Search

Background and purpose: Aneurysmal subarachnoid hemorrhage occurs in approximately 30,000 patients annually in the United States. Uncontrolled blood pressure is a major risk factor for aneurysmal subarachnoid hemorrhage. Clinical guidelines recommend maintaining blood pressure control until definitive aneurysm securement occurs. It is unknown whether racial differences exist regarding blood pressure control and outcomes (HLOS, discharge disposition) in aneurysmal subarachnoid hemorrhage. Here, we aim to assess whether racial differences exist in 1) presentation, 2) clinical course, and 3) outcomes, including time to blood pressure stabilization, for aSAH patients at a large tertiary care medical center. Methods: We conducted a retrospective review of adult aneurysmal subarachnoid hemorrhage cases from 2013 to 2019 at a single large tertiary medical center. Data extracted from the medical record included sex, age, race, insurance status, aneurysm location, aneurysm treatment, initial systolic and diastolic blood pressure, Hunt Hess grade, modified Fisher score, time to blood pressure control (defined as time in minutes from first blood pressure measurement to the first of three consecutive systolic blood pressure measurements under 140mmHg), hospital length of stay, and final discharge disposition. Results: 194 patients met inclusion criteria; 140 (72%) White and 54 (28%) Black. While White patients were more likely than Black patients to be privately insured (62.1% versus 33.3%, p < 0.001), Black patients were more likely than White patients to have Medicaid (55.6% versus 15.0%, p < 0.001). Compared to White patients, Black patients presented with a higher median systolic (165 mmHg versus 148 mmHg, p = 0.004) and diastolic (93 mmHg versus 84 mmHg, p = 0.02) blood pressure. Black patients had a longer median time to blood pressure control than White patients (200 minutes versus 90 minutes, p = 0.001). Black patients had a shorter median hospital length of stay than White patients (15 days versus 18 days, p < 0.031). There was a small but statistically significant difference in modified Fisher score between black and white patients (3.48 versus 3.17, p = 0.04).There were no significant racial differences present in sex, Hunt Hess grade, discharge disposition, complications, or need for further interventions. Conclusion: Black race was associated with higher blood pressure at presentation, longer time to blood pressure control, but shorter hospital length of stay. No racial differences were present in aneurysmal subarachnoid hemorrhage associated complications or interventions. [ABSTRACT FROM AUTHOR]

Recent literature has shown significant differences in meningioma incidence among different races, but minimal conclusive data exist on the role of race and ethnicity in overall survival for patients with high-grade intracranial meningioma. We conducted a systematic review to investigate the impact of race and ethnicity on survival in patients with high-grade intracranial meningioma. A systematic literature review was conducted for studies using Ovid, PubMed, Cochrane, Embase, and Scopus databases. Databases were queried for the following: Meningioma AND [Ethnic OR Demography, OR African American OR Arab OR Hispanic OR Asian, OR White OR race OR racial] AND [survival OR survival analysis OR survival rate OR treatment outcome OR Survivor OR Outcome]. A literature search yielded a total of 412 abstracts, which were screened according to criteria that were determined a priori, and a total of 129 full-text articles were reviewed. Four articles were included in the final analysis, reporting on a total of 13,424 patients. Three studies saw an overall survival benefit in White non-Hispanics compared with Black non-Hispanics, and 1 reported a survival benefit in White non-Hispanics and Black non-Hispanics among patients who received gross total resection. One study additionally reported an increased likelihood of White patients receiving gross total resection when compared with non-White patients. The limited data available suggest that White patients have improved measures of survival compared with nonw-White patients, for reasons that are likely complex and multifactorial. Further studies are needed to explore these survival differences seen. [ABSTRACT FROM AUTHOR]

Background: Factors associated with discharge disposition and mortality following aneurysmal subarachnoid hemorrhage (aSAH) are not well-characterized. We used a national all-payer database to identify factors associated with home discharge and in-hospital mortality., Methods: The National Inpatient Sample was queried for patients with aSAH within a 4-year range. Weighted multivariable logistic regression models were constructed and adjusted for age, sex, race, household income, insurance status, comorbidity burden, National Inpatient Sample SAH Severity Score, disease severity, treatment modality, in-hospital complications, and hospital characteristics (size, teaching status, and region)., Results: Our sample included 37,965 patients: 33,605 were discharged alive and 14,350 were discharged home. Black patients had lower odds of in-hospital mortality compared with White patients (adjusted odds ratio [aOR] = 0.67, 95% confidence interval [CI] 0.52-0.86, p = 0.002). Compared with patients with private insurance, those with Medicare were less likely to have a home discharge (aOR = 0.58, 95% CI 0.46-0.74, p < 0.001), whereas those with self-pay (aOR = 2.97, 95% CI 2.29-3.86, p < 0.001) and no charge (aOR = 3.21, 95% CI 1.57-6.55, p = 0.001) were more likely to have a home discharge. Household income percentile was not associated with discharge disposition or in-hospital mortality. Paradoxically, increased number of Elixhauser comorbidities was associated with significantly lower odds of in-hospital mortality., Conclusions: We demonstrate independent associations with hospital characteristics, patient characteristics, and treatment characteristics as related to discharge disposition and in-hospital mortality following aSAH, adjusted for disease severity., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

The investigational NEDD8-activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single-agent azacitidine in patients with higher-risk myelodysplastic syndrome (higher-risk MDS), higher-risk chronic myelomonocytic leukemia (higher-risk CMML), or low-blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia-inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug-related and disease-related intrinsic and extrinsic factors. A PubMed literature review (January 2000-November 2019) supported similarity in epidemiology of higher-risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose-escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug-related and disease-related intrinsic and extrinsic factors supported design of an Asia-inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia-inclusive MRCTs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Azacitidine is the standard of care for myelodysplastic syndromes/low-blast acute myeloid leukemia (AML) across Western and East Asian patients. The first-in-class small-molecule inhibitor of NEDD8-activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS? By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian-inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug-related and disease-related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These analyses provide scientific rationale for Asia-inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia-inclusive multiregional clinical trials., (© 2021 Millennium Pharmaceuticals Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival., Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2)., Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study., Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles., Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug)., Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug., Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted., Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

Objectives: Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients., Materials and Methods: A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design., Results: The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37)., Conclusions: These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.