Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study.

PURPOSE: To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. RESULTS: A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). CONCLUSION: Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

Proper Antibiotic Use in a Home-Based Primary Care Population Treated for Urinary Tract Infections.

OBJECTIVE: To evaluate the trends associated with diagnosis and treatment of urinary tract infections (UTI) in a home-based primary care population of Veterans Health System patients from 2006 to 2015. DESIGN: Retrospective cohort study. SETTING: Veterans Healthcare System. PARTICIPANTS: Home-based primary care patients treated for UTI from 2006 to 2015. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Appropriate therapy was determined based on the McGeer criteria. Multivariate logistic regression was used to determine factors leading to appropriate UTI treatment. RESULTS: Of 366 available patients, 68 (18.6%) were tested for a UTI. Appropriate therapy occurred in 26% of patients. Allergy to any antibiotic increased the odds of appropriate treatment (odds ratio [OR] = 5.6, 95% confidence interval [CI] 1.5-23.2). Flank pain and increased urinary frequency also increased the likelihood of being treated appropriately (OR = 25.9, 95% CI 2.9-584.0 and OR = 4.49, 95% CI 0.99-21.2, respectively). CONCLUSION: Antibiotics were overused for treating UTIs in the homebound population. Patients with flank pain, increased urinary frequency, and antibiotic allergy were more likely to receive appropriate treatment. Pharmacists, therefore, have a viable opportunity to increase appropriate antibiotic prescribing in the home-based primary care population.

Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome: A Systematic Review.

INTRODUCTION: Postural orthostatic tachycardia syndrome (POTS) impacts millions of patients, but there is currently no gold standard treatment for this condition. Ivabradine is a novel heart rate (HR) lowering agent that acts on the sinoatrial node cells by selectively inhibiting the If-current. OBJECTIVE: The objective of this systematic review is to evaluate the evidence for the efficacy and safety of ivabradine for the treatment of POTS. METHODS: MEDLINE (from 1956 to August 2017) and EMBASE (from 1957 to August 2017) were queried with the following search term: "postural orthostatic tachycardia syndrome" OR "postural tachycardia syndrome" OR "chronic orthostatic intolerance" AND "ivabradine." Articles in English with clinical outcomes of human patient(s) treated with ivabradine for POTS were included. RESULTS: The initial search identified 73 articles. After screening, 13 articles were included. Two prospective open-label trials, three retrospective cohort studies, and eight case reports evaluated the safety and efficacy of ivabradine in a total of 132 patients with postural tachycardia. Overall, ivabradine lowered HR and provided symptomatic relief of POTS without blood pressure lowering. Dizziness, nausea, headache, and fatigue were the most common side effects and often did not lead to discontinuation of treatment. CONCLUSION: Based on this small sample, ivabradine appears to be a reasonable option for patients with POTS who have failed or are unable to tolerate other treatment options, however, but a randomized controlled trial in this population is needed.

Purification technologies for colloidal nanocrystals.

Almost all applications of colloidal nanocrystals require some type of purification or surface modification process following nanocrystal growth. Nanocrystal purification - the separation of nanocrystals from undesired solution components - can perturb the surface chemistry and thereby the physical properties of colloidal nanocrystals due to changes in solvent, solute concentrations, and exposure of the nanocrystal surface to oxidation or hydrolysis. For example, nanocrystal quantum dots frequently exhibit decreased photoluminescence brightness after precipitation from the growth solvent and subsequent redissolution. Consequently, purification is an integral part of the synthetic chemistry of colloidal nanocrystals, and the effect of purification methods must be considered in order to accurately compare and predict the behavior of otherwise similar nanocrystal samples. In this Feature Article we examine established and emerging approaches to the purification of colloidal nanoparticles from a nanocrystal surface chemistry viewpoint. Purification is generally achieved by exploiting differences in properties between the impurities and the nanoparticles. Three distinct properties are typically manipulated: polarity (relative solubility), electrophoretic mobility, and size. We discuss precipitation, extraction, electrophoretic methods, and size-based methods including ultracentrifugation, ultrafiltration, diafiltration, and size-exclusion chromatography. The susceptibility of quantum dots to changes in surface chemistry, with changes in photoluminescence decay associated with surface chemical changes, extends even into the case of core/shell structures. Accordingly, the goal of a more complete description of quantum dot surface chemistry has been a driver of innovation in colloidal nanocrystal purification methods. We specifically examine the effect of purification on surface chemistry and photoluminescence in quantum dots as an example of the challenges associated with nanocrystal purification and how improved understanding can result from increasingly precise techniques, and associated surface-sensitive analytical methods.

Review of Safety and Efficacy of Sleep Medicines in Older Adults.

PURPOSE: Insomnia is problematic for older adults. After behavioral modifications fail to show adequate response, pharmacologic options are used. The pharmacokinetics of agents used to treat insomnia may be altered. This review focuses on the safety and efficacy of medications used to treat insomnia. METHODS: A literature search of Medline, PubMed, and Embase was conducted (January 1966-June 2016). It included systematic reviews, randomized controlled trials, observational studies, and case series that had an emphasis on insomnia in an older population. Search terms included medications approved by the US Food and Drug Administration for insomnia: benzodiazepines (triazolam, estazolam, temazepam, flurazepam, and quazepam), nonbenzodiazepine receptor agonists (non-BzRAs; zaleplon, zolpidem, and eszopiclone), suvorexant, ramelteon, doxepin and trazodone. Off-label drugs such as other antidepressants, antihistamines, antipsychotics, gabapentin, pramipexole, tiagabine, valerian, and melatonin were also included. FINDINGS: Cognitive behavioral therapy and sleep hygiene are considered initial therapy for insomnia. Benzodiazepines are discouraged in the geriatric population, especially for long-term use. Although non-BzRAs have improved safety profiles compared with benzodiazepines, their side effects include dementia, serious injury, and fractures, which should limit their use. Ramelteon has a minimal adverse effect profile and is effective for sleep-onset latency and increased total sleep time, making it a valuable first-line option. Although the data on suvorexant are limited, this drug improves sleep maintenance and has mild adverse effects, including somnolence; residual daytime sedation has been reported, however. Sedating low-dose antidepressants should only be used for insomnia when the patient has comorbid depression. Antipsychotic agents, pramipexole, and tiagabine have all been used for insomnia, but none has been extensively studied in an older population, and all have considerable adverse effects. Gabapentin may be useful in patients with restless leg syndrome or chronic neuropathic pain and insomnia. Diphenhydramine should be avoided in the elderly. Valerian and melatonin are unregulated products that have a small impact on sleep latency and can produce residual sedation. IMPLICATIONS: An ideal treatment for insomnia should help to improve sleep latency and sleep duration with limited awakenings and be without significant adverse effects such as daytime somnolence or decreased alertness. Cognitive behavioral therapy should always be first line treatment. Clinical inertia regarding previous prominent use of benzodiazepines and non-BzRAs will be a significant challenge for patients accustomed to their issuance. The future direction of insomnia treatment should have an emphasis on nonpharmacologic interventions, treating comorbid conditions, and focusing therapy on using benzodiazepines and non-BzRAs as last resorts.

Evidence of a clinically significant interaction between warfarin and intravesical gemcitabine.

PURPOSE: A case of supratherapeutic International Normalized Ratio (INR) values and hematomas subsequent to concomitant administration of warfarin and intravesical gemcitabine is reported. SUMMARY: A 90-year-old man with bladder cancer refractory to bacillius Calmette-Guérin was diagnosed with deep vein thrombosis (DVT) and started on warfarin one month before starting treatment with intravesical gemcitabine 2 g (one dose per week for six weeks). Before intravesical gemcitabine was started, the patient reached consecutive therapeutic INR values. During the first five cycles of intravesical gemcitabine, the patient began to experience critically elevated INRs, which resulted in hospitalization and led to the discovery of hematomas. At hospital discharge, the decision was made to discontinue warfarin permanently given the patient's history of critically elevated INRs. Instead, enoxaparin was initiated due to the patient's history of DVT and active malignancy. Enoxaparin was started at a therapeutic, renally adjusted dosage of 60 mg subcutaneously once daily after the patient's hematomas resolved and hemoglobin level stabilized. The patient was cleared for discharge to his home after 17 days of hospitalization. He was scheduled to follow up with both urology and hematology departments regarding any further treatment for bladder cancer. A week after discharge, the patient's family decided that he would not receive the last (sixth) cycle of intravesical gemcitabine. To our knowledge, this is the first reported case of an interaction between intravesical gemcitabine and warfarin. CONCLUSION: A 90-year-old man on a stable dose of warfarin experienced an increase in INR values after receiving intravesical gemcitabine for the treatment of bladder cancer.

Gel permeation chromatography as a multifunctional processor for nanocrystal purification and on-column ligand exchange chemistry.

This article illustrates the use of gel permeation chromatography (GPC, organic-phase size exclusion chromatography) to separate nanocrystals from weakly-bound small molecules, including solvent, on the basis of size. A variety of colloidal inorganic nanocrystals of different size, shape, composition, and surface termination are shown to yield purified samples with greatly reduced impurity concentrations. Additionally, the method is shown to be useful in achieving a change of solvent without requiring precipitation of the nanocrystals. By taking advantage of the different rates at which small molecules and nanoparticles travel through the column, we show that it is furthermore possible to use the GPC column as a multi-functional flow reactor that can accomplish in sequence the steps of initial purification, ligand exchange with controlled reactant concentration and interaction time, and subsequent cleanup without requiring a change of phase. This example of process intensification via GPC is shown to yield nearly complete displacement of the initial surface ligand population upon reaction with small molecule and macromolecular reactants to form ligand-exchanged nanocrystal products.

Quantum yield regeneration: influence of neutral ligand binding on photophysical properties in colloidal core/shell quantum dots.

This article describes an experiment designed to identify the role of specific molecular ligands in maintaining the high photoluminescence (PL) quantum yield (QY) observed in as-synthesized CdSe/CdZnS and CdSe/CdS quantum dots (QDs). Although it has been possible for many years to prepare core/shell quantum dots with near-unity quantum yield through high-temperature colloidal synthesis, purification of such colloidal particles is frequently accompanied by a reduction in quantum yield. Here, a recently established gel permeation chromatography (GPC) technique is used to remove weakly associated ligands without a change in solvent: a decrease in ensemble QY and average PL lifetime is observed. Minor components of the initial mixture that were removed by GPC are then added separately to purified QD samples to determine whether reintroduction of these components can restore the photophysical properties of the initial sample. We show that among these putative ligands trioctylphosphine and cadmium oleate can regenerate the initial high QY of all samples, but only the "L-type" ligands (trioctyphosphine and oleylamine) can restore the QY without changing the shapes of the optical spectra. On the basis of the PL decay analysis, we confirm that quenching in GPC-purified samples and regeneration in ligand-introduced samples are associated chiefly with changes in the relative population fraction of QDs with different decay rates. The reversibility of the QY regeneration process has also been studied; the introduction and removal of trioctylphosphine and oleylamine tend to be reversible, while cadmium oleate is not. Finally, isothermal titration calorimetry has been used to study the relationship between the binding strength of the neutral ligands to the surface and photophysical property changes in QD samples to which they are added.