ALBERT

Description: Performing a stereotyped behavior successfully over time requires both maintaining performance quality and adapting efficiently to environmental or physical changes affecting performance. The bird song system is a paradigmatic example of learning a stereotyped behavior and therefore is a good place to study the interaction of these two goals. Through a model of bird song learning, we show how instability in neural representation of stable behavior confers advantages for adaptation and maintenance with minimal cost to performance quality. A precise, temporally sparse sequence from the premotor nucleus HVC is crucial to the performance of song in songbirds. We find that learning in the presence of sequence variations facilitates rapid relearning after shifts in the target song or muscle structure and results in decreased error with neuron loss. This robustness is due to the prevention of the buildup of correlations in the learned connectivity. In the absence of sequence variations, these correlations grow, due to the relatively low dimensionality of the exploratory variation in comparison with the number of plastic synapses. Our results suggest one would expect to see variability in neural systems executing stereotyped behaviors, and this variability is an advantageous feature rather than a challenge to overcome.

Description: Learning and maintenance of skilled movements require exploration of motor space and selection of appropriate actions. Vocal learning and social context-dependent plasticity in songbirds depend on a basal ganglia circuit, which actively generates vocal variability. Dopamine in the basal ganglia reduces trial-to-trial neural variability when the bird engages in courtship song. Here, we present evidence for a unique, tonically active, excitatory interneuron in the songbird basal ganglia that makes strong synaptic connections onto output pallidal neurons, often linked in time with inhibitory events. Dopamine receptor activity modulates the coupling of these excitatory and inhibitory events in vitro, which results in a dynamic change in the synchrony of a modeled population of basal ganglia output neurons receiving excitatory and inhibitory inputs. The excitatory interneuron thus serves as one biophysical mechanism for the introduction or modulation of neural variability in this circuit.

Description: Background: P is used in combination with G-CSF to improve the mobilization of peripheral blood hematopoietic stem cells in poor mobilizers. Limited data are available in regard to effects of P on post-transplant outcomes in comparison with non-P chemomobilized patients. Methods: In this retrospective study, we compare the engraftment and the outcomes of 34 patients mobilized with P + G-CSF or just-in-time rescue P in combination with chemotherapy and G-CSF to 143 patients (control group) mobilized with G-CSF with or without chemotherapy in lymphoma and myeloma patients who underwent ASCT between February 2012 and April 2014 at the University of Maryland Greenebaum Cancer Center. Post-transplantation outcomes including infections, hematologic recovery, relapse, progression and survival were recorded. Results: The median number of collected of CD34+ cells/Kg was 5.9 x 10(6) in the P group and 12.3 x 10(6) in the control group (p=0.0002). Median time to neutrophil engraftment (〉0.5 × 10(9) /L) was comparable between the 2 groups: 12 days for the P group and 11 for the control group (p=0.28). There was a trend toward a shorter time to platelet engraftment (〉20 × 10(9) /L) in the control (12 days) compared to the P group (14 days) (p=0.056). Progression-free survival at 1 year after (ASCT) was 88.2% in the P group and 81.8% in the control group. There was no difference in the overall survival of both groups (p=0.62) Conclusions: Short and long-term engraftment and outcomes after ASCT seem to be comparable in lymphoma and myeloma patients receiving plerixafor compared to chemomobilized patients without plerixafor. This observation support the use of plerixafor + G-CSF or just-in-time rescue P in patients who mobilize poorly without P. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3858 Background: Standard therapy for high-risk MDS consists of one of two FDA-approved demethylating agents, azacitidine or decitabine. AML patients considered unfit for intensive chemotherapy are also frequently treated with one of these agents, both of which have activity in AML and an acceptable toxicity profile. These agents are not considered curative, and responses are of variable duration. When azacitidine or decitabine is not effective, or is no longer effective, few options are available. In view of differences in pharmacological properties between these two agents, it is not uncommon to switch demethylating agents after failure of initial demethylating agent therapy. To date, only two small studies have addressed the outcome of this intervention, with conflicting results. In a study of 14 MDS patients treated with decitabine following failure of, or progression on, azacitidine, 4 patients (28%) responded (Borthakur et al, Leuk Lymph 2008), while a subgroup analysis of 10 evaluable patients treated with decitabine following azacitidine failure demonstrated no complete or partial responses (Prebet et al, J Clin Oncol 2011). Here we report outcomes in a retrospective analysis of 22 MDS and AML patients who received decitabine after azacitidine. Methods: Charts of 22 MDS or AML patients who were evaluated at the University of Maryland Greenebaum Cancer Center between January 1, 2008 and March 31, 2012 and who received decitabine after azacitidine were reviewed. Results: Patient and disease characteristics for 13 MDS patients and 9 AML patients are shown in Table 1. All patients were initially treated with azacitidine before being switched to decitabine following lack of response to initial therapy or disease progression after initial response. Five of 9 AML patients received azacitidine as frontline therapy, while four received it after other induction chemotherapy regimens. Disease responses following azacitidine 75mg/m2 for 5–7 days in 28-day cycles were variable as shown in Table 1. The median number of courses of azacitidine to disease response for MDS and AML patients who responded was 5 (range, 2–10), median disease-free survival (DFS) was 6.1 months (range, 2.3–16), and median number of courses of azacitidine received was 9 (range, 1 to 17). All 22 MDS and AML patients were refractory to, or progressed after, subsequent decitabine therapy after receiving a median of 2 courses (range, 1–6). Conclusions: Our study population represents the largest to date and the first in which AML disease responses to decitabine after failure of azacitidine have been studied. All MDS and AML patients were refractory to decitabine therapy following initial treatment with azacitidine. Thus this approach should generally not be employed. New therapies are needed for patients for whom demethylating agent therapy is, or becomes, ineffective, and these patients should be enrolled on clinical trials whenever possible. Disclosures: Baer: Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding.