Locoregional Recurrence and Survival Outcomes by Type of Local Therapy and Trastuzumab Use Among Women with Node-Negative,HER2-Positive Breast Cancer

Background

While human epidermal growth factor receptor 2 (HER2) overexpression is an adverse breast cancer prognostic factor, it is unclear whether there are differences in outcomes between types of local treatment in this population. This retrospective study examined locoregional recurrence and survival in women with node-negative, HER2+ breast cancer treated with breast-conserving therapy (BCT) versus mastectomy.

Methods

Subjects were 748 patients with pT1–2, N0, M0 HER2+ breast cancer, treated with BCT (n = 422) or mastectomy (n = 326). Trastuzumab was used in 54 % of subjects. The 5-year Kaplan–Meier locoregional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), and overall survival (OS) were compared between cohorts treated with BCT versus mastectomy. Subgroup analyses of LRR and survival were performed separately among patients treated with BCT or mastectomy to examine the effect of trastuzumab on outcomes in each group.

Results

Median follow-up was 4.4 years. Patients treated with mastectomy had higher proportions of grade 3 histology (69 vs 60 %, p = 0.004) and lower rates of hormone therapy (51 vs 64 %, p < 0.001) and trastuzumab therapy (50 vs 57 %, p = 0.04). The 5-year outcomes in women treated with BCT compared with mastectomy were: LRRFS 98.0 versus 98.3 % (p = 0.88), BCSS 97.2 versus 96.1 % (p = 0.70), and OS 95.5 versus 93.4 % (p = 0.19). Trastuzumab was associated with similar LRRFS and improved OS in both local treatment groups.

Conclusions

BCT is safe in the population of women with pT1–2, N0, HER2+ breast cancer, providing high rates of locoregional control and survival equivalent to mastectomy. Trastuzumab was associated with improved survival in both groups.     

Development of Vorinostat-Loaded Solid Lipid Nanoparticles to Enhance Pharmacokinetics and Efficacy against Multidrug-Resistant Cancer Cells

Purpose

To investigate whether delivery of a histone deacetylase inhibitor, vorinostat (VOR), by using solid lipid nanoparticles (SLNs) enhanced its bioavailability and effects on multidrug-resistant cancer cells.

Methods

VOR-loaded SLNs (VOR-SLNs) were prepared by hot homogenization using an emulsification-sonication technique, and the formulation parameters were optimized. The cytotoxicity of the optimized formulation was evaluated in cancer cell lines (MCF-7, A549, and MDA-MB-231), and pharmacokinetic parameters were examined following oral and intravenous (IV) administration to rats.

Results

VOR-SLNs were spherical, with a narrowly distributed average size of ~100 nm, and were physically stable for 3 months. Drug release showed a typical bi-phasic pattern in vitro, and was independent of pH. VOR-SLNs were more cytotoxic than the free drug in both sensitive (MCF-7 and A549) and resistant (MDA-MB-231) cancer cells. Importantly, SLN formulations showed prominent cytotoxicity in MDA-MB-231 cells at low doses, suggesting an ability to effectively counter the P-glycoprotein-related drug efflux pumps. Pharmacokinetic studies clearly demonstrated that VOR-SLNs markedly improved VOR plasma circulation time and decreased its elimination rate constant. The areas under the VOR concentration-time curve produced by oral and IV administration of VOR-SLNs were significantly greater than those produced by free drug administration. These in vivo results clearly highlighted the remarkable potential of SLNs to augment the bioavailability of VOR.

Conclusions

VOR-SLNs successfully enhanced the oral bioavailability, circulation half-life, and chemotherapeutic potential of VOR.     

Assessing Student Pharmacists’ Ability to Identify Drug-Related Problems in Patients Within a Patient-Centered Medical Home

Objective. To quantify, describe, and categorize patient drug-related problems (DRPs) and recommendations identified by fourth-year (P4) student pharmacists during a live medication reconciliation activity within a patient-centered medical home (PCMH).Methods. Fourth-year student pharmacists conducted chart reviews, identified and documented DRPs, obtained live medication histories, and immediately provided findings and recommendations to the attending physicians. Documentation of DRPs and recommendations were analyzed retrospectively.Results. Thirty-eight students completed 99 medication reconciliation sessions from June 2011 to October 2012 during their advanced pharmacy practice experience (APPE). The students obtained 676 patient medication histories and identified or intervened on 1308 DRPs. The most common DRPs reported were incomplete medication list and diagnostic/laboratory testing needed. Physicians accepted 1,018 (approximately 78%) recommendations.Conclusion. Student pharmacists successfully identified and reduced DRPs through a live medication reconciliation process within an academic-based PCMH model. Their medication history-taking skills improved and medication use was optimized.     

Percutaneous Closure of Aortic and Mitral Paravalvular Leaks—Diagnostic and Therapeutic Considerations

Purpose of review

Prenatal diagnosis of congenital heart disease (CHD) is continuously evolving with each passing decade. Early efforts in fetal cardiology focused on identifying CHD in mid-gestation and understanding of fetal circulation in pathologic conditions. Improving prenatal detection rates for CHD remains an ongoing challenge and increasingly the field of fetal cardiology is moving to not only diagnosing CHD prenatally but also assessing the impact of prenatal diagnosis of CHD outcomes. Future directions include earlier diagnosis of fetal CHD, improved diagnostic rates, widespread sonographer education, and a better understanding of antenatal factors that impact outcomes. Our goal in this review is to describe the past, present, and future of prenatal diagnosis of CHD.

Recent findings

There has been a steady improvement in the prenatal diagnosis rate for CHD; however, there remains a significant variation between countries and within the USA. Prenatal diagnosis of CHD allows for counseling and delivery planning in those fetuses with critical CHD, thereby providing parents with resources and important tools while dealing with a challenging situation of carrying a child with heart disease and helping them with important decisions for their family and their future. There are several specific conditions which continue to pose a challenge from a diagnostic standpoint as they may appear mild at the time of initial diagnosis and may be missed but progress through the pregnancy and lead to significant CHD in the neonatal period.

Summary

In summary, continued efforts aimed at collaborative research and education are needed in order to be able to improve CHD detection rates. We need to cautiously assess lesions that appear minor in mid-gestation but have the potential to progress in late gestation. Earlier detection of CHD by means of a transvaginal or a first-trimester fetal echocardiogram may further help families with delivery planning and decision-making.

     

New dianthramide and cinnamic ester glucosides from the roots of Aconitum carmichaelii

Four new compounds N-salicyl-3-hydroxyanthranilic acid methyl ester (1), N-(2′-dehydroxysalicyl)-3-hydroxyanthranilic acid methyl ester (2), methyl-4-β-D-allopyranosyl-ferulate (3), and methyl-4-β-D-gulopyranosyl-cinnamate (4), along with six known compounds (5–10), were isolated from the roots of Aconitum carmichelii Debx. Their structures were elucidated on the basis of spectral data analysis, including 1D, 2D-NMR, and HR-ESI-MS. Compounds 1 and 2 showed the inhibition of nitric oxide (NO) production with IC₅₀ values of 9.13 and 19.94 μM, respectively.     

A Systematic Review of the Extent and Measurement of Healthcare Provider Racism

BACKGROUND

Although considered a key driver of racial disparities in healthcare, relatively little is known about the extent of interpersonal racism perpetrated by healthcare providers, nor is there a good understanding of how best to measure such racism.

OBJECTIVES

This paper reviews worldwide evidence (from 1995 onwards) for racism among healthcare providers; as well as comparing existing measurement approaches to emerging best practice, it focuses on the assessment of interpersonal racism, rather than internalized or systemic/institutional racism.

METHODS

The following databases and electronic journal collections were searched for articles published between 1995 and 2012: Medline, CINAHL, PsycInfo, Sociological Abstracts. Included studies were published empirical studies of any design measuring and/or reporting on healthcare provider racism in the English language. Data on study design and objectives; method of measurement, constructs measured, type of tool; study population and healthcare setting; country and language of study; and study outcomes were extracted from each study.

RESULTS

The 37 studies included in this review were almost solely conducted in the U.S. and with physicians. Statistically significant evidence of racist beliefs, emotions or practices among healthcare providers in relation to minority groups was evident in 26 of these studies. Although a number of measurement approaches were utilized, a limited range of constructs was assessed.

CONCLUSION

Despite burgeoning interest in racism as a contributor to racial disparities in healthcare, we still know little about the extent of healthcare provider racism or how best to measure it. Studies using more sophisticated approaches to assess healthcare provider racism are required to inform interventions aimed at reducing racial disparities in health.     

Glycemic index of American-grown jasmine rice classified as high

The primary objective was to determine the glycemic index (GI) of jasmine rice grown in the United States (US). Secondary objective was to compare the GI of US grown jasmine rice to those grown in Thailand. Twelve healthy subjects were served all four brands of jasmine rice and a reference food (glucose), each containing 50?g of available carbohydrate. Fingerstick blood glucose was measured at 0, 15, 30, 45, 60, 90, and 120?min after consumption following a fasting state. The GI was calculated using the standard equation. The GI values for test foods ranged from 96 to 116 and were all classified as high GI foods. No difference in GI was found between American-grown and Thailand-grown jasmine rice. Although not statistically significant, observations show glycemic response among Asian American participants may be different. GI should be considered when planning meals with jasmine rice as the main source carbohydrate.     

Sensitive quantification of mitochondrial mutation using new Taqman probes

The A3243G mitochondrial mutation is the major cause of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). The severity of the disease is correlated with the heteroplasmy level of the mutation. Here we describe for the first time the validation of a real-time polymerase chain reaction (PCR) assay with Taqman locked nucleic acid (LNA) fluorescent (FAM for mutant, HEX for wild type) probes for quantification of heteroplasmy levels in a total of 18 family members from 5 Vietnamese MELAS patients carrying A3243G. Almost no background of FAM signals was detected in normal samples, indicating that the probes were allele-specific. Standard curves indicate sensitive detection at 0.1% mutants and high reliability with R² > 0.985. The correlation line between measured % mutant and expected % mutant was highly reliable, with a slope of 0.993 and R² of 0.998. All positive A3243G mutant samples pre-screened by PCR-restriction fragment length polymorphism (RFLP) were confirmed, and their heteroplasmy levels quantified to be from 3.68 to 80.85%. The heteroplasmy levels in patients were higher than in their family members and generally correlated well with the severity of their clinical symptoms. Overall, this work is the first demonstration of the application of LNA probes for sensitive and highly reliable quantification of heteroplasmy levels in human mitochondria.     

Polyoxymethylene/silica/polylactic acid-grafted polyethylene glycol nanocomposites: structure,morphology, and mechanical properties and ozone and UV durability

Polyoxymethylene (POM) is a semicrystalline thermoplastic that displays high tensile strength, thermal stability, and chemical durability. However, its widespread application is limited by its low elongation at break and thermal durability. In the present study, nanosilica (NS) and polylactic acid-grafted polyethylene glycol (PELA) were used as enhancement additives to improve the performance of POM homopolymer. Specifically, the POM/PELA/NS nanocomposites with a fixed NS content and varying PELA contents were prepared by a melt mixing method. The influence of the additives on the processability, and dynamic thermo-mechanical and tensile properties of the nanocomposites was evaluated by comparing the torque, mixing energy at melt state, storage modulus, shear stress, loss modulus, tan δ, tensile strength, elongation at break and thermal degradation of the nanocomposites. The results showed that the combined addition of NS and PELA enhanced the thermal stability, tensile strength, elongation at break and chemical stability of the POM/PELA/NS nanocomposites owing to the good compatibility between PELA and the POM matrix. Furthermore, the morphology, and UV and ozone durability of POM and the nanocomposites were assessed and discussed.

The combined addition of nanosilica (NS) and polylactic acid-grafted polyethylene glycol (PELA) enhanced some properties of polyoxymethylene (POM).     

Regional synapse gain and loss accompany memory formation in larval zebrafish

Defining the structural and functional changes in the nervous system underlying learning and memory represents a major challenge for modern neuroscience. Although changes in neuronal activity following memory formation have been studied [B. F. Grewe et al., Nature 543, 670–675 (2017); M. T. Rogan, U. V. Stäubli, J. E. LeDoux, Nature 390, 604–607 (1997)], the underlying structural changes at the synapse level remain poorly understood. Here, we capture synaptic changes in the midlarval zebrafish brain that occur during associative memory formation by imaging excitatory synapses labeled with recombinant probes using selective plane illumination microscopy. Imaging the same subjects before and after classical conditioning at single-synapse resolution provides an unbiased mapping of synaptic changes accompanying memory formation. In control animals and animals that failed to learn the task, there were no significant changes in the spatial patterns of synapses in the pallium, which contains the equivalent of the mammalian amygdala and is essential for associative learning in teleost fish [M. Portavella, J. P. Vargas, B. Torres, C. Salas, Brain Res. Bull. 57, 397–399 (2002)]. In zebrafish that formed memories, we saw a dramatic increase in the number of synapses in the ventrolateral pallium, which contains neurons active during memory formation and retrieval. Concurrently, synapse loss predominated in the dorsomedial pallium. Surprisingly, we did not observe significant changes in the intensity of synaptic labeling, a proxy for synaptic strength, with memory formation in any region of the pallium. Our results suggest that memory formation due to classical conditioning is associated with reciprocal changes in synapse numbers in the pallium.

It is widely believed that memories are formed as a result of alterations in synaptic connections between axons and dendrites, an idea first proposed by Ramon y Cajal (1–4). Although synapse changes have been extensively studied in brain slices in the context of long-term potentiation (5, 6), less is known about how synapses in a living vertebrate are modified when a memory is formed.Memory formation has been widely studied using classical conditioning (CC), a robust and straightforward form of learning in which an animal is exposed to a neutral stimulus (conditioned stimulus, CS) paired with an appetitive or aversive stimulus (unconditioned stimulus, US) that evokes a specific behavioral response (UR, unconditioned response) (7, 8). As a result of the pairing, animals learn to associate the CS with the US, causing them to respond to the CS with a conditioned response (CR) identical to the UR, signifying memory retrieval (9, 10). Memory retrieval is also evoked by activating a cellular engram, a group of neurons active during memory formation and retrieval (11–18). The central locus of CC in mammals, the amygdala (19), is located in a relatively inaccessible area beneath the cortex (20). Thus, although numerous longitudinal imaging studies have documented experience-dependent changes in the structure of spines of cortical and hippocampal neurons (21, 22), few imaging studies have directly examined synaptic changes that occur in the amygdala during associative memory formation.Instead, synaptic changes that occur in the amygdala during CC (23) have been studied primarily using indirect measures of synaptic strength, such as the ratio of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor/N-methyl D-aspartate (AMPA/NMDA) currents in excitatory postsynaptic currents (EPSCs). Increases in AMPA/NMDA ratio in amygdalar neurons following auditory fear conditioning (FC), a type of CC (24–27), indicate that associative memory formation coincides with increases in synaptic strength. In addition, imaging experiments in brain regions beyond the amygdala have shown diverse effects following CC. For example, following contextual fear conditioning, engram neurons in the CA1 region of the hippocampus that receive inputs from CA3 engram neurons displayed spines that were larger and more densely packed than nonengram cells (28). Furthermore, experiments in which neuronal morphology was directly observed before and after FC found that neurons in the frontal association (29) and primary motor cortex (30) showed a decrease in the number of spines, whereas neurons in the auditory cortex showed an increase in spine number with memory formation (31).To obtain previously unavailable insight into memory formation within the central locus of associative memory storage, we developed a paradigm combining in vivo labeling and imaging with informatics and analysis tools. We used this paradigm to map synaptic changes that occur over time in the intact brain of a living vertebrate during memory formation. We imaged the pallium of teleost fish, which contains the putative homolog of the mammalian amygdala based on anatomy (32), gene expression (33), and function (34). The pallium is on the surface of the brain (35), and zebrafish larvae are highly transparent, allowing for intact, whole-brain imaging using selective plane illumination microscopy (SPIM) without the need for invasive intervention (36). In addition, while most studies of learning in zebrafish have used adults (37–40), at least one study showed that larval zebrafish can learn to associate a place with a positive valence US (41). These attributes suggest that larval zebrafish may be an ideal model organism for studying synaptic changes during memory formation due to CC. We have engaged this challenge by combining purpose-built experimental tools with data management software that enables transparent analyses of large and heterogeneous datasets. All data were characterized and stored at the time of creation in a customized data management system designed to conform to findability, accessibility, interoperability, and reusability (i.e., FAIR principles) (see Materials and Methods) (42).