CML and four with ALL were enrolled in the clinical studies to evaluate the efficacy according to the eligibility criteria related to intolerance to imatinib therapy. The toxicities reported during imatinib therapy were non-hematological toxicities in 23 patients and hematological toxicities in six patients. Patients were administered dasatinib 50-70 mg BID or 100 mg QD. Cross intolerance was observed in four patients who showed hematological toxicity after dasatinib treatment. However, it was possible to successfully continue therapy with only temporary interruption. No cross intolerance in non-hematological toxicity was found with the exception of one patient who showed cross intolerance, which did not result in treatment interruption. Dasatinib can be safely administered to imatinib-intolerant CML or Ph-positive ALL patients.

Summary We conducted a multi-center phase I/II trial of nonmyeloablative stem cell transplantation for patients with hematologic malignancies. The aim of this trial was to assess the safety and feasibility of this treatment modality for older or younger patients with significant organ dysfunction, who could not be treated with conventional high dose chemoradiotherapy. Twelve patients were treated with a conditioning regimen consisting of fludarabine and cyclophosphamide, followed by peripheral blood stem cell transplantation from human leukocyte antigen (HLA) identical siblings. Nonhematologic toxicities were mild. Median time to absolute neutrophils above 0.5 × 109/l, 1.0 × 109/l and platelets above 50 × 109/l were 8, 10 and 12 days, respectively. Donor dominant hematopoiesis was achieved in all patients, with or without donor leukocyte infusion. The cumulative incidence of acute and chronic graft-versus-host disease (GVHD) was 75 and 56%, respectively. Only one patient experienced early death within 100 days, caused by acute GVHD complicated by fungal infection. All patients except one achieved complete remission. With a median follow-up of 330 days, expected progression-free survival is 75%. Overall survival is 76%. Our study confirms that nonmyeloablative stem cell transplantation with cyclophosphamide and fludarabine conditioning is a safe and promising treatment for elderly patients with hematologic malignancies. A further study in large-scale setting is warranted.

To examine whether the percentage of myeloperoxidase (MPO)-positive blast cells is useful as a prognostic factor for acute myeloid leukemia (AML), cytochemical analysis of MPO was performed in 491 patients who were registered to the Japan Adult Leukemia Study Group-AML92 study. Patients were divided into two using the percentage of MPO-positive blast (high [>or=50%] and low (

We investigated the prognostic significance of genetic polymorphism in glutathione-S transferase mu 1 (GSTM1), glutathione-S transferase theta 1 (GSTT1), NAD(P)H:quinone oxidoreductase (NQO1) and myeloperoxidase (MPO), the products of which are associated with drug metabolism as well as with detoxication, in 193 patients with de novo acute myeloid leukemia (AML) other than M3. Of the patients, 64.2% were either homozygous or heterozygous for GSTT1 (GSTT1(+)), while 35.8% showed homozygous deletions of GSTT1 (GSTT1(-)). The GSTT1(-) group had a worse prognosis than the GSTT1(+) group (P = 0.04), whereas other genotypes did not affect the outcome. Multivariate analysis revealed that GSTT1(-) was an independent prognostic factor for overall survival (relative risk: 1.53; P = 0.026) but not for disease-free survival of 140 patients who achieved complete remission (CR). The rate of early death after the initiation of chemotherapy was higher in the GSTT1(-) group than the GSTT1(+) group (within 45 days after initial chemotherapy, P = 0.073; within 120 days, P = 0.028), whereas CR rates and relapse frequencies were similar. The null genotype of GSTT1 might be associated with increased toxicity after chemotherapy.

Successful engraftment of a second transplant from unrelated cord blood identifying acceptable HLA Ag mismatches as treatment for primary graft failure possibly mediated by anti-HLA Abs after ‘mega-dose’ haploidentical PBSC transplantation

To investigate the size effects of superfluid ${}^{3}\mathrm{He}$ in a slab geometry, we made a sample cell which has very uniform 1.1 \ensuremath{\mu}m spacing by stacking 440 films, where the static magnetic field for NMR was fixed parallel to the film surface. We performed cw NMR experiments in the superfluid state and observed the jump of resonance frequency shift at 10, 20, 24, and 27 bar. We attributed these phenomena to the A-B phase transition which occurs in 1.1 \ensuremath{\mu}m slab spacing at the temperature ${T}_{\mathrm{AB}}(1.1\ensuremath{\mu}\mathrm{m}).$ The A-B phase transition temperatures were suppressed by about 15% from those of the bulk liquid at higher pressures. When we coated the film surface with some ${}^{4}\mathrm{He}$ layers, we observed that the ${T}_{\mathrm{AB}}(1.1\ensuremath{\mu}\mathrm{m})$ became higher with increasing surface ${}^{4}\mathrm{He}$ layers.

The incidence, specificity and clinical significance of positivity for serum antineutrophil cytoplasmic antibody (ANCA) was investigated in 60 patients with primary Sjögren's syndrome (SjS). The indirect immunofluorescence (IIF) technique and an enzyme-linked immunosorbent assay (ELISA) were used to measure ANCA. Purified myeloperoxidase (MPO), lactoferrin (LF), cathepsin-G (CTG) and elastase (HLE) served as ANCA antigens for the ELISA. Ten (16.7%) of the 60 SjS patients showed positivity by IIF for perinuclear, but not cytoplasmic, ANCA. Four of the 60 sera were shown to be positive for LF, four for MPO, 0 for CTG and 0 for HLE by ELISA. There was no correlation between ANCA positivity and clinical features. ANCA in patients with SjS might be an epiphenomenon of polyclonal B-cell activation.

We report three acute myelogenous leukemia (AML) patients who developed intracerebral granulocytic sarcomas (GS) and were successfully treated with allogeneic BMT (allo-BMT). The diagnosis of one patient was AML M2 with myelofibrosis, and the other two patients were AML M4 with eosinophilia (AML M4 Eo), according to the FAB classification. Two patients first experienced a relapse in the brain that resulted in the formation of GS, followed by a relapse in the bone marrow. The remaining patient developed an optic nerve GS after suffering a bone marrow relapse. All three patients received irradiation for the GS and systemic chemotherapy before the allo-BMT. TBI was used for conditioning, and GVHD prophylaxis was with cyclosporine (CsA) and short-term MTX in all three cases. These patients are currently 9 to 37 months post-BMT without relapse. Thus, our experience suggests that allo-BMT is an effective treatment for AML patients with existing or pre-existing intracerebral GS.

We have measured the viscosity, η, and the slip length, ζ, of normal and superfluid3He using a torsional oscillator with a thick sample space. We coated the oscillating surface with 2.5 layers of4He film to study how the4He thin film changes the scattering mechanism of3He quasiparticles at the cell wall at 5 bar and 21 bar. In the normal phase, the temperature dependence of the viscosity was changed a little by the4He film at 21 bar but no change was observed at 5 bar. The slip length was enhanced by4He coating at 5 bar. This enhancement indicates the increase of specularity of3He quasiparticles scattering at the oscillating surface. On the other hand, a reduction of the slip length was observed at 21 bar. In the superfluid phase, the temperature dependence of ζ supports the existence of Andreev reflection even with4He film on the surface at 5 bar and 21 bar.

We have performedcwNMR experiments on superfluid3He confined to a parallel-plate geometry with a μm scale spacing for a wide pressure range. A static field was applied parallel or perpendicular to the plate surface. The spectra of two absorption signals, a main and a satellite, have been observed below the superfluid transition temperature in a parallel field. As the temperature decreased, the main signal decreased with shifts to higher frequencies, and the satellite grew with shifts to much higher frequencies. From the temperature dependence of these signals and the result in the perpendicular field, it is confirmed that the main signal and the satellite correspond to the A phase signal (ABM state) and the B phase signal (BW state), respectively. The temperature dependence of the two signals indicates that a phase transition from the A phase to the B phase occurs with decreasing temperature. By analyzing these signals, we determine A–B transition temperatures experimentaly. TheA–Btransition temperature normalized by the superfluid transition temperature is 0.95 at 20 bar, and decreased further to 0.70 at 0 bar for a thickness of 0.88 μm for pure3He. The values of TAB/TCwere slightly elevated when covering the surface with 4.5 layers of4He film, which suggests that this transition is also influenced by the surface condition.

A multicenter randomized study was conducted to compare the effect of interferon-alpha (IFN-alpha) with that of busulfan in newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase. From October 1988 to October 1991, 170 patients were randomized to receive either IFN-alpha or busulfan. Of 159 eligible patients, 31 (38.8%) of 80 patients in the IFN-alpha group and 43 (54.4%) of 79 patients in the busulfan group achieved complete hematologic remission, and 38.8% in the IFN-alpha group and 43.0% in the busulfan group achieved partial hematologic remission. A complete cytogenetic response was induced in seven (8.8%) of 80 patients treated with IFN-alpha and two (2.5%) of 79 patients treated with busulfan, and a partial cytogenetic response was 7.5% (6/80) and 2.5% (2/79), respectively. The difference in major (complete and partial) cytogenetic response between the two groups was significant (P = .046). At a median follow-up of 50 months, the predicted 5-year survival rate was 54% in the IFN-alpha group and 32% in the busulfan group (P = .0290), and the predicted 5-year rate of remaining in chronic phase was 41% in the IFN-alpha group and 29% in the busulfan group (P = .1165). As compared with the patients with no cytogenetic response, the patients with any cytogenetic response (complete, partial or minor) after the IFN-alpha or busulfan treatment were significantly superior in the duration of chronic phase (IFN-alpha group; P = .0017, busulfan group; P = .0010) even after correction for the time to response using the landmark analysis. However, there was no significant difference in survival rate in the IFN-alpha group (P = .1065). There was no significant difference in survival rate (P = .3923) and the duration of chronic phase (P = .6258) between the IFN- alpha and the busulfan group in the patients with a cytogenetic response (complete, partial or minor). These results demonstrate that IFN-alpha treatment produces a significantly superior cytogenetic response and survival rate as compared with the busulfan treatment, and unexpectedly, that busulfan can also eliminate Philadelphia chromosome positive clone in a few patients who showed prolonged survival rate and duration of chronic phase.

The efficacy of unrelated transplantation for patients with ALL who lack an HLA-matched sibling remains unclear. We performed a decision analysis to determine the efficacy of myeloablative transplantation from a genetically HLA-A, -B, -DRB1 allele-matched unrelated donor for patients with Ph chromosome-negative ALL aged 21-54 years. The transition probabilities were estimated from the Japan Adult Leukemia Study Group studies (ALL93; n=80, ALL97; n=82), and the Japan Marrow Donor Program database (transplantation in first CR (CR1): n=177). The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustment. Subgroup analyses were performed according to risk stratification based on the WBC count and cytogenetics, and according to age stratification. In all patients, unrelated transplantation in CR1 was shown to be superior in analyses both with and without QOL adjustment (40.8 vs 28.4% and 43.9 vs 29.0%, respectively). A similar tendency was observed in all subgroups. The decision model was sensitive to the probability of leukemia-free survival following chemotherapy and the probability of survival after transplantation in standard-risk and higher-aged patients. Unrelated transplantation in CR1 improves the long-term survival probability in patients who lack an HLA-matched sibling. However, recent improvements in treatment strategies may change this result.

Introduction Varicella zoster virus (VZV) disease is one of the major infectious complications that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Many reports have shown visceral VZV infection, a special type of VZV disease, to be rare. However, few studies so far have included a large number of patients. Findings Visceral VZV infection was found in 20 (0.8%) of 2411 patients who underwent allo-HSCT at our hospitals. Seventeen (85%) patients were taking immunosuppressive agents at the time of presentation with zoster. The presenting symptom was abdominal pain in 16 patients (80%), unconsciousness in 3 patients (15%), and no symptoms in 1 patient. The mean time interval from allo-HSCT to symptomatic visceral VZV infection was 273 days (103–800 days). The eruptions appeared within 3 days (0–13) after the first symptoms. Treatment with intravenous acyclovir was initiated before the appearance of eruptions in 3 of 18 patients (all 3 survived) with vesicular eruptions, the same day in 12 patients (11 survived, 1 died), and after the appearance in 3 patients (1 survived, 2 died). The overall mortality was 20%. Conclusion In conclusion, these data confirm that the incidence of visceral VZV infection is infrequent, but this disease is serious. When patients being treated with immunosuppressive agents demonstrate abdominal pain or unconsciousness, the possibility of visceral VZV infection should be considered as well as earlier therapeutic intervention.

Streptococcus mutans is a cariogenic pathogen in humans. To persist in the oral cavity, S. mutans is resistant against several antibacterial factors derived from the host. In this study, we investigated the mechanism of resistance to cationic antimicrobial peptides (AMPs), which are innate immune factors in humans. Because dltA-D (teichoic acid biosynthesis) was reported to affect the susceptibility to AMPs in other bacterial species, we evaluated the susceptibility of a dltC knockout mutant of S. mutans to the AMPs human beta-defensin-1 (hBD1), hBD2, hBD3 and LL37. The dltC mutant exhibited significantly increased susceptibility to AMPs. Regulation of dltC expression involved CiaRH, a two-component system. Expression of dltC in the wild-type strain was significantly increased in biofilm cells compared with that in planktonic cells, whereas expression was not increased in a ciaRH knockout mutant. In biofilm cells, we found that susceptibility to LL37 was increased in the ciaRH mutant compared with that in the wild type. From these results, it is concluded that Dlt is involved in the susceptibility of S. mutans to AMPs and is regulated by CiaRH in biofilm cells.

We have previously reported a new spontaneous recessive mutation that induces a generalized lack of lymph nodes (LNs) and Peyer's patches (PPs) accompanied by immunodeficiency in mice (gene symbol, aly). In this study, we have analyzed gut-associated lymphatic tissues of the mutant aly/aly mice and have compared the intestinal intraepithelial T lymphocytes (IEL) in aly/aly and normal aly/+ littermate mice. Immunohistochemical studies revealed that colonization of IEL and lamina propria T cells takes place in the absence of PPs and IgA-producing B cells in the lamina propria. Absolute numbers of Thy-1- IEL-alpha beta and -gamma delta are not altered in aly/aly mutant mice, whereas absolute numbers of Thy-1+ IEL-alpha beta and -gamma delta in aly/aly mice are about half of those in aly/+ mice. In IEL-alpha beta from aly/aly mice, the major CD8 alpha alpha+ and CD8 alpha beta+ subsets are maintained, whereas CD4+ and CD4+, CD8+ subsets are reduced. Although the population size of major CD8 alpha alpha+ and CD4-, CD8- IEL-gamma delta subsets is slightly reduced, the use of TCR-gamma- and -delta-chain variable gene segments by IEL-gamma delta remains almost the same in aly/aly mice. The constitutive cytolytic activity of IEL-alpha beta and -gamma delta is attenuated sharply in the aly/aly condition. This activity is, however, augmented significantly after in vitro stimulation with anti-CD3 mAb. These results indicate that most of the IEL subpopulations develop independently of passage through PPs and mesenteric LNs and that the aly mutation interrupts cytotoxic IEL development during relatively late differentiation steps that convert cytotoxic precursors to the constitutively cytolytic state.

Clinical studies using genetic randomization cannot accurately answer whether adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched sibling should undergo allogeneic hematopoietic stem cell transplantation (HSCT) or chemotherapy in first remission, as, in these studies, patients without a sibling donor undergo alternative donor transplantation or chemotherapy alone after a relapse. Therefore, we performed a decision analysis to identify the optimal strategy in this setting. Transition probabilities and utilities were estimated from prospective studies of the Japan Adult Leukemia Study Group, the database of the Japan Society for Hematopoietic Cell Transplantation and the literature. The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustments. Subgroup analyses were performed according to risk stratification on the basis of white blood cell count and cytogenetics, and according to age stratification. In analyses without QOL adjustments, allogeneic HSCT in first remission was superior in the whole population (48.3 vs 32.6%) and in all subgroups. With QOL adjustments, a similar tendency was conserved (44.9 vs 31.7% in the whole population). To improve the probability of long-term survival, allogeneic HSCT in first remission is recommended for patients who have an HLA-matched sibling.

(1992). Two β-Thalassemia Mutations in Japan: Codon 121 (Gaa→Taa) and IVS-I-130 (G→C) Hemoglobin: Vol. 16, No. 4, pp. 295-302.

To clarify the clinical and hematologic features of a rare numerical chromosome abnormality, we searched for trisomy 10 in acute myelogenous leukemias (AMLs) using the database of the Japan Adult Leukemia Study Group (JALSG) AML 92 and 95. Among the sequentially registered patients of JALSG-AML 92 (655 patients) and JALSG-AML 95 (531 patients), chromosome results were obtained in 1,074 patients (90.6%), and we found 3 patients with trisomy 10 as a sole abnormality. The first patient had an AML-M1 morphology with CD7 antigen; the patient obtained complete remission (CR) with the first course of chemotherapy. The second patient had an AML-M1 morphology without expressing CD7 antigen; this patient obtained CR, but relapsed 3 months later, and underwent allogeneic bone marrow transplantation. He suffered from chronic graft-versus-host disease and expired 38 months after the AML diagnosis. The third patient had AML-M0 with CD7 positivity. He obtained CR; however, brain abscess and cerebral hemorrhage occurred. In the literature, the mean age of patients with trisomy 10 AML is 57.8 years, the gender ratio is M/F = 1.5, and the frequency of M0/M1/M2 is 85.7%. A high incidence (81.8%) of CD7 expression of leukemia cells is notable. About 73% of patients survived for greater than 12 months.

In low rank coals much of the inorganic matter is present as cations associated with organic carboxyl groups in the coal rather than as discrete mineral phases. By treating the coal with acid the inorganic content is reduced by cation exchange, as well as by acid leaching of discrete minerals. Whole and acid treated samples of pulverized lignite were pyrolyzed in pilot scale (1 to 3 kg coal/h) and bench scale (60 to 100 g coal/h) fluidized bed reactors at atmospheric pressure, 0.45 second vapour-residence time, and temperatures ranging from 500 to 730°C. Yields of char, tar, water and light gases were determined. Removal of inorganic matter from a Saskatchewan lignite resulted in increased yields of tar and total volatile matter, with little effect on the yields of light gases. Increased yields of tar are largely a result of an increased asphaltene fraction in general and specifically of an increased catechol content. Char from acid-washed coal is less reactive to carbon dioxide than is char obtained from raw lignite.

Clinical features and prognosis of sixty patients with connective tissue disease accompanied by pulmonary hypertension (PH) (26 MCTD, 20 SLE, and 14 PSS) reported retrospectively by multi-institutions were compared. Though the obtained data were incomplete and lacking in uniformity, no significant difference in the clinical features among the three diseases were observed except high incidence of pulmonary fibrosis and low % VC in PSS and PH patients. Statistically significant difference, however, was observed between live and dead patients of three diseases gathered in post sternal pain, pulmonary diastolic murmur, right ventricular hypertrophy on ECG and mean pressure of pulmonary artery. Higher incidence of anti-nRNP antibody was observed in SLE with PH and PSS with PH patients than with the general population. A quicker occurrence of PH and shorter survival time were observed in MCTD patients with PH than in SLE and PSS patients with PH.

Background Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by lymphocyte infiltration in exocrine glands. Although most of the patients developed the disease in middle age, there are younger onset patients. Objectives To examine relationship between age at onset and clinical features including disease activity in patients with pSS. Methods Clinical data of 75 women with pSS who visited our hospital from Aug. 2010 to Dec. 2014 were collected from medical charts. Of them, ESSPRI1 and ESSDAI2 were assessed in 72 and 71 patients, respectively. Results Average age, age at onset, and duration of disease were 60.9±12.6, 48.3±13.9, and 12.8±7.3 years, respectively. Number of patients with low (ESSDAI

The translocation t(6;9)(p23;q34) is detected infrequently in subtypes of haematological malignancies including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). Although the t(6;9) leukaemia is commonly associated with bone marrow basophilia, the cytological characteristics of leukaemic cells are unclear. In the current study, we examined the in vitro effects of several cytokines on growth and differentiation of t(6;9) leukaemic cells. Isolated bone marrow mononuclear cells from four patients with t(6;9) (two MDS and two AML) were cultured for 14 d in the presence or absence of each cytokine. At the end of culture, viable cells were counted, and their histology was examined. Bone marrow cells obtained from 22 patients (10 AML, six AML from MDS, six MDS) lacking t(6;9) were used as controls. Compared with control cultures, significantly higher numbers of blasts appeared in the culture of bone marrow cells from t(6;9)-positive patients in response to stimulation with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF) or interleukin 3 (IL-3). Stem cell factor (SCF) had little effect. Neutrophil counts were also significantly increased in the presence of G-CSF or IL-3. SCF and IL-3 were potent in increasing basophil counts from t(6;9)-positive cultures. These findings suggest that bone marrow cells obtained from t(6;9) patients are highly sensitive to growth- and/or differentiation-promoting cytokines. Special attention should be paid to the use of "therapeutic" cytokines in these patients.

The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR'ABL-negative ALL. Patients aged 15'24 years (n = 139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58'75%) and 73% (95% CI 64'80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, Po0.001).These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR'ABL-negative ALL., Blood Cancer Journal, 4(10), e252; 2014

Background Novel disease activity indices for primary Sjogren9s syndrome, which are EULAR Sjogren9s syndrome patient reported index (ESSPRI) and EULAR Sjogren9s syndrome disease activity index (ESSDAI) have been recently developed. It is not clear that the relationship between each item of ESSPRI and each domain of ESSDAI. Objectives To examine correlation between each item of ESSPRI and each domain of ESSDAI. Methods Sixty-five female patients with primary Sjogren9s syndrome who visited our hospital completed ESSPRI and ESSDAI. Forty of them were assessed by these indices more than once at their revisit to our hospital. Average period of time between the assessments was 7.2 months. Multivariate analysis was used to test which domains of ESSDAI correlated with ESSPRI items (dryness, fatigue, and pain). Results Mean (SD) of ESSPRI and ESSDAI were 4.6 (2.0) and 3.7 (4.3), respectively. There was no correlation between ESSPRI and ESSDAI (r =0.08) as reported previously 1 , and also no correlation between ΔESSPRI and ΔESSDAI was found (r =0.16). There was no correlation between ESSPRI items and ESSDAI domains. In contrast, Δdryness inversely correlated with Δrenal domain ( p =0.015) and Δcutaneous domain ( p =0.03), and Δfatigue correlated with Δarticular domain ( p =0.037) and Δhematological domain ( p =0.009); however, there was no correlation between Δpain and any of ESSDAI domains. Conclusions Although ESSPRI items did not associate with ESSDAI domains, change in dryness and fatigue correlated with change in some domains of ESSDAI. This finding suggests that extraglandular worsening and improvement in specific domains may affect change in dryness and fatigue symptoms. References Seror R, et al. Arthritis Care Res. 2013;65:1358-1364. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5068

Background There are few articles show the difference of risk factor of osteoporosis between the lumbar spine and the femoral neck in SLE patients 1–6 . Objectives To compare the risk factor of osteoporosis between the lumbar spine and the femoral neck in SLE patients. Methods Consecutive 39 cases with SLE (mean age 49.1 years, 38 female, one male) who visited our hospital from Jun. 2012 to Dec. 2013 were studied. BMD was measured with dual-energy X-ray absorptiometry at the lumbar spine and the femoral neck, and correlations between BMD and age, disease duration, age of onset, disease activity (SLEDAI), glucocorticosteroid dose, thyroid function (TSH, freeT4), renal function (serum and urine β2-microglobuline, GFR, cystatin C) and other serum factors (C3, C4, 25-hydroxyvitamin D (25(OH)D), calcium, MMP-3) were examined by multivariate analysis. Results According to the WHO criteria, rates of osteoporosis, osteopenia, and normal BMD at the lumbar spine were 38%, 21%, and 41%, and at the femoral neck, 23%, 44%, and 33%, respectively. By stepwise regression, only MMP-3 negatively correlated with BMD at lumbar spine, but did not with BMD at the femoral neck. Although high rate (74%) of 25(OH)D deficiency were found, there was no correlation between BMD and serum level of 25(OH)D. Conclusions High prevalence of osteopenia and osteoporosis as well as 25(OH)D were found in patients with SLE. High level of serum MMP-3 may affect on decrease in BMD at lumbar spine, but at the femoral neck in SLE patients. Although the reason is unknown, we have to keep in mind high MMP-3 has possibility the cause of bone fragility at the lumbar spine in SLE patients. References Garcia-Carrasco M, et al. Osteoporosis in patients with systemic lupus erythematosus. Isr Med Assoc J. 2009; 11:486-91. Furukawa M, et al. Prevalence of and risk factors for low bone mineral density in Japanese female patients with systemic lupus erythematosus. Rheumatol Int. 2011; 31:365-76. Gilboe IM, et al. Bone mineral density in systemic lupus erythematosus: comparison with rheumatoid arthritis and healthy controls. Ann Rheum Dis 2000; 59: 110-15. Lakshminarayanan S, et al. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus. J Rheumatol 2001; 28: 102-8. Bultink, et al. Prevalence of and risk factors for low bone density and vertebral fractures in patients with systemic lupus erythematosus. Arthritis Rheum 2005; 54: 2044-50. Mok CC, et al. Bone mineral density in postmenopausal Chinese patients with systemic lupus erythematosus. Lupus 2005; 14: 106-12. Acknowledgements - Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2923

Background Cystatin C (CysC) is produced at a constant rate by all nucleated cells. It is freely filtered by the renal glomeruli and reabsorbed and catabolized in the proximal renal tubules. Compared with serum creatinine level, serum CysC concentration is not affected by gender and muscle mass, and therefore provides a more accurate measure of glomerular filtration rate (GFR). Patients with systemic lupus erythematosus (SLE) often develop glomerulonephritis and their quality of life and prognosis are impaired. Anti-DNA antibody and serum compliments are used as serum markers of developing renal damage. CysC can be used for early detection of renal damage. Moreover, CysC may be associated with inflammation in SLE 1 . Objectives To examine whether CysC correlates with SLE disease activity. Methods Fifty-two patients with SLE (50 women and 2 men) who visited our hospital from Jun. 2012 to Apr. 2013 were enrolled. Mean age (SD) was 47.9 (13.2) years. Median (range) of SLEDAI was 2 (0-35). Average dose of steroid (prednisone equivalent) was 7.4 mg/day. Blood samples were collected and serum creatinine, adjusted calcium concentration, levels of C3 and C4, anti-DNA antibody titers, TSH, free T4, matrix metalloproteinase-3 (MMP-3), and 25-OH vitamin D were examined. Stepwise regression was used for multivariate analysis to test which factors correlated with CysC. GFR was estimated by MDRD method. Results CysC correlated with creatinine, MMP-3, free T4, and SLEDAI scores. Of 52 patients, 10 had abnormal GFR ( 0.9 mg/L). Forty-two patients with normal GFR were divided into high level of CysC (n=23) and normal level of CysC (n=19). Patients with normal GFR and high CysC showed significantly higher titers of ant-DNA antibody and higher score of SLEDAI than those with normal GFR and normal CysC. Conclusions Thyroid function affects GFR 2 and serum MMP-3 lever is closely associated with clinical features relevant to lupus nephritis 3 . Besides creatinine and these renal associated factors, CysC independently correlated with SLEDAI. Moreover, Patients with normal GFR had high titers of anti-DNA antibody and high scores of SLEDAI if their CysC levels elevated, which suggests CysC associates with SLE disease activity independent of renal function. References Lertnawapan R, et al. Lupus 2012;21:279-287. A°svold BO, et al. Eur J Endocrinol 2011;164:101-105. Kotajima L, et al. Clin Exp Rheumatol. 1998;16:409-15. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5003

In a 10-year-old female with an impacted and completely transposed upper left canine, posterior temporal muscle activity and jaw movement during mastication were examined before and after orthodontic traction of the canine, alignment of teeth, and occlusal adjustment of the canine. After the orthodontic treatment, but before the occlusal adjustment, esthetic improvement in the static occlusion was achieved. The posterior temporal muscle on the non-chewing side exhibited earlier bursts in the electromyography. Jaw movement trajectory of the jaw-closing phase at a level close to the maximum intercuspation position was more to the medial side on the frontal view, and the jaw-closing velocity in the lateral direction was slower during left-sided chewing. Following occlusal adjustment of the transposed canine, however, the muscle activity and jaw movement patterns were improved to normal patterns. We suggest that it might be advisable to perform occlusal adjustment at an early stage during the retention period in such cases.

This case report examines the masticatory jaw movements and electromyograph (EMG) recordings of anterior and posterior temporal and masseter muscles before and after surgical orthodontic treatment in an adult patient with incisor crossbite and skeletal Class III jaw base relationship. The prescribed treatment resulted in a good occlusion and skeletal and dental Class I relationship. The chopping type jaw movement pattern during gum chewing was transformed to more of a grinding motion after treatment. But this motion was not as broad as is normally seen. This observation is indicative of the difficulties associated with improving the masticatory jaw movements in an adult patient to a completely normal pattern even after retention. In this patient, the high frequency of silent periods on the EMG that were observed in the early intercuspal phase before treatment were decreased to normal low levels after treatment. A similar decrease was also seen in the mean duration of the chewing cycle. We conjecture that this patient unsuccessfully attempted to compensate for the silent periods by increasing the period of his chewing cycle.

In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age

We searched for trisomy 11 in acute myelogenous leukemia (AML) patients using the Japan Adult Leukemia Study Group (JALSG) AML-92 and -95 databases to clarify the clinical and hematologic features of a rare numerical chromosome abnormality. Among the sequentially registered patients of JALSG AML-92 (655 patients) and JALSG AML-95 (531 patients), chromosome findings were obtained for 1074 patients (90.6%); we found 5 patients with trisomy 11 as the sole abnormality. The patients were 4 women and 1 man with trisomy 11 AML, all aged more than 45 years (median, 52 years), with 4 M1 morphologies and 1 M2. No patients manifested hepatosplenomegaly or lymph node enlargement, and no central nervous system leukemia or extramedullary lesions were detectable. All showed positivity for CD13 (5/5), CD33 (5/5), CD34 (3/3), CD38 (2/2), and HLA-DR (5/5). Except for 1 patient, all achieved complete remission after 1 course of induction chemotherapy, but 2 relapsed after discontinuation of chemotherapy. A third case of relapse occurred during intensification of chemotherapy, and the patient underwent allogenic bone marrow transplantation but died from interstitial pneumonia.

A new synthetic retinoid, Am80, is effective in treating acute promyelocytic leukemia relapsed from all-trans-retinoic acid-induced complete remission (CR). We report here the long-term clinical outcomes of patients who achieved second CR with Am80. Of 24 evaluable patients, 14 achieved a second CR by Am80 therapy. Of those patients, 4 relapsed within 6 months, despite subsequent consolidation chemotherapy. Six patients underwent sibling or unrelated HLA-matched allogeneic bone marrow transplantation (BMT), and 4 are alive without relase for more than 49 months after achieving second CR. Four of 8 patients who did not receive BMT are alive without relapse for more than 49 months. Promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) fusion transcript was undetectable by reverse transcriptase-polymerase chain reaction in all living patients. Therefore, if patients achieve second CR with Am80 and HLA-matched donors are available, BMT is the treatment of choice. However, it is noteworthy that CR was maintained for more than 49 months in half of the patients who did not receive BMT.

Long-term changes in the dentoskeletal pattern in a 6-year-old Japanese girl with Beckwith-Wiedemann syndrome were demonstrated. The patient showed macroglossia, which is the most common symptom of the syndrome, protruded lower lip, mandibular protrusion and anterior open bite. The jaw base relationship improved to skeletal Class I and the molar relationship to Angle Class I at the early preadolescent period following tongue reduction and phase I orthodontic treatment using a chin cap and tongue crib. Optimum intercuspation of teeth was achieved after edgewise treatment without orthognathic surgery, and a skeletal Class I apical base relationship and good facial profile were maintained after the retention period of 2 years. This case report suggests that early orthodontic treatment with tongue reduction can be effective in a case with Beckwith-Wiedemann syndrome to improve an abnormal dentoskeletal pattern.

A multicenter prospective randomized study was undertaken to assess the efficacy of etoposide added to the standard remission induction therapy for acute myeloid leukemia (AML). Consecutively registered newly diagnosed adult AML patients were randomized to receive either daunorubicin (40 mg/m2/day x 4 or more), behenoyl cytarabine (200 mg/m2/day x 10 or more) and 6-mercaptopurine (70 mg/m2/day x 10 or more) (BH-AC-DM), or the same three drugs plus etoposide (100 mg/m2/day x 5) (BH-AC-EDM) for response-oriented individualized induction therapy. The patients achieving complete remission (CR) received the same 3 courses of consolidation therapy followed by 6 courses of maintenance/intensification therapy. M3 was excluded and M0 was included. Of 667 patients registered, 655 were evaluable. The median age was 49 years (range, 15 to 85). CR rates were 77% in the BH-AC-DM group and 75% in the BH-AC-EDM group. In M4 patients, CR rates were 86% and 69% (p = 0.009), and, in M5, 80% and 77% (p = 0.810) in the BH-AC-DM and BH-AC-EDM groups, respectively. The predicted 6-year overall survival rates were 30% and 38% for BH-AC-DM and BH-AC-EDM groups, and the disease-free survival (DFS) rates of CR patients were 25% and 35% (p = 0.925), respectively. In conclusion, the present study failed to show any advantage of the addition of etoposide to the standard individualized induction therapy in adult AML, even among M4 and M5. These above data have already been published in the Int J Hematol (70: 87-104, 1999).

To clarify the clinical and hematologic features of a rare numerical chromosome abnormality, we searched for trisomy 10 in acute myelogenous leukemias (AMLs) using the database of the Japan Adult Leukemia Study Group (JALSG) AML 92 and 95. Among the sequentially registered patients of JALSG-AML 92 (655 patients) and JALSG-AML 95 (531 patients), chromosome results were obtained in 1,074 patients (90.6%), and we found 3 patients with trisomy 10 as a sole abnormality. The first patient had an AML-M1 morphology with CD7 antigen; the patient obtained complete remission (CR) with the first course of chemotherapy. The second patient had an AML-M1 morphology without expressing CD7 antigen; this patient obtained CR, but relapsed 3 months later, and underwent allogeneic bone marrow transplantation. He suffered from chronic graft-versus-host disease and expired 38 months after the AML diagnosis. The third patient had AML-M0 with CD7 positivity. He obtained CR; however, brain abscess and cerebral hemorrhage occurred. In the literature, the mean age of patients with trisomy 10 AML is 57.8 years, the gender ratio is M/F = 1.5, and the frequency of M0/M1/M2 is 85.7%. A high incidence (81. 8%) of CD7 expression of leukemia cells is notable. About 73% of patients survived for greater than 12 months.

In acute myeloid leukemia (AML), p53 mutations are reportedly infrequent but associated with a poor prognosis. The majority of mutations are missense mutations, which generally lead to accumulation of nuclear p53 protein. However, the prognostic significance of the accumulation remains unknown in AML. In this study, we compared the prognostic value of p53 mutations versus accumulation of the product. p53 mutations were found in 9 (4.5%) of 200 patients with de novo AML. The p53 mutation detectable (mutation+) group had a worse prognosis (p = 0.0009) than the mutation not detectable (mutation-) group. Multivariate analysis showed that the p53 mutation was an independent factor (p = 0.005) for short overall survival as well as 60 yr or older (p = 0.001) and unfavorable karyotypes (p = 0.001). In 79 of the 200 patients, the expression of p53 was studied by immunocytochemistry (ICC) using anti-p53 monoclonal antibody (DO-7). All samples carrying missense mutations (N = 6) were positive for ICC in over 15% of nuclei of each sample, chosen as the optimized cutoff value of p53 accumulation. Accumulation was thus found in 14 of the 79 patients. However, there was no prognostic difference according to the accumulation, because the mutation-/accumulation+ group (N = 8) tended to have a good prognosis. These findings indicate that molecular detection of p53 mutations yields better prognostic information than ICC. In a subset of AML, p53 protein might be accumulated without mutation presumably due to upstream signals of p53.

We conducted a multicenter phase II clinical study of fludarabine phosphate, a new purine nucleotide analogue, in patients with chronic lymphocytic leukemia (CLL). Fludarabine phosphate was administered at a dose of 20 mg/m2/day intravenously for 5 days every 4 weeks as one course. Six courses as a maximum were repeated. The response rate was 38.5% (95% confidence intervals: 20.2% to 59.4%), with 1 complete remission and 9 partial remissions out of 26 treated patients. Major drug-related adverse reactions were fever, nausea, weakness, and paresthesia of the fingers; as a grade-3 reaction, varicella was also reported. Neutropenia and thrombocytopenia were observed as manifestations of hematologic toxicity. Clinical laboratory test results revealed abnormalities in hepatic function, including increased GPT, but none of these was rated grade 3 or 4.

A 40-year-old male patient presented with leukocytosis and mild splenomegaly. Bone marrow aspirate showed myeloid hyperplasia and eosinophilia resembling chronic myelogenous leukemia in the chronic phase. Cytogenetic examination of bone marrow cells revealed an unusual karyotype, t(8;13)(p11;q12), in 20/20 metaphases. Not the BCR/ABL, but the ZNF198/FGFR1 chimeric mRNA was detected by reverse transcription-polymerase chain reaction. Since 1992, 12 patients with a similar atypical myeloproliferative disorder with T-cell non-Hodgkin's lymphoma or eosinophilia, associated with a t(8;13) translocation in both bone marrow and lymph node specimens, have been described. The present case is an additional one that should be classified into this new clinicopathologic entity.

There are few molecular biologic determinants that are prognostic for patients with acute myeloid leukemia (AML). Hence, we examined whether cellular levels of the cyclin-dependent kinase inhibitor p27Kip1 in acute myeloid leukemia could be used to predict clinical outcome in AML. Using immunoblot analysis, levels of p27 were assessed in blast cells from 72 AML patients who were registered and treated by the identical chemotherapy protocol. AML cases were classified into three groups on the basis of the percentage of the expression level of p27 compared to a control cell line. AML cases exhibiting p27 expression at low, moderate, and high levels were 43, 9, and 20 cases, respectively. No significant differences in the rates of complete remission (CR) were observed among the three groups. Although the level of p27 expression was not correlated with any other possible prognostic markers, such as age, white blood cell count, chromosome abnormalities, and FAB subclasses, patients with high p27 expression had a significantly increased disease-free survival (DFS) (78% vs 19%, P = 0.004). We further examined the expression of cyclin E at the protein level in all 72 AML cases. We observed a statistically significant correlation between a high cyclin E level and a high p27 level (P < 0.005). However, we failed to find any correlation between the rates of CR or DFS and cyclin E expression. The present study reveals that levels of p27 expression can be one of the useful prognostic molecular markers for AML. Leukemia (2000) 14, 28-33.

To assess the efficacy of etoposide added to the standard remission induction therapy for acute myeloid leukemia (AML), newly diagnosed adult AML patients were randomized to receive either daunorubicin (40 mg/m2/day x 4 or more), behenoyl cytarabine (200 mg/m2/day x 10 or more), and 6-mercaptopurine (70 mg/m2/day x 10 or more) (BHAC-DM), or the same three drugs plus etoposide (100 mg/m2/day x 5) (BHAC-EDM) for response-oriented individualized induction therapy. The patients achieving complete remission (CR) received the same 3 courses of consolidation therapy followed by 6 courses of maintenance/intensification therapy. M3 patients were excluded because all-trans retinoic acid was used. Of 667 patients registered, 655 were evaluable. The median age was 49 (range 15 to 85). CR rates were 77% in the BHAC-DM group and 75% in the BHAC-EDM group. In 173 M4 patients, CR rates were 86% and 69% (P = 0.009), and in 32 M5 patients, 80% and 77% (P = 0.810) in the BHAC-DM and the BHAC-EDM groups, respectively. The predicted 6-year overall survival rates were 30% and 38% (P = 0.925) for the BHAC-DM and BHAC-EDM groups, and the disease-free survival rates of CR patients were 25% and 35% (P = 0.352), respectively. Nonhematological toxicities after the first course of induction therapy were almost equal among the two groups, with the exception of a greater loss of hair (P = 0.024) and more frequent diarrhea (P = 0.013) in the BHAC-EDM group. We concluded that in the present study, the addition of etoposide to the standard individualized induction therapy showed no advantage in adult AML, even among M4 and M5 patients.