A Higher Dose of Dasatinib May Increase the Possibility of Crossing the Blood–brain Barrier in the Treatment of Patients With Philadelphia Chromosome–positive Acute Lymphoblastic Leukemia

PurposeDasatinib is a second-generation tyrosine kinase inhibitor with higher central nervous system (CNS) penetration compared with imatinib and nilotinib in in vitro studies. However, limited clinical data are available regarding the dosage and CNS penetration of dasatinib. The purpose of this study was to investigate the actual ability of dasatinib to cross the blood–brain barrier in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ ALL).MethodsPlasma and cerebrospinal fluid (CSF) samples collected from Ph⁺ ALL patients treated with dasatinib were analyzed by using an LC-MS/MS assay.FindingsOrally administered dasatinib 100 mg once daily was well absorbed by the patient but penetrated poorly into the CSF. The use of a higher drug dosage (140 mg/d) may increase systemic drug exposure and enhance the penetration of dasatinib into the CSF.ImplicationsBased on this study, the use of a higher dosage of dasatinib (140 mg/d) is recommended in patients at high risk of CNS relapse or patients who need treatment for CNS leukemia. ClinicalTrials.gov identifier: NCT02523976.     

Effect of prior vaccination on carriage rates of Streptococcus pneumoniae in older adults: A longitudinal surveillance study

IntroductionPneumococcus is a commensal of the upper respiratory tract and colonization is common in young children. Carriage studies have provided insights on vaccine effects in children and may also be useful for assessing vaccines in adults. However, culture based prevalence studies in older adults describe low colonization rates. Therefore, we assessed cumulative incidence of pneumococcal colonization in older adults using polymerase chain reaction (PCR) targeting the lytA gene and risk factors for carriage.Methods100 community-dwelling adults ≥65 years were enrolled the winter of 2015 and followed biweekly for 12 months. Medical, vaccination and illness history as well as nasopharyngeal (NP) and oropharyngeal (OP) samples were collected. Combined OP and NP were incubated in enrichment broth and screened using real-time lytA PCR. Samples from new colonization events (lytA PCR+) were cultured on gentamicin blood agar plates. Isolates identified by colony morphology as S. pneumoniae were serotyped using a multiplex combined immunoassay-PCR platform which classifies 96 serotypes. Cumulative incidence of pneumococcal carriage was calculated and risk factors for carriage assessed.ResultsThe cumulative incidence of colonization was 41% by PCR and 14% by culture. Monthly prevalence ranged from 0 to 17% by PCR and 1 to 4% by culture with peaks in the spring and fall. Demographics were similar between colonized and never colonized subjects although colonized were younger (72.4 vs. 75.0 years, P = 0.06). Vaccination with any pneumococcal vaccine before or during study period was associated with decreased risk of becoming colonized (p < 0.001) as was vaccination with either the 13-valent conjugated pneumococcal vaccine (PCV13) or 23-valent polysaccharide vaccine (PPSV23) (p < 0.001).ConclusionPneumococcal colonization in older adults as detected by lytA PCR is frequent and pneumococcal vaccination appears to be associated with decreased risk of carriage. Further study is needed to understand the biological significance of molecular detection of pneumococcus in adults.     

A de novo MYOC mutation detected in juvenile open angle glaucoma associated with reduced myocilin protein in aqueous humor

MYOC mutations were originally identified in patients with juvenile open angle glaucoma (JOAG). Cell culture and mouse studies suggest that MYOC mutations cause glaucoma through a dominant-negative effect on myocilin protein secretion. We tested this hypothesis with patient samples in this study. Glaucoma and control patients underwent complete ocular examination. DNA samples from glaucoma patients, unaffected relatives and controls were used for DNA sequencing of MYOC. Aqueous humor (AH) samples from glaucoma and control patients were obtained at the time of surgery. Myocilin protein in AH was detected by quantitative Western blot analysis. A de novo Val251Ala mutation of MYOC was found to segregate with disease in a family with autosomal dominant JOAG. Myocilin protein was detected in all control AH samples but was nearly undetectable in AH samples from a patient heterozygous for the Val251Ala mutation. Our results using human patient samples are consistent with a dominant-negative effect of pathogenic MYOC mutations on myocilin secretion.     

Catheter-Directed Thrombolysis for Pulmonary Embolism: The State of Practice

Acute pulmonary embolism (PE) is a major public health problem. It is the third most common cause of death in hospitalized patients. In the United States, there are up to 600,000 cases diagnosed per year with 100,000-180,000 acute PE-related deaths. Common risk factors include underlying genetic conditions, acquired conditions, and acquired hypercoagulable states. Acute PE increases the pulmonary vascular resistance and the load on the right ventricle (RV). Increased RV loading causes compensatory RV dilation, impaired contractility, tachycardia, and sympathetic activation. RV dilation and increased intramural pressure decrease diastolic coronary blood flow, leading to RV ischemia and myocardial necrosis. Ultimately, insufficient cardiac output from the RV causes left ventricular under-filling which results in systemic hypotension and cardiovascular collapse. Current prognostic stratification strategy separates acute PE into massive, submassive, and low-risk by presence or absence of sustained hypotension, RV dysfunction, and myocardial necrosis. Massive, submassive, and low-risk acute PE have mortality rates of 25%-65%, 3%, and <1%, respectively. Current PE management includes the use of anticoagulation alone, systemic thrombolysis, catheter-directed thrombolysis, and surgical embolectomy. This article will describe the current state of practice for catheter-directed thrombolysis and its role in the management of acute PE.