Fatty acids were determined by gas chromatography followed by principal component analysis (PCA) and soft independent modelling of class analogy (SIMCA) in the blubber of 18 female grey seals, Halichoerus grypus, in their milk and in the blubber of their 1-week-old nursing pups. Large individual differences were observed in both blubber and milk content of fatty acids. The fatty acid composition of the milk was systematically different from the composition in maternal blubber, with higher relative amounts of the saturated acids, the monounsaturated with 20 carbon atoms and the n3 polyunsaturated, except 18:3n3. The composition of the fatty acids in the blubber of the pups was different from that of the milk. The same fatty acids that were enriched in the milk were depleted in the blubber of the pups. Therefore the fatty acid composition in the blubber of the pups was similar to that in the adults, although not identical. The results from this investigation imply that the composition of the fatty acids in the blubber of female seals and in the blubber of their pups cannot be determined directly by analysis of fatty acid composition of milk.

It has been suggested that cocaine acts directly in the brain to enhance central sympathetic outflow. However, some studies suggested that the cardiovascular effects of cocaine are related to a peripheral action. To characterize further the site of cocaine's cardiovascular effect, we compared the hemodynamic effects of cocaine (2 mg/kg, i.v. bolus) with those observed after administration of an equimolar dose (2.62 mg/kg, i.v. bolus) of cocaine methiodide, a quaternary derivative of cocaine that does not penetrate the blood-brain barrier, by using sufentanil-sedated dogs. Cocaine produced significant (p < 0.05) increases in heart rate (+37+/-11 beats/min), mean arterial pressure (+55+/-11 mm Hg), left ventricular end-diastolic pressure (+5.3+/-1.0 mm Hg), and cardiac output (+2.4+/-0.9 L/min). Cocaine methiodide produced increases in heart rate (+57+/-11 beats/min), mean arterial pressure (+45+/-11 mm Hg), left ventricular end-diastolic pressure (+3.4+/-1.0 mm Hg), and cardiac output (1.1+/-0.9 L/min), which were not significantly different from those observed with cocaine. Because opiate sedation potentially might have attenuated central sympathetic outflow, we further confirmed the qualitative similarity of the actions of cocaine and cocaine methiodide on heart rate and blood pressure in unsedated, conscious dogs. Our data suggest that the cardiovascular effects of cocaine result primarily from a peripheral site of action.

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Novel agents, including Bruton tyrosine kinase inhibitors (BTKis), have become the standard of care for patients with chronic lymphocytic leukemia (CLL). We conducted a real-world retrospective analysis of CLL patients treated with acalabrutinib vs ibrutinib to compare outcomes utilizing the Flatiron Health Database. Patients with CLL were included if they initiated acalabrutinib or ibrutinib between 1/1/2018-2/28/2021. The primary outcome of interest was time to treatment discontinuation (TTD). Average treatment effect among the treated weighting was used to balance key baseline characteristics between cohorts. Kaplan-Meier analysis was used to estimate unweighted and weighted median TTD. A weighted Cox proportional-hazards model was used to compare TTD between cohorts. Out of 2509 patients included in the analysis, 89.6% received ibrutinib and 14.1% received acalabrutinib. TTD was not significantly different between cohorts in the unweighted analysis. After weighting, the cohorts were balanced on all baseline characteristics except cardiovascular risk factors and baseline medications use. The median (95% CI) TTD was not reached (NR; 25.1, NR) for the acalabrutinib cohort and was 23.4 months (18.1, 28.7) for the ibrutinib cohort. The discontinuation rate at 12 months was 22% for the weighted acalabrutinib cohort vs 31% for the weighted ibrutinib cohort (P = .005). After additional adjustments for prior BTKi use, the acalabrutinib cohort had a 41% lower risk of discontinuation vs. ibrutinib (HR 0.59; 0.43, 0.81; P = .001). In the largest available study comparing two BTKis, patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs ibrutinib.

Introduction: Chronic lymphocytic leukemia (CLL) is an indolent disease most common in elderly adults. While chemo-immunotherapy is a standard first-line (1L) therapy for physically fit patients, treatment options for all CLL patients have greatly increased with the approval of novel agents. Thus, treatment decision-making in CLL has become more challenging, as physicians and patients must consider the risk-benefit trade-offs inherent to treatment options. Yet, little is known about the attitudes, beliefs, and preferences that underlie treatment decision-making in real-world settings for CLL. We aimed to elucidate oncologist/hematologist (ONC) and patient (PT) preferences about key attributes associated with novel CLL treatments using qualitative methods. Methods: In May 2019, we conducted in-depth interviews with 10 ONCs who each manage ≥20 CLL PTs with systemic therapy, prescribe novel agents for CLL, and spend at least 50% of their time in direct PT care. In addition, we interviewed 10 adult PTs with CLL. A commercial healthcare database was used to recruit ONCs, and PTs were recruited via advocacy groups. A trained moderator used a semi-structured interview guide to facilitate interviews focused on attributes influencing CLL treatment decision-making; for ONCs, interviews also asked about factors used to decide whether to treat a PT (vs. active surveillance [AS]). A standardized qualitative coding procedure (content analysis) was used to identify key themes emerging from interview responses. Descriptive statistics are reported to summarize the results. Results: ONCs had a median of 10.5 (range: 7-30) years in practice; most (n=7, 70%) reported working in an academic setting. The decision on whether or not to initiate treatment (vs. AS) depended on multiple factors, primarily symptoms, with patient motivation, health status, and treatment goals playing a lesser role. All ONCs prioritized efficacy when selecting a CLL treatment; progression-free survival (PFS; n=9) and overall survival (OS; n=7) were the top 2 metrics considered. Shorter treatment duration was considered when preferred by the PT or where adherence was a concern. ONCs perceived novel CLL therapies to be effective and well-tolerated; tumor lysis syndrome (TLS; n=8), atrial fibrillation (n=7), and diarrhea (n=7) were among the adverse events (AEs) most often cited as being a concern. ONCs perceived dose reduction as a way to mitigate certain types of AEs. All non-academic ONCs (n=3, 100%) presented one specific treatment to their PTs, but most academic ONCs (n=5, 71%) also discussed options with PTs, even if one specific treatment was recommended. Among PTs, the median age was 62.5 (range: 54-78) years, and most (n=7, 70%) were female. Four (40%) PTs were in 1L, with 4 (40%) in second/later lines (2L+), of treatment for their CLL; 2 (20%) PTs were in AS. Efficacy (described in terms of long-term remission) and concern about the impact of AEs on quality of life (QoL) were of greatest importance to PTs in choosing a treatment. Half reported that their ONC presented a specific recommendation for 1L treatment. Among 1L and 2L+ PTs (n=8), most (n=6, 75%) reported that ONCs did not provide detailed information about AEs associated with their CLL treatment. Across all PTs, cardiac issues and TLS (each, n=7) were the serious AEs most frequently reported as being of concern; other potential AEs, including joint pain (n=5) and brittle fingernails (n=2), were also cited as being of concern. Most PTs (n=9, 90%) expressed their preference for the convenience of oral over intravenous therapy. PTs who had a dose reduction (n=3) reported less apprehension about the potential impact on treatment efficacy than those who never had a dose reduction (n=7). Conclusions: While there was overlap between ONCs and PTs in the most concerning AEs, some PTs cited additional AEs due to the potential impact to their QoL. Regarding treatment preferences, PTs placed high importance on the impact of AEs on QoL, although this was of less importance to ONCs. Unlike ONCs, who viewed dose reductions as a means of resolving certain AEs, some PTs tended to question whether a dose reduction would diminish treatment efficacy. A better understanding of factors that influence treatment preferences may help facilitate ONC-PT communication when selecting novel CLL therapies. Future research should verify if these findings generalize to a representative PT population. Disclosures Le: AstraZeneca: Employment, Other: Stocks. Pendergraft:AstraZeneca: Employment, Equity Ownership. Wahlstrom:AstraZeneca: Employment, Equity Ownership. Ryan:AstraZeneca: Employment, Equity Ownership. Mulvihill:Kantar: Employment. Campbell:Kantar: Employment. Maculaitis:Kantar: Employment. LeBlanc:Helsinn: Consultancy; Jazz Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Duke University: Research Funding; Flatiron: Consultancy; Celgene: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; CareVive: Consultancy; Astra Zeneca: Consultancy, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; NINR/NIH: Research Funding; Pfizer Inc: Consultancy; American Cancer Society: Research Funding; Heron: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees.