Citations

AbstractBrain tumours have a poor prognosis and lack effective treatments. The blood–brain barrier (BBB) represents a major hurdle to drug delivery to brain tumours. In some locations in the tumour, the BBB may be disrupted to form the blood–brain tumour barrier (BBTB). This leaky BBTB enables diagnosis of brain tumours by contrast enhanced magnetic resonance imaging; however, this disruption is heterogeneous throughout the tumour. Thus, relying on the disrupted BBTB for achieving effective drug concentrations in brain tumours has met with little clinical success. Because of this, it would be beneficial to design drugs and drug delivery strategies to overcome the ‘normal’ BBB to effectively treat the brain tumours. In this review, we discuss the role of BBB/BBTB in brain tumour diagnosis and treatment highlighting the heterogeneity of the BBTB. We also discuss various strategies to improve drug delivery across the BBB/BBTB to treat both primary and metastatic brain tumours. Recognizing that the BBB represents a critical determinant of drug efficacy in central nervous system tumours will allow a more rapid translation from basic science to clinical application. A more complete understanding of the factors, such as BBB–limited drug delivery, that have hindered progress in treating both primary and metastatic brain tumours, is necessary to develop more effective therapies.

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

Objective: To assess outcomes of women with uterine fibroids (UFs) and heavy menstrual bleeding (HMB) treated with 300 mg elagolix twice daily plus add-back therapy (E2 1 mg/NETA 0.5 mg once daily) or placebo who were not considered responders in pooled analysis of two phase 3, 6-month randomized clinical trials (Elaris UF-1 and UF-2). Methods: Responders were defined as women who met both primary end point bleeding criteria (<80 mL menstrual blood loss [MBL] during the final month and ≥50% reduction in MBL from baseline to the final month) and either completed the study or discontinued due to predefined reasons. Thus, women termed nonresponders who were analyzed in this study who met neither or one bleeding end point or met both criteria but prematurely discontinued treatment because of adverse events, perceived lack of efficacy, or required surgical or interventional treatment for UFs were analyzed in this study. This post hoc analysis assessed mean changes from baseline in MBL, as well as adverse events. Results: Among 367 women receiving elagolix with add-back with observed data, 89 (24%) were not considered responders. Within this subset, 17 (19%) women met both bleeding criteria but prematurely discontinued treatment for the reasons mentioned above, while 23 (26%) met one bleeding criterion and 49 (55%) met neither bleeding criteria, regardless of discontinuation status. Among all nonresponders, a numerical trend toward greater mean reductions in MBL was observed in those receiving elagolix with add-back, compared with placebo group nonresponders. No differences in adverse events were observed between responders and nonresponders. Conclusion: Forty of 89 (45%) women with HMB and UFs who were classified as nonresponders in the UF-1 or UF-2 trials may have had a clinically meaningful response to elagolix with add-back therapy because they met at least one of the objective bleeding criteria. Clinical Trial Registration: Clinicaltrials.gov, NCT02654054 and NCT02691494. (NEJM 2020; 382:328–340) DOI: 10.1056/NEJMoa1904351

Background Elderly patients have a higher burden of comorbidities that influence clinical outcomes. We aimed to compare in‐hospital outcomes in patients ≥80 years old to younger patients, and to determine the factors associated with increased risk of major adverse events (MAE) after left atrial appendage closure. Methods and Results The National Inpatient Sample was used to identify discharges after left atrial appendage closure between October 2015 and December 2018. The primary outcome was in‐hospital MAE defined as the composite of postprocedural bleeding, vascular and cardiac complications, acute kidney injury, stroke, and death. A total of 6779 hospitalizations were identified, of which, 2371 (35%) were ≥80 years old and 4408 (65%) were <80 years old. Patients ≥80 years old experienced a higher rate of MAE compared with those aged <80 years old (6.0% versus 4.6%, P =0.01), and this difference was driven by a numerically higher rate of cardiac complications (2.4% versus 1.8%, P =0.09) and death (0.3% versus 0.1%, P =0.05) among individuals ≥80 years old. In patients ≥80 years old, higher odds of in‐hospital MAE were observed in women (1.61‐fold), and those with preprocedural congestive heart failure (≈2‐fold), diabetes (≈1.5‐fold), renal disease (≈2.6‐fold), anemia (≈2.7‐fold), and dementia (≈5‐fold). In patients <80 years old, a higher risk of in‐hospital MAE was encountered among women (≈1.4‐fold) and those with diabetes (≈1.3‐fold), renal disease (≈2.6‐fold), anemia (≈2‐fold), and dyslipidemia (≈1.2‐fold). Conclusions Patients ≥80 years old had higher rates of in‐hospital MAE compared with patients aged <80 years old. Female sex and the presence of heart failure, diabetes, renal disease, and anemia were factors associated with in‐hospital MAE among both groups.

Abstract Aims We sought to determine whether the Diamond–Forrester classification using non-invasive haemodynamic measurements by 2-D and Doppler echocardiography would predict hospital mortality in cardiac intensive care unit (CICU) patients. Methods and results We retrospectively analysed unique patients admitted to the CICU at Mayo Clinic Rochester from 2007 to 2018. Doppler-derived cardiac index (CI) and ratio of mitral valve E velocity to medial mitral annulus e′ velocity (E/e′ ratio) were used to classify patients into four profiles: Profile I (warm/dry), Profile II (warm/wet), Profile III (cold/dry), and Profile IV (cold/wet). Logistic regression was used to determine predictors of hospital mortality, and Cox proportional-hazards analysis was used to determine predictors of mortality during one year of follow-up. We included 4563 patients with a mean age of 68.3 ± 14.3 years, including 36.2% female patients. The distribution of each profile was as follows: I, 47.4%; II, 36.2%; III, 7.9%; IV, 8.5%. A total of 5.8% patients died during hospitalization, and 18.1% died by 1 year. Patients with either low CI or elevated E/e′ ratio had higher in-hospital and 1 year mortality. Patients with elevated E/e′ ratio (i.e. Profiles II and IV) had an increased risk of death during hospitalization and at 1 year after multivariate adjustment (adjusted hazard ratio 1.72 and 2.17 for 1 year mortality, respectively, compared with Profile I, P &lt; 0.01). Conclusions Simple Doppler echocardiographic assessment can be used to identify haemodynamic profiles defined by the Diamond–Forester classification in patients admitted in CICU. These profiles predict outcomes and may be used to guide therapy in critically ill patients.

Abstract To discover lipidomic alterations during pregnancy in mothers who subsequently delivered small for gestational age (SGA) neonates and identify predictive lipid markers that can help recognize and manage these mothers, we carried out untargeted lipidomics on maternal serum samples collected between 24–28 weeks of gestation. We used a nested case-control study design and serum from mothers who delivered SGA and appropriate for gestational age babies. We applied untargeted lipidomics using mass spectrometry to characterize lipids and discover changes associated with SGA births during pregnancy. Multivariate pattern recognition software Collaborative Laboratory Integrated Reports (CLIR) was used for the post-analytical recognition of range differences in lipid ratios that could differentiate between SGA and control mothers and their integration for complete separation between the two groups. Here, we report changes in lipids from serum collected during pregnancy in mothers who delivered SGA neonates. In contrast to normal pregnancies where lysophosphatidic acid increased over the course of the pregnancy owing to increased activity of lysophospholipase D, we observed a decrease (32%; P = 0.05) of 20:4-lysophosphatidic acid in SGA mothers, which could potentially compromise fetal growth and development. Integration of lipid ratios in an interpretive tool (CLIR) could completely separate SGA mothers from controls demonstrating the power of untargeted lipidomic analyses for identifying novel predictive biomarkers. Additional studies are required for further assessment of the lipid biomarkers identified in this report.