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Building structures around the world have been designed using various framing methods. In Japan, the two-way moment-resisting frame structure, which is designed as a 3D seismic frame with beams connected to the columns, with moment connections in both directions, is traditionally constructed. In contrast, in the United States and many other countries in high seismic regions, the one-way moment-resisting frame structure, which is designed as separate seismic and gravity frame structure with only a few expensive moment connections in seismic frames, is typically constructed. Structures with these different framing systems are likely to exhibit different seismic response and collapse mechanism when subjected to large earthquake excitation. However, the simulation up to complete collapse has almost not been conducted and safety margin to complete collapse of these different framing systems has not been sufficiently understood. In this study, seismic simulation of U.S. and Japanese type three-story steel moment-resisting frame structures is conducted using general-purpose finite element analysis program. Practical macro models used for the simulation are based on beam and shell elements. It is found that composite effects of floor slab accelerate column yielding in both U.S. and Japanese type steel frame structures and drift concentration may occur at relatively small ground motion level and eventually result in complete collapse.

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset

// Fumito Abe 1, * , Akihiro Kitadate 1, * , Sho Ikeda 1 , Junsuke Yamashita 2 , Hiroki Nakanishi 3 , Naoto Takahashi 1 , Chikara Asaka 4 , Kazuaki Teshima 5 , Tomomitsu Miyagaki 6 , Makoto Sugaya 6 , Hiroyuki Tagawa 1 1 Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan 2 Division of Bioscience Center, Radioisotope, Akita University, Akita, Japan 3 Research Center for Biosignal, Akita University, Akita, Japan 4 Department of Otolaryngology, Noshiro Kousei Medical Center, Noshiro, Japan 5 Department of Hematology, Hiraka General Hospital, Yokote, Japan 6 Department of Dermatology, University of Tokyo, Tokyo, Japan * These authors share first authorship Correspondence to: Hiroyuki Tagawa, email: htagawa0279jp@yahoo.co.jp Keywords: HDACI, miR-150, CCR6, CTCL, metastasis Received: September 24, 2016 Accepted: November 24, 2016 Published: December 07, 2016 ABSTRACT Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.

Background Tacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT). Design and methods Twenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake. Results Thirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele. Conclusions CYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3060-4) contains supplementary material, which is available to authorized users.

Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-α inhibitors. However, the mechanisms of how HPS occurs and how a TNF-α inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-γ but not TNF-α, and it was suppressed by blockade of IFN-γ but not TNF-α. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-α, IL-6, and IFN-γ. Blocking of TNF-α, but not IL-6 or IFN-γ, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF-α–driven HPS in BMT mice and is effectively treated through TNF-α inhibition.

We recently demonstrated that upregulation of a chemokine receptor CCR6 and its ligand CCL20 led to metastasis of advanced cutaneous T-cell lymphoma (CTCL) cells, suggesting the involvement of CCL20-CCR6 interaction in initiating CTCL cell metastasis. In this study, we determined whether this interaction is functional in metastatic CTCL cells. We first demonstrated increased STAT3 expression during the progression of primary CTCL. STAT3 was spontaneously activated and mediated the transcription of CCL20 in CTCL cell lines. Next, to determine whether the transient knockdown of STAT3, CCL20, or CCR6 or treatment with neutralizing antibody against CCL20 (neutralizing CCL20 antibody) could reduce the migration ability of CTCL cells, we conducted an in vitro migration assay. All treatments reduced the nutrition-dependent migration activity of CTCL cells. Notably, treatment with neutralizing CCL20 antibody reduced the migration ability of the cells without decreasing the expression of CCL20 and CCR6. This demonstrated that the CCL20-CCR6 interaction is actually functional in metastatic CTCL cells. Finally, to examine the in vivo effect of neutralizing CCL20 antibody, we used NOD/Shi-scid IL-2γnul mice inoculated with CTCL cells. These mice were expected to die due to metastasis of CTCL cells into multiple organs. However, administration of neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice. These findings suggested that automatic activation of the STAT3/CCL20/CCR6 cascade was involved in CTCL lymphomagenesis and that disruption of CCL20-CCR6 interaction could be a key therapeutic strategy against advanced CTCL.

Background: Histone deacetylase inhibitors (HDACis) are promising agents for various T-cell lymphomas, including cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and adult T-cell lymphoma/leukemia (ATLL). CCR4 is an important therapeutic target molecule because mogamulizumab, an anti-CCR4 antibody, has shown promising efficacy against CTCL, PTCL, and ATLL. However, their combined effects and interactions have not been examined thus far. We previously showed that CCR6, a chemokine receptor, is overexpressed in cutaneous T-cell lymphomas (Ito et al., 2014 Blood). Moreover, we recently demonstrated that HDACis downregulate CCR6 expression in advanced cutaneous T-cell lymphomas (Abe et al., 2017 Oncotarget). These reports lead us to hypothesize that HDACis might also downregulate CCR4 in various T-cell lymphomas. In this study, we clarify the effect of the combined use of mogamulizumab and HDACis on various T-cell and NK-cell lymphomas. Based on our findings, we discuss what benefits or adverse effects might be assumed for patients if these molecular targeting agents are used in clinical practice. Methods: We evaluated changes in CCR4 expression and antibody-dependent cell-mediated cytotoxicity (ADCC) activities against mogamulizumab- and HDACi-treated T-cell and NK-cell lymphoma lines and primary cases. To determine which HDAC mainly regulated CCR4 expression, we used isoform-specific HDACis and induced knockdown of respective HDACs for T-cell lymphoma cell lines. To examine the effect of CCR4 downregulation by HDACis in clinical cases, we examined the CCR4 expression of CTCL skin samples, which were obtained from the same patients before and after HDACi treatment (n = 6). Results: We first examined the expression of CCR4 for 15 T-cell and NK-cell lymphoma cell lines and a peripheral blood mononuclear cell (PBMC) sample derived from healthy donors to investigate the effect of vorinostat, a pan-HDACi, on CCR4 expression. The expression of CCR4 was mostly expressed in the (11 out of 15) cell lines: ATLL (MT-1, MT-2, MT-4, and TL-Su), CTCL (My-La, HH, and MJ), and NK/T-cell lymphoma cell lines (Kai3, SNK6, HANK1, and SNK10). We found that vorinostat decreases mRNA expression and surface expression of CCR4 except for the cell lines without CCR4 expression. Next, we used isoform-specific HDACis to examine which isoform of HDAC is involved in the regulation of CCR4. We used the following class-specific HDACis: romidepsin as a class I selective HDACi, CI-994 as an HDAC1/HDAC2-selective inhibitor, RGFP966 as an HDAC3-selective inhibitor, ricolinostat as an HDAC6-selective inhibitor, and PCI-34051 as an HDAC8-selective inhibitor. When these drugs were exposed to T-cell lymphoma cells, romidepsin and CI-994 strongly suppressed CCR4 expression. These results suggest that class I HDACs might controls CCR4 expression. We further performed knockdown experiments using siRNAs against HDAC1, HDAC2, and HDAC3. When we compared the expression change of CCR4 in HDAC-knockdown cells, HDAC2 knockdown cells showed the most significantly decreased expression of CCR4. These results suggest that class I HDACs, especially HDAC2, might be deeply involved in CCR4 expression regulation. When we examined the CCR4 expression in skin samples from primary CTCL, obtained from the same patients before and after vorinostat treatment, we found that CCR4 expression was greatly reduced after vorinostat treatment. Finally, when we conducted an ADCC assay with mogamulizumab by using various lymphoma cell lines and primary T-cell lymphoma samples, we found that the efficacy of mogamulizumab was significantly reduced by pre-treatment with vorinostat. Conclusion: Our results suggest that the primary use of HDACis before treatment of mogamulizumab might not be suitable to obtain synergistic effects. Moreover, these results provide potential implications for optimal therapeutic sequences in various CCR4 positive T-cell and NK-cell lymphomas. Disclosures Kitadate: Kyowa Kirin: Research Funding; Fujimoto: Research Funding; Eisai: Research Funding; Otsuka: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Asahi Kasei: Research Funding; Chugai: Research Funding; Toyama kagaku: Research Funding. Abe: Kyowa Kirin: Research Funding; Fujimoto: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Otsuka: Research Funding; Toyama Kagaku: Research Funding; Chugai: Research Funding; Asahi Kasei: Research Funding; Eisai: Research Funding. Tagawa: TaNeDS (Daiichi Sankyo): Research Funding.

The aim of this study was to develop a model able to predict the area under the lenalidomide plasma concentration-time curve (AUC) in multiple myeloma (MM) patients using a limited sampling strategy.Forty-six hospitalized Japanese MM patients (25 men and 21 women) participated in this study. On days 3-10 of lenalidomide therapy, whole-blood samples were collected just before oral lenalidomide administration, and 1, 2, 4, 8, 12, and 24 hours thereafter. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry.The AUC0-24 predicted from a single lenalidomide plasma concentration measured 8 hours after the administration (C8h) showed the highest correlation with the measured AUC0-24 of lenalidomide (AUC0-24 = 13.0 × C8h + 1305.0; r = 0.832). To enhance the correlation between the predicted and the actual AUC0-24 of lenalidomide, we included information regarding lenalidomide elimination by entering creatinine clearance (CCr) data in the predictive formula of lenalidomide AUC0-24. Predicting the AUC0-24 of lenalidomide using data from 2 time points, C0h and C4h, along with CCr data further strengthened the correlation with the measured AUC0-24 of lenalidomide [AUC0-24 = 37.1 × C0h + 6.4 × C4h - 32.1 × CCr + 3265.6; r = 0.842].The AUC0-24 of lenalidomide can be predicted using plasma concentrations measured at only 2 time points, C0h and C4h, in combination with CCr. Our study also suggests that the limited sampling strategy approach might help to identify patients with renal function impairment and who, despite dose adjustments, accumulate the drug, leading to a high AUC.

(background) The drug resistance of multiple myeloma (MM) cells is thought to be induced by various factors of the bone marrow microenvironment. Of these factors, hypoxic stress may be associated with drug resistance in various hematologic malignancies, including MM. Hypoxic stress lead MM cells to induce distinct gene expressions. It has been reported that oncogenic transcription factors such as IRF4 and Myc are suppressed under hypoxia. Instead, accumulation of another transcription factor, HIF-1α upregulates anti-apoptotic proteins, increases glycolysis, and enhances neovascularization leading MM cells to represent anti-apoptotic phenotype. Autophagy is an intracellular process that encapsulates cytoplasmic components, which are directed to the lysosome for degradation. Autophagy and proteasomal degradation prevent apoptosis caused by endoplasmic reticulum (ER) stress. Although proteasome inhibitor such as bortezomib, is a key drug for MM, it may induce treatment resistance. This might be because autophagy is induced in hypoxic microenvironment. Autophagy associated molecules might be therapeutic target in MM cells adapted to hypoxia. (Aim and methods) To clarify the association of hypoxia inducible genes and autophagy, and to obtain rational basis for a new therapeutic strategy against MM, we performed following experiments in vitro using myeloma cell lines (MM.1S, KMS-12-PE, KMS-11, and H929) and primary samples (n=6) that were subjected to hypoxia (1% O2). (Results) First, we examined volcano plot analysis on our cDNA microarray data (GSE80545) of patient samples incubated in normoxia or hypoxia for 48 hours. 546 probes were significantly elevated in hypoxia (fold change > 2.0, p < 0.05). Gene ontology analysis revealed that "Glycolytic Process" contained 13 genes such as PFKFB4, ENO2, ALDOC, PFKFB3, HK2, PFKP, GPI, PGK1, LDHA, ALDOA, ENO1, PKM, and GAPDH. We focused on hexokinase-2 (HK2) because it has been reported that HK2 activates autophagy under stress conditions. Western blot analysis for patient samples revealed that HK2 expression was remarkably upregulated under hypoxia. Apoptosis assay showed that viable cells of HK2 knockdowned cell lines were significantly lower than that of control cells under hypoxia, but not under normoxia. Also, in hypoxia, we found that number of 3-bromopyruvate (3-BrPA, a HK2 inhibitor) subjected viable cells were significantly lower than that of normoxia. This suggested that HK2 contributes to anti-apoptotic phenotype of MM cells under hypoxia. Next, we examined the role of HK2 in autophagy under hypoxia. Because degradation of p62 and increase of LC3-II/LC3-I ratio is considered to be useful for autophagy detection, we examined these factors by Western blot analysis. We found that hypoxic stress decreased expression of p62 and increased the ratio of LC3-II/LC3-I in myeloma cell lines, indicating that hypoxia activates autophagy. However, under hypoxia, these changes were canceled by HK2 knockdown. We confirmed that the number of autophagosome were significantly decreased in HK2-knockdowned myeloma cells by electron microscopy analysis. These data suggested that HK2 is required for hypoxia-inducible autophagy in MM. Finally, we examined the effect of combined inhibition of HK2 and proteasome. In hypoxia, apoptosis by bortezomib was significantly increased in HK2-knockdowned myeloma cells when compared with control. Moreover, we found that the combination of 3-BrPA and bortezomib increased apoptotic cells in both normoxia and hypoxia. These results suggested that HK2-inhibition can induce apoptosis against MM cells with enhancement of sensitivity to proteasome inhibitors. (Conclusion) These results suggest that hypoxia induced HK2 promotes autophagy and inhibits apoptosis. Thus, the combination of proteasome inhibitors and HK2 inhibition may bring about a deep response against treatment resistant MM. Disclosures Ikeda: Nippon Shinyaku Research Grant: Research Funding. Takahashi:Bristol-Myers Squibb: Speakers Bureau; Eisai Pharmaceuticals: Research Funding; Pfizer: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Chug Pharmaceuticals: Research Funding; Ono Pharmaceutical: Research Funding; Novartis Pharmaceuticals: Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Asahi Kasei Pharma: Research Funding.

The purpose of this study was to investigate the interactions of itraconazole (ITCZ) with orally administered calcineurin inhibitors (CNIs) in Japanese allogeneic hematopoietic stem cell transplant (HSCT) recipients. Sixteen HSCT patients (8 patients each receiving tacrolimus or cyclosporine) were enrolled. An ITCZ oral solution was administered from day 30 after the initiation of ITCZ administration as a loading dose. Before the co-administration of ITCZ and CNI and 1 week daily thereafter, whole blood ITCZ and CNI (tacrolimus or cyclosporine) concentrations were measured in samples taken just before (C0h) and 2 h (C2h) after CNI administration. The median dose-adjusted C0h values of tacrolimus and cyclosporine on day 7 after the start of ITCZ co-administration were 5.6- and 2.7-fold higher, respectively, than the corresponding values obtained before the initiation of ITCZ treatment. On day 7 after ITCZ treatment, the mean single dosages of tacrolimus and cyclosporine were reduced to 33.7 and 66.5 % of the dosages before ITCZ co-administration, respectively, to adjust the CNI target concentration. Although ITCZ co-administration did not alter the dose-adjusted C0h values of tacrolimus in a patient with a CYP3A5*1/*1 allele, it did change this value of tacrolimus in patients with CYP3A5*3 alleles. However, in patients receiving cyclosporine, no such tendency was observed. The magnitude of the interaction between orally administered tacrolimus and ITCZ was significantly greater than that between cyclosporine and ITCZ. Prospective analysis of the CYP3A5 polymorphism may be important to ensure safe and reliable immunosuppressive therapy with tacrolimus in patients treated with ITCZ.

Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia. High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy. Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %. This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.

Background Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate ( S )-warfarin, and not the CYP3A4 substrate ( R )-warfarin, increased with itraconazole coadministration. Case A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200 mg/day) and was started on a warfarin dose of 2.0 mg/day. The plasma concentrations of ( S )- and ( R )-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of ( S )- and ( R )-warfarin were 341 and 605 ng/mL, respectively (INR 1.38). The concentration of ( R )-warfarin was not affected by itraconazole; however, the final ( S )-warfarin concentration had increased 7.3-fold. The ( S )-warfarin/( S )-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. Conclusions Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole.

We report a 47-year-old man with acute leukemia who survived a severe case of necrotizing fasciitis caused by Clostridium perfringens involving his right upper extremity. On day 5 after stem cell transplantation, progressive local tissue necrosis led to septicemia and disseminated intravascular coagulation. Early diagnosis and prompt initiation of appropriate therapy, including surgical debridement and broad-spectrum antibiotics, were crucial. A recombinant thrombomodulin might have not only resolved the coagulation problem but also prevented multiple organ failure associated with the systemic inflammatory response.

Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P=0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P=0.015). Moreover, previous studies have shown that the ABCG2 421C>A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C>A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.

Intravascular large B cell lymphoma (IVLBCL) is a rare type of non-Hodgkin lymphoma characterized by a disseminated intravascular proliferation of tumor cells in the lumina of small vessels. Although the kidney is one of the target organs of IVLBCL, it is extremely rare that lymphoma cells are localized only in the kidney. We report here a Japanese patient with kidney-limited IVLBCL. The patient presented with mild proteinuria and a good performance status without B symptoms at presentation. A renal biopsy showed large B cell neoplastic lymphocytes in the glomerular capillary lumina. Extensive systemic examinations showed no other organ involvement. The patient responded well to rituximab and anthracycline-based chemotherapy. A follow-up renal biopsy showed the disappearance of intraglomerular lymphoma cells with restoration of glomerular architecture. Within 20 months past the discontinuation of chemotherapy, no evidence of recurrence was observed. Although IVLBCL is commonly a fatal disease, favorable clinical courses were reported in some cases of IVLBCL, such as the cutaneous variant. To our knowledge, there are 8 reported cases of kidney-limited IVLBCL in the English literature. All 4 patients treated with intensive chemotherapy responded well to the treatment as our patient. We suggest that kidney-limited IVLBCL might be a distinct variant of IVLBCL.

The design criteria for SRC T-shaped and L-shaped beam-column joints utilizing mechanical anchorages are proposed. The design criteria are based on the formulation of the joint shear force demand at the ultimate strength of SRC beam or column bending as well as the joint shear force capacity. The specific features of the formulations include: (1) the influence of the variation of axial force in the beam on the joint force demand is considered for SRC L-shaped joint, similar to RC L-shaped joint proposed previously, (2) the influences of anchorage length of reinforcement and steel member on the joint concrete strength are considered in the formulation of the joint shear force capacity, similar to SRC exterior joint proposed previously. Proposed design criteria are verified through the experimental data on the 6 specimens of T-shaped and L-shaped beam-column joints.

Typical steel moment-resisting frame structures in the United States, similar to many super-high-rise framed-tube structures being constructed in Japan, have stiff beams and columns only around perimeters and often have none or few seismic beams inside the building. The lack of strength and stiffness of connections between perimeter frames and floors to support the out-of-plane behavior of perimeter frames may cause unstable behavior when perimeter frames are separated from the floors due to accidental or earthquake loading. This study analytically simulates progressive collapse when the attachment of perimeter frames to floors is lost and predicts the strength of the connections required to prevent progressive collapse during earthquakes.

In Architectural Institute of Japan (AIJ) standard for structural calculation of reinforced concrete structures and General Building Research Corporation (GBRC) design guideline for mechanical anchorage in reinforced concrete joints, development length of R/C sub-beam reinforcement into main-beam is specified as the value speculated by the required development length of main-beam reinforcement into beam-column joint. However, this adequacy is not verified by the experiments in the past. In this study, a number of experiments are carried out to identify the anchorage strength and required development length of R/C sub-beam reinforcement using mechanical and bent anchorages. Main parameters of experiments are type of anchorages, development length, concrete strength, and detailing of reinforcement. Consequently, design equations on required development length and the allowable stress of R/C sub-beam reinforcement are proposed and design examples are demonstrated.

This paper presents the results of a probabilistic evaluation of the seismic performance of 3D steel moment-frame structures. Two types of framing system are considered: one-way frames typical of construction in the United States and two-way frames typical of construction in Japan. For each framing system, four types of beam–column connections are considered: pre-Northridge welded-flange bolted-web, post-Northridge welded-flange welded-web, reduced-beam-section, and bolted-flange-plate connections. A suite of earthquake ground motions is used to compute the annual probability of exceedence (APE) for a series of drift demand levels and for member plastic-rotation capacity. Results are compared for the different framing systems and connection details. It is found that the two-way frames, which have a larger initial stiffness and strength than the one-way frames for the same beam and column volumes, have a smaller APE for small drift demands for which members exhibit no or minimal yielding, but have a larger APE for large drift demands for which members exhibit large plastic rotations. However, the one-way frames, which typically comprise a few seismic frames with large-sized members that have relatively small rotation capacities, may have a larger APE for member failure. The probabilistic approach presented in this study may be used to determine the most appropriate frame configuration to meet an owner's performance objectives. Copyright © 2008 John Wiley & Sons, Ltd.

Recent studies on systemic lupus erythematosus (SLE) revealed that microRNAs (miRNAs or miRs) were involved in its pathogenesis. However, only a limited number of miRNAs have been examined.We performed quantitative real-time reverse transcription-polymerase chain reaction analyses of peripheral blood mononuclear cells (PBMCs) obtained from 31 untreated SLE patients and 31 healthy subjects to examine the expression levels of miR-155, miR-17, and miR-181b, as well as those of activation-induced cytidine deaminase (AID) and interferon-α (IFN-α) messenger RNAs (mRNAs). We examined the relationship between miR-181b, AID, and IFN-α with a luciferase reporter assay.The expression levels of miR-155, miR-17, and miR-181b were significantly lower in SLE patients than those in healthy controls, whereas those of AID and IFN-α mRNAs were significantly higher in SLE patients than those in healthy controls. The expression levels of miR-155, miR-17, and miR-181b inversely correlated with those of AID and IFN-α mRNAs in SLE patients. The results of the luciferase reporter assay revealed that miR-181b negatively regulated AID and IFN-α.The results of the present study demonstrated for the first time that there is a differential expression and inverse correlation between the levels the miR-155, miR-17, and miR-181b and target molecules, AID and IFN-α mRNAs, in PBMCs of untreated SLE patients. These alterations may contribute to the pathogenesis of SLE.

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct peripheral T-cell lymphoma entity exhibiting peculiar clinical features and poor prognosis. Its clinical characteristics and prognostic factors are not well established. To clarify the clinical characteristics and prognostic features of AITL, we conducted a multicenter, retrospective study. Fifty-six patients were enrolled. The median patient age was 68 years. Immunohistochemical examinations of tumor cells showed positivity for CD10 and T-cell markers, and chromosomal examination detected several types of abnormalities. More than 80 % of patients show advanced disease at diagnosis and poor prognostic scores. A high proportion of patients showed accompanying B symptoms, splenomegaly, and hepatomegaly at diagnosis. The 5-year overall survival (OS) rate was 48 % and progression-free survival was 25 %. Univariate analysis revealed higher age, fever, poor performance status, anemia, and low albumin level to be poor prognostic factors for OS. In addition to these factors, both IPI and PIT were also predictive of OS. Multivariate analysis indicated only a low level of serum albumin to be a significant prognostic factor for OS. Serum albumin may be one of the important prognostic factors for AITL. Further investigation is needed to confirm these results.

Three-dimensional nonlinear dynamic time-history analyses of a three-story steel moment-resisting frame designed according to the Uniform Building Code for Los Angeles seismicity were carried out. Beams in both directions had moment connections to the hollow rectangular columns. Code drift limits, rather than code considerations for bidirectional horizontal shaking, governed the member sizes. It was found that design level shaking caused the structure to exceed story yield drifts in both directions simultaneously and significant column yielding occurred above the base. Shaking in the direction orthogonal to the main shaking direction increased drifts in the main shaking direction by 46 and 64% for the design level and near-fault records, respectively, indicating that 2D analyses would not estimate the 3D response well. Also, maximum horizontal seismic components of axial force in the corner columns and side columns were 4.87 and 5.30 times the code estimations, respectively. It was shown that by increasing the column strength above the present code levels, that drifts during near-fault shaking were significantly decreased. A methodology to encourage strong-column weak-beam behavior, and to more realistically estimate the column axial forces during design level shaking is described. Building structures in seismic zones in the United States have traditionally been designed to resist lateral force with seismic frames. Other frames, referred to as gravity frames, are designed to resist gravity forces only. This design ap- proach, with separate seismic and gravity frames, requires only a few expensive moment connections, the load path is easy to follow, and 2D frame analyses may be used to model 3D frame behavior. However, as a result of the 1994 Northridge earth- quake, fracture occurred at many welded beam-column con- nections in these moment-resisting steel seismic frames (Yang and Popov 1995). The occurrence of fracture was influenced by a large number of factors, including the use of large mem- ber sizes and large welds. The lack of redundancy in these frames (Roeder 1997) and the possibility of yield in gravity columns (Mattheis 1998) are also of concern. An alternative design method in which structures are de- signed as a 3D seismic frame with beams connected to the columns, with moment connections in both directions, has some advantages. It increases the redundancy, no columns are designed to carry gravity force only, and beam and weld sizes are smaller. While many more seismic connections are re- quired, all members contribute to the frame lateral stiffness and strength allowing drift limits to be met with less material volume. However, the possibility of undesirable behavior due to significant column bidirectional loading effects should be considered. A brief summary of considerations for column bi- directional loading effects in 3D steel moment-resisting frames due to bidirectional ground shaking is given herein. The Uniform Building Code (UBC) (ICBO 1997) states that bidirectional orthogonal shaking effects must be considered if a column of a structure forms part of two or more intersecting lateral-force-resisting systems and that ''the requirement that orthogonal effects be considered may be satisfied by designing such elements for 100% of the prescribed design seismic forces in one direction plus 30% of the prescribed design seis- mic forces in the perpendicular direction. The combination re- quiring the greater component strength shall be used for de- sign. Alternatively, the effects of the two orthogonal directions may be combined on a Square Root of the Sum of the Squares (SRSS) basis.'' (ICBO 1997). The SRSS procedure (Clough and Penzien 1993) is based on the assumption that superpo- sition of the actions due to loading in each direction indepen- dently may be combined to obtain the total response. Phase incoherency of response, which may result from ground mo- tions in each direction not being in-phase or from significantly different response periods in each direction, is also assumed. The 30% rule (ICBO 1997) is based on the following con- siderations (Mattheis 1998; Tagawa 2000) following the rea- soning of Clough and Penzien (1993). If the ratio of the re- sponse due to y-direction shaking divided by that due to x-direction shaking of equal magnitude is B, and if the shaking magnitude in the y-direction is a of that in the orthogonal x-direction, then the response due to y-direction shaking, R y, is related to that due to x-direction shaking, Rx ,a s

Background: It is known that gene expression patterns in tumor cells are heterogeneous even in the same individual, not only in solid tumors but also in hematological malignancies, including multiple myeloma (MM). MM is characterized by the accumulation of a population of malignant plasma cells within the bone marrow (BM) and microenvironment (endosteal and vascular niches). Hypoxic oxygen stress occurs in the microenvironment, leading to various epigenetic gene alterations. For instance, hypoxia lead to cell cycle arrest, glycolysis, epithelial-mesenchymal transition (EMT)-related machinery, drug resistance and immature phenotype decreasing expression of CD138 and IRF4. Recently, it is reported that a microRNA (miRNA) in exosomes of myeloma treated in hypoxia induces vessel formation and promotes survival of myeloma cells via upregulation of HIF-1. However, to the best of our knowledge, there have been no reports describing expression changes of miRNAs in myeloma cells during hypoxia. The aim of this study was to detect epigenetically regulated miRNA and essential targets that could be affected by hypoxia in MM. Methods: To identify hypoxia-induced miRNA(s) and their target gene(s), we conducted whole miRNA and mRNA microarray screening using myeloma cell lines (MM.1S, RPMI-8226, KMS12BM, KMS11, and U266) and primary samples (n=4) that were subjected to chronic hypoxia conditions (1% O2 for 48 hr). We purified CD38++ cells (CD38: a marker for activated B-cells and plasma cells) from primary samples, and then conducted functional analysis of target gene/proteins of identified hypoxia inducible miRNA. Results: We recognized a significant upregulation of microRNA-210 (miR-210) under chronic hypoxia. We explored target genes of miR-210 as well as downregulated genes by hypoxia comprehensively, and we found that five candidate genes including DIMT1, CIAPIN1, TTC13, ARMC1, and NOL12 by TargetScan program. Among these, 18S rRNA base methyltransferase DIMT1, which is necessary for the production of ribosome, was the most likely candidate target of miR-210 in myeloma cells because the product was only directly reduced by miR-210 transduction of myeloma cells. We confirmed significant upregulation of miR-210 and downregulation of DIMT1 in primary samples (n=15) cultured in hypoxia by q-RT-PCR. In the examination of the myeloma patient samples on several GEO data sets, we found that expression of DIMT1 increased significantly with disease progression, and that DIMT1 had a positive correlation of IRF4. Notably, immunohistochemical analysis revealed that DIMT1 was strongly stained at myeloma cells but not other BM cells including various lymphocytes. The knock down of DIMT1 for MM.1S, H929, and KMS11 cell lines lead to apoptosis and downregulation of IRF4. Interestingly, miR-210 transduction also reduces expression of IRF4. Furthermore, we found that pan-HDAC inhibitors (panobinostat and vorinostat) inhibit cell survival via downregulation of the DIMT1-IRF4 axis in myeloma cells. Conclusion: By screening for targets of hypoxia inducible miR-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM. Our results suggest that the master antiapoptosis regulator might be different between normoxia and hypoxia. In hypoxia, HIFs and/or the HIF-miR-210 axis may convert myeloma cells to an antiapoptotic phenotype. However, in normoxia, DIMT1 was highly expressed in myeloma cells and, herein, activation might convert myeloma cells to the antiapoptotic phenotype. Figure Figure. Disclosures Ikeda: Novartis: Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Toyama Chemical: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Fujimoto: Research Funding. Kitadate:Daiichi Sankyo: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Toyama Chemical: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Fujimoto: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Abe:Novartis: Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Toyama Chemical: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Fujimoto: Research Funding. Takahashi:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria, Research Funding. Tagawa:Kyowa Kirin: Research Funding; Otsuka: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Toyama Chemical: Research Funding; Fujimoto: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Background: Various types of histone deacetylase inhibitor (HDACi) are currently under development or being used for non-Hodgkin's lymphomas including cutaneous T-cell lymphoma (CTCL). However, there is little molecular-based evidence to support the proposed efficacy of HDACi against advanced CTCL or information on the possible pivotal target genes of HDACi. We have shown that a tumor suppressive microRNA (miRNA), miR-150 inhibits metastasis via combining "seed sequence" of messenger RNA of a chemokine receptor CCR6 in advanced CTCL (Blood 2014). Because HDACi yielded excellent outcome for treating advanced CTCL, HDACi might have a potential to reduce metastasis capability of CTCL via targeting miR-150 and CCR6. Indeed we previously showed that a tumor suppressive miRNA, miR-16 was epigenetically downregulated and HDACi restored its expression leading to induce cellular senescence or apoptosis in various T-cell lymphomas (Oncogene 2015). This led us to consider that HDACis might upregulate variety of tumor suppressive miRNAs and there might be deep association of restoration for some critical gene(s) or/and miRNA(s) expression with HDACis in CTCL oncogenesis. In this study, we focused on to investigate relationship between miRNAs and HDACis, especially focused on to detect CCR6 associated miRNA(s). Methods: My-La, HH, and HUT78 (CTCL cell lines) were used for functional analysis because their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) shortened survival, owing to multiple metastases. To investigate changes of miRNA expression by HDACis, we conducted miRNA microarray analysis. To examine the expression of miR-150 in primary CTCL, we conducted a qRT-PCR analysis of samples from early (patch and/or plaque phase, n = 26) and advanced cases (tumor phase, n = 14). The control samples were obtained from patients with atopic dermatitis (AD, n = 18). Results: We demonstrated that pan-HDACis (vorinostat and panobinostat) inhibited migration of CTCL cells with downregulating CCR6. When we examined miRNA array against CTCL cells treated with and without respective HDACi, 161 miRNAs were commonly upregulated by pan-HDACis in My-La, HH and HUT78. Among these 161 miRNAs, 35 miRNAs that possesses seed sequence of CCR6 showed upregulation by HDACis treatment (e.g., miR-150, miR-96, miR-183, miR-185, miR-194, miR-320a, miR-371a, miR-3135b). To examine the miRNAs that has a functional role in CTCL metastasis, we conducted northern blot analysis of these candidate miRNAs in the CTCL cell lines and primary tissue samples. We found that the miR-150 was strongly expressed in normal CD4+ cells with downregulation of advanced CTCL samples, but the others showed very low or no expressions. In addition, the transduction of candidate miRNAs against the CTCL cells revealed that miR-150 downregulated CCR6 and inhibited their migration most efficiently. These data strongly suggest that the most likely target miRNA of the pan-HDACis in metastasis inhibition was the miR-150 in the metastatic CTCL. To examine whether there was a change in miR-150 expression during disease progression of primary CTCL, we conducted a qRT-PCR analysis of samples from early and advanced cases. The qRT-PCR demonstrated that the expression of miR-150 was significantly lower in the advanced specimens than it was in samples from patients with AD. The miR-150 levels did not significantly differ between the early and the AD specimens, but a significant difference was detected between the early and advanced specimens. These results suggest that miR-150 expression declines with disease progression in CTCL. Finally, we conducted in vivo experiment to examine whether miR-150 indeed inhibit tumor metastasis. We demonstrated that administration of miR-150 against CTCL model mice led to prolong their survivals. Conclusion: miR-150 and CCR6 are essential targets of pan-HDACi in advanced CTCL. Our results provide rational reasons for using pan-HDACi against metastatic CTCL. Furthermore, these results suggest that miR-150 could be not only powerful biomarker for molecular diagnosis, and predictive of metastasis, but also novel therapeutic molecule in advanced CTCL. Disclosures Kitadate: Daiichi Sankyo: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Toyama Chemical: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Fujimoto: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Abe:AsahiKasei: Research Funding; Chugai: Research Funding; Otsuka: Research Funding; Kyowa Kirin: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Eisai: Research Funding; Toyama Chemical: Research Funding; Fujimoto: Research Funding. Ikeda:AsahiKasei: Research Funding; Chugai: Research Funding; Otsuka: Research Funding; Kyowa Kirin: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Eisai: Research Funding; Toyama Chemical: Research Funding; Fujimoto: Research Funding. Takahashi:BMS: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Tagawa:Daiichi Sankyo: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Toyama Chemical: Research Funding; Fujimoto: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

A 44-year-old woman was admitted with generalized lymphadenopathy, which was diagnosed as angioimmunoblastic T-cell lymphoma (AITL). The patient showed autoimmune hemolytic anemia (AIHA), polyclonal hypergammaglobulinemia and a high antinuclear antibody titer. Moreover, a human immunodeficiency virus (HIV)-1/2 screening test using the particle agglutination method was reactive. After chemotherapy for AITL, the AIHA was eliminated, and the false-positive HIV results were no longer detected. Autoimmunity associated with AITL is the likely cause of the cross-reaction with HIV and the AIHA. It is important to recognize that the cross-reaction with HIV can be a potential complication in AITL as well as AIHA.

Stenotrophomonas maltophilia is increasingly emerging as a multiresistant pathogen in the hospital environment. In immunosuppressed patients, this bacterium may cause severe infections associated with sepsis and multiple organ dysfunction. We report on a 57-year-old woman treated with intensive chemotherapy for non-Hodgkin lymphoma who developed severe neutropenia, hemorrhagic pneumonia, and acute respiratory failure, which led to her death within 36 h of onset of pneumonia. Postmortem examination revealed bilateral extensive intraalveolar hemorrhage associated with severe infection by the gram-negative bacterium Stenotrophomonas maltophilia. In vitro susceptibility testing showed resistance to carbapenem, cephalosporines and aminoglycosides, but sensitivity to minocycline, ciprofloxacin, levofloxacin, and trimethoprim/sulfamethoxazole (cotrimoxazole). Early diagnosis and adequate antibiotic treatment were difficult, as the clinical course was rapid and fulminant, and this bacterium is resistant to multiple antibiotics. To improve prognosis in such cases, it will be necessary to develop an effective prophylactic strategy for high-risk patients.

We have developed a method that cells exhibiting typical dendritic cell (DC) characteristics are generated from human CD34(+) cells and phagocytose cogenerating erythroid progenitor cells in the presence of tumor necrosis factor-alpha (TNF-alpha), interleukin-3, stem cell factor and erythropoietin. Using this system, we titrated the effects of TNF antagonists, etanercept and infliximab, on TNF-alpha activity. We found that 1 microg/ml etanercept dramatically inhibited the generation of CD11c(+) cells accompanying with a complete recovery of the generation of erythroid progenitors. Infliximab at 200 microg/ml exhibited a similar effect to that observed for etanercept. The delayed addition of etanercept to this culture system at day five resulted in significant inhibitory effects on the generation of CD11c(+), CD4(+) and CD86(+) cells. These results indicate that TNF antagonists administered at a concentration that is achievable in vivo, neutralize the biologic effects of TNF-alpha in generating CD11c(+) cells and that a delay in the administration of these antagonists for as long as 5 days partially inhibits the biologic activity of TNF-alpha. These findings may contribute to a great understanding of anti-TNF therapy in patients with an overproduction of cytokines such as hemophagocytic syndromes.

Inelastic dynamic time-history analyses of nine steel frames were performed to understand effect of ground motion characteristic on structural response. Particular ground motion characteristics studied were the effect of near-fault ground shaking, soft-soil shaking and vertical shaking. Record frequency content and magnitude effects were also investigated. It was found that near-fault strike-normal records caused demands as high as 6.7%, residual displacements were approximately 52% of the peak inelastic displacements, and the SRSS method for predicting the maximum increase in column axial force for simultaneous vertical and horizontal shaking was non-conservative due to frame inelasticity. Soft-soil records increased displacements of a 3 story frame by up to 56% above those from design level motions. Drifts did not increase linearly with increasing earthquake ground acceleration and showed significant variation depending on the earthquake record. Changing the record frequency content while maintaining the spectral response at the fundamental period of the structure affected the story in which peak drift demand occurred.

Abstract 4921 Introduction: Lenalidomide, a novel therapeutic agent, has been found to be effective for the treatment of relapsed or refractory myeloma. However, the ideal lenalidomide dose to obtain sufficient therapeutic efficacy without causing hematologic toxicity is yet to be determined. Although Dimopoulos et al. reported that the initial lenalidomide dose can determined on the basis of renal function (i. e., creatinine clearance) and peripheral blood cell counts (namely, neutrophil and platelet counts), dose adjustments, particularly after drug administration, were necessary in some cases because of interindividual differences in pharmacokinetics. We believe that it might be possible to determine the ideal dose by measuring the plasma concentration of lenalidomide. Purpose: We aimed to develop an equation for the predicted total area under the observed plasma concentration–time curve (AUC) of lenalidomide and to set the ideal lenalidomide dose in patients with multiple myelomas by using only 1 or 2 sampling points. Methods: Twenty-one myeloma patients treated with lenalidomide according to the dose recommended by Dimopoulos et al. were enrolled in this study after obtaining written informed consent. Plasma concentrations of lenalidomide from samples obtained just prior to and 1, 2, 4, 8, and 12 h after oral administration of lenalidomide were analyzed using high-performance liquid chromatography (HPLC) (Figure A). Pharmacokinetic analysis of lenalidomide was carried out with a standard non-compartmental method using WinNonlin (Pharsight Co., CA, version 4. 0. 1). The AUC0–24 was calculated using the linear trapezoidal rule. Results: The plasma concentrations of lenalidomide at 2 and 4 h (C2h and C4h, respectively) after its administration were highly correlated with the AUC0–24 value for lenalidomide. The correlation observed between the measured and predicted AUC0–24 values for lenalidomide by using only the C2h and C4h sampling points in the equation (predicted AUC0–24 = 2. 0·C2h + 6. 8 ·C4h +55. 3) is shown in Figure B. The coefficient of determination between the predicted and measured AUC0–24 values was 0. 9213 (P < 0. 0001). In 4 patients for whom the drug was discontinued or administered at a lower dose because of the development of hematologic toxicity in a subsequent course of therapy, the measured AUC0–24 values were significantly higher than the corresponding values in 17 patients who continued to receive lenalidomide (1162 ng·h/ml vs. 646 ng·h/ml, P = 0. 004). Moreover, the results of receiver-operating characteristic curve (ROC) analysis of best sensitivity (100%) and specificity (94. 1%) showed that the ideal AUC0–24 of lenalidomide could be set below 940 ng·h/ml to avoid hematological toxicity. The area under the ROC curve was 0. 985 +-0. 023. Conclusion: The predicted AUC0–24 value might be a new indicator for the management of lenalidomide therapy. In this study, the threshold predicted AUC0–24 values suggested that 4 of 21 patients (19%) should have received a lower initial dose than that recommended by Dimopoulos, et al. It is possible to adjust the ideal dose by using the equation for AUC0–24 with the C2h and C4h values in a test before lenalidomide therapy is actually initiated. Therapeutic drug management (TDM) of lenalidomide can be performed by establishing the minimum effective concentration and the minimum toxic concentration in a large prospective study in the future. These findings should provide economic benefits and facilitate personalized medicine in myeloma therapy with lenalidomide. Disclosures: No relevant conflicts of interest to declare.

Abstract 1807 Dasatinib (DA) is approved for use in imatinib-resistant or intolerant chronic myeloid leukemia (CML)/Philadelphia-positive acute lymphoid leukemia (Ph+ALL) and may also be useful for central nervous system (CNS) leukemia accompanied with CML/Ph+ALL; however, little is known about the relationship between DA pharmacokinetics and its ability to penetrate the blood-brain barrier. Consequently, we measured DA plasma and cerebrospinal fluid (CSF) levels by high-performance liquid chromatography in 20 samples obtained from 11 DA-treated patients (seven Ph+ALL and four lymphoid crisis CML). DA was detected in 10 CSF samples from five patients who were treated with 100 mg QD of DA (CSF C4h of detectable group; 3.526±2.604 ng/mL, 1.11–7.95 ng/mL), which was above the IC50 level for wild type BCR-ABL positive leukemia cells in vitro (0.8 nM = 0.39 ng/mL). However, DA was not detected in 10 CSF samples from 7 patients (CSF C4h of non-detectable group; Disclosures: No relevant conflicts of interest to declare.