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Background An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. Methods and findings The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10–60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat − control], −0.007 mm [95% confidence interval (CI) −0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, −0.016 mm [95% CI −0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI −0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI −0.5% to 3.3%] in the control group (n = 193); mean between-group difference, −0.2% [95% CI −2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI −0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, −2.62 mg/dL [95% CI −2.86 mg/dL to −2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia. Conclusions In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. Trial registration University Hospital Medical Information Network Clinical Trial Registry UMIN000012911., In a randomized, controlled trial, Atsushi Tanaka and colleagues test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia., Author summary Why was this study done? Elevated levels of serum uric acid (SUA) increase the risk of gout and may be associated with the risk of developing cardiometabolic disorders and subsequent cardiovascular disease. Translational research suggests that urate-lowering therapy by inhibition of xanthine oxidase (XO) may attenuate experimental atherosclerosis. However, the clinical effects of XO inhibitors on atherosclerosis in patients with asymptomatic hyperuricemia remain uncertain. Carotid intima-media thickness (IMT) measurement is a simple and noninvasive method to monitor atherosclerosis. We therefore investigated whether treatment with febuxostat, a non-purine selective inhibitor of XO, delayed the progression of carotid atherosclerosis compared to non-pharmacological care for hyperuricemia in this patient population. What did the researchers do and find? The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial on 483 eligible participants (mean age 69.1 [standard deviation 10.4], female 19.7%) with asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery ≥1.1 mm. The results showed that there was no significant difference between febuxostat and non-pharmacological care for hyperuricemia in the progression of carotid atherosclerosis assessed by IMT over 24 months of follow-up. Febuxostat treatment was well tolerated and did not increase the incidence of cardiovascular and all-cause mortality. What do these findings mean? Our findings do not support the use of febuxostat to delay carotid atherosclerosis in patients with asymptomatic hyperuricemia. Further research is needed to determine the effects of febuxostat on atherosclerosis and cardiovascular safety in patients with hyperuricemia irrespective of the presence of gout.

[Introduction] AKAP13 (Protein Kinase A Anchoring Protein 13) is a guanine nucleotides exchange factor (GEF) that activates RhoA as well as a scaffold protein integrating multiple signaling cascades. Previous study has shown that Akap13 hetero knockout mice develop osteoporotic changes and result in decreased osteogenesis and we believe AKAP13 is involved in the early stages of osteogenesis. On the other hand, the involvement of Wnt signaling in bone metabolism has been extensively studied, however the detailed mechanism has not been elucidated. Recent study showed that focal adhesion kinase (FAK)-integrin contributes to bone formation via Wnt signaling pathway. Thus, it is suggested that Akap13 may influence osteogenesis via Wnt signaling through FAK mediated integrin pathway that is linked to Rho GTPase. In this study, we investigated the involvement of AKAP13 in bone formation and the relationship with Wnt signaling. [Methods] uCT analyses of femurs of Akap13 heterozygous-conventional knock-out mice were performed. We transfected the Akap13 or control siRNA into osteoblastic cells and examined the Wnt-related genes expression and osteogenic markers by real time RT-PCR. Osteogenic marker expression was examined after application of RhoA expression vector with or without Akap13 siRNA to osteoblastic cells. [Results] Mice haploinsufficient for Akap13 (Akap13+/-) displayed reduced bone mineral density resembling the changes observed in osteoporotic bone. Colony forming unit-fibroblast numbers were diminished in Akap13+/- mice. Osteoblast numbers in periosteum and extracellular matrix production in Akap13+/- mice was reduced compared to control littermates. Runx2 and Alp mRNAs were both reduced in femora of Akap13+/- mice. Akap13 knockdown showed a significant decrease of Lef1 mRNA expression in MC3T3-E1 cells as well as a reduction of Runx2 and ALP mRNA expression in immortalized bone marrow stem cells (BMSCs). RhoA overexpression in BMSCs showed Alp mRNA increment in RhoA induction dose dependent manner. Reduction of Alp mRNA by AKAP13 knockdown was amplified in higher RhoA overexpression. [Discussion] The Akap13 knockdown showed decreased expression of Wnt-related genes in osteoblastic cells, suggesting the possibility that AKAP13 plays an important role in regulating osteogenesis through Wnt signaling. AKAP13 may be involved in or contribute directly to Wnt signaling through interaction with RhoA by mechanical stress or stimulation of extracellular matrix.

Adrenal vein (AV) sampling (AVS) is the diagnostic gold standard for primary aldosteronism (PA), but right-sided AVS is difficult. We compared detection of AVs by selective retrograde CT adrenal venography (SRCTAV) with digital subtraction angiography (DSA).Data on 29 subjects (11 males, mean age 55 y) with increased serum aldosterone concentrations (SAC) and a diagnosed right or left aldosterone-producing tumor (APT) by AVS who underwent laparoscopic adrenalectomy were retrospectively analyzed. Before AVS, visualizing AVs was attempted by DSA and SRCTAV (Aquilion). If after the adrenocorticotropic hormone loading test serum cortisol concentration (SCC) from either AV was200 μg/dl, AVS was considered successful. If the SAC/SCC ratio for one side was ≥4 times higher than the other side, we diagnosed a one-sided APT.Left and right AV, respectively, were visualized in 29 (100%) and 22 subjects (76%) by DSA and 29 (100%) and 28 subjects (97%) by SRCTAV, with right-AV detection significantly higher by SRCTAV (p0.05). Cannulations were regarded successful in 28 subjects having both AVs observed on SRCTAV but not in the remaining subject whose adrenocortical scintigram was positive, however. Adrenalectomy was performed with a diagnosis of adenoma. Among 28 subjects with successful AVS, histopathological diagnoses included adenoma (25), nodular hyperplasia (2) and normal (1). After adrenalectomy, antihypertensive drug usage in 28 patients was reduced or stopped with decreases in SAC (97%).Detection of AV was significantly higher by SRCTAV than DSA, especially on the right side, in 29 subjects diagnosed with one-sided APT.

Epidemiological studies have shown that the incidence of coronary artery disease increases as the LDL- C, TC1-9), and TG10, 11) levels rise and the HDL-C level lowers5, 8, 12) both in Japan and in Western countries (Fig.1). At present, prevalence of coronary artery disease in Japan is much lower than that in Western countries13-16). However, recent increases in the LDL-C and TC levels in Japanese associated with so-called Westernization of diet implies future increases in coronary artery disease. In this guideline, therefore, criteria for the diagnosis of dyslipidemia were defined as in Table 1, with a greater emphasis on the prevention of coronary artery disease.The first step in this diagnostic procedure is to measure TC, TG, and HDL-C levels after overnight fasting. LDL-C level is then calculated by use of the Friedewald equation (LDL-C=TC – HDL-C – TG/5). The LDL-C level may be measured by a homogenous method especially in the case of postprandial examination or when the TG level is 400 mg/dL or higher.

Successful treatment with rituximab and donor lymphocyte infusions for fulminant EBV-associated lymphoproliferative disorder that developed 14 years after unrelated BMT

CD4(+) T cells play a central role in the development of inflammatory bowel disease (IBD) via high-level production of effector cytokines such as IFN-γ and TNF-α. To better characterize the colitogenic CD4(+) T cells, we examined their expression of CXCR6, a chemokine receptor that is expressed by T cells upon activation and is upregulated in several inflammatory diseases. We found that 80% of colonic lamina propria CD4(+) T cells expressed CXCR6 in the CD45RB(high) T cell-transferred colitis model. CXCR6 expression was similarly upregulated in inflamed mucosa of patients with Crohn's disease. Although surface marker analysis demonstrated that both CXCR6(+) and CXCR6(-) CD4(+) T-cell subsets consist of the cells with effector and effector-memory cells, the more cells in the CXCR6(+) subset produced IFN-γ and TNF-α compared to CXCR6(-) subset, and only the CXCR6(+) subset produced IL-17A. Nevertheless, adoptive retransfer of lamina propria CXCR6(+) T cells into Rag1 (-/-) recipients failed to induce the disease due to limited expansion of the transferred cells. By contrast, retransfer of CXCR6(-) cells evoked colitis similar to that observed in CD4(+)CD45RB(high) T cell-transferred mice, and resulted in their conversion into CXCR6(+) cells. Collectively, these observations suggest that the CXCR6(+)CD4(+) T-cell subset consists of terminally differentiated effector cells that serve as the major source of effector cytokines in the inflamed tissue, whereas CXCR6(-)CD4(+) T-cell subset serves as a colitogenic memory compartment that retains the ability to proliferate and differentiate into CXCR6(+)CD4(+) T cells.

Low-dose trimethoprim–sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT

Abstract 2673 Introduction: Follicular Lymphoma International Prognostic Index 2 (FLIPI-2) is a widely accepted tool for risk assessment of follicular lymphoma (FL), which is based on age, hemoglobin level, presence of bone marrow (BM) invasion, tumor size, and b2-microgloblin levels. Although it is easy to evaluate in clinical practice, it is a combination of tumor burden and patient physical condition, and a simple and powerful biomarker reflecting the tumor burden and its character is still not established. LR11 (also called SorLA or SORL1) was identified and characterized as a regulator of uPAR function through complex formation with uPAR. We have identified that serum soluble LR11 (sLR11) levels are significantly elevated in patients with acute leukemia and B cell lymphomas, and are associated with tumor burden and BM invasion (Sakai et al 2012). We have also found that high sLR11 levels had a significant negative prognostic impact on progression-free survival (PFS) in FL. Therefore, we have retrospectively evaluated the clinical characteristics of sLR11 and its prognostic impact on FL, in a larger patient cohort. Patients and Methods: Sixty-one patients with FL treated at Chiba University Hospital and affiliated hospitals from 2002 to 2012 were evaluated. The majority of patients were treated by the R-CHOP regimen (rituximab 375 mg/m2 on day 1; cyclophosphamide, 750 mg/m2 on day 1; adriamycin, 50 mg/m2 on day 1; vincristine, 1.4 mg/m2 on day 1; and prednisolone, 100 mg/body on day 1–5). Serum sLR11 levels were measured by ELISA method. Patient laboratory data and treatment outcome were obtained retrospectively. Results: Serum sLR11 levels of patients with lymphoma were significantly increased (mean ± SD: 19.4 ± 17.1 ng/ml) compared with those of normal control subjects (8.8 ± 1.79 ng/ml, P15.4 ng/ml at diagnosis compared with those with ≤15.4 ng/ml (Figure 1, 9.7 % vs 100 %, P15.4 ng/ml at diagnosis was a significant prognostic factor for PFS (hazard ratio: 2.65 × 107, 95% CI: NA). Conclusions: Serum sLR11 levels in FL patients were associated with BM invasion, lower Hb levels and elevated b2-microglobulin, which are 3 of 5 variables in FLIPI-2. This suggests that serum sLR11 is a useful tool to predict “high” FLIPI-2 score, especially highlighting those with high tumor burden by simple serum evaluation and can be a promising biomarker in patients with FL. Disclosures: No relevant conflicts of interest to declare.

Abstract 5104 Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of malignant lymphoma, characterized by the selective growth of lymphoma cells within the lumina of vessels in various organs. Although recent reports showed that prompt and accurate diagnosis lead to better outcomes, absence of typical clinical manifestations and its aggressive behavior frequently makes it difficult. LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a soluble form (sLR11) is released by proteolytic shedding. sLR11 is originally known to be a biomarker of carotid intima-media thickness. We have recently found that LR11 is expressed on human leukemia cell lines, and sLR11 is released in its culture medium. Serum sLR11 levels are significantly elevated in patient serum samples with acute leukemia and B cell lymphomas, and are associated with tumor burden and bone marrow invasion. Based on these findings, we hypothesized that LR11 may be also expressed and released from IVLBCL cells; therefore we evaluated its clinical importance in IVLBCL. Materials and methods: Serum samples and paraffin embedded tumor specimens were obtained from 6 patients who were histologically diagnosed as IVLBCL from 2009 to 2012. Specimens were subjected to immunostaining using anti-LR11 antibody, and serum sLR11 levels were measured by ELISA method. Patient laboratory and clinical data were collected retrospectively. Also, serum samples from 75 healthy volunteers, and 10 patients with collagen diseases presenting similar clinical manifestations as IVLBCL were analyzed. Results: Tissue samples of IVLBCL were obtained by bone marrow biopsy (N=2), transbronchial lung biopsy (N=2), and random skin biopsy (N=2). Biopsy specimens showed that cytoplasm of IVLBCL cells were specifically immunoreacted against the anti-LR11 antibody (Figure 1). Median serum sLR11 level of IVLBCL patients was 86. 0 ng/ml (mean ± SD: 201. 8 ± 260. 0 ng/ml), which was significantly elevated than those of healthy volunteers (median: 8. 4 ng/ml, mean±SD: 8. 8 ± 1. 8 ng/ml, p Conclusions: We have identified LR11 as a novel molecule which was proven to be expressed in IVLBCL cells and circulated in patients' serum. LR11 immunostaining clearly highlights the tumor cells and sLR11 enables to distinguish IVLBCL from other differential diagnosis by serum evaluation. These findings suggest that LR11 is a useful diagnostic tool for IVLBCL, and serum sLR11 is a sensitive biomarker for diagnosis and disease monitoring of this challenging disease. Disclosures: No relevant conflicts of interest to declare.