Search

Supplementary Table S1. Overall activity and predictors of treatment failure (PD or less than partial response by IWG criteria). Supplementary Figure S1. BCL-2 family protein index at screening. Supplementary Figure S2. Mean (+ SD) venetoclax plasma concentration-time profile at week 6 day 1 (800 mg). Supplementary Figure S3. Study design.

Bendamustine + rituximab (BR) has demonstrated high response rates in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). However, progression-free survival (PFS) after BR is

Introduction: CPAP compliance is a challenge in the management of obstructive sleep apnoea (OSA), particularly in patients undergoing bariatric surgery. We investigated possible determinants of CPAP compliance in patients with OSA at a specialist bariatric centre. Methods: Retrospective cross-sectional study of all bariatric patients screened for OSA between 2013 and 2015. Case records and CPAP compliance at 28 days were reviewed for those with confirmed OSA and treated with CPAP. Multivariate analysis was performed on CPAP compliance against demographics, anthropometrics, Epworth Sleepiness Scale (ESS), objective measure of OSA and CPAP pressure. Results: 826 patients were screened, 92(11.1%) of whom had OSA and were commenced on CPAP. 51(55%) of the 92 patients were female, median (IQR) age 51(43-56) years, BMI 51.8(46.8-57) kgm −2 , baseline ODI 24.2(13.1-37.7) and baseline ESS 10(6-15). 34(37%) patients used their CPAP for ≥75% of nights and the mean(±SD) hours used per night was 4.0(±2.0). Humidification was the only factor which was related to mean hours of use of CPAP per night (β=0.235; p 0.05). None of the factors above were related to the proportion of nights with ≥3 hours of CPAP use (p>0.114). Conclusion: OSA prevalence and CPAP compliance in bariatric patients are low. Humidification was the only factor associated with CPAP compliance. There was no relationship between CPAP compliance and demographics, anthropometrics, OSA severity or CPAP pressure. Further study is warranted to investigate other possible determinants of CPAP compliance in this cohort.

We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features. Significance: Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106–17. ©2016 AACR. See related commentary by Pullarkat and Newman, p. 1082. This article is highlighted in the In This Issue feature, p. 1069

From research carried out over the last few years, it has become apparent that the visual world of the newborn baby (0-7 days from birth) is highly organised. It is also clear that the newborn infant is an extremely competent learner. These themes are illustrated with respect to two areas of research, face perception and intermodal learning. Evidence is presented suggesting that the human face is "special" in that newborns respond to them as faces, rather than merely collections of stimulus elements. Additional evidence is presented which demonstrates that newborns can form auditory-visual associations after only a short exposure to the stimulation. These lines of evidence suggest that innate capacities, or modules, facilitate and direct early learning in order to allow newborn infants to understand their newly encountered world.

To compare the scar outcome of video-assisted parathyroidectomy (VAP) with traditional bilateral cervical exploration (BCE) using previously validated scar assessment scales, and to examine the feasibility of introducing VAP into a general otolaryngology-head and neck practice.A retrospective review of medical records from a prospectively obtained database of patients and long-term follow-up of scar analysis.The records of 60 patients undergoing parathyroidectomy were reviewed: 29 patients underwent VAP and 31 patients underwent an open procedure with BCE. The groups were matched for age and sex. A total of 46 patients were followed up to assess scar outcome.The primary outcome was a comparison of patient and observer scar satisfaction between VAP and traditional BCE using validated scar assessment tools: the Patient Scar Assessment Scale and the Manchester Scar Scale. The secondary outcomes were to retrospectively evaluate our results with VAP and to assess the suitability of introducing this technique into a general otolaryngology-head and neck practice.The average scar length in the VAP group was 1.7 cm, and the average scar length in the BCE group was 4.3 cm. The patients in the BCE group scored higher than the patients in the VAP group on the Manchester Scar Scale (P.01) and on the Patient and Observer Scar Scales (P = .02), indicating a worse scar outcome. The mean operative time in the VAP group was 41 minutes compared with 115 minutes in the open procedure BCE group. There was no difference between the 2 groups in terms of postoperative complications.Video-assisted parathyroidectomy is a safe and feasible procedure in the setting of a general otolaryngology-head and neck practice, with outcomes and complication rates that are comparable to those of traditional bilateral neck exploration. Both patient and observer analysis demonstrated that VAP was associated with a more favorable scar outcome when compared with BCE.

This paper presents a method for improving the runtime of an optimal heuristic path planner (A*) so that it can run repeatedly, in real-time, in a dynamic environment. This is necessary for mobile robots navigating in dynamic environments that have moving obstacles with associated costs, such as personal space around people or buffer zones around dangerous vehicles. Our approach is to modify the search space used by the A* algorithm, increasing the size of grid cells further from the robot. This approach relies on the notion that only the area closest to the robot needs to be searched carefully; areas further from the robot can be searched more coarsely. Because the planner is assumed to run repeatedly as the robot moves, the robot will always have a fine-grained path defined for its next action. We have experimentally verified in simulation that this algorithm can be run in real-time and produces paths that are comparable to full-resolution planning.

This paper introduces the COMPANION framework: a Constraint-Optimizing Method for Person-Acceptable NavigatION. In this framework, human social conventions, such as personal space and tending to one side of hallways, are represented as constraints on the robot's navigation. These constraints are accounted for at the global planning level. In this paper, we present the rationale for, and implementation of, this framework, and we describe the experiments we have run in simulation to verify that the method produces human-like behavior in a mobile robot. Our approach is novel in that it can express an arbitrary number of social conventions and explicitly accounts for these conventions in the planning phase.

Introduction: BCL-2 has been implicated in hematologic malignancies and associated with drug resistance and poor prognosis in acute myelogenous leukemia (AML). Patients (pts) with relapsed/refractory (R/R) AML have poor prognosis with limited overall survival. ABT-199 is a selective, potent, orally bioavailable small molecule BCL-2 inhibitor. ABT-199 has demonstrated pre-clinical efficacy inhibiting the growth of AML cell lines or AML-pt derived primary cells systemically engrafted into immunocompromised mice. The current study evaluates ABT-199 monotherapy in pts with high-risk R/R AML and those unfit for chemotherapy. Methods: The primary objective of this phase 2, open-label, multicenter trial was to evaluate preliminary efficacy of ABT-199 in R/R AML or as frontline therapy for pts unfit for intensive therapy. Secondary objectives included safety and phamacodynamic assessments. An intra-pt dose escalation was implemented in which pts received 20 mg ABT-199 on Week (Wk) 1 Day 1, with daily escalation to a final target dose of 800 mg on Day 6 and daily thereafter. Pts without a complete response (CR) or complete response with incomplete blood count recovery (CRi) at first scheduled assessment (end of Wk 4) were able to escalate to 1200 mg. Safety analyses were performed for all pts. Adverse events (AEs) were reported according to the NCI-CTCAE version 4.0. Responses were evaluated using the revised guidelines by the International Working Group for AML. Samples were collected over 24 hours at Wk 6 to evaluate ABT-199 pharmacokinetics. Results: As of July 8, 2014, 32 pts enrolled with a median time on study of 81 (range 13-187) days. The median age was 71 (range 19–84) years and 16 (50%) were male. Thirty (93.8%) pts had R/R disease. Twelve (37.5%) had a history of myelodysplastic syndrome and 2 (6%) had a history of myeloproliferative neoplasms. Fourteen (44%) had received more than three prior treatments and 22 (69%) had received one or both hypomethylating agents. Isocitrate dehydrogenase (IDH) 1 and 2 mutations (mt) were reported in 2 (6%) and 9 (28%) pts, respectively. In addition, 6 (19%) were shown to have FLT3-ITD mt (2 of these also had IDH2 mt). The most common treatment-emergent AEs (in ≥25% of pts) were nausea (14/32, 44%), diarrhea (12/32, 38%), fatigue (9/32, 28%), neutropenia and vomiting (each 8/32, 25%). Grade 3/4 AEs (in ≥3 pts) were febrile neutropenia (8/32, 25%), anemia and pneumonia (each 3/32, 9%). There were no reported events of clinical or laboratory tumor lysis syndrome. There were no AEs leading to death. The median bone marrow blast count was 50% (range 5–97; n=25) at baseline. Twenty eight pts were evaluable at first assessment and the median bone marrow blast count decreased to 21% (range 1–87.5; n=25; 1 patient had marrow aplasia, 1 had hemodilute aspirate and another had clinical progression), a 36% decrease from baseline. One pt had a CR (3%) and 4 (12.5%) had a CRi at first assessment. Of the 4 CRi, 1 achieved CR by Wk 20. Of the pts with CR/CRi, 3 had IDH mt; two pts with IDH2 mt were MRD negative by flow cytometry and the third with IDH1 mt remained MRD positive. Three more pts with IDH mt experienced anti-leukemic activity that did not meet IWG response criteria due to lack of hematologic recovery. Six of 32 (19%) pts had at least 50% bone marrow blast reduction at first assessment. Ten progressed before the first assessment. Two pts with coexisting IDH2 and FLT3 mt had no evidence of antileukemic activity. The overall response rate (CR/CRi by IWG response criteria) was 15.5% (5/32). All 3 pts with IDH mt relapsed before Wk 12. Two IDH wild type (WT) pts remain in CR/CRi, respectively, and 2 additional IDH WT pts continue to show hematologic improvement without meeting IWG response criteria. Mean (CV%) ABT-199 peak concentration and AUC24 for 15 pts on 800 mg dose at Wk 6 was 3.62 (49) µg/mL and 56.7 (73) µg•h/mL, respectively, which is similar to that seen in pts with lymphoid malignancies. Conclusions: These preliminary data indicate that ABT-199 employed as a single agent has considerable clinical activity in pts with poor prognosis R/R AML and that pts with IDH mt may be particularly sensitive. ABT-199 monotherapy demonstrated an acceptable safety profile in these pts. ABT-199 demonstrates promising clinical activity in R/R AML pts who have limited available treatment options. This agent is being actively developed and evaluated in AML. Disclosures Konopleva: AbbVie, Inc: Research Funding; Genentech: Research Funding. Potluri:AbbVie, Inc: Employment. Chyla:AbbVie, Inc: Employment. Busman:AbbVie, Inc: Employment. McKeegan:AbbVie, Inc: Employment. Salem:AbbVie, Inc: Employment. Zhu:AbbVie, Inc: Employment. Ricker:AbbVie, Inc: Employment. Blum:Genentech: Consultancy. Dunbar:AbbVie, Inc: Employment. Kirby:AbbVie, Inc: Employment. Falotico:AbbVie, Inc: Employment. Leverson:abbvie: Employment, Equity Ownership. Humerickhouse:AbbVie, Inc: Employment. Mabry:AbbVie, Inc: Employment. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Letai:AbbVie, Inc: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

Abstract 3647 Introduction: BR chemoimmunotherapy was shown to have an overall response rate (ORR) of 59%, a median progression-free survival (PFS) of 14.7 months, and an acceptable toxicity profile in R/R CLL (Fischer K, et al. J Clin Oncol 2011). Given the single-agent activity of lenalidomide in R/R CLL/SLL, we hypothesized that maintenance lenalidomide after BR induction could improve PFS. Methods: Thirty-four patients requiring therapy for R/R CLL/SLL were treated with bendamustine 90 mg/m2 IV on days 1 & 2 and rituximab 375 mg/m2 IV on day 1 every 28 days for a maximum of 6 cycles. Growth factor support was permitted. Patients achieving at least a minor response (objective improvement even if not meeting criteria for partial response) were eligible to proceed with 12 cycles of maintenance therapy with lenalidomide 5–10 mg/day orally given continuously in each 28-day cycle. Patients were eligible if they had histologically proven CLL/SLL and had received >1 but ≤5 prior cytotoxic chemotherapy regimens (retreatment with an identical regimen was not counted as a separate treatment). The primary endpoint was PFS. Results: Baseline characteristics include median age 67 (range 38–86), 25 men/9 women, 26 CLL/8 SLL, and median of 2 prior therapies (range 1–4). Cytogenetic profiling by FISH analysis was available in 22 patients (65%), with 11/22 demonstrating presence of 17p and/or 11q deletions. Twenty-five patients (74%) completed 6 cycles of induction BR. Two patients died from toxicities of pneumonia and heart failure during cycle 1; 7 patients received Conclusions: In our multicenter trial for patients with R/R CLL/SLL, the BR induction produced an ORR that is comparable to historical observations (65% vs 59%). However, the median PFS is longer (24.3 vs 14.7 months), suggesting maintenance lenalidomide may be contributing to an improved response duration. Based upon these promising results, we have initiated a successor study in which patients will receive lenalidomide plus rituximab maintenance after a BR induction. Disclosures: Chang: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: Lenalidomide as maintenance therapy for CLL after induction rituximab + bendamustine chemoimmunotherapy. Fenske:Spectrum Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kahl:Millennium: Consultancy, Research Funding; Roche: Consultancy; Genentech: Consultancy, Research Funding.

Smoking habits and related attitudes were assessed in a sample of 4059 11- to 16-year-olds who also identified their best friends from among their fellow respondents. Subjects' responses were directly collated with those of their friends and indicated a clear covariation of smoking status (controlling for sex and age) as anticipated from previous research in which adolescents have been asked to report on the smoking habits of their friends. Such covariation, however, was not specific to smoking habits, but generalized to related measures of attitude and normative beliefs, alcohol use, health locus of control, school performance, spending habits and socio-economic status. Similarities on these other attributes were much the same, whether or not friends shared each others' smoking habits. It is concluded that these data argue against a simplistic view of unidirectional ‘peer group influence’ and invite an interpretation of friendship choice based on multiple dimensions of similarity.

In two experiments, rats were trained to deposit ball bearings down a hole in the floor, using an algorithmic version of shaping. The experimenter coded responses expected to be precursors of the target response, ball bearing deposit; a computer program reinforced these responses, or not, according to an algorithm that mimicked the processes thought to occur in conventional shaping. In the first experiment, 8 of 10 rats were successfully shaped; in the second, 5 of 5 were successfully shaped, and the median number of sessions required was the same as for a control group trained using conventional shaping. In both experiments, "misbehavior," that is, excessive handling and chewing of the ball bearings, was observed, and when the algorithmic shaping procedure was used, misbehavior could be shown to occur in spite of reduced reinforcement for the responses involved.