Citations

Abstract Background: Alzheimer’s disease (AD) is an epidemic with tremendous public health impacts because there are currently no disease-modifying therapeutics. Randomized controlled trials (RCTs) for prevention of AD dementia often use clinical endpoints that take years to manifest (e.g., cognition) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI]). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive, but little is known about their value as surrogate endpoints for treatment responses in the prevention of AD dementia. Methods: The objective of this study is to investigate blood neuropathological, neurodegenerative, and neurotrophic biomarkers as surrogate endpoints for treatment responses to 3 interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise; cognitive training; and combined aerobic exercise and cognitive training (ACT). We chose these three sets of biomarkers for their unique mechanistic associations with AD pathology, neurodegeneration and neurogenesis. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2×2 factorial Phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n=128). In this ACT Trial Blood Biomarkers Study, we will enroll 120 ACT Trial aMCI participants and measure blood biomarkers at baseline, 3, 6, 12 and 18 months. The goals are to: (1) Determine the effect of interventions on blood biomarkers over 6 months; (2) Evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months; and (3; exploratory) Examine blood biomarkers as surrogate endpoints for predicting brain MRI biomarker responses to interventions over 18 months. Discussion: This study aims to identify new blood biomarkers that can track cognitive decline or AD-related brain atrophy among aMCI patients subjected to a regimen of aerobic exercise and cognitive training. Findings from this study will drive the further use of blood biomarkers in developing effective prevention and treatment strategies for AD dementia. Trial registration number: This study is an ancillary study of the ACT Trial which was registered with ClinicalTrials.gov, NCT03313895.

AbstractDisruptions in circadian rhythms are risk factors for excessive alcohol drinking. The ethanol‐sensitive adenosine equilibrative nucleoside transporter type 1 (ENT1, slc29a1) regulates ethanol‐related behaviors, sleep, and entrainment of circadian rhythms. However, the mechanism underlying the increased ethanol consumption in ENT1 knockout (KO) mice in constant light (LL) and whether there are sex differences in ethanol consumption in ENT1 mice are less studied. Here, we investigated the effects of loss of ENT1, LL, and sex on ethanol drinking using two‐bottle choice. In addition, we monitored the locomotor activity rhythms. We found that LL increased ethanol drinking and reduced accumbal ENT1 expression and adenosine levels in male but not female mice, compared with control mice. Interestingly, only LL‐exposed male, not female, ENT1 KO mice exhibited higher ethanol drinking and a longer circadian period with a higher amplitude compared with wild‐type (WT) mice. Furthermore, viral‐mediated rescue of ENT1 expression in the NAc of ENT1 KO mice reduced ethanol drinking, demonstrating a possible causal link between ENT1 expression and ethanol drinking in males. Together, our findings indicate that deficiency of ENT1 expression contributes to excessive ethanol drinking in a sex‐dependent manner.

Favorable long-term functional outcomes after severe traumatic brain injury (TBI) may be underestimated. We analyzed 24-month functional outcomes from a consecutive series of severe TBI survivors. A prospective, observational database of severe TBI survivors from a single institution was analyzed. Glasgow Outcome Scale-Extended (GOS-E) scores were obtained at 3, 6, 12, and 24 months post-injury. GOS-E scores were dichotomized into unfavorable and favorable outcomes, and the proportion of survivors changing from unfavorable to favorable outcomes was calculated using Wilcoxon signed-rank tests. Surviving adults ( N = 304; mean age ± standard deviation = 35.06 ± 15.11; 80.92% male; mode of initial GCS = 7) were analyzed. A statistically significant mean increase in GOS-E was noted from 3 to 6, 6 to 12, 12 to 24, and 6 to 24 months after injury (0.65 [ p < 0.0001], 0.42 [ p < 0.0001], 0.23 [ p = 0.020], and 0.61 [ p < 0.0001], respectively). Moreover, 43% of survivors from 3 to 6 months, 36% from 6 to 12 months, 38% from 12 to 24 months, and 54% from 6 to 24 months progressed from an unfavorable to a favorable outcome. Two thirds of survivors in the unfavorable category at 3 months had favorable outcomes at 2 years. Overall, 74% of surviving adults with a documented GOS-E at 2 years after injury had a favorable outcome. Severe TBI survivors demonstrated significant improvement in functional outcomes from 3 to 24 months after injury. At 2 years, three fourths of survivors had a favorable outcome. Long-term prognosis in severe TBI is better than broadly appreciated.

Citrate is critical for acid-base homeostasis and to prevent calcium nephrolithiasis. Both metabolic acidosis and hypokalemia decrease citrate excretion and increase expression of Na+-dicarboxylate cotransporter 1 (NaDC1; SLC13A2), the primary protein involved in citrate reabsorption. However, the mechanisms transducing extracellular signals and mediating these responses are incompletely understood. The purpose of the present study was to determine the role of the Na+-coupled electrogenic bicarbonate cotransporter (NBCe1) A variant (NBCe1-A) in citrate metabolism under basal conditions and in response to acid loading and hypokalemia. NBCe1-A deletion increased citrate excretion and decreased NaDC1 expression in the proximal convoluted tubules (PCT) and proximal straight tubules (PST) in the medullary ray (PST-MR) but not in the PST in the outer medulla (PST-OM). Acid loading wild-type (WT) mice decreased citrate excretion. NaDC1 expression increased only in the PCT and PST-MR and not in the PST-MR. In NBCe1-A knockout (KO) mice, the acid loading change in citrate excretion was unaffected, changes in PCT NaDC1 expression were blocked, and there was an adaptive increase in PST-MR. Hypokalemia in WT mice decreased citrate excretion; NaDC1 expression increased only in the PCT and PST-MR. NBCe1-A KO blocked both the citrate and NaDC1 changes. We conclude that 1) adaptive changes in NaDC1 expression in response to metabolic acidosis and hypokalemia occur specifically in the PCT and PST-MR, i.e., in cortical proximal tubule segments; 2) NBCe1-A is necessary for normal basal, metabolic acidosis and hypokalemia-stimulated citrate metabolism and does so by regulating NaDC1 expression in cortical proximal tubule segments; and 3) adaptive increases in PST-OM NaDC1 expression occur in NBCe1-A KO mice in response to acid loading that do not occur in WT mice.

Abstract Background: Mammographic breast density declines during menopause. We assessed changes in volumetric breast density across the menopausal transition and factors that influence these changes. Methods: Women without a history of breast cancer, who had full field digital mammograms during both pre- and postmenopausal periods, at least 2 years apart, were sampled from four facilities within the San Francisco Mammography Registry from 2007 to 2013. Dense breast volume (DV) was assessed using Volpara on mammograms across the time period. Annualized change in DV from pre- to postmenopause was estimated using linear mixed models adjusted for covariates and per-woman random effects. Multiplicative interactions were evaluated between premenopausal risk factors and time to determine whether these covariates modified the annualized changes. Results: Among the 2,586 eligible women, 1,802 had one premenopausal and one postmenopausal mammogram, 628 had an additional perimenopausal mammogram, and 156 had two perimenopausal mammograms. Women experienced an annualized decrease in DV [−2.2 cm3 (95% confidence interval, −2.7 to −1.7)] over the menopausal transition. Declines were greater among women with a premenopausal DV above the median (54 cm3) versus below (DV, −3.5 cm3 vs. −1.0 cm3; P &lt; 0.0001). Other breast cancer risk factors, including race, body mass index, family history, alcohol, and postmenopausal hormone therapy, had no effect on change in DV over the menopausal transition. Conclusions: High premenopausal DV was a strong predictor of greater reductions in DV across the menopausal transition. Impact: We found that few factors other than premenopausal density influence changes in DV across the menopausal transition, limiting targeted prevention efforts.

e20639 Background: Multiple randomized controlled trials (RCTs) have shown a robust benefit of immunotherapy with immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). We did a meta-analysis to examine the benefit of ICI in various subgroups. Methods: PubMed was searched up to Jan 15, 2019 for RCTs comparing overall survival (OS) between ICI and control (without ICI) arms. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated for each subgroup. Interaction tests were done to compare relative benefit between opposed subgroups of interest (eg. men vs women; reported as Pheterogeneity). All analyses were performed with a random effects model in Comprehensive Meta Analysis (v2). Results: Twelve phase 2/3 RCTs involving 7244 patients were included. A significant OS benefit of ICI was found in both squamous and non-squamous histology. Current/former smokers, EGFR wild-type, and KRAS mutant patients had a significant OS benefit from ICI, but never smokers, EGFR mutant, and KRAS wild-type patients did not. An OS benefit of ICI was found in patients with or without baseline brain metastasis, PD-L1 < 1% or ≥1%, men or women, age < 65 or ≥65, and ECOG PS 0 or ≥1. No significant difference of relative benefit from ICI over control was found in patients with different PD-L1 expression, sex, age, or ECOG PS (Table). Conclusions: OS benefit of ICI in NSCLC was associated with a smoking history, wild-type EGFR or KRAS mutation. However, the OS benefit of ICI was seen regardless of histology, PD-L1 expression, sex, age, and ECOG PS. [Table: see text]

e18367 Background: Regorafenib at 160mg daily 21/28 days is a standard therapeutic option in patients with metastatic colorectal cancer. However, the cost of treatment and management of its side-effects is more than the cost-effectiveness threshold for oncology drugs in US and many countries around the world. ReDOS (Regorafenib Dose Optimization Study), is a randomized phase II trial in refractory mCRC and established that weekly dose escalation of regorafenib over the conventional dosing is superior in the composite endpoint of safety and efficacy. We explored the impact of the new dosing strategy on CE of regorafenib. Methods: A Markov model was constructed to compare costs and effectiveness of regorafenib (standard), regorafenib (ReDOS), and best supportive care (BSC). Model inputs for clinical efficacy and safety were from the CORRECT trial for regorafenib (standard) and BSC, and the ReDOS study for regorafenib (ReDOS). The incremental cost-effectiveness ratios (ICERs) were reported to compare treatments. Model robustness was checked with univariate and probabilistic sensitivity analyses. The model used a US payer’s perspective with 5% annual discount rate, and all costs were measured in 2018 US dollars. Results: Regorafenib (ReDOS) dominated regorafenib (standard), producing higher quality-adjusted life years at a lower cost. When compared to BSC, regorafenib (ReDOS) resulted in the ICER of $112,705 while regorafenib (standard) resulted in the ICER of $384,687. The most influential parameters on the ICERs were efficacy and health state utility parameters under univariate sensitivity analysis. In probabilistic sensitivity analysis using cost-effectiveness acceptability curves, regorafenib (ReDOS) was more cost-effective than regorafenib (standard) and BSC in 70% of repetition at the willingness-to-pay threshold of $120,000 per QALY (Quality-Adjusted Life Year) and 98% at a WTP threshold of $150,000. Conclusions: Based on the outcomes demonstrated in the ReDOS study, the dose optimization strategy of regorafenib results in favorable cost-effectiveness under a typical US willingness-to-pay threshold of $150,000 per QALY.

6592 Background: Sex, age and ECOG performance status (PS) may affect immune response and the efficacy of cancer immunotherapy with immune checkpoint inhibitors (ICI). We did a meta-analysis to assess the potential sex, age and ECOG PS differences of immunotherapy efficacy in advanced cancer. Methods: PubMed was searched up to January 15, 2019 for randomized controlled trials (RCT) comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs control therapy (without ICI). For sex difference analysis, pooled hazard ratio (HR) of death for men and women was calculated separately, and the heterogeneity between the two estimates was assessed using an interaction test by pooling study-specific interaction HR. Age ( < 65 vs ≥65) and ECOG PS (0 vs ≥1) difference was analyzed similarly. Subgroup analysis by cancer type and line of therapy (frontline vs subsequent) was explored. All analyses were done in Comprehensive Meta Analysis (v2) with random effects models. Results: Thirty phase 2/3 RCTs involving 17,728 patients were included. An OS benefit of immunotherapy was found for both men (HR 0.75, 95% confidence interval [CI] 0.69-0.81, P < 0.01) and women (HR 0.79, 95% CI 0.69-0.90, P < 0.01); for both younger ( < 65; HR 0.75, 95% CI 0.68-0.83, P < 0.01) and older (≥65; HR 0.76, 95% CI 0.69-0.83, P < 0.01) patients; and for both ECOG PS 0 (HR 0.78, 95% CI 0.69-0.89, P < 0.01) and PS ≥1 (HR 0.77, 95% CI 0.71-0.84, P < 0.01) patients. No significant difference of relative benefit from immunotherapy over control therapy was found in patients with different sex ( P = 0.283), age ( P = 0.906) or ECOG PS ( P = 0.783). In melanoma RCTs, compared with women (HR 0.77, 95% CI 0.64-0.94, P < 0.01), men (HR 0.56, 95% CI 0.42-0.76, P < 0.01) had more OS benefit from immunotherapy ( P = 0.037). No significant difference was found in other subgroup analyses by cancer types or line of therapy. Conclusions: Overall we found no evidence of association of sex, age, or ECOG PS with cancer immunotherapy efficacy. However, in melanoma, men might benefit more from immunotherapy than women.