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Background: The usefulness of positron emission tomography with computed tomography (PET–CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. Methods: We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET–CT after achieving complete metabolic response (CMR) following primary therapy. Results: Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8–133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI)

Objectives . Significant obesity is considered to be a relative contraindication to laparoscopic surgery. This study reviews the complications encountered in massively obese patients undergoing urologic laparoscopic surgery. Methods . Body mass index (BMI) was used as an objective index to indicate massive obesity. Eleven institutions compiled retrospective data on 125 patients having a BMI greater than 30. Procedures performed included 76 pelvic lymph node dissections, 14 nephrectomies, 7 bladder neck suspensions, and 28 miscellaneous procedures. Results . For the group as a whole, the mean BMI was 35.1 (range 30.1 to 57.2). Mean operative time was 202 minutes (range 60 to 480). Conversion to open surgery occurred in 15 of the 125 patients (12%). Complication rates (minor and major) were 22% (27 occurrences in 125 patients) intraoperatively and 26% (33 occurrences in 125 patients) postoperatively. The major complications included 2 trocar injuries to abdominal wall vessels, 1 bladder injury, 3 peripheral nerve injuries, 1 dysrhythmia, 1 deep vein thrombosis, 1 wound seroma, 1 nephrocutaneous fistula, 1 incisional hernia, and 1 death. Conclusions . In this review, complication rates for urologic laparoscopic surgery on massively obese patientswere higher than in the general population undergoing laparoscopic surgery (0.3% to 21%).

Introduction: Hypomethylating agents (HMA), including AZA, used to treat cytopenias in MDS patients (pts), can exacerbate thrombocytopenia. Such pts are usually treated with repeated platelet transfusions and AZA dose adjustments. Relieving thrombocytopenia may reduce platelet transfusion requirements and allow optimal AZA dosing. Eltrombopag is an oral TPO receptor agonist approved for the treatment of pts with chronic ITP, hepatitis C virus-related thrombocytopenia, and recurrent severe aplastic anemia. SUPPORT was a randomized, double-blind, placebo-controlled trial investigating the platelet supportive care effects of eltrombopag versus placebo in pts with intermediate (int)-1, int-2 or high-risk MDS receiving AZA. Methods :Adult pts with no previous exposure to HMA, baseline (BL) platelets Results:356 pts (median age 70 [range 24-89] years) received eltrombopag (n=179; n=64 int-1, n=77 int-2, n=38 high-risk) or placebo (n=177; n=61 int-1, n=83 int-2, n=33 high-risk). 29 (16%) eltrombopag and 37 (21%) placebo pts were platelet-transfusion dependent at BL. Median time on AZA plus eltrombopag or placebo was 83 (range 1-477) vs 149 (8-503) days. Most common reasons (≥10%) for treatment discontinuation on eltrombopag or placebo, respectively, were study termination (32 vs 44%), AZA discontinuation (30 vs 26%) and AEs (22 vs 14%). Median eltrombopag or placebo doses were 113 (range 60-148) vs 122 (81-147) mg/day in East Asians and 200 (65-293) vs 262 (107-316) mg/day in non-East Asians. At an interim analysis (n=147 evaluable pts), 13/79 (16%) eltrombopag and 27/68 (40%) placebo pts were platelet-transfusion independent [OR: 0.25, 95% CI: 0.11, 0.61; one-sided P=1.000], crossing the pre-defined futility boundary. At premature (primary and final analysis) study termination (n=356), 28/179 (16%) eltrombopag and 55/177 (31%) placebo pts were platelet-transfusion independent during the first 4 cycles of AZA (OR: 0.37, 95% CI: 0.21, 0.65; one-sided P=1.000). At study closure, 57 (32%) and 51 (29%) pts had died in the eltrombopag and placebo arms, respectively, with 33 (19%) and 29 (16%) deaths within 30 days after end of treatment; the main causes of death (≥10%) were disease under study (16 vs 12%) and sepsis (10 vs 7%). Disease progression (investigator-assessed) had occurred in 38 (21%) and 30 (17%) pts in the eltrombopag and placebo groups, respectively, at the time of study discontinuation. The most common AEs for eltrombopag are summarized (Table). Conclusions: In contrast to published reports on eltrombopag monotherapy inducing platelet transfusion independence in MDS pts, eltrombopag given concomitantly with AZA was inferior to placebo/AZA. There was no difference in overall deaths between the two groups. A complete assessment of disease progression, including AML progression at the time of study termination, is in progress. Pharmacodynamic antagonism between AZA and eltrombopag is proposed as one potential explanation for these results; further analyses and preclinical studies are ongoing to determine a possible mechanism of drug-drug interaction and the impact of drug sequencing on this potential association. Disclosures Dickinson: GlaxoSmithKline: Consultancy, Research Funding. Fenaux:Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celegene, Novartis, Teva: Honoraria. Mittleman:Celgene, Novartis, Janssen: Speakers Bureau; Novartis, Pfizer, Janssen, Roche: Consultancy. Portella:Novartis: Employment. Burgess:Novartis: Employment. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Background: Bromodomains (BRDs) are domains found in a variety of proteins that recognize and bind to acetylated lysine residues in histone and other target proteins. The BRD and extra-terminal (BET) family of BRD-containing proteins bind to acetylated histone tails, alters chromatin structure and facilitates transcriptional complex localization to specific genes, thereby regulating gene transcription. The investigational agent GSK525762 is a potent small molecule inhibitor of the BET family of proteins that prevents assembly of macromolecular complexes and transcriptional response. GSK525762 inhibits growth in a broad spectrum of human hematological cancer cell lines, including cell lines derived from human patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), and multiple myeloma (MM). GSK525762 is orally bio-available and can cause tumor reduction and improved animal survival in in vivo xenograft models of hematologic malignancies. Methods: This is a Phase I/II, open-label, 2-part study. Part 1 is a dose-escalation phase to determine the safety, tolerability, and recommended Phase 2 dose (RP2D) of GSK525762 in adult subjects with relapsed/refractory AML, NHL, and MM. Dose escalation is performed independently for each of these three cohorts. An accelerated dose titration was employed with one subject per dose level until the occurrence of a ≥Grade 2 drug-related toxicity or dose-limiting toxicity; thereafter, subjects have been enrolled in a standard 3+3 design. A Neuenschwander continual reassessment method (N-CRM) model is used at each dose escalation decision to provide guidance for the next dose escalation level. Starting dose is 5 mg GSK525762 orally once daily and dose escalation continues until the MTD is identified. All data, including safety, tolerability, pharmacokinetics (PK), and efficacy, are used to identify the RP2D. In Part 1, approximately 60-70 subjects will be enrolled (approximately 20 in each of three disease-specific cohorts); no hypothesis is being tested, and all analysis will be descriptive and exploratory. In Part 2, the clinical activity of GSK525762 (overall response rate) will be evaluated in expansion cohorts of subjects with AML, NHL, and MM. Up to 32 subjects may be enrolled into the AML and NHL cohorts, and up to 37 subjects may be enrolled in the MM cohort. Cohorts may be closed early if they do not exceed futility assessment. In addition, an exploratory cohort of subjects with double-hit lymphoma (DHL) and triple-hit lymphoma (THL) will be enrolled to evaluate clinical activity in this patient population. Additional study objectives include analysis of PK after single and repeat dosing, evaluation of pharmacodynamics (PD) and the relationship between GSK525762 exposure and safety/efficacy/PD parameters. Recruitment is ongoing across five centers (USA, UK, and Australia). Currently, 40 subjects have been enrolled (29 AML, 8 NHL, and 3 with MM). Study funded by GSK. Disclosures Stein: Seattle Genetics: Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Consultancy. Huntly:Novartis: Speakers Bureau; BMS: Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Speakers Bureau. Dickinson:GlaxoSmithKline: Consultancy, Research Funding. Horner:GlaxoSmithKline: Employment. Brennan:GlaxoSmithKline: Employment. Baron:GlaxoSmithKline: Employment. Kremer:GlaxoSmithKline: Employment, Equity Ownership. Dhar:GlaxoSmithKline: Employment.

Introduction. Despite considerable efforts towards novel therapeutics research and discovery, outcomes in AML remain poor. Although composite Complete Remission (cCR; CR, CRp, CRi) is routinely used as a measure of therapeutic clinical activity, cCR frequently does not translate to survival benefit. On this basis, the characterization and tracking of minimal residual disease (MRD) has emerged as a tool to help better define the depth of such cCR to offer prognostic utility on AML patients likely to experience survival benefit from a given experimental therapeutic. The MDM2 antagonist idasanutlin has shown promising clinical activity in AML. Idasanutlin enhances p53 activity through antagonism of the MDM2:p53 interaction. Disruption of this protein:protein interaction inhibits MDM2 targeting of p53 for ubiquitination and degradation, thus stabilizing p53 protein to exert tumor suppressor transcriptional regulation and induction of apoptotic pathways. Patients and Methods. Trial NP28679 (NCT01773408) is a Phase 1/1b study evaluating idasanutlin as monotherapy or in combination with cytarabine in relapsed or refractory AML patients with safety as primary and complete remission as secondary endpoints, respectively (Martinelli, EHA, 2016.) Duration of response was available as exploratory clinical data for a subset of patient. Patients' pre-treatment bone marrow aspirate specimens were evaluated by multiparametric flow cytometry using an 18 marker surface antigen-based panel. MRD assessment occurred per protocol recommendation at the time of hematological malignancy response assessment (HMRA) at Day 28 and for those patients initially experiencing cCR at each subsequent HMRA. Further flow cytometry analyses were conducted for expression changes of known p53 regulated proteins in CD45+(dim) blasts correlating with drug exposure, consistent with mechanistic engagement. Results. PFS analyses for cCR patients versus non-CR Kaplan-Meier plots indicate the median for responders is 315d (95%CI: 282, NA) versus non-responders is 43.5d (95%CI: 30, NA). When MRD1% is applied as a cut-point, analytics show a statistical association with median PFS (log-rank p-value < .001) at 367d (95%CI: 219, NA) for 1% is 84d (95%CI: 30, NA.) Median MRD values for CR/CRp/CRi vs PR/HI vs PD are 0.42%, 1.79%, and 19.16%, respectively, again consistent with MRD serving as a surrogate for clinical activity (log rank test for trend p-value = .001) Additionally, multiparametric flow cytometry analysis of idasanutlin pharmacodynamic (PD) protein expression changes comparing pretreatment patient blood specimens to 24 hours following first dose administration indicates that increases in both p53 and MDM2 in CD45+(dim) blasts is associated with steady state drug exposure levels ([Spearman's Correlation =0.27; p=.013] and [Spearman's Correlation=0.24; p=.026,] respectively.) Interestingly, these changes in protein expression for p53 and MDM2 are associated with orthologous PD changes in serum protein macrophage inhibitory cytokine 1 (MIC-1) ([Spearman's Correlation=0.23; p=.035] and [Spearman's Correlation=0.22; p=.042,] respectively.) These PD changes are mechanistically consistent with enhanced p53 resulting from diminished MDM2 ubiquitination and degradation of p53. Conclusions. In summary, the results presented here are consistent with multiparametric flow cytometry MRD assessment as an early indication aligning with cCR in relapsed/refractory AML patients treated with idasanutlin. Further, assessment for association with progression-free survival indicates that the lowest quartile patients by MRD flow cytometry measurement (1%). As such, the data presented here support inclusion of MRD assessment by flow cytometry as a prognostic indicator to provide guiding information for assignment of depth of AML patient response. We will continue to monitor this biomarker for diagnostic potential as a prognostic indicator of survival-based outcomes in future randomized clinical studies of idasanutlin. Disclosures Lanza: Roche-Genentech: Employment. Martinelli:Pfizer: Consultancy, Speakers Bureau; MSD: Consultancy; Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; Celgene: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jukofsky:Roche Pharma: Employment. Reis:Roche Pharma: Employment. Blotner:Roche Pharma: Employment. Drummond:Pfizer: Honoraria, Speakers Bureau; celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Vey:Sunesis: Honoraria. Dickinson:GlaxoSmithKline: Consultancy, Research Funding. Kelly:Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Speakers Bureau. Theron:Roche Pharma: Employment. Venstrom:Roche-Genentech: Employment. Middleton:Roche Pharma: Employment. Chen:Roche Pharma: Employment. Kinnersley:Roche-Genentech: Employment, Equity Ownership. Nichols:Roche Pharma: Employment. Pierceall:Roche Pharma: Employment.

Histone deacetylase inhibitors (HDACi) are approved for the treatment of cutaneous T-Cell lymphoma (CTCL) and Multiple Myeloma. In colon cancer cells HDACi-induced apoptosis is linked to induction of a specific transcriptional response involving upregulation of the immediate-early (IE) response genes FOS, JUN, EGR1, EGR3 and ATF3. To determine if this transcriptional response underpins HDACi-induced apoptosis across multiple tumour types, including CTCL and MM, 50 cell lines derived from common solid and haematological cancers were screened for sensitivity to HDACi-induced apoptosis, and response correlated with IE gene induction. HDACi treatment robustly induced IE gene mRNA and protein expression in multiple tumour lines. IE gene induction was sustained over 24 hours and dependent on the Sp1/Sp3 transcription factors and was also observed in vivo in CTCL patients treated with the HDACi panobinostat. The magnitude of induction of FOS, JUN and ATF3 expression correlated significantly with HDACi-induced apoptosis. The induction of ATF3 was critical for HDACi induced apoptosis as ATF3 downregulation markedly attenuated HDACi-induced apoptosis in multiple tumour lines, and ATF3 knockout MEFs were refractory to HDACi-induced apoptosis. To identify downstream targets of ATF3, the magnitude of ATF3 induction following HDACi treatment was correlated with altered expression of pro and anti-apoptotic genes involved in the intrinsic apoptotic pathway. The magnitude of ATF3 induction correlated inversely with repression of the anti-apoptotic gene Bcl-XL, and ATF3 knockdown attenuated HDACi-mediated Bcl-XL repression. Notably, combinatorial treatment of refractory cell lines with an HDACi and a Bcl-XL inhibitor significantly enhanced HDACi-induced apoptosis. This study demonstrates that IE gene induction is a universal feature of HDACi-induced apoptosis, and that ATF3 as a key driver of HDACi-induced apoptosis through repression of Bcl-XL. These findings establish a method for rapid assessment of HDACi response, and identify a combination strategy for enhancing the activity of these compounds. Citation Format: Anderly C. Chueh, Janson Tse, Paul Ioannidis, Lars Tögel, Bee S. Tan, Mercedes Davlos-Salas, Rebecca Nightingale, Matthew R. Thompson, Bryan Williams, Michael Dickinson, Amardeep S. Dhillon, John M. Mariadason. Histone deacetylase inhibitors induce apoptosis in multiple tumor types through induction of ATF3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4728.

Cutaneous T-cell lymphoma (CTCL) is challenging to treat. Patients with advanced disease typically only enjoy brief responses to conventional chemotherapeutics, and are at particularly high risk of infectious complications during the treatment with chemotherapy. Combination and intensification of conventional chemotherapeutics fails to cure the vast majority of patients with CTCL or other forms of peripheral T-cell lymphoma (PTCL). In this context, biological agents, and in particular the histone deacetylase inhibitors (HDACis), present an attractive alternative because they lack many of the side effects of conventional chemotherapy and appear to overcome chemotherapy resistance.

In a recent edition of this journal, Fianchi et al . [1] retrospectively analyzed the outcomes of 31 patients with chronic myelomonocytic leukemia (CMML) treated with the hypomethylating agent azacitidine. Th ere was variation in the dose schedule of azacitidine, although the majority of patients received 75 mg/m 2 subcutaneously over a 7-day period. After a median number of 6 cycles, the overall response rate was 51%, including 42% of patients achieving complete remission. Th e median overall survival from commencement of azacitidine was 37 months. Analysis of this cohort was signifi cant, given the limited data available on the effi cacy of azacitidine in chronic myelomonocytic leukemia (CMML). Th e large phase III trials describing the effi cacy of azacitidine and decitabine in patients with myelodysplastic syndromes (MDS) included only 35 patients with CMML treated with either agent [2 – 4]. As a result, the generalizability of the results of these trials to patients with CMML is unclear, and therefore retrospective case series provide the best available data to establish the effi cacy of these agents in this setting. To investigate whether our own clinical experience refl ected the fi ndings of Fianchi et al ., we retrospectively reviewed the outcomes of 11 patients with CMML treated with azacitidine at our center between 2008 and 2012. Patients fulfi lling the 2008 World Health Organization (WHO) criteria [5] for diagnosis of CMML and who had received at least one cycle of azacitidine were included. Treatment consisted of azacitidine at a schedule of 75 mg/m 2 subcutaneously daily for 7 days per cycle, with a planned cycle length of 28 days. One patient had a shortened cycle length of 21 days due to highly proliferative disease. Six patients (55%) received concurrent therapy with either thalidomide or lenalidomide within clinical trials [6]. Responses were assessed using the modifi ed International Working Group Criteria (2006) [7]. Patient characteristics are shown in Table I. Seven patients (64%) had CMML-1 and four (36%) had CMML-2. Our cohort included a signifi cant proportion of patients with an elevated baseline white cell count (WCC): four (36%) patients had WCC 13 10 9 /L. Five were red cell transfusion-dependent at baseline. Of the 10 patients who had cytogenetic analysis performed at baseline, two (18%) had poor-risk cytogenetics including abnormalities of chromosome 7. Our patient cohort received a median number of 8 cycles (range 2 – 29) of therapy and had a median follow-up time of 15.9 months (range 2.8 – 38.1months). At the time of analysis, four patients continued to receive treatment with azacitidine. Th e overall response rate was 55% (95% confi dence interval [CI] 28 – 79%). Th is comprised one complete response (CR), three marrow CR, one partial response (PR) and one patient who achieved a hematologic improvement (HI) in erythroid and platelet lineages. Four patients had stable disease and one had progressive disease as their best response. In the patients who attained a disease response, the median time to fi rst response and duration of response were 4.1 months (range 1.6 – 8.2) and 7.0 months (range 2.3 – 13.4), respectively. Response rates appeared similar between patients with CMML-1 or -2 (50% vs. 57%). Th e response rate was numerically higher in patients with a lower white cell count ( 13 10 9 /L) or monocyte count

The transformation of follicular lymphoma to an aggressive lymphoma is a well-recognised complication that occurs at a rate of approximately 3 % a year for the first 10 years of observation. Transformation is accompanied by increased risk of refractoriness and a poor expectation of survival. Genetic and epigenetic triggers for transformation have been described. Prior to routine use of rituximab, transformed lymphoma was managed in a fashion similar to that for de novo diffuse large B-cell lymphoma, with generally poor results. Rituximab appears to have improved outcomes. Some centres, including our own, use high-dose chemotherapy with stem cell transplantation as consolidation for those with responsive disease. Here, we focus on transformed follicular lymphoma, and provide an overview of the current literature and our approach to management.

Cutaneous T-cell lymphomas (CTCL) are relatively rare lymphomas with an annual incidence of approximately 0.2 to 0.8/100,000 and comprise a variety of clinical entities; mycosis fungoides or its leukemic variant Sezary syndrome account for the majority of cases. Advanced-stage disease is typically treated with bexarotene (a retinoid), interferon, or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors, which modify the epigenome, are an attractive addition to the armamentarium. On the basis of 2 large phase II studies, the U.S. Food and Drug Administration approved intravenous romidepsin for patients with relapsed and/or refractory CTCL. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side effect profile. Clin Cancer Res; 18(13); 3509–15. ©2012 AACR.

The utility of ([18F])fluoro-2-deoxy- d-glucose positron-emission tomography (FDG-PET) for predicting outcome after autologous stem cell transplantation (ASCT) for diffuse large B cell lymphoma (DLBCL) is uncertain - existing studies include a range of histological subtypes or have a limited duration of follow-up. Thirty-nine patients with primary-refractory or relapsed DLBCL with pre-ASCT PET scans were analysed. The median follow-up was 3 years. The 3-year progression-free survival (PFS) for patients with positive PET scans pre-ASCT was 35% vs. 81% for those who had negative PET scans (P = 0.003). The overall survival (OS) in these groups was 39% and 81% (P = 0.01), respectively. In a multivariate analysis, PET result, number of salvage cycles and the presence of relapsed or refractory disease were shown to predict a longer PFS; PET negativity (P = 0.04) was predictive of a longer OS. PET is useful for defining those with an excellent prognosis post-ASCT. Although those with positive scans can still be salvaged with current treatments, PET may useful for selecting patients eligible for novel consolidation strategies after salvage therapies.

The utility of ([18F])fluoro-2-deoxy- d-glucose positron-emission tomography (FDG-PET) for predicting outcome after autologous stem cell transplantation (ASCT) for diffuse large B cell lymphoma (DLBCL) is uncertain - existing studies include a range of histological subtypes or have a limited duration of follow-up. Thirty-nine patients with primary-refractory or relapsed DLBCL with pre-ASCT PET scans were analysed. The median follow-up was 3 years. The 3-year progression-free survival (PFS) for patients with positive PET scans pre-ASCT was 35% vs. 81% for those who had negative PET scans (P = 0.003). The overall survival (OS) in these groups was 39% and 81% (P = 0.01), respectively. In a multivariate analysis, PET result, number of salvage cycles and the presence of relapsed or refractory disease were shown to predict a longer PFS; PET negativity (P = 0.04) was predictive of a longer OS. PET is useful for defining those with an excellent prognosis post-ASCT. Although those with positive scans can still be salvaged with current treatments, PET may useful for selecting patients eligible for novel consolidation strategies after salvage therapies.

This paper presents the issues encountered in the development of a robot based on the biometric influence of a bear. One of the main aims of this research was to explore the possibilities of a robot, which could move between the different styles of motion. The bear offers a unique example of an animal with high mass and bulk, which can move between being a quadruped and a biped. Our earlier research had explored the development of a robotic dog. A quadruped robot design, suitable for use as a player in the RoboCup Four Legged League, which used the parameters of the existing Sony Aibo robot as a starting point. The outcomes of this research have been discussed in papers by Chalup and Lawrence. The current research has extended the previous platform development and reset the objective to a robot with both bipedal and quadrupedal motion possibilities. The original objectives of developing a high quality design with enhanced research programming possibilities, which also coveys a positive and engaging image of Science and Engineering through its form, were maintained. This is specially so, when considering the robot's ability to create interest in the general public, who will view the robot from a perspective outside of discipline specific interests. The introduction presents the biological inspiration for the current design, including the preparation and material production considerations. This is followed by a discussion of specific features of the robotic bear design, which has been given the name HyKim, followed by a conclusion.

There are many commercially available robots that display biomimetic influences. Sony's Aibo and DasaRobot's Genibo are two examples where robot dog designs have drawn from nature. Aldebaran's Nao and Hanson Robotics' Zeno are examples of humanoids robots that have drawn influences from the human body. This paper presents the design of an autonomous 21 degree of freedom (DOF) robot bear, named HyKim and discusses the relevant biomimetic influences. After discussing the motivation for creating a robot bear, the biomimetic principles that were applied to the mechanical design, to ensure the resulting robot was dasiabear-likepsila, are presented. The design of the computer and electronic architecture was based on four essential design criteria - open architecture, performance, modularity and reliability. How these criteria were met is then presented, followed by a discussion on future research projects that will be based on or include HyKim. Finally a conclusion summarising the design is presented.

Introduction. Despite years of translational research and discovery, outcomes in Acute Myeloid Leukemia remain poor. The MDM2 antagonist idasanutlin has shown promising clinical activity in solid tumors and acute leukemias. Idasanutlin enhances the activity of the tumor suppressor, p53, through antagonism of MDM2:p53 interaction. Such protein:protein disruption abolishes MDM2 targeting of p53 for ubiquitination and degradation. Subsequent stabilization of the p53 protein allows it to exert tumor suppressor transcriptional regulation and induction of apoptotic pathways. Identification of patients in whom functional p53 activation drives efficacy may translate into improved outcomes for patients treated with idasanutlin. Patients and Methods. Trial NP28679 (NCT01773408) is a Phase 1/1b study evaluating idasanutlin (as monotherapy or in combination with cytarabine) in relapsed or refractory AML patients, with clinical response as the primary endpoint. To identify biomarkers of response, patients' pre-treatment peripheral blood specimens were evaluated for MDM2 protein expression levels in leukemic blasts and leukemic stem cells. Association of MDM2 percent cell positivity with clinical outcomes was evaluated using intracellular flow cytometry gated on CD45dim leukemic blasts and CD45dim/CD117+/CD34+ leukemic stem cells. Results. We observed in a proof-of-principle training data set that MDM2 expression in leukemic blasts was associated with patients more likely to exhibit Complete Remission (CR, CRp, CRi) versus Progressive Disease (PD, HI, PR) [n=61; Wilcoxon p = .0041 (AUC = .74; 95%CI[.57, .91])] TP53 mutational status alone was not tightly associated with patient response (Fisher's Exact Test p = .19 [AUC = .60; 95%CI [.52,.67.])] When MDM2 protein expression and TP53 mutational status were analyzed as co-variates, an enhanced association with patient CR was observed (AUC = .76; 95% CI [.59, .93.]) A separate group of patients treated with an optimized idasanutlin formulation was utilized as a validation set. Association of CR with MDM2 expression in blasts was also shown in this separate patient population [n=24; Wilcoxon p = .0052 (AUC = .82; 95% CI [.64, 1.00.]) Comparable results were observed for proof-of-principle and validation set analyses of response association with MDM2 protein expression in AML patients CD45dim/CD117+/CD34+ stem cell subpopulations. Conclusions. In summary, training and validation sets reveal that MDM2 protein expression in leukemic blasts and stem cells are associated with idasanutlin-induced CR in patients with AML. We will continue to monitor this potentially predictive biomarker in future randomized clinical studies of idasanutlin. On a broader level, the data presented here support the concept that leukemic blasts may be "oncogene-addicted" to MDM2 in AML, i.e. that AML tumor cells may rely on a dominant oncogene for growth and survival, such that inhibition of the function of this specific oncogene is sufficient to halt the neoplastic phenotype. Thus, the concept of oncogene addiction may apply not only to mutated kinases but also to ubiquitin ligases such as MDM2. Disclosures Reis: Roche Pharma: Employment, Equity Ownership. Jukofsky:Roche Pharma: Employment, Equity Ownership. Chen:Roche Pharma: Employment, Equity Ownership. Martinelli:BMS: Speakers Bureau; MSD: Consultancy; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy. Zhong:Roche Pharma: Employment, Equity Ownership. So:Roche Pharma: Employment, Equity Ownership. Drummond:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Assouline:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Hashemyan:Roche Pharma: Employment, Equity Ownership. Theron:Roche Pharma: Employment, Equity Ownership. Blotner:Roche Pharma: Employment, Equity Ownership. Rueger:Roche Pharma: Employment, Equity Ownership. Middleton:Roche Pharma: Employment, Equity Ownership. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Nichols:Roche Pharma: Employment, Equity Ownership. Chen:Roche Pharma: Employment, Equity Ownership. Pierceall:Roche Pharma: Employment, Equity Ownership.

This paper identifies the theoretical stimulants and impediments associated with the implementation of PFI/PPP (Private Finance Initiative/Public Private Partnership)projects. A current defect of this procurement approach is the unintentional constraint upon the innovations incorporated into the development of PFI projects. A critical evaluation of the published literature has been utilized to synthesize a theoretical model. The paper proposes a theoretical model for the identification of potential innovation stimulants and impediments within this type of procurement. This theoretical model is then utilised to evaluate four previously completed PFI projects. These project case‐studies have been examined in detail. The evaluation demonstrates how ineffective current procedures are. The application of this model before project letting could eliminate unintentional constraints and stimulate improved innovation within the process.The implementation of the model could improve the successful delivery of innovation within the entire PFI/PPP procurement process.

TO THEEDITOR:Transformationoffollicularlymphoma(tFL) in the prerituximab era was associated with poor treatment responseandmediansurvivalratesofonly7to20months, 1-3 leading manycenterstoadopthigh-dosetherapyandautologousstem-cell transplantation (autoSCT) as standard treatment for this condition. 4,5 In the rituximab era, little is known about whether the results of rituximab-containing chemotherapy (R-chemotherapy) havealteredtheoutcomeoftFLsufficientlytoremovetheneedfor consolidation with autoSCT, especially for patients in complete remission after chemotherapy. This is an important question as autoSCTisassociatedwithamodestriskoftransplantation-related mortality and demands substantial use of health resources. 6 The Canadian Blood and Marrow Transplant Group’s report on tFL sheds valuable insight into the role of autoSCT in the rituximab era. 7 Although the 5-year overall survival rate (OS) of patients treated with autoSCT was not significantly different from that of those treated with R-chemotherapy (without transplantation) on univariate analysis (65% v 61%; P .24 for comparison across allogeneic SCT, autoSCT, and R-chemotherapy), the multivariate analysis (MVA) of OS unexpectedly showed a significant advantage favoring autoSCT (hazard ratio, 0.13; P .001). The authorsconcludedthat“ourdatasuggestthateligiblepatientswith tFL may benefit from autoSCT because it improves OS compared with R-chemotherapy.” 7 We believe that there may be important, practice-changing messages that could emerge from further exploration of this unusual Cox regression result. In particular, we believe that it is important to investigate why the MVA should uncover a new finding of inferior OS in patients treated with R-chemotherapy compared with autoSCT, when the R-chemotherapy group had a higher proportion of patients with adverse risk factors including age older than 60 years and elevated lactate dehydrogenase at transformation(riskfactorsproventobeindependentlyassociated

When Hans Christian Andersen wrote 'The Little Match Girl' [1] he was not writing a product endorsement. Far from it. But we have been left with a glowing example of a product that was affective. The experience may have been fleeting, but the euphoric pleasure experienced by the girl was real. As we explore the notion of pleasure in the designed object we must not forget how much pleasure is context-driven. As designers, we must understand that context is not always in our control; that our designs, like our children, will live their own lives. Pleasure is found when the moment is right, when events align.This happens despite our planning and skill, or our analysis and rigour. The message of this paper, wrapped in the style of an Andersen story, looks at the relationship between two objects. One is desired, enjoyed, treasured, and the other an ordinary matchbox. Unwrap at your pleasure.

Background: RG7388 is a new, potent, oral, nutlin-class MDM2 antagonist. This trial evaluated its use in AML to determine the recommended phase 2 dose (RP2D), dose-limiting toxicities (DLTs), pharmacokinetics (PK), pharmacodynamics and clinical responses. Methods: This multicenter, open-label phase 1/1b dose escalation (DE) study evaluated RG7388 as monotherapy (daily ´ 5 d q28d) (Part 1 DE) and in combination with cytarabine (ara-C 1 g/m2 IV x 6 d q28d) (Part 2 DE). Extensions (Ex) were initiated at the RP2D. Part 1Ex (RG7388) included pts > 70 y or > 60 y with comorbidities. Part 2Ex pts (RG7388 ± ara-C) had relapsed/refractory (R/R) AML, ≤ 2 regimens and no antecedent hematologic disorders (AHD) or transplant (ASCT). Blood and marrow analyses included PK, TP53 mutations (mt) by AmpliChip, serum MIC-1 and MDM2 gene expression. Results: To date, 86 pts have been treated. DE is complete, Part 1Ex was discontinued after 9 pts and 34 of 40 planned pts are enrolled in Part 2Ex. One DLT of prolonged myelosuppression was reported. RP2D is 1200 mg/d (600 mg bid) x 5 d q28d for both mono- and combination therapy due to diarrhea not formally a DLT but felt to be dose-limiting. The most common adverse events were GI (diarrhea reported by > 85% of pts) or infection-related (> 70% of pts). Twenty pts received monotherapy during Part 1 DE at 400 (n = 2), 800 (n = 6) and 1600 mg (n = 12) daily x 5 d. Median age was 68.5 y (range 28-83 y), median prior therapies = 2 (range 0-4), 1 pt had ASCT and 8 had AHD. Four pts died in the first 30 days. Five pts achieved either a CR (n = 2) or CRi/MLFS (n = 3). In Part 1Ex, 9 pts were treated with RG7388 at the RP2D. Median age was 75 y (range 66-83), 8 pts had AHD (6 prior hypomethylators, 3 pts lower intensity therapy) and 1 had prior solid tumor. Best responses reported were 1 CRi/MLFS, 1 PR, 1HI, 3 PD. Three pts died in the first 30 days. Further enrollment in this arm was discontinued as induction of prolonged myelosuppression increased the risks of infection and early deaths. Combination treatment with lower RG7388 doses may be better tolerated in this fragile elderly population. Twenty-three pts were enrolled in Part 2 DE (RG7388 + ara-C) at daily doses of 400 (n = 10), 800 (n = 7), and 1200 mg (n = 6); median age 64 y (range 32-76); median prior therapies = 1.5 (range 0-5); prior ASCT 2; AHD 4; 5 had prior malignancies. Four pts died in the first 30 days. Six relapsed AML pts achieved CRs (4 received prior ara-C and 2 had prior hypomethylators). To date, 34 of 40 planned pts with R/R AML have been enrolled to Part 2Ex (RG7388 ± ara-C); 23 pts have responses reported, with 4 CRs, 1 CRi, 1 PR, 1 HI, 16 PD. Three pts died in the first 30 days. T1/2 is ≈ 1 d, irrespective of age, concomitant azoles or ara-C. Bone marrow levels are ≈ 70% of plasma drug levels at steady state. CRs were seen in diverse pts, including varied risk groups, prior AHD, therapy-related AML (t-AML), p53 mt, R/R and de novo AML. All pts who achieved a CR during DE were relapse free for > 60 d. One pt on monotherapy and 2 on combination therapy remained relapse free for > 400 d and > 200 d from start of study, respectively. A potential predictive gene expression signature correlated with RG7388 therapy (AUC = 0.73, p = 0.021). Conclusions: We report the Ph1/1b PK, safety and clinical activity of a new, potent MDM2 antagonist in AML. CRs occur rapidly and are durable (> 60 d) in elderly AML pts with RG7388 monotherapy and in R/R pts with combination therapy. | Part 1 DE (N = 20) 16 responses | | ------------------------------- | ---------------------------------- | | Best response | 2 CR; 3CRi/MLFS | 3 PR | 4 HI | 4 PD | | TP53 status | WT | WT | 1 MT, 3 WT | 1 V | | ELN* AHD(responders) | 4 I, 1 A 3 (MDS, MF, CMML) | 3 I 2 (MDS, CMML) | | | | Part 1Ex (N = 9) 6 responses | | Best response | 1 CRi/MLFS | 0 PR | 2 HI | 3 PD | | TP53 status | WT | | WT, MT | 2 WT, 1 U | | ELN* AHD(responders) | I ET | | | | | | | | | | | Part 2 DE (N = 23) 20 responses | | Best response | 6 CR | 2 PR | 2 HI | 10 PD | | TP53 status | 1 MT | WT | WT | 1 MT, 1 V | | ELN* AHD(responders) | 1 F, 3 I, 2 A 1 t-AML | 1 I, 1 A | | | | Part 2Ex (N = 34) 23 responses | | Best response | 4 CR; 1 CRi/MLFS | 1 PR | 1 HI | 16 PD | | TP53 status | 4 WT, 1 U | WT | WT | 1 MT, 5 WT, 10 U | | ELN*(responders) | 1 F, 3 I, 1 A | A | | | * CR, complete remission; CRi, complete remission with incomplete recovery; HI, hematologic improvement; MLFS, morphologic leukemia-free state; PD, progressive disease; PR, partial response; WT, wild type; V, splice variant; U, unknown/pending; AHD, includes myelodysplastic syndrome (MDS), essential thrombocythemia (ET), chronic myelomonocytic leukemia (CMML), myelofibrosis(MF) * *ELN: Risk by European Leukemia Net: favorable (F), Intermediate I and II (I), or adverse (A) Table Patient characteristics by response to treatment Disclosures Yee: Roche: Research Funding. Martinelli: Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau. Vey: Roche: Honoraria. Assouline: Roche: Honoraria, Research Funding; Janssen: Honoraria. Drummond: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Blotner: Roche: Employment. Higgins: Roche: Employment. Middleton: Roche: Employment. Nichols: Roche: Employment. Chen: Roche: Employment. Zhong: Roche: Employment. Pierceall: Roche: Employment. Zhi: Roche: Employment. Chen: Roche: Employment.

Background: Pre-existing thrombocytopenia in MDS/AML is worsened during the initial cycles of azacitidine (AZA) therapy, resulting in bleeding risk and possible platelet transfusion. Eltrombopag (EPG) is an oral TPO-receptor agonist. In vitro, it has anti-proliferative effects on AML blasts. Aim: To assess the safety of escalated doses of EPG in patients undergoing AZA for MDS/AML Method An investigator-initiated phase-II, single arm, study of EPG with AZA. Inclusion: relapsed or de-novo MDS/CMML/AML (blasts 5-30%); or symptomatic cytopenia; or blasts 31-50% if >/=65 years or previously-treated disease; and platelets Result Of 25 patients, 10 had prior therapy, which was chemo in 7; of these 6 had blasts >/=10%, 2 with blasts 20% or above. Of the 15 de-novo patients, 7 had blasts >/=20% (AML) and a further 2 had blasts between 10 and 19%. The median platelet count was 38x10^9/L (range 8-127). A median 11(2-24) cycles AZA and 6 cycles of EPG were delivered. One patient developed GrII EPG-related LFT abnormalities (resolved). Grade 3 fatigue was attributed to the combination in one patient. Thrombocytosis (>450 x109/L) resulting in EPG cessation occurred in 6 (at 50, 50, 150 and three at 200mg), without complications. 10 patients experienced reversible skin yellowing. Response/improvement was seen in 18 (72%): 7CR, 3CRm, 5HI-P,1 HI-N,2 with >50% blast reduction from >20% (8%). 5 patients had progression at first response. There were 19 events in total (17 progressions, 2 with worsening haematology). Median PFS was 12.0 months (95% CI 5.6 to 24.3 months). Median OS was 15.3 months (95% CI 11.9 to 31.7 months). Platelet improvement was seen in 54% (13/24) of patients with baseline platelets Conclusion Eltrombopag could be safely delivered at these doses. A phase III international study has commenced to better define the role of this combination as supportive care for patients undergoing treatment with azacitidine. Table:Characteristics and best responses observed.MDS/AML CharacteristicsBest ResponseMDS /=20%, De Novo (N=8)1CR, 1PR, 3 Hi-P, 1SD, 2 PDPrior therapy for MDS/AMLBlasts /=20% (N=3)2PD, 1 Hi-P Figure: Overall survival of the trial population. Figure:. Overall survival of the trial population. Disclosures Dickinson: GSK: Consultancy; Celgene: Honoraria. Off Label Use: Eltrombopag for MDS. Sardjono:GSK: Employment. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Kenealy:Celgene: Honoraria, Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding.

This paper examines transformational changes in the UK traditional contracting systems based on its organisation and management. The paper is based on a literature review, two case studies of local authority projects, statistical analysis, and extensive interview of a contractor’s top management team. The findings indicate a shift in the traditional contractor’s contractual role from active participation in construction activities to a mere management role. This is due to the allocation of responsibilities as well as the transfer of financial and technical risks to subcontractors. Secondly, the findings show organisational similarities between traditional and management contracting systems which are an indicative explanation as to why management contracts are diminishing in UK practice. Thirdly, the structure of the industry supports these forms of transformation and the present economic climate will exacerbate the trend. The study can serve as a learning opportunity on the importance of management systems over point of responsibilities as well as promoting innovative systems of contracting.

Aim/Background HDACi induce cancer cell apoptosis and are in use for T-cell lymphoma. Prior studies have indicated that HDACi are immune-suppressive. In this study, we address this issue by examining the effects of two different HDACi on human monocyte derived dendritic cell (hmDC) biology. Methods hmDC were activated by TLR stimuli (LPS or poly:IC). HDACi effect on TLR-induced hmDC activation was assessed by up regulation of co-stimulatory molecules CD80, CD86 and CD83 along with secretion of IL-12p70, IL-10 and IL1β. To address the mechanism for drug-induced altered cytokine secretion mRNA for IL-12p70, IL-10 and IL1β were assessed followed by mir-155 mRNA and SOCS-1 protein. The functional outcome was assessed in an allogeneic MLR. Results At doses sub-optimal to induce myeloma cell death, both drugs significantly inhibited TLR-induced hmDC increase in CD80 and CD83, but not CD86. TLR-induced secretion of IL-10 and IL12p70 was reduced while IL-1β secretion was increased. This occurred regardless of drug sequencing. HDACi did not significantly alter expression of IL-12p70, IL-10 or IL-1β mRNA despite changes in protein levels. To reveal the mechanism for the HDACi-induced hmDC IL-12p70 defect, the upstream molecules miR-155 and SOCS-1 were examined. Interestingly, panobinostat but not romidepsin induced mir-155 down-regulation and SOCS-1 protein increase. Subsequently, allogeneic T-cells co-cultured with HDACi/TLR-ligand-treated hmDC secreted lower levels of cytokines (decreased secretion of IFN-γ, IL-2, TNF, IL-4 and IL-17) compared to those allogeneic T cells co-cultured with control hmDC. Conclusion In this study, we show that whilst HDACi impair DC maturation and modulate subsequent T cell responses. Our findings suggest that panobinostat induces the IL-12p70 effect via the mir-155/SOCS-1 pathway, whereas romidepsin induces the effect via a mir-155 independent pathway. This data suggests that HDACi affect the hmDC maturation response to pathogen, and that these drugs may alter the ability of treated patients to raise an effective immune response to pathogens or, indeed, tumour antigens. Disclosures: No relevant conflicts of interest to declare.

Aim/Background CNS relapse in DLBCL is a devastating complication and the optimum strategy for prevention remains unclear. Methods We performed a multi-centre, retrospective analysis of CNS relapse rates in patients (pts) identified at risk of CNS relapse according to the type of CNS-directed prophylaxis administered. Pts receiving initial therapy for DLBCL between 1996 and 2011 (to allow ≥2 years of follow up) were included; DLBCL after histologic transformation of low-grade lymphoma and HIV-associated DLBCL were included, however pts with Burkitt or Burkitt-like lymphoma or CNS involvement at diagnosis were excluded. Selection for CNS prophylaxis strategy was by the primary managing hematologist if they fulfilled ≥2 of the following criteria: 1) multiple extranodal sites 2) raised serum LDH 3) B-symptoms, OR involvement of specific high-risk anatomical sites. We compared 3 prophylaxis strategies: prior to 2003 intrathecal (IT) methotrexate (MTX) in conjunction with CHOP chemotherapy “group 1” was the main strategy; from 2003 onwards, R-CHOP (mostly) with IT MTX was followed by two cycles of high dose intravenous (IV) MTX (1-3g/m2) “group 2”; patients Results Overall, 208 pts were identified, with 32, 134 and 42 in groups 1, 2 and 3 respectively. Markedly fewer pts in group 1 received rituximab and pts selected for intensive approaches (group 3) were younger, had higher risk disease features (higher serum LDH ratio, more extranodal sites and more B-symptoms) and received fewer doses of IT chemotherapy. The distribution of extranodal sites for each of the three groups was similar, except for epidural/paraspinal disease which was more frequent in group 1 (18%, 5%, 0% in groups 1-3 respectively, P=0.004). With a median follow up of 3.7 years (range 0.4 – 18.6) years, 19 CNS relapses occurred (7, 11 and 1 in groups 1-3 respectively). The 3-year actuarial incidence of CNS relapse was 17.6% (3.5 – 32.7%), 7.3% (3.7 – 11.9%) and 2.4% (0 – 7.1%) in groups 1, 2 and 3 respectively (P=0.026). The 3-year event free survival (EFS) was 70% (53 - 86%), 83% (76 – 90%) and 70% (56 – 84%) in Groups 1 – 3, respectively (P=0.15, data not shown). Use of rituximab, presence of paraspinal disease and decade of treatment were not associated with CNS relapse by univariate analysis. However amongst pts receiving IT MTX, there was a trend toward reduction in CNS relapse for pts receiving 4-6 doses of IT MTX compared to 1-3 (P=0.052) and patients receiving their first dose of IT MTX within seven days of diagnosis (P=0.08). Conclusion The use of IV MTX and dose-intense chemotherapy was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. Download : Download high-res image (85KB) Download : Download full-size image Disclosures: No relevant conflicts of interest to declare. group 1 CHOP + intrathecal MTX group 2 R-CHOP-like chemo +high dose intravenous MTX group 3 HyperCVAD or CODOXM/IVAC +/- rituximab patients 32 134 42 Time period 1992-2003 2003 - 2011 1991-2011 median age, years (range) 55 (29-79) 62 (19-84) yrs 45 (16-74) yrs male (%) 22 (68%) 87 (65%) 24 (57%) stage III/IV (%) 21/31 (68%) 103/132 (82%) 38 (93%) B symptoms 10 (32%) 47 (36%) 27 (64%) median serum LDH ratio (range) 1.1 (0.3-5.9) 1.3 (0.3 – 11.4) 1.7 (0.8 – 25.7) ECOG PS ≥1 17 (55%) 67 (55%) 19 (46%) IPI 3-5 15 (44%) 78 (63%) 26 (65%) extranodal sites ≥2 15 (48%) 45 (51%) 30 (86%) chemotherapy CHOP 30 RCHOP 2 CHOP 2 R-CHOP 122 R-MACOPB 8 Hyper CVAD 22 R-Hyper CVAD 16 R-CODOXMIVAC 2 CODOXMIVAC 1 rituximab 2 (6%) 122 (98%) 18 (43%) IT methotrexate (any) 4-6 doses 1-3 doses no IT 32 (100%) 26 (81%) 6 (19%) 0 (0%) 84/104 (81%) 75 (72%) 9 (9%) 20 (19%) 28/33 (85%) 21 (64%) 7 (21%) 5 (15%)

Second generation chimeric antigen receptor (CAR) T cells were used to treat patients with acute myeloid leukemia (AML) in a phase I clinical study. Autologous T cells were genetically modified to express a CAR which re-directed T cell effector function to the LeY tumor associated carbohydrate antigen on AML cells. CAR-T cell therapy safety, AML disease response, and CAR-T cell trafficking and persistence post-infusion were investigated. Five patients received GMP grade CAR-T cells (LeY-T). Post infusion, no patients experienced grade 3 or 4 toxicities. Patient AML responses to LeY-T cell infusion included a transient cytogenetic response and a reduction in peripheral blood leukemic blast count. In all patients, LeY-T cells trafficked thru peripheral blood, and persisted in the bone marrow. In one patient, leukemia cutis was associated with trafficking of the LeY-T cells to the skin at sites of AML blast infiltration. Despite LeY-T cells being present at the disease site, relapse with LeY-expressing AML blasts occurred in all patients (range 29 days to 23 months) post-infusion. Further studies indicated LeY-T cell CAR expression was downregulated post-infusion in vivo, this was also observed post-LeY antigen exposure and long term culture in vitro. This study provides important safety and feasibility data to support the application of CAR-T cell therapy to treat AML. Furthermore, we provide a potential mechanism for tumor escape from LeY-T cell surveillance in vivo.

34 AUTOLOGOUS PERIPHERAL BLOOD T LYMPHOCYTES TRANSDUCED WITH AN ANTI LEWISY CHIMERIC RECEPTOR GENE CAN BE INFUSED SAFELY AND PERSIST IN PATIENTS WITH LEWISY POSITIVE ACUTE MYELOID LEUKAEMIA A Khot, D Ritchie, P Neeson, S Peinert, T Tai, L Kravets, K Chen, D Hoenemann, M Shin, K Tainton, J Westwood, M Kershaw, J Haurat, J Trapani, M Smyth, P Darcy, A Scott, D Wall, P Gambell, M Dickinson, D Westerman, R Hicks, M Prince Peter MacCallum Cancer Centre, East Melbourne, Australia, Ludwig Institute for Cancer Research, Heidelberg, Australia

Abstract 2652 Introduction Despite improvements in cure rates for patients with diffuse large B-cell lymphoma (DLBCL), up to 40% relapse after achieving initial remission, mostly within 18 months from treatment. There is no consensus as to role, or most appropriate form of post-remission surveillance. Our aim was to explore the role of Positron Emission Tomography combined with computer tomography (PET-CT) scanning in the follow up of patients with diffuse large B-cell lymphoma (DLBCL) achieving complete metabolic response (CMR) after primary therapy, identify patterns of relapse and define a risk-adapted strategy. Results We included 116 patients with de novo DLBCL treated at our centre between 2002 and 2009 with a negative post-treatment PET-CT, and at least one surveillance PET-CT scan. International Prognostic Index (IPI) was PET-CT had very high sensitivity (100%), specificity (98%) and negative predictive value (NPV, 100%) with positive predictive value (PPV) 56% in the cohort of patients with a low IPI ( Conclusion The achievement of CMR at the completion of primary therapy identifies a group of patients with favourable outlook and a low risk of relapse. Surveillance PET-CT scanning within this select cohort has high sensitivity, specificity and NPV and despite the low number of relapses retains a high PPV, particularly in patients with IPI≥3. Surveillance PET-CT is useful in the first 18 months following completion of primary therapy in patients in whom IPI at diagnosis is ≥3. We feel that such a strategy would be appropriate to evaluate in a prospective comparative trial. Disclosures: No relevant conflicts of interest to declare.

A selective, sensitive and rapid procedure based on liquid chromatography coupled to electrospray ionisation in positive mode high resolution mass spectrometry (LC-ESI-HR-MS) has been developed and single laboratory validated for the determination of natamycin, a naturally occurring fungicide, in white and red wine. This technique allowed accurate masses to be measured and interferences excluded from the extracted ion chromatograms. Natamycin measured at a high mass accuracy of m/z 666.31069 and a confirmatory ion at m/z 503.22672 facilitated the use of minimal sample preparation procedures. This allowed for the direct injection (20 µL) of wine, thereby minimising the photosensitive analyte degradation. Chromatographic separation was achieved on a C18 column using a mobile phase gradient of 10% to 90% methanol : acetic acid (97 : 3, v/v) over 25 minutes with a total run time of 30 minutes. The limits of detection and quantification were 3 and 5 µg L−1 respectively. The method was successfully validated to show the standard range linearity, sensitivity, accuracy and precision in the matrices tested. The method was applied to 190 commercial wines, with 50 (26%) positive results (>5 µg L−1) over a period of three months between December 2009 and February 2010, with concentrations ranging from 7 to 2134 µg L−1. Natamycin is not permitted for use in wine within the European Union and this method may be used to aid enforcement of regulations.

The study focuses on managing risk and uncertainty in construction project due to the owner dissatisfaction in project outcome and dynamism within agile construction environment. The aim of the paper is to examine the agility gap created by risk and uncertainty in the supply chain processes through procurement routes. The paper identifies some areas in supply chain processes which are prone to greater risks and uncertainty and proposes an agile management principle based on the concept of integration and fragmentation in product development and execution processes respectively, resulting in agile specialists' involvement. The paper is based on extensive literature review and a comprehensive single case study of 3-office block complex in Finland. The paper concludes that the involvement of the agile specialists mitigates against risks and uncertainty, enhances the project quality and permits a modular approach to design that permits the use of experts' knowledge in design and construction. The proposed model serves as an agile management tool in preventing both predictable and unpredictable external and internal project changes through the early involvement of agile specialists and their integrated attributes in product development through to construction and project startup.

Introduction FDG-PET imaging is a powerful predictor of both positive and negative outcome of initial therapy for DLBCL. Existing data on the utility of PET to predict outcome of ASCT have included a range of histological subtypes, limiting its direct applicability to the setting of DLBCL. Methods Data from 41 consecutive patients who had PET scans immediately prior to undergoing ASCT for treatment of first relapse of de novo DLBCL were analysed. We compared the clinical characteristics, event free survival (EFS) and overall survival (OS) of those with residual FDG avid disease (n=21) against those without FDG avid disease (n=20). Results The median age was 53(18–71). Patient characteristics are shown in the table. At 3 years, the OS was 67(±8)%, and the EFS was the 62(±8)%. EFS for PET positive patients was 38(±12)% vs 79(±9%) for PET negative patients (p=0.04). OS was 37(±17%) vs 81(±10%) (p=0.08) respectively. Conclusion Excellent EFS and OS can be anticipated from ASCT when undertaken in those who have achieved a PET negative remission following salvage chemotherapy. Conversely, failure to achieve a PET negative remission after salvage chemotherapy in relapsed DLBCL predicts for a poorer, but not irretrievable outcome after ASCT, suggesting that a proportion of PET positive patients can be successfully salvaged by either ASCT or post-ASCT salvage therapies. Patient Characteristics PET Positive (n=21) PET negative (n=20) PET negative (n=20) Female 28% 40% Median Age (Range) 53 (28–65) 53(81–71) Salvage Regimen ICE ±R 66% ICE ±R 80% Conditioning Regimen BEAM 47%, SBCNU 23% BuMel 14% other 16% BEAM 25%, SBCNU 25% , BuMel 25% other 25% Rituximab with salvage 71% 95% Rituximab in initial therapy 33% 25% RT with salvage or ASCT 43% 25%

The overall aim of the study is to examine the problems associated with the prevalent procurement routes, subsequent changes in supply chain management and introduction of alternative procurement routes which are innovative and agile in their nature. The trend in the UK seems to favour an integrated supply chain from the outset of a project, resulting into a transition from rigidity to agility within the development process. Client's role within the whole process is quite crucial and this paper shows the practical contribution of public sector clients in initiating as well as implementing innovative procurement routes that integrates the supply chain. The study is conducted via extensive literature review covering policy documents and a case study. The paper presents the techniques used by the public clients such as aggregation of demand to get aggregated supply result in agility and integration among supply chain participants and subcontractors along side the main contractors. The paper concludes that innovative procurement and supply chain integration have contributed towards agility of the involved participants within the construction industry in the detailed mentioned case study. The study can be beneficial to all the stakeholders especially the client in managing supply chain.

The role of allogeneic (allo-) and autologous stem cell transplantation (auto-SCT) in the management of patients with transformed indolent nonfollicular non-Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n = 47) or auto-SCT (n = 199) across the same institutions and time frame. Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%) small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or platinum-containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%) subsequently underwent allo-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT 40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3-year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P = .38, P = .69, and P = .54, respectively). Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT.