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The ACOSOG Z0011 trial has essentially eliminated axillary lymph node dissection (ALND) in breast conserving therapy (BCT) patients with clinical T1/T2 and 1-2 positive sentinel lymph nodes (SLNs). Currently, ALND is recommended for positive SLNs unless ACOSOG Z0011 criteria are applicable. We aimed to assess the national trends and axillary management before and after the publication of ACOSOG Z0011 for larger tumors. An IRB-approved study evaluated the National Cancer Database from 2006 to 2016. Women with clinical T3/T4, N0 who otherwise fit ACOSOG Z0011 criteria were included. Neoadjuvant systemic therapy or known nodal disease was excluded. Clinicopathologic data were compared between two timeframes based on ACOSOZ Z0011 publication and by axillary management. Patients were categorized into SLNB alone (1-5 lymph nodes examined) and ALND (≥10 lymph nodes examined) groups. A total of 230 women fit inclusion criteria, of whom 36% underwent ALND. ALND use decreased from 54% in 2006 to 14% in 2016 (P < 0.01). Comparing ALND to SLNB alone within the pre-Z0011 era, comprehensive community cancer programs had higher proportions of ALND, whereas academic centers had higher rates of SLND alone (P = 0.03). Comparing similar axillary management between eras, SLNB-alone patients in the post-Z0011 era had higher pT and pN stages, were less likely to be Her2 positive, and were more likely to receive systemic treatment. There is a national trend to forgo ALND in women who have tumors larger than those included in the Z0011 criteria without any clear clinicopathologic indications. [ABSTRACT FROM AUTHOR]

Hypothermic circulatory arrest (HCA) is a technique used for complex repair of the aorta, but it can be associated with neurologic morbidity. To better understand the molecular changes that underlie ischemic brain injury, we assessed gene expression and cytokine/chemokine polypeptide concentration in brain tissue and cerebrospinal fluid (CSF) of canines that underwent two hours of HCA. Materials and Methods: Adult male canines were cannulated peripherally for cardiopulmonary bypass, cooled to 18°C, and arrested for two hours. Animals were euthanized two, eight, or 24 hours post-HCA (n = 8 per group), and their brains were compared to brains from eight normal canines, using gene expression microarray analysis, cytokine assay, and histopathology. Two to eight hours after HCA, pro-inflammatory cytokine mRNAs increased markedly, and gene expression was enriched within signaling pathways related to neuroinflammation or ischemic injury. Concentrations of pro-inflammatory cytokine polypeptides IL-6, IL-8, IL-1β, and CCL2 were very low in normal canine brain, whereas anti-inflammatory IL-10 and TGF-β1 were expressed at moderate levels. Pro-inflammatory cytokine concentrations rose robustly in cerebral tissue and CSF after HCA. IL-6 and IL-8 peaked at eight hours and declined at 24 hours, while IL-1β and CCL2 remained elevated. Concentrations of anti-inflammatory IL-10 and TGF-β1 were maintained after HCA, with a significant increase in TGF-β1 at 24 hours. These cytokines represent potential diagnostic markers for ischemic neurologic injury that could be used to assess neurologic injury in patients undergoing HCA. The cellular mechanisms underlying this pro-inflammatory, ischemic-induced injury represent potential targets for neuroprotection in the future. [ABSTRACT FROM AUTHOR]

Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we hypothesized that the N-methyl-D-aspartate receptor antagonist MK801 would provide neuroprotection and that MK801 conjugation to dendrimer nanoparticles would improve efficacy. Male hound dogs were placed on cardiopulmonary bypass, cooled to 18°C, and underwent 90 min of HCA. Dendrimer conjugates (d-MK801) were prepared by covalently linking dendrimer surface OH groups to MK801. Six experimental groups received either saline (control), medium- (0.15 mg/kg) or high-dose (1.56 mg/kg) MK801, or low- (0.05 mg/kg), medium-, or high-dose d-MK801. At 24, 48, and 72 h after HCA, animals were scored by a standardized neurobehavioral paradigm (higher scores indicate increasing deficits). Cerebrospinal fluid was obtained at baseline, eight, 24, 48, and 72 h after HCA. At 72 h, brains were examined for histopathologic injury in a blinded manner (higher scores indicate more injury). Neurobehavioral deficit scores were reduced by low-dose d-MK801 on postoperative day two (P < 0.05) and by medium-dose d-MK801 on postoperative day 3 (P = 0.05) compared with saline controls, but free drug had no effect. In contrast, high-dose free MK801 significantly improved histopathology scores compared with saline (P < 0.05) and altered biomarkers of injury in cerebrospinal fluid, with a significant reduction in phosphorylated neurofilament-H for high-dose MK801 versus saline (P < 0.05). Treatment with MK-801 demonstrated significant improvement in neurobehavioral and histopathology scores after HCA, although not consistently across doses and conjugates. • Hypothermic circulatory arrest (HCA) is a technique used for thoracic aorta work. • We tested MK801, an NMDA receptor antagonist, as a neuroprotectant during HCA. • To reduce side effects, we tested MK801 conjugated to dendrimer, a nanoparticle. • Treatment inconsistently improved postoperative behavior and brain histopathology. [ABSTRACT FROM AUTHOR]

Abstract We tested the claim that the dopaminergic dysfunction of Rett Syndrome (RTT) also occurs in Mecp2-deficient mice that serve as a model of the syndrome. We used positron emission tomography (PET) to image dopamine D 2 receptors (D 2 R) and transporters (DAT) in women with RTT and in Mecp2-deficient mice, and D 1 R and D 2 R density was measured in postmortem human tissue by autoradiography. Results showed 1) significantly reduced D 2 R density in the striatum of women with RTT compared to control subjects. 2) PET imaging of mouse striatum similarly demonstrated significant reductions in D 2 R density of 7–10 week-old hemizygous ( Mecp2 -null) and heterozygous (HET) mice compared to wild type (WT) mice. With age, the density of D 2 R declined in WT mice but not HET mice. 3) In contrast, postmortem autoradiography revealed no group differences in the density of D 1 R and D 2 R in the caudate and putamen of RTT versus normal control subjects. 4) In humans and in the mouse model, PET revealed only marginal group differences in DAT. The results confirm that dopaminergic dysfunction in RTT is also present in Mecp2-deficient mice and that reductions in D 2 R more likely explain the impaired ambulation and progressive rigidity observed rather than alterations in DAT. Highlights • PET imaging of dopamine function was performed in MeCP2-deficient humans and mice. • D 2 receptor binding is reduced in Rett syndrome and in Mecp2-deficient mice. • Dopamine transporters are less affected than D 2 receptors by MeCP2 deficiency. • Mecp2-deficient mice model dopamine dysfunction in Rett Syndrome • D 2 receptors may play a role in motor deficits in Rett Syndrome. [ABSTRACT FROM AUTHOR]

• Structural changes in MeCP2 deficient mouse models are similar to those in RTT. • Region-specific modifications in structure often coincide with phenotype onset. • Whisker follicle plasticity within the barrel cortex is altered by MeCP2 deficiency. • MeCP2 has non-cell autonomous effects on neuronal and glial structure and function. Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues. [ABSTRACT FROM AUTHOR]