Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder that has poor long-term outcomes and remains a major public health concern. Recent theories have proposed that ADHD arises from alterations in multiple neural pathways. Alterations in reward circuits are hypothesized as one core dysfunction, leading to altered processing of anticipated rewards. The nucleus accumbens (NAcc) is particularly important for reward processes; task-based fMRI studies have found atypical activation of this region while the participants performed a reward task. Understanding how reward circuits are involved with ADHD may be further enhanced by considering how the NAcc interacts with other brain regions. Here we used the technique of resting-state functional connectivity MRI (rs-fcMRI) to examine the alterations in the NAcc interactions and how they relate to impulsive decision making in ADHD. Using rs-fcMRI, this study: examined differences in functional connectivity of the NAcc between children with ADHD and control children; correlated the functional connectivity of NAcc with impulsivity, as measured by a delay discounting task; and combined these two initial segments to identify the atypical NAcc connections that were associated with impulsive decision making in ADHD. We found that functional connectivity of NAcc was atypical in children with ADHD and the ADHD-related increased connectivity between NAcc and the prefrontal cortex was associated with greater impulsivity (steeper delayed-reward discounting). These findings are consistent with the hypothesis that atypical signaling of the NAcc to the prefrontal cortex in ADHD may lead to excessive approach and failure in estimating future consequences; thus, leading to impulsive behavior.

Introduction: Attention deficit hyperactivity disorder (ADHD) captures a heterogeneous group of children, who are characterized by a range of cognitive and behavioral symptoms. Previous resting-state functional connectivity MRI (rs-fcMRI) studies have sought to understand the neural correlates of ADHD by comparing connectivity measurements between those with and without the disorder, focusing primarily on cortical–striatal circuits mediated by the thalamus. To integrate the multiple phenotypic features associated with ADHD and help resolve its heterogeneity, it is helpful to determine how specific circuits relate to unique cognitive domains of the ADHD syndrome. Spatial working memory has been proposed as a key mechanism in the pathophysiology of ADHD. Methods: We correlated the rs-fcMRI of five thalamic regions of interest (ROIs) with spatial span working memory scores in a sample of 67 children aged 7–11 years [ADHD and typically developing children (TDC)]. In an independent dataset, we then examined group differences in thalamo-striatal functional connectivity between 70 ADHD and 89 TDC (7–11 years) from the ADHD-200 dataset. Thalamic ROIs were created based on previous methods that utilize known thalamo-cortical loops and rs-fcMRI to identify functional boundaries in the thalamus. Results/Conclusion: Using these thalamic regions, we found atypical rs-fcMRI between specific thalamic groupings with the basal ganglia. To identify the thalamic connections that relate to spatial working memory in ADHD, only connections identified in both the correlational and comparative analyses were considered. Multiple connections between the thalamus and basal ganglia, particularly between medial and anterior dorsal thalamus and the putamen, were related to spatial working memory and also altered in ADHD. These thalamo-striatal disruptions may be one of multiple atypical neural and cognitive mechanisms that relate to the ADHD clinical phenotype.

B-cell receptor (BCR) signaling kinases are important targets in therapy of CLL. Resistance of lymphoid niche-resident CLL cells to BCR-signaling inhibition is fostered by the tumor microenvironment. We found that stromal B-cell activation factor (BAFF)-mediated activation of spleen tyrosine kinase (SYK) triggered BCR signaling, thereby contributing to apoptosis resistance in CLL cells (Paiva et al, 2017). The SYK inhibitor entospletinib (ENTO) abrogated BAFF-mediated BCR signaling accompanied by a decrease in pSTAT3 and MCL1 in vitro. We designed a Phase I/II investigator-sponsored trial of ENTO in combination with Obinutuzumab (Obin) in patients (pts) with relapsed/refractory CLL and non-Hodgkin lymphoma (NHL). Eligible pts were aged ≥18 years, had CLL/NHL (Phase I) or CLL (Phase II), relapsed and/or refractory to ≥1 prior therapies (no prior SYK inhibitor), ECOG performance status ≤2 and preserved organ function. The Phase I part of the study followed a standard 3+3 design with two dose levels (DL1: ENTO 200 mg PO BID; DL2 - ENTO 400 mg PO BID). ENTO was given for 7 days (run-in). Subsequently, Obin was given IV concurrently with ENTO on days 1, 2, 8, 15 of Cycle 1 and Day 1 of Cycles 2-6 in standard doses. ENTO was given until disease progression. Primary study objectives were toxicity (Phase I) and efficacy (objective response rate (ORR); Phase II). Correlative analysis of samples was performed at baseline, after run-in phase (7 days of entospletinib single agent) and after 6 cycles of combination therapy. Reverse protein phase array was performed at the RPPA core facility at MD Anderson Cancer Center. T cell populations and cytokine production were analyzed by flow cytometry. At DL1 of Phase I, six pts were enrolled (4 - CLL; 2 - follicular lymphoma). One pt experienced a dose-limiting toxicity (DLT: grade 3 asymptomatic LFT abnormalities which failed to resolve within 72 hours) attributed to ENTO. Other grade 3-4 toxicities included 2 grade 3 infusion reactions and one transient grade 4 neutropenia (attributed to Obin). Two pts remain on therapy after a median follow-up of 15 months. Three pts were enrolled at DL2 without DLTs. In Phase 2, 18 pts with CLL received ENTO 400 mg PO BID (in combination with Obin). One pt was deemed ineligible due to Richter's transformation at study entry. Of the 17 evaluable pts, 71% were men. Median age was 66 years (range 47-76), and 76% were aged >65 years. 94% had ECOG performance status ≤1. Six pts (35%) had a complex karyotype, 6 (35%) had a TP53 aberration, 2 - NOTCH1 and 3 - SF3B1 mutation. Median number of prior therapies was 2 (range, 1-6): 47% had received prior fludarabine, 53% - bendamustine, 35% - ibrutinib (5 pts with intolerance, 1 with progression). As of July 1, 2019, with median follow-up of 9.5 months (range, 3-17 months), 71% of pts remain on treatment. Median relative dose intensity of ENTO (ratio of actual to planned cumulative dose during drug exposure period) was 97%. ORR was 82%, 11 (65%) pts with partial response, three (17%) pts had CR (two MRD-negative in the bone marrow). All patients had a reduction in lymphadenopathy. Median duration of response and median progression-free survival (PFS) were not reached. All pts are alive. Five (29%) pts discontinued treatment (1 withdrawal of consent; 1 with recurrent LFT abnormalities; 1 for concomitant comorbidity and 2 with progression of disease). The most frequently occurring adverse events of all grades were infusion-related reactions, neutropenia and fatigue (Table). There were no Grade 5 events. Treatment with ENTO for 7 days during run-in phase led to downmodulation of pSTAT3 and MCL1 in CLL cells (RPPA assay), consistent with our pre-clinical observations. MCL1 has been previously implicated in survival of T cells at multiple stages of development. At the end of cycle 6, we observed a decrease in CD19+ and concomitant increase in CD3+ cells compared with baseline. There was no change in naïve, T-effector memory and T central memory cells within the CD4+ or CD8+ populations. Treatment with ENTO led to decreased PD-1 expression in CD4+ (22.6±3.8 vs. 31.5±5.4%, p=0.02) and CD8+ cells (p=0.05; Figure). Meanwhile, CTLA-4 expression was unchanged. PMA/ionomycin-stimulated CD4+ T cells demonstrated a decrease in IFNγ and IL-4. In summary, a combination of ENTO and Obin was effective and well tolerated in patients with R/R CLL, and was accompanied by downmodulation of MCL1 in CLL cells and PD-1 in T cells. Disclosures Persky: Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy; Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee. Spurgeon:Janssen: Research Funding; Astra Zeneca: Research Funding; Bayer: Other: drug support only, Research Funding; Ariad: Other: drug support only, Research Funding; KITE: Other: drug support only, Research Funding; Acerta: Research Funding; Bristol Myers Squibb: Research Funding; Genentech: Honoraria, Research Funding; Novartis: Other: drug support only, Research Funding. Danilov:Gilead Sciences: Consultancy, Research Funding; Abbvie: Consultancy; Takeda Oncology: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Aptose Biosciences: Research Funding; AstraZeneca: Consultancy, Research Funding; MEI: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy. OffLabel Disclosure: Entospletinib in CLL

No abstract

Not available.