Citations

Local production of growth factors within the airway with autocrine/paracrine effects can promote features of asthma. Here, we show that glial-derived neurotrophic factor (GDNF) is a procontractile and proremodeling factor that contributes to allergen-induced airway hyperreactivity and tissue remodeling in a mouse model of asthma. Blocking GDNF signaling attenuates allergen-induced airway hyperreactivity and remodeling, suggesting a novel approach to alleviating structural and functional changes in the asthmatic airway.

Chronic airway disease is a short- and long-term consequence of premature birth. Understanding effects of O2 exposure during the perinatal period is key to identify targetable mechanisms that initiate and sustain adverse airway changes. Our findings show a beneficial effect of exogenous H2S on developing mouse airway structure and function with notable sex differences. H2S donors alleviate effects of O2 on airway hyperreactivity, contractility, airway smooth muscle thickness, and extracellular matrix deposition.

Abstract Purpose: We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models. Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination. Results: AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)–methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone. Conclusions: The combination of three key features—PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule—supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217

Purpose To develop a culturally-tailored American Indian/Alaska Native (AI/AN) women’s Facebook group supporting opioid recovery as an adjunct to medication. Design Community-based, qualitative approach. Setting Minnesota, U.S. Participants AI/AN women in opioid recovery, interested parties, and a Community Advisory Committee (CAC) of AI/AN women with lived experience, health care providers, and community members. Intervention We developed evidence-based content focusing on stress/trauma and substance use, mindfulness, responding to triggers, and supportive community resources. Additional content centered on AI/AN culture was also selected. Method Interviews were conducted by two women, then transcribed and coded using content analysis with NVivo software. Results were presented to CAC for further content refinement. Results CAC members (n = 10) guided study methods, intervention development, and dissemination activities. 14 AI/AN women (mean age 36.4 years; mean 6.7 months opioid abstinence) and 12 interested parties (7 men, 5 women) were receptive to an AI/AN gender-specific Facebook group, preferring content with AI/AN people and/or text resonating with AI/AN culture (e.g., Native traditions, family, personal stories, historical trauma). Recommendations included (1) protect confidentiality, (2) retain positivity, (3) incorporate resources and exercises to build coping skills, and (4) moderators should be authentic and relatable to build trust. Conclusions Our approach provides a model for developing culturally tailored, appealing and effective social media interventions to support AI/AN women in recovery from opioid use disorder.

Abstract Identification of key phenotypic regions such as necrosis, contrast enhancement, and edema on magnetic resonance imaging (MRI) is important for understanding disease evolution and treatment response in patients with glioma. Manual delineation is time intensive and not feasible for a clinical workflow. Automating phenotypic region segmentation overcomes many issues with manual segmentation, however, current glioma segmentation datasets focus on pre-treatment, diagnostic scans, where treat-ment effects and surgical cavities are not present. Thus, existing automatic segmenta-tion models are not applicable to post-treatment imaging that is used for longitudinal evaluation of care. Here, we present a comparison of three-dimensional convolutional neural networks (nnU-Net architecture) trained on large temporally defined pre-treatment, post-treatment, and mixed cohorts. We used a total of 1563 imaging timepoints from 854 patients curated from 13 different institutions as well as diverse public data sets to understand the capabilities and limitations of automatic segmenta-tion on glioma images with different phenotypic and treatment appearance. We as-sessed the performance of models using Dice coefficients on test cases from each group comparing predictions with manual segmentations generated by trained techni-cians. We demonstrate that training a combined model can be as effective as models trained on just one temporal group. The results highlight the importance of a diverse training set, that includes images from the course of disease and with effects from treatment, in the creation of a model that can accurately segment glioma MRIs at multiple treatment time points.

Abstract BACKGROUND Leveraging external data has the potential to increase efficiency and precision of drug development in glioblastoma by complementing or replacing data from in-trial controls. We used an external control arm (ECA) to re-analyze data of the abemaciclib, neratinib and CC-115 arms of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. METHODS INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. The initial experimental arms (abemaciclib, neratinib, CC-115) have not shown a survival benefit relative to the shared control arm. We re-analyzed the experimental arm data and replaced the shared control arm with an ECA. The ECA was developed from a collection of trial datasets and real-world data available through the Glioblastoma External (GBM-X) Data Platform (). Propensity score matching was used to adjust for possible differences between pretreatment covariates (age, sex, resection, KPS) in the ECA and shared control arm. Cox proportional hazards models were used to estimate treatment effects. RESULTS On INSIGhT, patients were randomized to abemaciclib (n = 74), neratinib (n = 80), and CC-115 (n = 12). There were 687 unmethylated MGMT patients in the GBM-X ECA. After propensity score matching, there was no significant treatment effect associated with abemaciclib (HR 1.091, 95%CI:0.834-1.433, p = 0.536), neratinib (HR = 1.043, 95%CI:0.787-1.383, p = 0.770), or CC-115 (HR 1.088, 95%CI:0.834-1.433, p = 0.794) compared to the ECA. CONCLUSION In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma.

Abstract PURPOSE Previous analysis of NRG-CC001 suggested pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggested patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not standard-WBRT. The current analysis examined the relationship between changes in MR-determined WMI and NCF 6-months following WBRT+memantine+/-HA. METHODS NCF-testing was performed at baseline, 2, 4, 6, and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR-volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (met vol) (FLAIR-volume/(whole brain volume–met-vol). Pearson correlation coefficients were used to assess the correlation between pre-treatment WMI and change from baseline to 6-months for each standardized NCF score. RESULTS Of the 518 randomized patients, 443 (217 patients WBRT+Memantine and 226 HA-WBRT+Memantine) had WMI data available at baseline, and of those, 162 patients (89 patients WBRT+Memantine and 73 HA-WBRT+Memantine) had both baseline and 6-month imaging available. For these patients, there was only a trend toward significance for change in corrected FLAIR-volume from baseline to 6-months (p = 0.174) but no significant change in met-vol (p = 0.438) or whole brain volume (p = 0.977). The change in standardized TMT Part A and B and the change in composite 6-month change scores were moderately correlated with change in corrected FLAIR volume adjusted for met-vol but only in the WBRT+Memantine arm (rho=-0.35, -0.34, -0.39 and p-value = 0.003, 0.006, 0.001). CONCLUSIONS Despite an increase in post-WBRT MR-WMI at 6-months, analysis did not show strong correlation between NCF and MR-WMI as determined by FLAIR-volume change between baseline and 6-months. Similar analyses are underway for the NRG-CC003 imaging data.

Abstract PURPOSE Hippocampal volume (HV) is a predictor of neurocognitive function (NCF) in neurodegenerative disease. The role of patient-specific anatomic variables has not been well investigated in patients with brain metastases. This work aimed to evaluate HV at baseline and 6 months as a predictor of NCF and differential benefit from HA-WBRT for patients enrolled on CC001. MATERIALS HV was calculated at baseline and 6 months. HV at baseline and 6 months were correlated with baseline and 2, 4, and 6-month NCF scores (HVLT-R Total and Delayed Recall, Delayed Recognition, TMT Parts A and B, and COWA) using Pearson correlation. Correlation was defined as weak if ρ ≤0.35. A cox proportional hazards model was used to determine the impact of baseline HV on time to NCF failure. RESULTS Of 518 patients randomized on CC001, 277 had baseline imaging, and 135 had 6-month imaging. However, only 87 patients were analyzable at both baseline and 6-month periods. At baseline, HV was not significantly associated with NCF score for any measure (p-value range: 0.06-0.72). Additionally, there was no association between baseline HV and time to NCF failure (p = 0.16). Additionally, the impact of treatment arm allocation on HV was examined but found to be non-significant (p = 0.06). Lastly, baseline HV and NCF scores were noted to have weak correlation at 2, 4, 6, and 12 month timepoints (ρ: range, -0.17-0.15; P-value range, 0.04-0.98). At 6 months, the correlation between HV, baseline NCF change, and 6 month standardized NCF change were also noted to be weak (ρ: range, 0.05-0.16; P-value range, 0.06-0.76). CONCLUSIONS Radiotherapy is known to have deleterious effects on neurocognition. In neurodegenerative disease, HV and rate of HV change are known predictors for NCF. However, baseline HV is not an independent predictor of neurocognitive changes after WBRT or HA-WBRT for patients with brain metastases.

Abstract OBJECTIVES This study describes coronary revascularization strategies used by sex and age in the USA. METHODS A sex-stratified cohort study from the National Inpatient Sample from the Agency for Healthcare Research and Quality (USA) including patients admitted for coronary revascularization with primary or secondary diagnoses of chronic coronary syndrome or non-ST elevation myocardial infarction who underwent ≥3-vessel coronary artery bypass grafting or percutaneous coronary intervention from January 2019 to December 2020. The primary outcome was the use rate of coronary artery bypass grafting or multivessel percutaneous coronary intervention. Prespecified subgroups included age and non-ST elevation myocardial infarction. RESULTS Among 121 150 patients (21.7% women), there were no sex differences in age (women: 66.6 [66.5–66.7], men: 67.6 [67.5–67.7], standardized mean difference: 0.1) or non-ST elevation myocardial infarction incidence (women: 37.4%, men: 45.7%, standardized mean difference: 0.17). The majority of women (74.2%) and men (84.9%) underwent bypass grafting, which was unaffected by age, race or non-ST elevation myocardial infarction. Women were less likely to undergo bypass grafting than percutaneous intervention (adjusted odds ratio 0.49, 95% confidence interval 0.44–0.54; P < 0.001) and a disparity most pronounced in patients >80 years old (adjusted odds ratio 0.31, 95% confidence interval 0.22–0.45; P < 0.001). CONCLUSIONS Most patients with multivessel coronary artery disease needing revascularization undergo bypass grafting, irrespective of sex, age or clinical presentation. The sex disparity in the use of bypass grafting is mostly seen among patients >80 years old.

Background Little is known about the prognostic significance of monoclonal gammopathy of undetermined and renal significance (MGUS and MGRS) in patients with CKD. The objective of this study was to determine the clinical and kidney outcomes of patients with CKD with either MGUS or MGRS compared with those with CKD without MGUS or MGRS. Methods We conducted a retrospective cohort study from 2013 to 2018. Patients who had both CKD diagnosis and monoclonal testing were identified. Patients were divided into MGRS, MGUS, and no monoclonal gammopathy groups. Cumulative incidence functions and Cox proportional hazards regression were used to model time to event data and to evaluate the association between monoclonal gammopathy status and risk of kidney failure, with death treated as a competing risk. Results Among 1535 patients, 59 (4%) had MGRS, 648 (42%) had MGUS, and 828 (54%) had no monoclonal gammopathy. Unadjusted analysis showed that compared with no monoclonal gammopathy patients, patients with MGRS were at higher risk of kidney failure (hazard ratio [HR] [95% confidence interval]: 2.5 [1.5 to 4.2] but not patients with MGUS (HR [95% confidence interval]: 1.3 [0.97 to 1.6]), after taking death into account as a competing risk. However, in the multivariable analysis, after adjusting for age, sex, eGFR, proteinuria, and Charlson Comorbidity Index, the risk of progression to kidney failure (with death as competing risk) in the MGRS group was no longer statistically significant (HR: 0.9 [0.5 to 1.8]). The same was also true for the MGUS group compared with the group with no monoclonal gammopathy (HR: 1.3 [0.95 to 1.6]). When evaluating the association between MGUS/MGRS status and overall survival, MGRS was significantly associated with mortality in fully adjusted models compared with the group with no monoclonal gammopathy, while MGUS was not. Conclusions After adjusting for traditional risk factors, MGUS/MGRS status was not associated with a greater risk of kidney failure, but MGRS was associated with a higher risk of mortality compared with patients with no monoclonal gammopathy.