Search

Jonathan Corren,1 Sarbjit S Saini,2 Remi Gagnon,3 Mark H Moss,4 Gordon Sussman,5 Joshua Jacobs,6 Elizabeth Laws,7 Elinore S Chung,8 Tatiana Constant,8 Yiping Sun,8 Jennifer Maloney,8 Jennifer D Hamilton,8 Marcella Ruddy,8 Claire Q Wang,8 Meagan P O’Brien8 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Department of Internal Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA; 3Clinique Spécialisée en Allergie de la Capitale, Québec, QC, Canada; 4Departments of Medicine and Pediatrics, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 5Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Allergy and Asthma Clinical Research, Inc, Walnut Creek, CA, USA; 7Sanofi, Bridgewater, NJ, USA; 8Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USACorrespondence: Meagan P O’BrienRegeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USATel +1 914 826-5271Email meagan.obrien@regeneron.comJonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095, USATel +1 310 312-5050, ext 250Email jcorren@ucla.eduBackground: Subcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases.Objective: To evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.Methods: This phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0– 1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.Results: Although 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0– 1 h) following NAC at Week 17 vs SCIT (least squares mean − 56.76% vs − 52.03%), a higher proportion of SCIT+dupilumab-treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.Conclusion: In SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.Clinical Study Number: NCT03558997.Keywords: dupilumab, seasonal allergic rhinitis, subcutaneous immunotherapy, nasal allergen responses

There are three main disadvantages including time-consuming task, high cost and complex detection procedures in the semen quality measurement to heighten the roosters’ reproductive capability in breeder flocks. Another solution is to select the breeder roosters with fine phenotypic characteristics by humans, while it is also a considerably labor-intensive task and even increases the risk of zoonoses at a poultry farm. To solve these problems, this paper proposes a strategy that effective promoting factors applied to Progressive Multi-Granularity (PMG) network ensures the accuracy of entire image and improves the accuracy of fine-grained image. This strategy allows the basic networks boost the classification performance in the case of specific combination. Given the same images inputted into our model, two groups of questionnaires for practitioners and non-practitioners judging the fertility by the rooster’s phenotypic traits, the experimental results show that our method has raised the accuracy by almost 10% by comparison with the results of questionnaire survey.

Objective Patients with cardiac surgery–associated acute kidney injury are at risk of renal replacement therapy and in-hospital death. We aimed to develop and validate a novel predictive model for poor in-hospital outcomes among patients with cardiac surgery–associated acute kidney injury. Methods A total of 196 patients diagnosed with cardiac surgery–associated acute kidney injury were enrolled in this study as the training cohort, and 32 blood cytokines were measured. Least absolute shrinkage and selection operator regression and random forest quantile-classifier were performed to identify the key blood predictors for in-hospital composite outcomes (requiring renal replacement therapy or in-hospital death). The logistic regression model incorporating the selected predictors was validated internally using bootstrapping and externally in an independent cohort (n = 52). Results A change in serum creatinine (delta serum creatinine) and interleukin 16 and interleukin 8 were selected as key predictors for composite outcomes. The logistic regression model incorporating interleukin 16, interleukin 8, and delta serum creatinine yielded the optimal performance, with decent discrimination (area under the receiver operating characteristic curve: 0.947; area under the precision-recall curve: 0.809) and excellent calibration (Brier score: 0.056, Hosmer–Lemeshow test P = .651). Application of the model in the validation cohort yielded good discrimination. A nomogram was generated for clinical use, and decision curve analysis demonstrated that the new model adds more net benefit than delta serum creatinine. Conclusions We developed and validated a promising predictive model for in-hospital composite outcomes among patients with cardiac surgery–associated acute kidney injury and demonstrated interleukin-16 and interleukin-8 as useful predictors to improve risk stratification for poor in-hospital outcomes among those with cardiac surgery–associated acute kidney injury.

MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post-transcriptionally modulate the expression of their target genes, have been implicated as critical regulatory molecules in ischemia-/reperfusion-induced cardiac injury. In the present study, we report on the role of miR-208a in myocardial I/R injury and the underlying cardio-protective mechanism. The gain-of-function and loss-of-function were used to explore the effects of miR-208a on cardiac injury induced by H2O2 in cardiomyocytes. As predicted, knockdown of endogenous miR-208a significantly decreased the level of cellular reactive oxygen species (ROS) and reduced cardiomyocyte apoptosis. In addition, miR-208a overexpression increased the ROS level and attenuated cell apoptosis in cardiomyocytes. Furthermore, protein tyrosine phosphatase receptor type G (PTPRG) and protein tyrosine phosphatase, non-receptor type 4 (PTPN4), which participate in regulating the level of cellular protein tyrosine phosphorylation balance, were predicted and verified as potential miR-208a targets using bioinformatics and luciferase assay. In summary, this study demonstrated that miR-208a plays a critical protective role in ROS-induced cardiac apoptosis.

Non-rigid object tracking is an important yet challenging task in computer vision. In this paper, a multi-patch neural network (MPNet) model is presented to address the problem of non-rigid object tracking. The model learns a multiple patch based framework, which mainly consists of two branches of neural networks. One branch is to track the global target and the other branch partitions the target into multiple patches which are tracked separately. The global tracking and the multiple patch tracking are combined to compute the final tracking results. Compared with the existing methods, our model exploits the trajectories of various parts of a non-rigid object and therefore can accurately track the non-rigid object. Experiments on visual tracking datasets prove the strength of the proposed method.

Anomaly detection on system logs is to report system failures with utilization of console logs collected from devices, which ensures the reliability of systems. Most previous researches split logs into sequential time windows and regarded each window as an independent instance for classification using popular machine learning methods like support vector machine(SVM), however, neglected the time patterns under logs. Those approaches also suffer from information loss due to the vector representation, and high dimensionality if there is a large number of log events. To make up these deficiencies, unlike most traditional methods that used a vector to represent a period behavior at the macro level, we construct a 2D matrix to reveal more detailed system behaviors in the time period by dividing each window into sequential subwindows. To provide a more efficient representation, we further use the ant colony optimization algorithm to find a highly-coupled event template as the horizontal index of the 2D window matrix to replace the disordered one. To capture time dependencies, a multi-module convolutional auto-encoder is configured as that different paralleled modules scan among different time intervals to extract information respectively. These features are then concatenated in latent space as the final input, which contains diversified time information, for classification by SVM. The experiments on Blue Gene/L log dataset showed that our proposed method outperforms the state-of-art SVM method.

In relation classification, previous work focused on either whole sentence or key words, meeting problems when sentence contains noise or key words are extracted falsely. In this paper, we propose coarse and fine-grained networks for relation classification, which combine sentence and key words together to be more robust. Then, we propose a word selection network under shortest dependency path (SDP) supervision to select key words automatically instead of pre-processed key words and attention, which guides word selection network to a better feature space. A novel opposite loss is also proposed by pushing useful information in unselected words back to selected ones. In SemEval-2010 Task 8, results show that under the same features, proposed method outperforms state-of-the-art methods for relation classification.

The protective effects of dioscin, a natural steroidal saponin from some medicinal plants including Dioscorea nipponica Makino, against lipopolysaccharide (LPS)- induced acute liver and renal damages have been reported in our previous works. However, its effect on LPS-induced acute lung injury (ALI) remains unknown. In the present study, the effects and possible mechanisms of dioscin against LPS-induced ALI in vitro and in vivo were investigated. The results showed that dioscin effectively inhibited cell proliferation and markedly decreased reactive oxidative species (ROS) level in 16HBE cells treated by LPS. In addition, dioscin significantly attenuated LPS-induced histological alterations, suppressed the infiltration of inflammatory cells, as well as decreased the levels of MDA, SOD, NO and iNOS in mice and rats (p < 0.05). Mechanistically, dioscin significantly decreased the protein levels of TLR4, MyD88, TRAF6, TKB1, TRAF3, phosphorylation levels of PI3K, Akt, IκBα, NF-κB, and the mRNA levels of IL-1β, IL-6 and TNF-α against oxidative stress and inflammation (p < 0.05). TLR4 overexpression was also decreased by dioscin, leading to the markedly decreased the levels of MyD88, TRAF6, TKB1, TRAF3, p-PI3K, p-Akt, p-IκBα and p-NF-κB. These findings provide new insights that dioscin exhibited protective effect against LPS-induced ALI via adjusting TLR4/MyD88- mediated oxidative stress and inflammation, which should be developed as one potent candidate for the treatment of ALI in the future.

Introduction Ataluren functions by interacting with ribosomes to promote read-through of nonsense mutations in CF. Ataluren9s activity was shown to be inhibited by certain aminoglycosides such as tobramycin that also bind to the ribosome. Aim To investigate the effect of ataluren on lung function (LF) and pulmonary exacerbations. Methods A post-hoc analysis was performed on a recent randomized, double-blind, placebo-controlled, phase 3 study to determine the efficacy and safety of ataluren in patients with nonsense mutation cystic fibrosis (nmCF) (Kerem E, et al. Lancet Respir Med. 2014;2:539-47) on %-predicted FEV 1 (ppFEV 1 ) and exacerbations by use of chronic inhaled tobramycin at baseline. Results Patients not receiving chronic inhaled tobramycin (non-TOBI; n=146), showed a 5.7% difference in relative ppFEV 1 between ataluren and placebo (−0.7% vs −6.4%; p=0.0082) and 40% fewer exacerbations (1.42 vs 2.18; p=0.0061). Non-TOBI patients ≥6 to 1 between ataluren and placebo (4.9% vs −3.3%; p=0.026) and a 60% lower exacerbation rate favoring ataluren (p=0.030). In all intent-to-treat patients (N=232) at week 48, including tobramycin patients, neither relative change from baseline in ppFEV 1 (−2.5% vs −5.5%; p=0.12), nor number of exacerbations (1.42 vs 1.78; p=0.099) significantly differed between ataluren and placebo. Conclusions Ataluren significantly reduced exacerbations and improved LF in nmCF patients not receiving chronic inhaled tobramycin, with markedly improved treatment effect in children and adolescents. Ataluren thus shows promise as a disease-modifying therapy in nmCF.

Background Myocardial infarction (MI) remains the most common cause of heart failure (HF) worldwide. For almost 50 years, HF has been recognized as a determinant of adverse prognosis after MI, but efforts to promote myocardial repair have failed to be translated into clinical therapies. Aims In this study, we investigated the effects of BRD4 on cardiac function and the underlying mechanism. Material and methods The in vivo rat model of AMI and in vitro neonatal cardiomyocytes were established and cultured respectively, the BRD4 and NPPA/NPPB expression levels were detected by qPCR and Western blot, and interaction of BRD4 with acetylation RelA or NPPA/B promoters were examined by co-immunoprecipitation and chromatin immunoprecipitation assays, respectively. Results We found that BRD4 protein expression was significantly increased in cardiomyocytes of MI rat model and cardiomyocytes under hypoxia, accompanied by the expression of natriuretic peptide A (NPPA) and natriuretic peptide B (NPPB). Functionally, knockdown of BRD4 greatly downregulated the NPPA and NPPB in vivo and in vitro, improved the hemodynamic and biometric parameters in rat with heart failure, as well as decreased the apoptosis occurrence. In vitro studies further demonstrated that BRD4 bound with acetylated RelA to enhance the activation of NF-κb signaling, which resulted in activation of NPPA and NPPB transcriptions. Conclusions Taken together, our findings suggest that inhibition of BRD4 attenuated cardiomyocyte apoptosis via NF-κB pathway in myocardial infarction, and this study sheds light on developing new strategies to overcome myocardial damage.

Delay in diagnosis of leprosy can increase the risk of nerve function impairments and promote the transmission of the infection in a community. In order to understand the factors associated with the delays in diagnosis of leprosy, a questionnaire-based interview was conducted to collect information on the delays among 88 newly diagnosed leprosy patients. The results showed that delay was common and associated with the high rate of disability in the study population. The total mean delay was 50.18 months (median 36 months). The mean patient delay was 24-4 months (median 9.5 months) and the mean health service delay was 257 months (median 12 months). Patients with leprosy reported a variety of symptoms/signs at an early stage of the disease, particularly numbness and tingling. Ignorance of the illness was reported to be the main reason for the patient's delay. Health seeking actions ranged from 1 to 50 with a mean of 7.2 after becoming aware of the first symptom/sign. The effectiveness of early diagnosis of leprosy through health promotion in the population needs to be validated and continuous training on leprosy among healthcare providers is needed.

Background: Isolated monomorphic premature ventricular contractions (PVCs) are not uncommon in the pediatric population. The degree of cardiac dysfunction caused by PVCs in children without structural heart disease is unknown. Purpose: To investigate the influence of PVCs on echocardiographic left ventricular (LV) systolic function in children without structural heart disease. Methods: Forty asymptomatic children with isolated monomorphic PVCs without structural heart disease were selected. The median age was 6 years, range of 3–12 years. The following subgroups were compared: frequent vs. infrequent PVCs (> or ≤10/min); short vs. long coupling interval (RR′/RR ratio ≤ or >0.6); and short vs. long QT interval (QT ≤ or >400 ms). Using echocardiography the left ventricular ejection fraction (LVEF in percentage) and cardiac index (CI in L/min/m2) were measured for both normal sinus beats (SB-LVEF and CI), PVCs (PVC-LVEF and CI) and the average LVEF and CI were calculated. All values were expressed as means ± SD. Results: In all children LV dimensions and the SB-LVEF and CI were within normal limits. The PVC-LVEF (48 ± 5) and PVC-CI (1.57 ± 0.19) were significantly decreased and the average CI was 2.41 ± 0.29. In 27 pts with >10 PVCs/min the average LVEF and CI decreased to 53 ± 5 and 2.08 ± 0.24 respectively. In 16 pts with PVCs and a short coupling interval (RR′/RR ≤ 0.6) the PVC-LVEF and PVC-CI was 43 ± 0.03 and 1.50 ± 0.14, which was significantly lower than in 24 pts with a long coupling interval (58 ± 4, 1.88 ± 0.11). In 11 pts with a prolonged QT interval (>400 ms) the PVC-LVEF and PVC-CI was significantly lower than in the 29 children with a shorter QT interval, 41 ± 5 vs. 55 ± 4 and 1.46 ± 0.13 vs. 1.86 ± 0.15 respectively (all p 10/min), have a short coupling interval or a prolonged QT interval.

Background One of the beneficial effects of exercise training in chronic heart failure (CHF) is an improvement in baroreflex sensitivity (BRS), a prognostic index in CHF. In our hypothesis-generating study we propose that at least part of this effect is mediated by neural afferent information, and more specifically, by exercise-induced somatosensory nerve traffic. Objective To compare the effects of periodic electrical somatosensory stimulation on BRS in patients with CHF with the effects of exercise training and with usual care. Methods We compared in stable CHF patients the effect of transcutaneous electrical nerve stimulation (TENS, N =23, LVEF 30±9%) with the effects of bicycle exercise training (EXTR, N =20, LVEF 32±7%). To mimic exercise-associated somatosensory ergoreceptor stimulation, we applied periodic (2/s, marching pace) burst TENS to both feet. TENS and EXTR sessions were held during two successive days. Results BRS, measured prior to the first intervention session and one day after the second intervention session, increased by 28% from 3.07±2.06 to 4.24±2.61ms/mmHg in the TENS group, but did not change in the EXTR group (baseline: 3.37±2.53ms/mmHg; effect: 3.26±2.54ms/mmHg) ( P (TENS vs EXTR)=0.02). Heart rate and systolic blood pressure did not change in either group. Conclusions We demonstrated that periodic somatosensory input alone is sufficient and efficient in increasing BRS in CHF patients. This concept constitutes a basis for studies towards more effective exercise training regimens in the diseased/impaired, in whom training aimed at BRS improvement should possibly focus more on the somatosensory aspect.

Although the precise mechanisms of transient hypotension after intravenous infusion of hypertonic saline (HTS) are not yet clarified, a rapid infusion of HTS is widely used as the initial therapy of hypovolemia. We investigated the effect of the intravenous infusion of a small dose of 0.97-9.7% NaCl solutions in anesthetized rats. Intravenous infusion of HTS at a rate of 0.3 ml/kg/min for 1 min produced the transient hypotension lasting for several minutes. The depressor response to HTS was not abolished by bilateral cervical vagotomy. The HTS infusion into the femoral vein evoked the depressor response with a larger magnitude and a shorter latency than that into the aortic arch. While the arterial baroreceptor pressure was kept constant at the baseline level of systemic arterial pressure, HTS-induced hypotension was significantly augmented. The gain factor of the arterial baroreflex was reduced by intravenous HTS. Pretreatment with bretylium tosylate completely abolished the depressor response without affecting the baseline level of arterial pressure. These results suggest that the depressor response to the very small dose of intravenous HTS is the sympathosympathetic neural reflex with cardiopulmonary afferents and vasomotor efferents.

s / Biol Blood Marrow Transplant 19 (2013) S178eS193 S186 may be warranted to discern if DM pts may benefit from different methods of mobilization or if long term transplant outcomes are impacted.

The phase function of an SAR signal in the two dimensional wavenumber domain is usually derived by using the principal of stationary phase. From this phase function, the phase error of the conventional range-Doppler algorithm when used for high resolution large squint angle SAR imaging is obvious [Bamler 1992]. The secondary range compression and other approximate wavenumber domain algorithm can be derived based on the phase function. But the physical meaning of the secondary range compression can not be directly perceived. In this paper we derive the phase function from SAR imaging geometry by using the Doppler-azimuth coordinate relationship in different RF frequency. From this point of view, it is easy to understand the phase error originated from the range-Doppler algorithm.

A data-aided method of joint frequency offset and chromatic dispersion estimation based on the Chu training sequences is shown in 112 Gb/s polarization-multiplexed (PM) quadrature phase-shift keying and 224 Gb/s PM-16-quadrature amplitude modulation with different pulse-shaping filters, respectively. The proposed method achieves a good accuracy and is verified to be robust to polarization mode dispersion.

P.R.ChinaABSTRACTIn this paper we show the relationship among the Lagrange invariant, the interference invariant and thespace bandwidth product. they are important in geometrical optics, physical optics and information optics. Andwe gie a method of caIcuating the space bandvidth product of opticai system.I . INTRODUCTIONThe Lagrange invariant is important in geometrical optics such as in aberration calculations and in thephotometry of optical instruments. in this paper we will ihtroduce a new invariant — interference invariant — inphysical optics. it shows the conditions for forming clear interference fringes and for space coherence of lightfield. And it is well known that the space bandwidth product is significant in holography and optical informationprocessing. It can be used for describing information quantity of optical imaging system and capability of opticalprocessing system and storage capability of hologram etc. Furthermore, we Will

Abstract 3080 Background: Salvage therapeutic options are limited for multiple myeloma (MM) patients who relapse after autologous hematopoietic stem cell transplantation (ASCT). A second ASCT using a different conditioning regimen may provide long-term disease control. We report efficacy and safety of daily intravenous busulfan (IV Bu) conditioning given with bortezomib for second ASCT. Materials and Methods: In this prospective, multicenter, Phase IIa study, thirty MM patients who relapsed ≥ 1 year after initial ASCT and were candidates for second ASCT were enrolled at eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between Days -12 and -9 prior to ASCT. Pharmacokinetic (PK) analysis from test dose determined Bu exposure as area under the concentration-time curve (AUC). This analysis was used to determine individualized Bu PK-directed dosing for the conditioning regimen in order to achieve a total regimen AUC of 20,000 mM*min. IV Bu was administered over 3 hours once daily from Day -5 to Day -2. Confirmatory PK analysis was conducted in all patients on Day -5. Bu doses were adjusted on Days -3 and -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. Disease response was evaluated prior to the ASCT and at 3 and 6 months post-transplant, based on the International Myeloma Working Group uniform response criteria in 2006. Results: Patient Demographics: Median age at second ASCT was 59 years (range: 48–73). All patients had previously been treated with bortezomib (86.7%), thalidomide (46.7%), and/or lenalidomide (66.7%). All subjects underwent first ASCT with high-dose melphalan. Median time from first ASCT to second ASCT was 28.0 months (range: 12–119). The disease status at second ASCT was seven very good partial response (VGPR; 23.3%), twelve partial response (PR; 40.0%), two stable disease (SD; 6.7%); and nine progressive disease (PD; 30.0%). Safety: The most common grade 3 or 4 adverse event (CTCAE v3.0) was febrile neutropenia in 15 patients (50.0%), followed by stomatitis in 13 patients (43.3%), nausea in four (13.3%) and hypokalemia in three (10.0%). One transplant-related death due to pulmonary complications was reported for a patient with Parkinsonism on post-transplant Day 20. There was no instance of seizure, worsening neuropathy, or hepatic veno-occlusive disease (VOD) meeting the Baltimore criteria. Efficacy: 28 patients had evaluable disease response at least at one time point after second ASCT. Disease response at 3 months were two complete responses (CR; 6.7%), five VGPR (16.7%), four PR (13.3%), eight SD (26.7%), nine PD (30.0%), and two cases without evaluable assessment (6.7%). Two patients who achieved CR at 3 months had PD and VGPR prior to ASCT, respectively. Disease response at 6 months were one stringent CR (sCR; 3.3%), one CR (3.3%), four VGPR (13.3%), seven SD (23.3%), fourteen PD (46.7%), and three cases without evaluable assessment (10.0%). Median progression-free survival was 191 days, while median overall survival has not been reached yet. PK: 40.0% (n=12/30) of patients had AUC outside the expected range from pre-transplant test dose, 0.8 mg/kg of IV Bu: eleven cases with AUC 1,500 μM*min. If only weight was used (e.g. 3.2 mg/kg daily) to determine the dose without considering difference in individual busulfan metabolism, this 40% would have been dosed outside the total target AUC range. Based on test PK, IV Bu dosing for conditioning was individualized ranging between 1.99 and 4.73 mg/kg, which resulted in 93.3% of patients (n=28/30) falling between 16,000 and 24,000 μM*min as a total target AUC without any further dose alteration during conditioning. Only 2 patients (6.7%) needed dose reduction on Days -3 and -2. Mean Bu clearance for test dose and on Day -5 were comparable, 3.00 and 2.92 ml/min/kg, respectively. Conclusions: Disclosures: Stadtmauer: Millenium: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Off Label Use: IV busulfan and bortezomib-based conditioning regimen prior to transplant for myeloma. Freytes:Otsuka Pharmaceuticals: Research Funding. Shaughnessy:Otsuka: Honoraria, Speakers Bureau. White:Otsuka: Honoraria, Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka Pharmaceutical Development & Commercialization, Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialisation., Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millinneum Pharmaceuticals: Research Funding; Merck: Consultancy, Honoraria, Research Funding.

Abstract 813 Background: Published reports indicate that oral or intravenous (IV) busulfan in combination with cyclophosphamide and VP-16 (BuCyVP-16) is an effective conditioning regimen with acceptable safety profile for lymphoma patients prior to autologous hematopoietic stem cell transplantation (ASCT). Since the therapeutic window of Bu is narrow, it is important to standardize the systemic exposure during conditioning. Although the IV formulation of Bu eliminates the problem of variable drug absorption, unpredictable systemic exposure can still occur due to interpatient differences in Bu clearance. Therefore, tighter control of systemic Bu exposure using pharmacokinetics (PK) may lead to improved efficacy and further decrease in toxicity. The aim of this multi-center, single-arm, Phase II study was to prospectively evaluate the safety and efficacy of IV BuCyVP-16 regimen in lymphoma patients undergoing ASCT, after optimizing Bu exposure using PK-directed dosing. Methods: Patients with chemosensitive, relapsed or primary-refractory Hodgkin and B-cell non-Hodgkin lymphoma undergoing the first ASCT received a test dose of IV Bu (0.8 mg/kg) given as a 2-hour infusion 11 to 14 days before transplant. Bu exposure was determined as area under the concentration-time curve (AUC) using six serial blood samples after the test dose administration. Doses for the conditioning regimen were then calculated to result in total AUC (conditioning + test) of 20,000 mM*min. One-fourth of the resulting calculated Bu dose was given as a 3-hour infusion on Day -8, followed by a second, confirmatory PK analysis. The same daily Bu dose was administered on the next 3 days, unless the confirmatory PK analysis showed that this would result in total AUC outside the target range (>24,000 mM*min or Results: A total of 202 subjects with Hodgkin (n=65) and non-Hodgkin lymphoma (n=137) were enrolled from 32 centers in the US and Canada. 196 subjects had both test PK and confirmatory PK results. Test PK demonstrated that 36.2% (n=71) of the patients had exposure outside of expected range (1,250 μM*min ± 20%): higher AUC (>1,500 μM*min) in five patients (2.6 %) and lower AUC ( An early subset-analysis by age in June 2011 revealed that 4 of 18 subjects older than 65 years suffered TRM. Consequently, the protocol was amended to lower the inclusion age limit to 65. The final TRM at day 100 was 4/18 (22.2% [95%CI; 6.4–47.6%]) for patients older than 65 years and 5/184 (2.7% [95%CI; 0.9–6.2%]) for those 65 years old or younger. PK results indicated no extraordinary Bu exposure in TRM cases. The most frequently observed grade ≥ 3 adverse events (CTCAE ver. 3.0) were febrile neutropenia 55.1 % (Grade 3: 52.2%; Grade 4: 2.9%; no Grade 5), stomatitis 37.7% (all Grade 3 events) and nausea 9.7% (all Grade 3 events). No case of hepatic veno-occlusive disease (HVOD) meeting Baltimore criteria was reported. Conclusions: A pre-conditioning test dose estimated individual PK parameters and accurately predicted Day-8 PK in 95% of the subjects. This strategy personalized the dosing for optimal Bu exposure preventing the Bu overexposure or underexposure that would have occurred in over a third of patients. The toxicity of PK-guided IV BuCyVP-16 preparative regimen was low for patients younger than 66 years of age. This approach resulted in no incidence of HVOD. Disclosures: Costa: Otsuka: Research Funding. Off Label Use: Off label use of busulfan in non hodgkin and hodgkin lymphoma. Waller:Outsuka: Research Funding. Freytes:Otsuka Pharmaceuticals: Research Funding. Shea:Otsuka : Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka America Pharmaceuticals Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Vaughan:Pierre Fabre: Honoraria.

Abstract 4509 BACKGROUND: Once multiple myeloma (MM) relapses after a first autologous hematopoietic stem cell transplantation (HSCT), long-term disease control is challenging because of limited therapeutic options. A second autologous HSCT is one of the options although the choice of conditioning regimens has not been thoroughly investigated. Past studies demonstrated that adding oral busulfan (Bu) to melphalan for conditioning regimen prior to a first HSCT resulted in better disease control of MM than melphalan single administration [Lahuerta et al, Haematologica. 2010;95:1913]. Nonetheless, the risk of hepatic veno-occlusive disease (VOD) hinders the use of oral Bu as a part of the conditioning regimen. Intravenous (IV) Bu eliminates the unpredictable bioavailability of the oral drug, whereas pharmacokinetic (PK)-directed dose optimization reduces inter-individual variability in the metabolism of Bu, resulting in decreased incidence of VOD and improvement in the control of hematologic malignancies [Andersson et al, Biol Blood Marrow Transplant 2002;8:477]. In addition, a proteasome inhibitor like bortezomib may have synergy with an alkylating agent for conditioning prior to HSCT in myeloma [Lonial et al, Clin Cancer Res 2010; 16: 5079], but the safety of a combination with Bu has not been investigated to date. Here we report results from a multicenter, prospective Phase 2 study to examine the pharmacokinetics of IV Bu and safety with bortezomib as a conditioning regimen for a second autologous HSCT. METHODS: 30 patients with relapsed MM who had a first autologous HSCT ≥1 year prior to the planned HSCT were enrolled from eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between days 12 and 9 prior to HSCT. Serial blood samples were drawn up to 360 min after the start of the infusion. A central laboratory measured Bu concentrations, determined Bu exposure as area under the concentration-time curve (AUC) using WinNonlin software, and recommended individualized PK-directed dosing in order to achieve a total regimen AUC of 20,000 μM·min. Using the patient-specific PK-directed dose, IV Bu was administered over 3 hours once daily from Day -5 to Day -2. In all patients, a second PK analysis was conducted on Day -5 to confirm the PK-directed dose. Bu doses were adjusted on Day -3 and Day -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. RESULTS: All 30 patients who enrolled in this study had been treated with high dose melphalan before a first HSCT. The median time from the first to second HSCT was 31.4 months (range 12.0 – 119.2 months). Disease status prior to the second HSCT was VGPR (n=6), PR (n=12), SD (n=2), and PD (n=10). Test PK revealed that 40.0 % (n=12/30) of the patients had doses outside of target range (1,250 μM·min +/− 20%), based on expected exposure using a fixed dose of 0.8 mg/kg. Specifically, infusion of the test dose resulted in 1,500 μM·min or higher AUC in 3.3% (n=1/30) and 1,000 μM·min or lower AUC in 36.7% (n=11/30) of patients. In order to achieve the target AUC, daily PK-directed dose of IV Bu when conditioning started on Day -5 ranged between 1.99 mg/kg and 4.73 mg/kg: lower than 3.2 mg/kg in 12 subjects and higher than 3.2 mg/kg in the remaining 18. Confirmatory PK on Day -5 demonstrated that mean Bu clearances were comparable to that from test PK: 3.03 ml/min/kg for test dose and 2.93 ml/min/kg for Day - 5. Consequently, using a test dose followed by PK-directed Bu dosing, 93.3% of patients (n=28/30) fell within the target range (AUC, 20,000 μM·min +/−20%). Only two patients (6.7%) needed subsequent daily dose adjustment on Day -3 and Day -2. No instances of VOD, seizure, or worsening neuropathy have been reported to date. One death was reported by Day 30 after transplant in a patient with Parkinsonism who died of pulmonary complications. CONCLUSION: This multicenter, prospective study reveals that a pre-transplant test dose PK allows accurate targeting of busulfan dosing. The conditioning regimen of bortezomib and IV busulfan with PK-directed dose optimization is well tolerated in patients with relapsed MM who undergo second autologous HSCT. Disclosures: Freytes: Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfex and bortezomib as conditioning regimen for autologous transplant in patients with multiple myeloma. Yeh:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Shaughnessy:Otsuka: Consultancy, Honoraria, Speakers Bureau. White:Otsuka: Consultancy, Honoraria. Rodriguez:Millennium: Research Funding, Speakers Bureau; Otsuka: Research Funding. Yu:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka Pharmaceutical Development and Commercialization, Inc.: Employment. Elekes:Otsuka Pharmaceutical: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Johnson & Johnson: Research Funding.