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Regioselective mono and dis-chloromethylation of cavitands have been prepared as an intermediate of a new cavitand derivative. Mono- and bis-aza-15-crown-5 modified cavitands ( 4 and 5 , respectively) have been obtained from mono- and bis-chloromethylated cavitands, respectively. The metal binding properties of native cavitand ( 1 ), 4 and 5 were studied by 1 H-NMR and UV-Vis spectroscopy.

In the present study, we assessed the effects of commercially pure titanium (cpTi) by anodic oxidation and hydrothermal treatment (SA-treated cpTi) on osteoblastic differentiation and interfacial bone formation through parallel in vitro and in vivo investigations. Osteoblast cells were cultured on SA-treated cpTi disks for 5, 7, 10, and 14 days. Bone matrix mineralization was assessed by EPMA. The levels of collagen I, alkaline phosphatase, osteocalcin, osteopontin, bone sialoprotein, and β-actin mRNA were analyzed using RT-PCR. In addition, SA-treated cpTi implants were placed in the mandibles of beagles for 14 days, and then examined histologically by light microscopy. Widespread Ca and P signals were observed early in the in vitro culturing period, and mRNA expression was up-regulated in cells that were in contact with the SA-treated cpTi. The bone-to-implant contact formed at the mandible SA-treated cpTi implant sites involved direct contact of the implant with the surrounding bone tissue. These results demonstrate the potential of SA-treated cpTi surfaces for enhancing surface-specific expression of osteoblastic phenotypes and for inducing changes in bone matrix gene expression.

This case report presents the robotically assisted multivessel minimally invasive direct coronary artery bypass grafting (MIDCAB) technique using the bilateral internal thoracic arteries. A 54-year-old man with multivessel coronary artery disease was considered eligible for a robotically assisted myocardial revascularization. The bilateral internal thoracic arteries were harvested completely in a totally skeletonized fashion through three 1-2-cm-long incisions on the left thoracic wall. A small left anterior thoracotomy was then performed. The left internal thoracic artery was anastomosed to the left anterior descending coronary artery, and the composite radial artery graft from the right internal thoracic artery was sequentially anastomosed to the first diagonal branch, the obtuse marginal branch, and the distal right coronary artery on the beating heart without cardiopulmonary bypass. The harvesting time of the grafts was 66 min, and the total operative time was 5 h 58 min. Postoperative angiography revealed that all grafts were widely patent. The postoperative course was uneventful, and the patient was discharged 10 days after the operation. Robotically assisted MIDCAB using the bilateral thoracic arteries is a safe and effective means of myocardial revascularization for patients with multivesssel disease. (Circ J 2007; 71: 1496 - 1498)

partial, PR (dFLC decrease > 50%) and no response (NR). Patients with baseline and day 100 post-transplant FLC among the CIBMTR cohort were the subjects of this study. Baseline characteristics were assessed. Progression free and overall survival (PFS, OS) were assessed based on the 2012 criteria using the KaplanMeier method. Results: Of 1536 patients, FLC data was available in 104, from 28 North American centers. Median age at transplant was 57 years (Table). Cardiac involvement was reported in 40%; 13% had 4/> organs involved. Majority of patients (71%) had no prior therapy. Day 100 responses were: CR (13), VGPR (65), PR (15) and NR (11). Median follow up was 50 months with 18 deaths (15 from AL). Kaplan-Meier curves for PFS and OS (figure) showed that patients with CR had the best outcomes followed by VGPR. Patients with PR and NR appeared to have equally worse outcomes. Upon combining CR/VGPR versus PR/NR responses, there was a significant difference in OS (p 0.005). Conclusions: In this highly selected AL cohort from a multi-institutional transplant registry, we validate the 2012 criteria. Patients with CR/VGPR have excellent outcomes compared to those with PR/NR. Figure Progression-Free Survival PO-175 The incidence and clinical features of HBV reactivation in multiple myeloma patients treated with novel agents and/or ASCT: a retrospective multicenter study in Japan Y. Tsukune, M. Sasaki, Y. Yahata, H. Tamura, A. Onodera, M. Koike, S. Ito, Y. Ishida, Y. Imai, J. Tanaka, A. Isoda, M. Matsumoto, S. Tanosaki, J. Hua, M. Hagihara, H. Sugimori, T. Odajima, N. Komatsu Department of Hematology, Juntendo University School of medicine; Division of Hematology, Nippon Medical School; Department of Hematology, Juntendo University Shizuoka Hospital; Department of Medical Oncology, Iwate Medical University School of Medicine; Hematology/Oncology, Iwate Medical Department of Hematology, University School of Medicine; Department of Hematology, Tokyo Women’s Medical University; National Hospital Organization Hishigunma Hospital; Department of Hematology, The Fraternity Memorial Hospital; Department of Hematology, Eiju General Hospital; Daito Bunka University. Graduate School of Sports and Health Science, Dept. of Preventive Medicine; Daito Bunka University School of Sports and Health Science, Faculty of Health Science Background: An estimated 2 billion people worldwide have been or are currently infected with hepatitis B virus (HBV), HBV seroprevalence is particularly high in Eastern Asia. HBV reactivation during or after immunosuppressive or cytotoxic therapy has been reported not only in HBsAg positive patients but also in some patients with resolved HBV infection who are negative for HBsAg but seropositive for anti-HBc and/or anti-HBs. Antiviral therapy initiated after hepatitis onset is often insufficient to control HBV reactivation and may lead to death from fulminant hepatitis. In the era of novel agents (bortezomib, thalidomide, and lenalidomide), there have been few reports about HBV reactivation in multiple myeloma (MM) patients and the standard prophylaxis strategy for hepatitis is yet to be established. Patients and Methods: Between January 2006 and June 2014, 99 symptomatic myeloma patients with HBsAg positivity or resolved HBV infection who were treated with novel agents and/or autologous stem cell transplantation (ASCT) were included. Data analyzed included age, gender, M-protein, stage (Durie-Salmon stage, international staging system), laboratory findings, treatment and outcomes using questionnaires. Results: One of 9 HBsAg positive patients developed hepatitis. Among 90 MM patients with resolved HBV infection, HBV reactivation occurred in 15.8% (3 of 19 patients) in the ASCT group and 7.8% (5 of 71 patients) in the non-ASCT group, after 64.5 (7-140) months from the start of chemotherapy; none of them developed hepatitis by means of monitoring HBV DNA levels monthly and administering entecavir. In 5 of these 8 cases, HBV reactivation was noted during bortezomib administration. HBV reactivation has no significant association with age, gender, stage, laboratory findings, and treatment. Conclusion: Since the introduction of rituximab, HBV reactivation has been reported in some malignant lymphoma patients with resolved HBV infection who received rituximab and steroid containing regimen. In the era of novel 15th International Myeloma Workshop, September 23-26, 2015 e183

The arterial wall injury associated with arterial graft implantation causes smooth muscle cells (SMCs) in the media to migrate and proliferate in the intima at the graft-artery junction resulting in anastomotic intimal hyperplasia (AIH). An important step in devel oping a small-diameter prosthesis may be to stimulate endothelialization and thereby inhibit AIH. In this study, we investigated the effect of coacervated and crosslinked α-elastin on proliferation of SMCs and endothelial cells (ECs) in vitro. Coacervation is an important step in the conversion of proelastin to make an elastin fiber in vivo. SMCs and ECs were prepared from porcine aortic media and endothelium, respec tively. SMCs and ECs (three to five passages, 4 x 10 4 cells/well) were seeded onto 12 well plates, coated and crosslinked with 0 or 10 mg/mL of coacervated α-elastin. After the 1st, 2nd, or 3rd day of cultivation, proliferation was assayed by scintillation counting of [3H]-thymidine incorporation. For the 4th day only, 0, 0.1, 1, 10 mg/mL concentration of coacervated α-elastin was coated and crosslinked. (continued on next page) SMC proliferation (1st, 2nd day: p These results suggest that coating and crosslinking a coacervated α-elastin into the structure of arterial prosthesis may inhibit AIH and stimulate endothelialization.

女性の生理的に起こりうる全身的変化として閉経がある。この生理的なホルモン分泌の減少期が歯周疾患の進行に与える影響を調査する目的で, 閉経前と閉経後の女性歯周疾患罹患患者を被験者として, 臨床パラメーターと歯槽骨吸収量とを比較した。被験者総数は233名 (閉経前群125名, 閉経後群108名) であり, 全身疾患および歯周治療の既往がなく, 咬合性外傷, 若年性歯周炎と診断されたものは除外した。女性歯周病患者各群は閉経前群と閉経後群に, 閉経後群は閉経1～5年群, 閉経6～10年群および閉経11年以上群に分類した。さらに男性歯周病患者106名を対象群とした。被験者は10年ごとの年齢層, 閉経後年数, 歯周疾患進行度により分類した。臨床パラメーターとして現在歯数, プラークコントロールレコード, プロービングによるポケット深さ, Gingival Index, 動揺度, Gingival Bleeding Indexを測定し, さらに歯槽骨吸収量をデンタルX線写真を用いて測定した。歯槽骨吸収量および臨床パラメーターは女性患者の閉経前後群および男性患者群とを比較した。その結果, 閉経前群と比較して閉経後群が歯槽骨吸収量は大きく, 前歯部に閉経後歯槽骨吸収量が大きかった。閉経後群の女性を同年齢層の男性患者群と比較すると, 閉経後問もない50歳代で歯槽骨吸収量が有意に大きくなったことから, 女性の歯周疾患患者における歯槽骨吸収量の増加には閉経というホルモン分泌の激減する全身的変化の影響が考えられた。

Background: This study was performed to investigate the diagnostic accuracy of intraportal endovascular ultrasonography (IPEUS) in assessing vascular invasion by biliary tract cancer. Methods: A prospective study of 31 consecutive patients with biliary tract cancer was performed. All patients underwent surgery. The sonographic criterion for right hepatic artery invasion was interruption of the hyperechoic layer or encasement by tumor. The sonographic criterion for portal vein invasion was obliteration of the echogenic band of the portal vein. IPEUS findings were confirmed by surgical exploration and pathologic examination of resected specimens. Results: Right hepatic artery invasion was confirmed in resected specimens in seven patients and by operative findings in four patients. Portal vein invasion was confirmed in resected specimens in six patients and by operative findings in five patients. For diagnosis of right hepatic artery invasion, the sensitivity, specificity, and overall accuracy of IPEUS were all 100%; respective values were 63.6%, 84.2%, and 76.7% for angiography. For diagnosis of portal vein invasion, the sensitivity, specificity, and overall accuracy of IPEUS were 100%, 95%, and 96.8%, respectively. The corresponding values were 63.6%, 89.5%, and 80% for portography and 54.5%, 85%, and 74.2%, respectively, for CT. Conclusion: IPEUS will improve the assessment of vascular invasion at the hepatic hilum by biliary tract cancer. (Gastrointest Endosc 1998; 47:33-41.)

In this study, we evaluated the safety and efficacy of the percutaneous vascular surgery device (Prostar) for sealing the femoral artery puncture site after coronary interventions. We also compared the results with Prostar (n = 167) and conventional manual compression methods (n = 50) in a nonrandomized fashion. The average time to hemostasis in the Prostar system group was 13.5 minutes, versus 36.6 minutes in the compression group. The average time to ambulation was 2.2 hours in the Prostar system group, versus 17.8 hours in the manual group. Bleeding was observed in 1.2% of the subjects in the Prostar system group, versus 12% in the manual compression group. One emergency surgery was required in the manual compression group, whereas no surgical intervention was required in the Prostar group. We conclude that the Prostar system for percutaneous vascular closure appears to be a safe technique for achieving an early hemostasis and ambulation after coronary intervention.

We have investigated a neural network classifier based on CT findings extracted by a radiologist for the differential diagnosis between the pancreatic ductal adenocarcinoma and mass-forming pancreatitis, and compared its classification performance with that of Bayesian analysis, Hayashi's quantification method II, and radiologists. The three computerized classification methods were designed to classify categorized CT findings extracted by a radiologist, and were trained and tested on 71 cases. There was comparable performance between the neural the network, the Bayesian analysis, Hayashi's quantification method II, and the radiologists, in classifying pancreatic carcinoma and inflammatory mass.

〈目的〉急性心筋梗塞に対する再灌流療法後の成否をホルター心電図のST変化の推移により評価した.〈方法〉発症12時間以内に血栓溶解療法を施行し, 梗塞責任冠動脈がTlMl2以上を血流改善を得た48例を再疎通成功群とした.血栓溶解療法施行直後よりホルター心電図を用いて24時間におけるST変化の推移を観察した.〈結果〉再疎通成功群の22.9%にホルター心電図上のST変化が認められた.1週間後のホルター心電図上のST変化出現率は再疎通成功群では直後22.9%から1週間後3%と減少した.ST変化のタイプをST変化無し, resolution type, transient tyaeの3群に分けて退院時左心機能を比較検討すると, ST変化無しの群では左室駆出率57.4±13.2%, resolution type ST変化群は72.4±8.8%を示し, transient type ST変化群は66.1±12.4%を示した.再閉塞はresolution type ST変化群は認めず, transient type ST変化群では25%に, reelevation type ST変化群では50%に認めた.〈結語〉血栓溶解療法後再疎通成否, 梗塞責任冠動脈の開存状況, 左心機能保持効果の推測にホルター心電図を用いたST変化推移の検討は有用であった.

毛束反復回転式電動歯ブラシ (電動歯ブラシ) のプラーク除去効果および使用感について手用歯ブラシとの比較を行った。被験者は健康歯肉および軽度歯肉炎と診断された成人30名 (平均年齢26.8歳) とし2群 (A, B: 15名ずつ) に分けた。両群とも実験開始1週間前に電動歯ブラシの使用法およびバス法を指導し, 同時にプラークフリーとした。7日間の通常のブラッシング後, 実験期間1において, 被験者は6日間の手用歯ブラシあるいは電動歯ブラシによるブラッシングを行い, その後1日ブラッシングを停止させ, 7日目に同じ歯ブラシによる十分なブラッシングを行い, その前後のプラーク付着量を6歯について測定した。再びプラークブリーにし, 7日間の通常のブラッシング後, 実験期間IIにおいて, 被験者は実験期間1と別の歯ブラシを用いてブラッシングを行い, その後実験期間Iと同様にプラーク付着量を測定した。また実験期間終了後, 各被験者に対しブラッシングによる軟組織への損傷の診査および各歯ブラシの使用感に関するアンケートを実施した。その結果, 1) 電動歯ブラシは手用歯ブラシと比較して各群とも歯種, 歯面 (とくに隣接面で) 共有意にプラーク除去効果に優れていた。2) 両群間における各歯ブラシの使用順序によるプラーク除去効果に差を認めなかった。3) アンケートによる電動歯ブラシの使用感も良好であり, 軟組織の損傷は実験期間中認めなかった。これらの結果から本電動歯ブラシのプラーク除去効果が示された。

Non-invasive quantitative measurements are useful for clinical study as these are simple and pain-free procedures. A new non-invasive semi-automatic quantitative measurement method, the improved brain uptake ratio (IBUR) method using 99m Tc-ECD SPECT, has recently been reported. If an automatic ROI setting algorithm could be developed to determine the input function for the IBUR method, analysis of regional cerebral blood flow (rCBF) can be completed within a few min without recourse to complex techniques, through a fully automatic rCBF analysis program. The purpose of this study was to develop an automatic input function determination program for 99m Tc-ECD non-invasive cerebral blood flow quantification and to confirm the feasibility of use of this program. The images of 15 consecutive patients who underwent both 99m Tc-ECD chest RI angiography and SPECT examinations were used for development of the automatic arterial input function program. The images of 69 consecutive patients were used for validation of the program. The coincidence ratio between the ROI automatic method and the manual setting method was 98%. The mean difference in the ROI location was ±6.4 mm in the X direction and ±8.6 mm in the Y direction. Individual rCBF values obtained using these independent techniques were also reasonably well correlated ( r = 0.95). The total time for the IBUR analysis using the automatic method is 2–3 min as compared to 20–30 min for the current analysis method. This technique improves the throughput of nuclear medical examinations.

Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of patients with aggressive ATL remains poor because ATL cells acquire resistance to conventional cytotoxic agents. Therefore, development of novel agents is urgently needed. We examined the effects of resveratrol, a well-known polyphenolic compound, on cell proliferation and survival of HTLV-1-infected T-cell lines, MT-2 and HUT-102. We found that resveratrol suppressed cell proliferation and induced cell death of MT-2 and HUT-102 cells. Immunoblot analysis showed inhibition of myeloid cell leukemia sequence (Mcl)-1 and cellular inhibitor of apoptosis protein (cIAP)-2 expression as well as signal transducers and activators of transcription (STAT) 3 phosphorylation at Tyr(705) and Ser(727) in resveratrol-treated cells. We also observed cleavage of caspase-3 and poly(ADP-ribose) polymerase in resveratrol-treated cells, indicating that resveratrol induces caspase-dependent apoptosis in MT-2 and HUT-102 cells. In addition, the STAT3 inhibitor S3I-201 not only induced cell growth arrest and cell death but also activated caspase-3 in MT-2 and HUT-102 cells, indicating that STAT3 may be a therapeutic target for ATL. These results suggest that resveratrol presents a potent anti-proliferative effect in part via the suppression of STAT3 phosphorylation and Mcl-1 and cIAP-2 expression in HTLV-1-infected T cells. Resveratrol merits further investigation as a potential chemotherapeutic agent for ATL.

(INTRODUCTION) Several clinical studies have revealed that dasatinib demonstrated deep and fast responses. We report a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study). (PATIRNTS AND METHODS) Between July 2011 and June 2013, a total of 79 consecutive patients with CML-CP received 100 mg dasatinib daily as a first-line therapy. Treatment was continued until disease progression or until toxicity became unacceptable. The primary end-point was the rate of major molecular response by 12 months. Secondary end-points included the rate of complete cytogenetic response, rate of molecular responses with a 4.5 log reduction (MR4.5) by 12 months, and adverse events. The median age was 62 years, ranging from 27 to 80 years. Patients older than 65 years comprised 41.7% of all patients. Two-thirds of patients (68.4%) were male. Nearly all patients were ECOG performance status 0. Most patients (83.6%) had low and intermediate Sokal scores. The BCR-ABL1 International Scale (BCR-ABL1 IS) in the peripheral blood was measured by the central laboratory center (BML, Tokyo, Japan). (RESULTS) The median BCR-ABL1 IS before therapy was 54.0% (7.8-230.2). Seventy patients (88.6%) received dasatinib therapy for 12 months. The median BCR-ABL1 ISs were 0.25 % at 3 months (range 0.0002-52.2 %, n =77), 0.03 % at 6 months (range not detected-29.2 %, n = 75) and 0.008 % at 12 months (not detected -0.86 %, n = 70). MMR rate was 77.2% (95% CI, 67.9-86.5 %) by 12 months. The rates of CCyR and MR4.5 by 12 months were 88.6% (95% CI; 81.5-95.7 %) and 35.4% (95% CI; 24.8-46.1 %), respectively (Figure 1). Multivariate analysis of MMR or MR4.5 by 12 months showed that female sex (odds ratio 1.1, P = 0.92, odds ratio 1.7, P = 0.35, respectively), low and intermediate Sokal score (odds ratio 0.9, P = 0.90, odds ratio 3.2, P =0.23, respectively), and BCR-ABL1 IS less than 54% at diagnosis (RR =odds ratio 0.8, P = 0.74, odds ratio 0.7, P = 0.55, respectively) were not significantly correlated with MMR by 12 months nor MR4.5 by 12 months (Table 1). However, patients who were more than 62 years old were significantly correlated with MR4.0 and MR4.5 by 12 months (odds ratio 2.8, P =0.04, odds ratio 3.5, P =0.01). Treatment-related all AEs were reported in 98.7% patients (78 of 79). Grade 3/4 non-hematologic AEs were observed in only a few cases. Lymphocytosis (more than 4x 109/L) was observed in 34.1% of patients, which was within grade 2. Only 9 patients withdrew the study because of adverse events (4 patients), ineffectiveness (3 patients), and others (2 patients). (DISCUSSION AND CONCLUSION) The incidence of lymphocyte predominance may depend on a history of previous cytomegalovirus (CMV) infection in CML-CP patients (Leukemia. 2011 25(10): 1587-97). Although the frequency of CMV-positive patients was unknown in this study, that of blood donors in Japan was almost positive in the ages with 60s or older. The median age of CML-CP patients in this study was 62 years. Therefore, we assumed that some immunological effects induced by dasatinib might have improved the clinical efficacy in Japanese CML-CP patients compared to those worldwide. Our phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed CML-CP in Japan revealed that the first-line dasatinib treatment of CML-CP leads to earlier achievement of MMR and MR4.5 with high safety. Elder age patients (>62 years) were significantly associated with achievement of MR4.5. Disclosures Shindo: Sysmex Corporation: Research Funding. Sakamoto:Yakult: Other: Remuneration; Takeda Pharmaceutical: Consultancy.

Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality in neutropenic patients with hematological malignancies (HEM) after chemotherapy. The risk for these infections is related to the intensity and duration of neutropenia, and varies from 2% to 40%. Mortality rates associated with documented IFIs are considerable, reportedly ranging from 30% to 60%. Empirical antifungal therapy is the standard care for neutropenic patients with HEM, who remain febrile despite broad-spectrum antibacterial treatment. Several antifungal agents including voriconazole (VRCZ) or liposomal amphotericin B (L-AMB) have been studied as empirical therapy for febrile neutropenia (FN). However, limited data are available concerning the efficacy of micafungin (MCFG) in FN patients with acute myeloid leukemia (AML). Methods: We conducted a randomized, cooperative group, open-label trial comparing MCFG (150 mg once daily) with L-AMB (2.5 mg/kg once daily) as a first-line empirical antifungal treatment for 102 hospitalized FN patients with AML (MCFG, 53; L-AMB, 49). The efficacy end point was a favorable overall response, as determined by a five-component end point according to the criteria of Walsh et al (N Engl J Med 2004; 351: 1391). Results: At the time of enrolment, there were no significant differences in the demographics or baseline characteristics between the two groups. The mean treatment duration for MCFG and L-AMB was 14.8 and 17.1 days, respectively. The efficacy rates of MCFG and L-AMB were not significantly different (58.5% vs. 44.9%, p = 0.1698*), evaluated based on: (1) successful treatment of baseline fungal infection (3/5cases (5.7%) vs. 0/1case (0%), p = 0.170*), (2) absence of breakthrough fungal infection (90.6% vs. 98.0%, p = 0.112*), (3) survival for ≥7 days after study completion (88.7% vs. 89.8%, p = 0.855*), (4) absence of premature study drug discontinuation due to poor efficacy or drug-related adverse events (67.9% vs. 75.5%, p = 0.396*), and (5) resolution of fever during neutropenia (66.0% vs. 55.1%, p = 0.258*). However, discontinuation due to drug-related adverse events occurred less frequently in the MCFG group (1.9% vs. 12.2%, p = 0.038*). In safety evaluation, adverse events of creatinine increase and hypokalemia were less often in the MCFG group than in the L-AMB group (9.4% vs. 26.5%, P=0.023*, 22.6% vs. 57.1%, P=0.0004*). *: Chi square test. Conclusions: MCFG was as effective as L-AMB, and better tolerated than L-AMB as an empirical antifungal therapy in FN patients with AML. Disclosures Ishida: Kyowa Hakko Kirin Co: Research Funding; Nippon Shinyaku Co: Research Funding; CHUGAI PHARMACEUTICAL CO: Research Funding; Astellas Pharma Inc.: Other: Astellas Pharma Inc. (Tokyo, Japan) supported this clinical study with a grant; the sponsor was not involved in the design of study, the enrollment of patients, the collection, analysis, interpretation of the data., Research Funding.

Background: Adult T-cell leukemia-lymphoma (ATL) is a rare and refractory malignancy of regulatory T /TH2 cell associated with human T-lymphotropic virus type I (HTLV-1). In recent years, the introduction of intensive chemotherapy, allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and mogamulizumab (anti-CCR4 antibody, which was approved in Japan in May 2012 for relapsed/refractory ATL, and in Dec. 2014 for newly diagnosed ATL) are expected to improve the prognosis of ATL. Meanwhile, the aging tendency of the ATL patient population has been recognized recently in Japan. Therefore, for the development of future treatment strategies for ATL, it is important to assess the therapeutic utilization and prognosis in patients with ATL not only in clinical trials but also in clinical practices. Aim: To report the current clinical features and outcomes of patients with ATL who were newly diagnosed during 2010-2011 from 114 hospitals in Japan. Methods: A questionnaire for each of 996 patients was sent to the hospitals, requesting information on treatment options and outcomes in detail. Statistical analysis was undertaken using Chi-squared tests to identify significant differences in the proportion, and using Kaplan-Meier curves to estimate the probability of overall survival (OS) with the log-rank test to identify significant differences in the probability, according to age, subtypes, and initial treatment. Results: We received 94.7% response rate from hospitals. Among 800 patients registered in this prognosis survey, 45 patients were not assessable for outcomes because of insufficient data, therefore, 755 (male 397, female 355, unknown 3) were included in the outcome analysis. The median age at diagnosis was 68 years old for all and the median follow-up time was 49 months for survivors. The distributions of ATL subtypes according to Shimoyama criteria were 382 (51%) for acute, 192 (25%) for lymphoma, 86 (11%) for chronic, and 95 (13%) for smoldering types, respectively. The median survival time and 2-year survival rate were: acute (n=377) (264 days, 24%), lymphoma (n=212) (293 days, 26%), chronic (n=71) (1,094 days, 56%), and smoldering (n=99) (1,900 days, 80%), respectively. Overall, the initial therapy-regimens used for aggressive ATL (acute and lymphoma subtypes) were VCAP-AMP-VECP-like regimen in 49%, CHOP-like regimen in 42%, and others in 9%. However, the utilization percentage of each option varied with age, VCAP-AMP-VECP-like regimen was used 68% of those aged 65 or younger but 32% of those over 65, respectively. CHOP-like regimen was used 29% for those aged 65 or younger but 52% for those over 65, respectively. Allo-HSCT for aggressive ATL was performed about 50% for those aged 55 or younger, 30% for those aged 56-65, but only 1% for those aged over 66, respectively. A total of 75 (10%) patients were treated with mogamulizumab. Fifty-six of them were treated with mogamulizumab after May 2012, when mogamulizumab was approved and generally adopted in Japan. When comparing the OS by pre- or post- general adoption of mogamulizumab, the 2-year OS was significantly worse in those treated after general adoption (18%) than those before (61%). When the response to initial chemotherapies was poor, the prognosis was worse regardless of treatment options, i.e., chemotherapy, allo-HSCT, and mogamulizumab. Response rate to initial chemotherapy differed by age, i.e., the older the age, the worse the response rate. Conclusion: This work highlights the difference in the treatment and the prognosis by age in patients with ATL in the current clinical practice in Japan. Intensive chemotherapy and allo-HSCT are not fully applicable for the elderly patients, who account for more than half of the ATL patients. Better strategies are required to improve clinical outcomes of the primary treatment, especially of the elderly ATL patients. Funding : This work was supported by Health and Labor Science Research Grant, Grant Number H26-ganseisaku-ippan-006. Disclosures Utsunomiya: Daiichi Sankyo Co., Ltd.: Speakers Bureau. Tobinai:Kyowa Hakko Kirin: Research Funding; Eisai: Honoraria, Research Funding; Abbvie: Research Funding; Chugai Pharma: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Mundipharma KK: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

In this report, PEM scanner using a Pr:LuAG scintillator crystal will be discussed. We have developed the PEM scanner with planer detectors which can change the angle and the distance depending on the condition of diagnosis. The planer detectors were composed of four units respectively and one unit consisted of a 20 × 64 pixels scintillator array optically coupled with three H8500 multi anode photomultipliers. As a scintillator Pr:LuAG was installed which possesses interesting properties such as a very fast decay time of 20 ns and a good energy resolution of 4.2 %. The Pr:LuAG pixel size was 2.1 mm × 2.1 mm × 15 mm and the BaSO4-type reflector was used for the array assembly. Based on this PEM system we have performed the clinical studies and compared with the images detected by the PET scanner. Because the spatial resolution of PEM is better than PET, advantages of PEM scanner were clearly shown.

A Positron Emission Mammograph (PEM) with a pair of planer detectors dedicated for breast cancer detection is developed under collaborations of Tohoku University, Kobe City Collage of Technology, and Furukawa Co., Ltd. It uses thin crystals made of a scintillator Pr:Lu3A15O12 (Pr:LuAG) of 2.1×2.1×15.0 mm in size combined with H8500 position sensitive Photo multi tubes (PMTs) from Hamamatsu. The PEM system is comprised of two opposing detectors that have 140×200 cm2 field of view (FOV). We present its basic architecture with fundamental performance, such as spatial resolution, time resolution, energy resolution, and data acquisition count rate. The Spatial resolution measured using a 22Na point sauce was found to be 1.1 mm FWHM for image planes parallel to the detector faces. Time resolution was 3.1 ns FWHM. And, energy resolution was 11.6 % FWHM (@511 keV) at the center of detector blocks. Coincident count rate was improved dramatically for optimizing energy windows level and implementation a new offset correction method.

Determination of the input function for the (99m)Tc-ethyl cysteinate dimmer brain uptake ratio ((99m)Tc-ECD BUR) method as a non-invasive quantitative measurement of cerebral blood flow measurement is of critical importance in order to improve the accuracy of this method. The input functions were experimentally obtained by setting the regions of interest (ROIs) in the ascending aorta, aortic arch, and descending aorta on the 49 chest RI-angio images. rCBFs by the BUR method with 3 input functions of the 6 cases were compared with those by the (123)I-iodoamphetamine (IMP) continuous arterial blood sampling method in order to determine the best location for the ROI of the input function. The input function of the ascending aorta was higher than those of the aortic arch and the descending aorta. The input functions of the aortic arch and the descending aorta decreased due to the origin of the three branches of the right brachiocephalic artery, left subclavian artery, and left common carotid artery. A good correlation was found in the regional cerebral blood flow (rCBF) values between the (123)I-IMP continuous arterial blood sampling method and the (99m)Tc-ECD BUR method with the input function of the ascending aorta. Therefore, the ascending aorta is the best location for the ROI of the input function for the (99m)Tc-ECD BUR method.

We isolated from soil 160 bacterial strains which are tolerant to high concentrations of oleic acid, and examined their ability to transform oleic acid to new fatty acid derivatives. One of the isolated strains, Alcaligenes sp. 5–18, produced several compounds from oleic acid: 3-hydroxyoleic acid, 3-hydroxyhexadecenoic acid, octadecadienoic acid, hexadecadienoic acid, and tetradecadienoic acid. These compounds are intermediates in the β-oxidation pathway of oleic acid, and their accumulation is probably due to defective β-oxidation of oleic acid in the microorganism. Neither hydroxy nor enoic derivatives of fatty acids with a carbon chain length shorter than 14 were produced.

The brain uptake ratio (BUR) method for the (99m)Tc-ECD SPECT, a non-invasive measurement method of rCBF, has been used in clinical practice in Japan, because it is simple to use. However, the accuracy of this method is limited, as it has problems in the determination of input function and the regression equation. The purpose of this study is to improve the BUR method by reconstructing the determination process of the input function and regression equation based on measurement of the rCBF by H (2) (15) O PET.The input function was obtained by setting the region of interest on the ascending aorta instead of the aortic arch. The 3DSRT algorithm was used to obtain the anatomically standardized rCBF, and developed a semi-automatic analyzing software using C++ in order to stabilize the repeatability of the improved BUR (IBUR) method. The regression equation for the IBUR method was obtained by the H (2) (15) O PET rCBFs in 15 patients with the arterial blood sampling method. All the measurements in this study were performed with the patient in the resting state.A good correlation was observed between the rCBF values measured by H (2) (15) O PET and the regional BURs measured by the IBUR method (r = 0.86, p 0.0001). The rCBF values were calculated for only 5 min using a semi-automatic analyzing software.The BUR method was improved by changing the location of the input function from the aortic arch to the ascending aorta based on arterial blood flow dynamics, and reconstructing regression equation based on the rCBF values obtained using H (2) (15) O PET. This finding indicates the potential clinical usefulness of this method.

To clarify the clinical outcome of peripheral T-cell lymphomas (PTCLs), we conducted a retrospective review comparing the outcomes of patients with PTCL (nodal peripheral T-cell lymphoma, unspecified, n=34 ; angioimmunoblastic T-cell lymphoma, n=12) to those with diffuse large B-cell lymphoma (DLBCL, n=48). All patients received CHOP-based chemotherapy without rituximab. PTCL patients presented at a more advanced clinical stage (91% vs. 65%, P

Nine acyclic polyethers incorporating oxygen, nitrogen and/or sulfur atoms were synthesized, which possess two heterocyclic groups at both ends of an ether chain, and metal ion extractabilities of these compounds were estimated using 1,2-dichloroethane - H2O system. On the solvent extraction of some transition metal ions as the nitrates, Ag+, Cu+ and Hg2+ were more effectively extracted with most of the reagents than the other metal ions. Addition of picrate ion into the aqueous phase of AgNO3 increased Ag+ extractability remarkably.

Purpose: To evaluate the technical quality and visibility of the biliary tree and pancreatic duct on magnetic resonance cholangiopancreatography (MRCP) images obtained with a single-breath-hold three-dimensional (3D) fast-recovery fast spin-echo (FRFSE) sequence in several different slice thicknesses. Materials and Methods: As a fundamental study, tubes of various inside diameters filled gadolinium solutions were acquired at 1.5 T in 3D-FRFSE. We observed error rate changes of volume inside the tubes and the visibility of thinner tubes. MRCP was performed at 1.5 T in 8 consecutive patients (4 men and 4 women, aged 22-58 years). Seven radiologists graded images obtained with each slice thickness in a blind fashion. Furthermore, we compared 1.4 mm slice thickness images with 1.8 mm slice thickness images in a continuous rating scale for the same patient. We assessed differences in technical quality, overall visibility, and six individual ductal segments of the biliary tree and pancreatic duct. Results: If slice thickness were thinner relative to diameter, the error rate would be closer to zero. But, when slice thickness was 0.8 mm, the error rate became clearly higher because of low intensity. In the fundamental study, we thought that the appropriate slice thickness is between 1.0 mm and 2.4 mm. The visibility of images of thinner tubes could be improved by having a thinner slice thickness. In particular, MRCP overall images generated from a 1.4 mm slice thickness were found to be significantly superior to those generated from a 1.8 mm slice thickness (p

A palmitoyl conjugate of an insect pentapeptide that occurs in diapausing insects causes a reversible cell-cycle arrest and suppresses mitochondrial respiration. This peptide compound also causes growth arrest in murine leukemic cell line expressing human gene Bcr/Abl and a farnesoyl peptide induces embryonic diapause in Bombyx mori. These results demonstrate that the insect peptide compounds can lead to the understanding of a common pathway in developmental arrest in animals and may provide a new peptidominetic analog in the development of biopharmaceuticals and pest management.

Nackenverletzungen, welche wahrend Autounfallen auftreten, konnen zu chronischen Symptomen, inklusive Nacken- und Schulterschmerzen, Muskelkater, Kopfschmerzen, Schwindel, verschwommenem Sehen und Gedachtnisverlust fuhren [11,31]. Die geschatzten jahrlichen Sozialausgaben belaufen sich auf 10 Milliarden Dollar in den USA und 10 Milliarden Euro in Europa [2, 12, 46]. Von Weichteilverletzungen der Halswirbelsaule wurde bei allen Kollisionsrichtungen berichtet, jedoch ist der Heckaufprall mit dem hochsten Risiko der Weichteilverletzung verbunden.

A method for determining half value layers (HVLs) of inverter-type X-ray equipment using a computed radiography (CR) systems was developed. This method is similar to the traditional method, where the air kerma (K) is measured using an ionization based dosimeter and increasing aluminum (Al) absorber thickness, but utilized an imaging plate (IP) and the sensitivity index (S number) of the CR system as the dosimeter and the dosimeter reading, respectively. The IP and the S number were calibrated using an ionization chamber having traceability to the National Standard Ionization Chamber. A modified version of the S number definition equation K = a × S − b was used to translate the S number to K values for X-ray beams produced using tube voltages ranging from 50 to 120 kV and additional Al filtration up to 2.5 mm. The coefficient ‘a’ varied depending on the beam quality, while the coefficient ‘b’ showed a constant value of 0.991. The HVLs in the range from 1.8 to 5.5 mm Al that were obtained with this method were in good agreement with those obtained with the traditional method, as uncertainties were between −7 and 4%. This method can be used to determine the HVLs of inverter-type X-ray equipment within an acceptable accuracy.

This study demonstrates images obtained by 90Y bremsstrahlung emission computed tomography (BECT), and characterizes the system performance of gamma cameras. 90Y BECT images of phantoms were acquired using a gamma camera equipped with a medium energy general purpose parallel-hole collimator. Three energy window widths of 50% (57–94 keV) centered at 75 keV, 30% (102–138 keV) at 120 keV, and 50% (139–232 keV) at 185 keV were set on a 90Y bremsstrahlung spectrum. The images obtained with three energy windows were reconstructed using filtered back projection (FBP) and ordered subsets expectation maximization (OSEM) methods. The images of the sum window were obtained by fusing the images of the 75, 120, and 185 keV windows. The OSEM method improved the full width at half maximum by 20% and the standard deviation by 9% compared with the FBP method. BECT displayed 90Y biodistribution and quantified 90Y activity. BECT images obtained with OSEM method using the 120 keV window showed the highest resolution and lowest uncertainty. The sum window showed the highest sensitivity, while its resolution was 10% inferior to that of the 120 keV window. One whole-body image can be taken over 100 min using the sum window. An absorber to cover the body surface reduced background by 30%. 90Y BECT imaging can be used for patient assessment without modifying current treatment procedures.

We have developed a simple technique for establishing high-quality intraoperative fluorescence imaging in off-pump coronary artery bypass grafting. The technique of transaortic injection of indocyanine green is an effective method of achieving clear fluorescence imaging and for evaluating the quality of graft anastomoses. We consider the images obtained with this technique to be equivalent to those obtained by conventional coronary angiography with selective enhancement of the graft.

The purpose of this study was to investigate the effects of different methods of brushing on plaque removal, using O'Leary's plaque Control Record during initial preparation. The results were as follows: 1. There were many 40-50 year-old patients and they showed a 63.0 percent first visit Plaque Control Record average. 2. Many of the patients entering the clinic had periodontal disease in mild stages. 3. In most cases the toothbrushing methods were the Rolling method and the Modified Stillman's method. Of the patients, 73.5% achieved Plaque Control scores at the 20 percent level. 4. Of the patients who had achieved a Plaque Control Record at the 20 percent level, half of the patients instructed to brush using the Rolling method had developed moderate forms of periodontal diseases, and half of the patients instructed to use the Modified Stillman's method had developed mild forms of periodontal disease. There is a close relationship between toothbrushing methods and the progression of diseases, and this shows that Plaque removal methods should be controlled.

歯肉の形態に影響を及ぼす因子としての主要な臨床所見の症状に着目し, それぞれの所見との関連性を検索した。その結果, 様々な歯肉形態め出現率に, 臨床所見の症状である歯周ポケット, 歯槽骨の吸収, プラーク, 歯石, 不良修復物等が影響し, 歯周疾患と歯肉形態には密接な関係があることが示唆された。各検査項目間の相関性の検討においてもcleft form以外で有為な相関性が認められた。これらの関連性を把握することは, 治療計画, 治療方法, 予後の推測等において重要な役割を果たすものと考えられる。

A system for taking static thyroid (99m)Tc images was devised by using multiple imaging plates (IPs) and a low-energy high resolution collimator. System spatial resolution of the IP systems and the gamma camera was determined by referring to standards set by the National Electrical Manufacturers Association. Sensitivity was represented by using lower detection limits (LDLs). The sensitivity and resolution of IP systems using 16 IP probes connecting two collimators and 9 IPs were determined by using a 20 ml thyroid phantom, and compared with the sensitivity of gamma cameras. The sensitivity of the IP systems increased in proportion to the number of IPs. The sensitivity and resolution of a probe using 6 IPs and a high resolution collimator were equivalent to or superior to the gamma camera for taking static thyroid (99m)Tc images. IP systems can be applied clinically as mobile static nuclear imaging devices. The performance of IP systems should be thoroughly investigated for combinations of various collimators and the number of IPs in order to verify their efficacy for imaging all organs.

Tolerogenic dendritic cells (DCs) may be valuable in transplantation for silencing immune reaction. Macrophage colony-stimulating factor (M-CSF)/IL-4 induces differentiation of cord blood (CB) monocytes into DCs (M-DCs) with tolerogenic phenotype/function. We assessed whether factors produced by tolerogenic DCs could modulate hematopoiesis. TGF-β1 added to CB M-DC cultures induced bona fide DC morphology (TGF-M-DCs), similar to that of DCs generated with TGF-β and granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-4 (TGF-GM-DCs). Of conditioned media (CM) produced from TGF-M-DCs, TGF-GM-DCs, M-DCs, and GM-DCs, TGF-M-DC CM was the only one that enhanced SCF, Flt3 ligand, and TPO expansion of myeloid progenitor cells ex vivo. This effect was blocked by neutralizing anti–M-CSF Ab, but protein analysis of CM suggested that M-CSF alone was not manifesting enhanced expansion of myeloid progenitors. LPS-stimulated TGF-M-DCs induced T-cell tolerance/anergy as effectively as M-DCs. TGF-M-DCs secreted significantly lower concentrations of progenitor cell inhibitory cytokines and were less potent in activating T cells than TGF-GM-DCs. Functional differences between TGF-M-DCs and TGF-GM-DCs included enhanced responses to LPS-induced ERK, JNK, and P38 activation in TGF-M-DCs and their immune suppressive–skewed cytokine release profiles. TGF-M-DCs appear unique among culture-generated DCs in their capability for silencing immunity while promoting expansion of myeloid progenitors, events that may be of therapeutic value.

Previous clinical studies have identified the cervical facet joint, including the capsular ligaments, as sources of pain in whiplash patients. The goal of this study was to determine whether whiplash caused increased capsular ligament laxity by applying quasi-static loading to whiplash-exposed and control capsular ligaments.A total of 66 capsular ligament specimens (C2/3 to C7/T1) were prepared from 12 cervical spines (6 whiplash-exposed and 6 control). The whiplash-exposed spines had been previously rear impacted at a maximum peak T1 horizontal acceleration of 8 g. Capsular ligaments were elongated at 1mm/s in increments of 0.05 mm until a tensile force of 5 N was achieved and subsequently returned to neutral position. Four pre-conditioning cycles were performed and data from the load phase of the fifth cycle were used for subsequent analyses. Ligament elongation was computed at tensile forces of 0, 0.25, 0.5, 0.75, 1.0, 2.5, and 5.0 N. Two factor, non-repeated measures ANOVA (P0.05) was performed to determine significant differences in the average ligament elongation at tensile forces of 0 and 5 N between the whiplash-exposed and control groups and between spinal levels.Average elongation of the whiplash-exposed capsular ligaments was significantly greater than that of the control ligaments at tensile forces of 0 and 5 N. No significant differences between spinal levels were observed.Capsular ligament injuries, in the form of increased laxity, may be one component perpetuating chronic pain and clinical instability in whiplash patients.

The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor, CXCR4, are involved in a number of facets of the regulation of hematopoiesis at the level of hematopoietic stem (HSCs) and progenitor (HPCs) cells. Modulation of this ligand-receptor interaction may be of clinical utility. We now report that: (1) the CC chemokine, macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) synergizes with AMD3100 (an antagonist of the binding of SDF-1/CXCL12 to CXCR4) to rapidly mobilize HPCs to the blood of mice; moreover, the combination of granulocyte colony-stimulating factor (G-CSF) with AMD3100 and MIP-1alpha/CCL3, given in a specific sequence, mobilizes the greatest number of HPCs compared to any combination of two of these mobilizing agents; (2) pretreatment of recipient mice with Diprotin A, an inhibitor of CD26/Dipeptidylpeptidase IV (DPPIV), enhances the competitive HSCs repopulating capacity of untreated donor cells; (3) the survival-enhancing effects of SDF-1/CXCL12 on HPCs subjected in vitro to delayed addition of growth factors (GFs) are mediated in part through the cell cycle-related proteins p21(cip1/waf1) (as assessed using p21(cip1/waf1) -/- and +/+ mice) and Mad2 (using Mad2 +/- and +/+ mice); and (4) deletion of CD26/DPPIV on mouse bone marrow cells increases the survival-enhancing effects of SDF-1/CXCL12 on HPCs. These results demonstrate the means to increase the mobilization of HPCs, the engrafting capability of HSCs, and responsiveness of HPCs to the survival-enhancing activity of SDF-1/CXCL12, effects that may be of practical value.

Dosimetry using an imaging plate (IP) of computed radiography (CR) systems was developed for quality control of output of the x-ray equipment. Sensitivity index, or the S number, of the CR systems was used for estimating exposure dose under the routine condition: exposure dose from 1.0 to 1.0 x 10(2) microC kg(-1), tube voltages from 50 to 120 kV, and added filtration from 0 to 4.0 mm Al. The IP was calibrated by using a 6 cc ionization chamber having traceability to the National Standard Ionization Chamber. The uncertainty concerning the fading effect was suppressed less than 1.9% by reading the latent image 4 min+/-5 s after irradiation at the room temperature 25.9+/-1.0 degrees C. The S number decreased linearly on the logarithmic graph regardless of the beam quality as exposure dose increased. The relationship between the exposure dose (E) and the S number was fitted by the equation E=a' X S(-b). The coefficient a' decreased when the added filtration and the tube voltage were increased. The coefficient b was 0.977+/-0.007 in all beam qualities. The dosimetry using the IP and the equation can estimate the exposure dose in a range from 9.0 x 10(-2) to 5.0 microC kg(-1) within an uncertainty of +/-5% required by the Japanese Industry Standard. This dose range partially included the doses under routine condition. The doses between 1.0 and 1.0 x 10(2) microC kg(-1) under the routine condition can be shifted to the 5% region by using an absorber. The IP dosimetry is applicable to the quality control of the CR systems.

BACKGROUND: Febrile neutropenia (FN) is often observed in hematological malignancy (HEM). Although most are considered to be due to bacterial infections, it is often difficult to specify the focuses and pathogens of infections in FN patients. Presepsin (Pre-SEP) is a subtype of soluble CD14, which is a receptor for lipopolysaccharide (LPS)/LPS-binding protein complexes and is expressed on the myeloid and monocytic cells' surface. Recently, Pre-SEP has been shown to be a useful biomarker for assessing the severity of sepsis. However, little is known about the biological characteristics of Pre-SEP in FN patients. Therefore, we compared the Per-CEP to the established infection markers including procalcitonin (PCT) and C-reactive protein (CRP) continually in FN patients. METHODS: We measured Pre-SEP concentration in the plasma, PCT and CRP on Day 0, 2, 4, 7 and 14 after the onset of FN and compared them to those of non-febrile neutropenic patients. Furthermore we evaluated the impact of Pre-SEP, PCT and CRP on the diagnosis and assessment of active infection status in FN, using the cut-off value by setting to 314 pg/ml, 0.50 ng/ml and 0.30 mg/ml. Correlation analysis was performed using Peason's correlation coefficient test. RESULTS: Sixty-two hospitalized FN patients with HEM (AML 14, ALL 9, MDS 14, NHL 13, MM 8, ATL 2, others 2 cases) were treated according to IDSA guideline. Figure 1 showed the each data in Pre-SEP, PCT and CRP value on day 0, 2, 4, 7 and 14. The frequency of less than the cut-off value at day 0 of FN onset were 33.8 %, 77.4 % and 37.1 % in Pre-SEP, PCT and CRP respectively, indicating that Pre-SEP showed the highest sensitivity. On day 0, a significant correlation was not observed between Pre-SEP and PCT (P=0.457, correlation coefficient: 0.096) but it was observed between Pre-SEP and CRP (P CONCLUSION: (1) Pre-SEP is available even in neutropenia. (2) Pre-SEP is a useful biomarker for infection on the onset of FN as well as CRP. (3) Pre-SEP can help more sensitive assessment of infection. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: In vitro observations have indicated that preplatelets, which are anucleate discoid particles that can reversibly into proplatelet fragments, are one of platelet progenitos from cultured megakaryocytes (MKs) (Thon JN, et al. JBC 2010). Recently, we identified that bone marrow (BM) MKs form and release two types of platelet progenitors, using intra-vital imaging and ultra-structural analysis of mice BM (Kowata S, et al. Thrombosis and Haemostasis 2014). However, in vivo, how the platelet progenitors translate into individual platelets after leaving BM remains poorly understood. To elucidate whether platelet progenitors have an ability of conversion into individual platelets, we performed following experiments. Methods: We isolated platelet progenitors rich fraction from whole blood of enhanced green fluorescence protein (EGFP) transgenic mice by the centrifugation (100 g, 15 min) and bovine serum albumin gradient. Mature platelets were isolated from whole blood of EGFP mice by the centrrifugation (100 g, 15 min). In vivo: The freshly enriched progenitor rich fraction or mature platelets, both of which were positive for EGFP, was transfused into wild type mice. The peripheral blood was obtained and analyzed by flow cytometry continually. The EGFP positive mature platelets in platelet gate were counted. In vitro: The freshly enriched progenitor isolates were cultured in IMDM medium at 37°C. The continual change of their characteristics in the shape and size were assessed using fluorescent microscopy with high resolution. Time-lapse images of the processes were also captured. All animal procedures were approved by the Institutional Animal Care and Use Committee of Iwate Medical University. Results: The length and size of platelet progenitors were extremely varied (Fig. 1). The red, yellow, green, and dark blue segments in the bar chart indicate the platelet progenitors (5um). The frequency of platelet progenitor was 4% at normal condition (Fig. 1 graph on the left), but increased remarkably to 3-fold at recovery from acute thrombocytopenia (Fig.1 graphs in the middle). The maximum length of platelet progenitor was more than 200 µm (Fig. 1 picture in the top right). These data were consisted with the concept from our previous study of intra-vital imaging of BM MKs (Thrombosis and Haemostasis 2014). In vivo: Flow cytometric analysis showed that there was a time-dependent increase in EGFP platelet number in the gate of mature platelet, after the injection of EGFP positive platelet progenitor rich fraction. The control was carried out using EGFP positive mature platelets instead of platelet progenitors rich fraction. (mean ± SD, 0 h: 100%, 3h: 111 ± 6.8%, 6h: 105 ± 7.1% n=3, control 0 h: 100%, 3h: 101± 6.0%, 6h: 94 ± 5.2% n=3, Data were shown as % of the number of EGFP positive mature platelets at 0 h. P Figure 1. Figure 1. Disclosures Ishida: Bristol-Myers Squibb: Honoraria.

[Graphic][1] Introduction: Adult T-cell leukemia-lymphoma (ATL), a distinct subtype of peripheral T-cell lymphoma (PTCL), is caused by human T-lymphotropic virus type-I (HTLV-1). Although rare in the rest of the world, ATL accounts for 25% of PTCL cases diagnosed in Japan, where ATL cases are clustered in areas endemic for HTLV-1 infection. Studies of lenalidomide, an oral immunomodulatory agent that has antiproliferative and direct antineoplastic activity in cutaneous T-cell lymphoma and PTCL, have reported encouraging clinical activity. On the basis of the results from the ATLL-001 dose-finding study of lenalidomide (Uike et al. ASH 2012. Abstract 2737), this multicenter phase II study (ATLL-002) was designed to investigate the efficacy and safety of single-agent lenalidomide in Japanese patients with relapsed ATL. Methods: Patients with relapsed acute, lymphoma, or the unfavorable chronic subtype of ATL who were at least 20 years of age, had ECOG performance status 0-2, no prior allogeneic stem cell transplant, and who had failed at least 1 chemotherapy were included in the study. Patients refractory to their last prior therapy were excluded. Treatment consisted of oral lenalidomide 25 mg/day administered continuously until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Response was assessed by central review using the criteria proposed by Tsukasaki et al in their international consensus report (J Clin Oncol. 2009;27:453-459.); safety was assessed per NCI CTCAE v4.0 criteria. The estimated number of patients required was 25, for 90% power to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold of ORR, based on the assumptions that the minimum required ORR to a new drug for relapsed or recurrent ATL is 5% and the expected ORR to lenalidomide is 25%. Results: Twenty-six patients were enrolled and received lenalidomide. The median age was 68.5 years (range, 53-81), with 15 (58%) acute, 7 (27%) lymphoma, and 4 (15%) unfavorable chronic type ATL patients. Patients had received a median of 2 (range, 1-4) prior chemotherapeutic or antibody agents for ATL, 11 (42%) of whom received prior mogamulizumab (anti-CCR4 antibody). At a median 3.8-month follow-up, lenalidomide met the primary endpoint by exhibiting an ORR of 42% (11/26; 95% CI, 23-63) (acute 33% [5/15], lymphoma 57% [4/7], unfavorable chronic 50% [2/4]), including 5 (19%) complete responses (CR)/CR unconfirmed (95% CI, 7 to 39; Table 1). Stable disease was 31%, and progressive disease was 27%. The median time to response was 1.9 months (95% CI, 1.8 to 3.7). Although the data were immature at the time of analysis, median DOR for all responders was not reached (NR) (95% CI, 0.5 months to NR), median PFS was 3.8 months (95% CI, 1.9 months to NR), and median OS was 20.3 months (95% CI, 9.1 months to NR). At the time of the data cut-off, 5 (19%) patients remained on lenalidomide treatment. The most common grade 3/4 adverse events (AEs), accounting for at least 10% of all cases, were neutropenia (65%), leukopenia (39%), lymphopenia (39%), thrombocytopenia (23%), anemia (19%), and hypokalemia (12%). Serious AEs were reported in 9 (35%) patients; only thrombocytopenia (2 patients [8%]) was observed in >1 patient. AEs led to dose reduction/interruption in 17 (65%) patients and study discontinuation in 6 (23%). Seven deaths occurred during the study, 6 due to disease progression and 1 due to pneumonia unrelated to lenalidomide treatment. Conclusions: In this multicenter, open-label, phase II study, lenalidomide monotherapy demonstrated a 42% ORR and acceptable tolerability profile. These results support the potential for lenalidomide monotherapy becoming a treatment option for patients with relapsed ATL. | ATL type | All patients (N = 26) | Acute (n = 15) | Lymphoma (n = 7) | Unfavorable chronic (n = 4) | | ------------- | ------------------------------ | ----------------------- | ------------------------- | --------------------------- | | ORR, n (%) | 11 (42) | 5 (33) | 4 (57) | 2 (50) | | CR/CRu, n (%) | 5 (19) | 3 (20) | 2 (29) | | | PR, n (%) | 6 (23) | 2 (13) | 2 (29) | 2 (50) | | SD, n (%) | 8 (31) | 6 (40) | | 2 (50) | | PD, n (%) | 7 (27) | 4 (27) | 3 (43) | | * CR, complete response; CRu, CR unconfirmed; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Table. Best response to lenalidomide in relapsed ATL Disclosures Fujiwara: Celgene: Honoraria, Other: Research funding to my institution; travel, accommodations, expenses. Off Label Use: Lenalidomide to treat ATL. Ishida: Celgene K.K.: Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution. Moriuchi: Celgene: Other: Research Funding to my institution; travel, accommodations, expenses, Speakers Bureau. Jo: Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria. Ishizawa: Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Research Funding; GSK: Research Funding; Takeda: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Pfizer: Speakers Bureau; Celgin: Speakers Bureau. Tobinai: Gilead Sciences: Research Funding. Tsukasaki: Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Mundipharma: Research Funding; Kyowa Kirin Hakkou: Research Funding. Ogura: Mundipharma: Consultancy, Research Funding; MeijiSeika Pharma: Consultancy; Zenyaku: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Solaisia: Research Funding. Midorikawa: Celgene K.K.: Employment; Celgene Corporation: Equity Ownership. Ruiz: Celgene K.K.: Employment. Ohtsu: Celgene: Employment, Equity Ownership, Other: travel, accommodations, expenses. [1]: /embed/inline-graphic-2.gif

Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM. Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS. Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age >65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS. Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. Disclosures No relevant conflicts of interest to declare.

[Background] Survivin is a member of the inhibitor of apoptosis protein (IAP) family with its dual roles in mitosis and apoptosis, and emerges as an attractive target for cancer therapy. YM155, a novel molecular targeted agent, suppresses survivin, which is overexpressed in many tumor types. However, the effect of this agent on multiple myeloma (MM) cells remains unclear. [Materials & Methods] Five human MM cell lines, RPMI8226, U266, KMS20, KMS28PE, and KMS34 were used in this study. Cell proliferation and cell death were evaluated by MTT assay and by flow cytometric analysis with annexin V/PI staining. Gene and protein expressions were analyzed with quantitative PCR (qPCR) and immunoblot, respectively. For proteasome inhibitory assay, cells were treated with YM155 and/or proteasome inhibitor MG132 for 6 hours. [Results] YM155 inhibited cell proliferation of these cells in a dose- and time-dependent manner. Annexin V assay showed that YM155 induced apoptosis in these cells. To better understand these effects of YM155 on MM cells, we evaluated the intracellular signaling and apoptosis-associated protein status. Immunoblot analyses showed that YM155 reduced not only survivin but also Mcl-1 and XIAP expressions. We also observed the activation of caspase-3 and PARP in YM155-treated cells, indicating that YM155 induces caspase-dependent apoptosis. In contrast, YM155 did not affect phosphorylation status of Erk1/2 and STAT3. Interestingly, YM155 suppressed c-Myc and IRF4 protein expressions, both of which are recognized as an important transcription factor in the pathogenesis of MM. In addition, qPCR assay showed that YM155 treatment did not reduce c-Myc mRNA level. On the other hand, proteasome inhibitor prevented the suppression of c-Myc expression by YM155 treatment, indicating a proteasomal degradation of c-Myc by YM155. [Conclusion] YM155 suppresses cell proliferation and survival in MM cells in part via not only inhibiting anti-apoptotic proteins such as survivin, Mcl-1 and XIAP but also suppressing c-Myc oncoprotein expression. Further study is needed to clarify the molecular mechanism of c-Myc degradation induced by YM155. Our results may provide a new concept in c-Myc-targeting therapy for MM because c-Myc oncoprotein have been considered undruggable. Disclosures Ishida: Bristol-Myers Squibb: Honoraria.

Background: Autologous stem cell transplantation (ASCT) in conjunction with therapeutic drugs such as bortezomib, thalidomide, and lenalidomide can dramatically improve response rates and the prognosis of patients with multiple myeloma (MM). However, most patients with MM are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Here we utilized a next-generation sequencing (NGS) approach for MRD assessment, which offers at least 1 to 2 logs greater sensitivity (10-6) compared to allele-specific oligonucleotide PCR (ASO-PCR) and flow cytometry, respectively (Faham et al Blood 2012). Previous studies have shown that NGS-based MRD assessment 90 days post-ASCT has prognostic value (Martinez-Lopez et al Blood 2014). In this study, we compared the prognostic value of MRD assessment in autografts and bone marrow (BM) samples from MM patients in the ASCT setting. Methods: One hundred and twenty-three Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients received ASCT and were followed between June 15, 2004 and April 25, 2015. All patients had achieved a partial response (PR) or better after ASCT. Analyzed samples included: (1) BM slides from 96 MM patients at diagnosis, (2) fresh/frozen BM cells from 27 MM patients at diagnosis, (3) autografts and/or (4) post-ASCT BM cells obtained at the time of best response based on serum and urine tests. IGH-based ASO-PCR was performed as described previously (Methods Mol Biol 2009). NGS-based MRD assessment was performed using the immunosequencing platform (Adaptive Biotechnologies, South San Francisco, CA) (Martinez-Lopez et al Blood 2014). Results: We compared MRD results in 51 samples assessed by ASO-PCR and NGS. We observed a high correlation between NGS and ASO-PCR results at MRD levels of 10-5 or higher (r=0.86, P Conclusions: In this study, we show the prognostic value of NGS-based MRD assessment in autografts of patients with MM. The NGS platform has improved sensitivity compared with ASO-qPCR in detecting MRD in autografts. Importantly, this retrospective study suggests that therapeutic intervention based on NGS-based MRD positivity has a significant effect on patient outcome in the post-ASCT setting. Disclosures Zheng: Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder.