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Although there are many commercially available statistical software packages, only a few implement a competing risk analysis or a proportional hazards regression model with time-dependent covariates, which are necessary in studies on hematopoietic SCT. In addition, most packages are not clinician friendly, as they require that commands be written based on statistical languages. This report describes the statistical software ‘EZR’ (Easy R), which is based on R and R commander. EZR enables the application of statistical functions that are frequently used in clinical studies, such as survival analyses, including competing risk analyses and the use of time-dependent covariates, receiver operating characteristics analyses, meta-analyses, sample size calculation and so on, by point-and-click access. EZR is freely available on our website ( http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html ) and runs on both Windows (Microsoft Corporation, USA) and Mac OS X (Apple, USA). This report provides instructions for the installation and operation of EZR.

Background:Rituximab and tocilizumab exhibit potential as molecular targeted therapies for skin fibrosis in patients with systemic sclerosis. While rituximab has demonstrated improvement in skin fibrosis in a limited number of double-blind studies, tocilizumab has shown a favorable trend in a larger double-blind study. However, there is insufficient data on the real-world effectiveness of both drugs in daily clinical practice, and prognostic factors remain unclear.Objectives:To assess and compare the efficacy of rituximab and tocilizumab in treating skin fibrosis relative to standard of care (SoC), while also investigating the factors influencing the effectiveness of each treatment.Methods:In a comparative analysis, 32 patients treated with rituximab alongside SoC, 29 patients receiving tocilizumab with SoC, and 32 patients in the SoC-only group were examined. To mitigate potential selection bias in patient backgrounds across the three groups, propensity score-based inverse probability of treatment weighting was applied. The primary endpoint was the alteration in the modified Rodnan skin score (mRSS) after 24 weeks. Additionally, flow cytometric immune cell profiling, known as the “Human Immunology Project” by NIH/FOCIS, was conducted, and microvascular damages were assessed using nailfold video capillaroscopy. As an exploratory endpoint, we examined peripheral blood immunophenotypic characteristics and the extent of microvascular damages in cases exhibiting improved skin fibrosis.Results:The mRSS values were 14.0, 13.1, and 13.5 for the rituximab, tocilizumab, and SoC groups, respectively, with no significant differences among the three groups. Other parameters such as disease duration (7.2, 8.1, and 7.9 years) and age (59.9, 60.7, and 60.2 years) also exhibited no notable differences. After 6 months of treatment, the improvement in skin score was -3.6 points for rituximab, -2.1 points for tocilizumab, and +0.9 points for SoC. Both rituximab and tocilizumab demonstrated significant improvement compared to SoC (p < 0.001, p = 0.005), with no significant difference between rituximab and tocilizumab (p = 0.24) (Figure 1). The analysis of factors contributing to the effectiveness of each drug revealed that neither rituximab nor tocilizumab exhibited a clinical background predictive of efficacy. Peripheral blood immunophenotyping revealed associations between the percentages of effector memory CD4+ T cells, central memory CD4+ T cells, Th1, Th17, plasmablasts, and CD16+ NK cells and improved skin fibrosis at 24 weeks with rituximab. In multivariate analysis, only plasmablasts were inversely correlated with the efficacy of rituximab (p = 0.003) (Table 1). Conversely, no immune cells contributed to predicting the effectiveness of tocilizumab. Nailfold capillaries analysis showed that tocilizumab tended to improve cases with normal or giant capillaries, while those with hemorrhage or loss of capillaries were less likely to improve (p = 0.20).Conclusion:Both rituximab and tocilizumab exhibited improvement in skin fibrosis compared to SoC. For rituximab, the immunophenotype may be useful in treatment selection. However, there is no identified indicator for tocilizumab, necessitating further biomarker studies.Table 1.Pearson correlation coefficientunivariate analysismultivariate analysisCD4+ T cellsNaive0.0240.895Central memory-0.4020.020.982Effector memory-0.3750.0310.207TEMRA0.1630.365Activated-0.1360.451CD8+ T cellsNaive0.2530.156Central memory-0.2180.224Effector memory0.0080.967TEMRA0.0360.841Activated0.0990.584CD4+ T cell subsetsTh1-0.3580.0410.352Activated Th1-0.130.471Th17-0.3920.0240.063Activated Th170.0490.785Tfh0.0180.923Activated Tfh-0.0190.916Naive Treg0.0850.637Memory Treg0.0020.991Activated Treg0.0940.601B cellsNaive-0.3170.073IgM memory0.0050.976Class-switched memory-0.1050.562Double negative-0.2980.092Plasmablasts0.5460.0010.003NK cellsCD16+ NK cell0.3580.0410.954CD16- NK cell-0.2760.119MonocytesClassical0.2740.122Non classical0.3260.064Dendritic cellsMyeloid0.1160.522Plasmacytoid0.0980.589Figure 1.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Satoshi Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, Bristol-Myers, Abbvie, Eisai, Pfizer, Astra-Zeneca., has received research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Yurie Satoh-Kanda: None declared, Yasuyuki Todoroki: None declared, Ryuichiro Kanda: None declared, Hiroaki Tanaka: None declared, Masanobu Ueno: None declared, Yoshino Inoue: None declared, Yusuke Miyazaki has received speaking fees from Eli Lilly and GlaxoSmithKline., Ippei Miyagawa: None declared, Kentaro Hanami: None declared, Shingo Nakayamada has received speaking fees from Bristol-Myers, UCB, Astellas, Abbvie, Eisai, Pfizer, and Takeda, has received research grants from Mitsubishi-Tanabe, Novartis, and MSD., Yoshiya Tanaka has received speaking fees from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho., has received research grants from Mitsubishi-Tanabe, Eisai, Chugai, Taisho.

HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD ( n =2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n =109) with those of 1MMUD without ATG (1MM-ATG(−); n =1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0–11.0 mg/kg) in the 1MM-ATG(+) group. The rates of grade III–IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(−) group (hazard ratio (HR) 0.77, P =0.016; HR 0.74; P <0.001; and HR 0.87, P =0.020, respectively). Likewise, the rates of grade III–IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(−) group (HR 0.42, P =0.035; HR 0.35, P <0.001; and HR 0.71, P =0.042, respectively). The outcome of allo-HCT from 1MM-ATG(−) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.

Aims/hypothesis We investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice. Methods Male db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR. Results Liraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/db mice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/db mice, but GSIS, insulin and triacylglycerol content were not affected. In db/db mice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/db mice islets were consistent with the results of the gene expression analysis. Conclusions/interpretation Liraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.

Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database ( N =8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P =0.02) and pre-transplant liver dysfunction (HR, 1.85; P <0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades ( P <0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.

Background:It is unclear as to which SLE patients respond favorably to belimumab (BEL), and the impact of such treatment on peripheral blood immunophenotype in this population remains unknown.Objectives:This study aimed to clarify peripheral immunophenotype of patients with SLE who successfully discontinued glucocorticoids (GC) by intervention with BEL in the maintenance phase.Methods:Patients with SLE (n=146), who were in the maintenance therapy phase with a SELENA-SLEDAI score of less than 10 and receiving glucocorticoid therapy at a prednisolone-equivalent dose of 0.2 mg/kg/day or less, were assessed. They were divided into the standard of care (SoC) group (46 patients who received hydroxychloroquine or mycophenolate mofetil) and the BEL group (100 patients who received BEL with SoC). The efficacy of BEL group was compared with SoC group after adjustment by propensity score-based inverse probability of treatment weighting (PS-IPTW). Based on the standard human immune cell subset classification protocol by NIH/FOCIS, peripheral immunophenotypes were analyzed in BEL group and SoC group, and were compared.Results:After PS-IPTW adjustment, no differences in patient characteristics were shown between the SoC and BEL groups. The retention rate of BEL at 52w was 98.0%. SELENA-SLEDAI scores improved after 52w in both groups. The BEL group also had significantly lower GC doses at 52w (p=0.0028) and 31.8% of the BEL group successfully discontinued GC, whereas on 2.1% of the SoC group did (p=0.0043). The incidence of infections was significantly lower in the BEL group compared to the SoC group before PS-IPTW (BEL, 4.0% vs. SoC, 17.5%, p=0.089). The baseline peripheral immunophenotypes were similar between the two groups. In the BEL group, the proportion of activated T follicular helper cells (p=0.0073), IgD-CD27-B (DNB) cells (p=0.0088) and plasmocytes (p=0.0092) decreased significantly at 26w. There were no significant changes in the SoC group. At 26 weeks, the proportion of DNB cells (p=0.0328) and plasmocytes (p=0.0415) was significantly lower in patients who discontinued glucocorticoids (GCs) compared to those who were unable to discontinue them. Multiple logistic regression analysis showed that GC discontinuation was associated with low GC doses, low SLEDAI scores at BEL initiation, decreased IgG levels at 52w, and a low percentage of DNB cells and plasmocytes at 26w.Of those who discontinued GCs in the BEL group, 81.3% (6/26) did not experience a flare-up of SLE one year after discontinuation. In peripheral blood immunophenotyping six months after discontinuation of GC, the proportion of DN Bcells and plasmocytes was increased in patients who relapsed after discontinuation of GC. On the other hand, the proportion of DN Bcells and plasmocytes did not change in those who did not relapse after discontinuation of GC.Conclusion:Intervention with BEL in patients with SLE reduced DNB cells and plasmocytes, thereby controlling the disease activity and enabling GC discontinuation. Among patients who received low GC doses and had low SLEDAI scores, those with decreased IgG levels at 52w successfully discontinued GCs.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Yusuke Miyazaki Y. Miyazaki has received lecture fees from AstraZeneca, GlaxoSmithKline, Astellas, Eli Lilly., Shingo Nakayamada: None declared, Satoshi Kubo Satoshi Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, Bristol-Myers, Abbvie, Eisai, Pfizer, Astra-Zeneca and also research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Hiroaki Tanaka: None declared, Kentaro Hanami: None declared, Shunsuke Fukuyo: None declared, Ippei Miyagawa: None declared, Yasuyuki Todoroki: None declared, Yoshino Inoue: None declared, Yurie Satoh-Kanda: None declared, Masanobu Ueno: None declared, Yoshiya Tanaka Y. Tanaka has received Speakers bureau from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho., Y. Tanaka has received Grant/research support from Mitsubishi-Tanabe, Eisai, Chugai, Taisho.

Background:Achievement and maintenance of the Lupus Low Disease Activity State (LLDAS) are necessary for the long-term prevention of organ damage progression in patients with systemic lupus erythematosus (SLE); however, minor flares lower the achievement and maintenance rates, and consequent treatment changes such as glucocorticoid (GC) dose increase. Therefore, there is a demand for therapeutic strategies to control disease activity and achieve dose reduction or discontinuation of GCs using molecular targeted drugs.Objectives:This study aimed to analyze the safety and efficacy of anifrolumab in patients with SLE who experience minor flares after achieving LLDAS in real-world clinical practice.Methods:In this retrospective observational study, we assessed 65 SLE patients who experienced minor flares after achieving LLDAS. Of these, 30 were treated with the addition of glucocorticoids (GCs) or immunosuppressants, forming the standard of care (SoC) group. The remaining 35 patients were treated with the additon of only anifrolumab, constituting the anifrolumab group. Minor flare was defined as the revised Safety of Estrogens in Lupus Erythematosus National Assessment Flare Index. The LLDAS achievement rate at 26 weeks in the SoC and anifrolumab group were compared after adjusting with inverse probability of treatment weighting using propensity score (PS-IPTW).Results:The retention rate of anifrolumab was 97.1% (34/35 patients) at week 26. No significant difference was observed in the patient background between the two groups after adjustment by PS-IPTW. There was no difference between the two groups in either the LLDAS achievement rate or the DORIS remission rate at week 12 after the onset of minor flares followed by treatment intensification. At week 26, the anifrolumab group had a higher the rate of LLDAS achievement (SoC: anifrolumab=53.3:85.7%, p=0.0042) and DORIS remission (SoC: anifrolumab=6.7:25.7 %, p=0.0412). The SoC group did not exhibit a significant decrease in GC dose at 26 weeks, while the anifrolumab group exhibited a significant decrease. GC doses at week 26 were lower in the anifrolumab group (SoC: anifrolumab=6.9±3.5: 3.1±3.8mg/day, prednisolone equivalent, p<0.0001). The incidence of adverse events were fewer in the anifrolumab group (p=0.0012), especially infections (p=0.0169).Compared with patients treated for minor flares by GC dose increase (GC dose increase group, n=18) after adjustment by PS-IPTW, the anifrolumab group had a higher rate of LLDAS achievement (GC dose increase: anifrolumab=39.8:89.1%, p<0.0001) and DORIS remission (GC dose increase: anifrolumab=12.4:40.8%, p=0.0011). GC dose at week 26 was lower in the anifrolumab group (GC dose increase: anifrolumab=7.2±2.6:3.1±3.8 mg/day, prednisolone equivalent, p=0.0001). In anifrolumab group, three cases discontinued GC 26weeks after introduction of anifrolumab. The incidence of adverse events (p=0.0086) and infection (p=0.0442) were significant lower in the anifrolumab group.Conclusion:The current study demonstrated the safety and efficacy of anifrolumab in patients with minor flares who once achieved LLDAS but had difficulty maintaining LLDAS. These findings suggested that disease activity could be improved by initiating anifrolumab therapy alone without GC dose increase in patients with minor flares. Anifrolumab may prevent the accumulation of disease-induced organ damage caused by SLE and drug-induced organ damage caused by GCs, thereby improving long-term QOL and prognosis in patients with SLE.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Yusuke Miyazaki Y.Miyazaki has received speaking feesfrom Bristol-Myers, Pfizer, GlaxoSmithKline, Astellas, Asahi-Kasei, and Boehringer Ingelheim., Shingo Nakayamada: None declared, Satoshi Kubo Satoshi Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, Bristol-Myers, Abbvie, Eisai, Pfizer, Astra-Zeneca. research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Satoshi Kubo has received research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Satsuki Matsunaga: None declared, Hiroaki Tanaka: None declared, Kentaro Hanami: None declared, Shunsuke Fukuyo: None declared, Yurie Satoh-Kanda: None declared, Yoshino Inoue: None declared, Yasuyuki Todoroki: None declared, Masanobu Ueno: None declared, Yoshiya Tanaka Y. Tanaka has received Speakers bureau from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho, Y. Tanaka has received Grant/research support from Mitsubishi-Tanabe, Eisai, Chugai, Taisho.

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (⩾12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (⩾13.2 Gy)-based myeloablative conditioning. Tacrolimus ( n =35) or CYA ( n =22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (⩾38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66–88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus ( P <0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality ( P =0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation.

Various biomarkers have been investigated with regard to their ability to predict the outcome of allogeneic hematopoietic SCT (HSCT). In this study, we retrospectively reviewed 90 recipients who received HSCT between 2007 and 2011 in our institution, and evaluated the predictive value of the baseline serum C-reactive protein (CRP) levels just before the initiation of conditioning for transplant-related complications after allogeneic HSCT. A receiver-operating characteristic curve revealed that the baseline serum CRP levels had an excellent predictive value for non-relapse mortality (NRM), with an area under the curve of 0.83. The sensitivity and specificity for NRM were 80% and 87%, respectively, with a cutoff of 0.6 mg/dL. With this cutoff value, multivariate analyses revealed that a higher baseline CRP level was an independent risk factor for NRM (HR 6.21, P <0.01), grade III–IV acute GVHD (HR 3.91, P =0.03) and poor overall survival (HR 3.27, P =0.0018). On the other hand, the baseline CRP level did not predict infectious events. These findings suggested that CRP levels before conditioning may be a useful predictive biomarker for poor survival.

The longitudinal and transverse piezoresistance coefficients of Ge at room temperature are represented graphically as a function of the crystal directions for orientation (001), (110) and (211) planes. Many valley model of conduction band and stress decoupling decoupling of the degenerate valence band into two bands of prolate and oblate ellipsoidal energy surface are shown to explain origin of the piezoresistance. One this basis, comparison between piezoresistance coefficient and theoretical model is discussed.