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1.
J Surg Oncol ; 113(3): 256-63, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26394558

ABSTRACT

Achieving negative margins with "no tumor on ink" is an appropriate goal in breast conserving therapy (BCT). Wider margins do not decrease recurrence rates, and re-excision in patients with microscopic positive margins is warranted. Several strategies exist to increase rates of negative margins, including techniques to improve tumor localization, intraoperative assessment of margins and oncoplastic techniques. Negative margins should be the goal of BCT, as this will improve both local control and long-term survival.


Subject(s)
Breast Neoplasms/pathology , Breast Neoplasms/prevention & control , Breast Neoplasms/surgery , Mastectomy, Segmental/standards , Neoplasm Recurrence, Local/prevention & control , Breast Neoplasms/therapy , Chemotherapy, Adjuvant , Female , Humans , Neoplasm, Residual/prevention & control , Prognosis , Radiotherapy, Adjuvant , Treatment Outcome
2.
Am J Physiol Heart Circ Physiol ; 309(1): H137-46, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25910802

ABSTRACT

Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support for infants and children with postoperative cardiopulmonary failure. Nutritional support is mandatory during ECMO although specific actions for substrates on the heart have not been delineated. Prior work shows that enhancing pyruvate oxidation promotes successful weaning from ECMO. Accordingly, we tested the hypothesis that prolonged systemic pyruvate supplementation activates pyruvate oxidation in an immature swine model in vivo. Twelve male mixed-breed Yorkshire piglets (age 30-49 days) received systemic infusion of either normal saline (group C) or pyruvate (group P) during the final 6 h of 8 h of ECMO. Over the final hour, piglets received [2-(13)C] pyruvate, as a reference substrate for oxidation, and [(13)C6]-l-leucine, as an indicator for amino acid oxidation and protein synthesis. A significant increase in lactate and pyruvate concentrations occurred, along with an increase in the absolute concentration of the citric acid cycle intermediates. An increase in anaplerotic flux through pyruvate carboxylation in group P occurred compared with no change in pyruvate oxidation. Additionally, pyruvate promoted an increase in the phosphorylation state of several nutrient-sensitive enzymes, like AMP-activated protein kinase and acetyl CoA carboxylase, suggesting activation for fatty acid oxidation. Pyruvate also promoted O-GlcNAcylation through the hexosamine biosynthetic pathway. In conclusion, although prolonged pyruvate supplementation did not alter pyruvate oxidation, it did elicit changes in nutrient- and energy-sensitive pathways. Therefore, the observed results support the further study of pyruvate and its downstream effect on cardiac function.


Subject(s)
Energy Metabolism/drug effects , Extracorporeal Membrane Oxygenation , Heart/drug effects , Myocardium/metabolism , Pyruvic Acid/pharmacology , AMP-Activated Protein Kinases/drug effects , AMP-Activated Protein Kinases/metabolism , Acetyl-CoA Carboxylase/drug effects , Acetyl-CoA Carboxylase/metabolism , Amino Acids/drug effects , Amino Acids/metabolism , Animals , Carbon Radioisotopes , Fatty Acids/metabolism , Leucine/metabolism , Oxidation-Reduction/drug effects , Phosphorylation/drug effects , Proton Magnetic Resonance Spectroscopy , Swine
3.
J Am Heart Assoc ; 3(2): e000680, 2014 Mar 20.
Article in English | MEDLINE | ID: mdl-24650924

ABSTRACT

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides a bridge to recovery after myocardial injury in infants and children, yet morbidity and mortality remain high. Weaning from the circuit requires adequate cardiac contractile function, which can be impaired by metabolic disturbances induced either by ischemia-reperfusion and/or by ECMO. We tested the hypothesis that although ECMO partially ameliorates metabolic abnormalities induced by ischemia-reperfusion, these abnormalities persist or recur with weaning. We also determined if thyroid hormone supplementation (triiodothyronine) during ECMO improves oxidative metabolism and cardiac function. METHODS AND RESULTS: Neonatal piglets underwent transient coronary ischemia to induce cardiac injury then were separated into 4 groups based on loading status. Piglets without coronary ischemia served as controls. We infused into the left coronary artery [2-(13)C]pyruvate and [(13)C6, (15)N]l-leucine to evaluate oxidative metabolism by gas chromatography-mass spectroscopy and nuclear magnetic resonance methods. ECMO improved survival, increased oxidative substrate contribution through pyruvate dehydrogenase, reduced succinate and fumarate accumulation, and ameliorated ATP depletion induced by ischemia. The functional and metabolic benefit of ECMO was lost with weaning, yet triiodothyronine supplementation during ECMO restored function, increased relative pyruvate dehydrogenase flux, reduced succinate and fumarate, and preserved ATP stores. CONCLUSIONS: Although ECMO provides metabolic rest by decreasing energy demand, metabolic impairments persist, and are exacerbated with weaning. Treating ECMO-induced thyroid depression with triiodothyronine improves substrate flux, myocardial oxidative capacity and cardiac contractile function. This translational model suggests that metabolic targeting can improve weaning.


Subject(s)
Cardiotonic Agents/pharmacology , Energy Metabolism/drug effects , Extracorporeal Membrane Oxygenation , Mitochondria, Heart/drug effects , Myocardial Reperfusion Injury/therapy , Triiodothyronine/pharmacology , Animals , Animals, Newborn , Disease Models, Animal , Extracorporeal Membrane Oxygenation/adverse effects , Male , Mitochondria, Heart/metabolism , Myocardial Contraction/drug effects , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Myocardium/metabolism , Recovery of Function , Swine , Time Factors , Ventricular Function, Left/drug effects
4.
J Am Heart Assoc ; 2(4): e000106, 2013 Aug 19.
Article in English | MEDLINE | ID: mdl-23959443

ABSTRACT

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) unloads the heart, providing a bridge to recovery in children after myocardial stunning. ECMO also induces stress which can adversely affect the ability to reload or wean the heart from the circuit. Metabolic impairments induced by altered loading and/or stress conditions may impact weaning. However, cardiac substrate and amino acid requirements upon weaning are unknown. We assessed the hypothesis that ventricular reloading with ECMO modulates both substrate entry into the citric acid cycle (CAC) and myocardial protein synthesis. METHODS AND RESULTS: Sixteen immature piglets (7.8 to 15.6 kg) were separated into 2 groups based on ventricular loading status: 8-hour ECMO (UNLOAD) and postwean from ECMO (RELOAD). We infused into the coronary artery [2-(13)C]-pyruvate as an oxidative substrate and [(13)C6]-L-leucine as an indicator for amino acid oxidation and protein synthesis. Upon RELOAD, each functional parameter, which were decreased substantially by ECMO, recovered to near-baseline level with the exclusion of minimum dP/dt. Accordingly, myocardial oxygen consumption was also increased, indicating that overall mitochondrial metabolism was reestablished. At the metabolic level, when compared to UNLOAD, RELOAD altered the contribution of various substrates/pathways to tissue pyruvate formation, favoring exogenous pyruvate versus glycolysis, and acetyl-CoA formation, shifting away from pyruvate decarboxylation to endogenous substrate, presumably fatty acids. Furthermore, there was also a significant increase of tissue concentrations for all CAC intermediates (≈80%), suggesting enhanced anaplerosis, and of fractional protein synthesis rates (>70%). CONCLUSIONS: RELOAD alters both cytosolic and mitochondrial energy substrate metabolism, while favoring leucine incorporation into protein synthesis rather than oxidation in the CAC. Improved understanding of factors governing these metabolic perturbations may serve as a basis for interventions and thereby improve success rate from weaning from ECMO.


Subject(s)
Amino Acids/metabolism , Energy Metabolism , Extracorporeal Membrane Oxygenation , Muscle Proteins/biosynthesis , Myocardium/metabolism , Age Factors , Animals , Citric Acid Cycle , Extracorporeal Membrane Oxygenation/adverse effects , Gas Chromatography-Mass Spectrometry , Magnetic Resonance Spectroscopy , Male , Mitochondria, Heart/metabolism , Oxidation-Reduction , Oxygen Consumption , Recovery of Function , Swine , Time Factors , Ventricular Function, Left , Ventricular Pressure
5.
J Mol Cell Cardiol ; 62: 144-52, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23727393

ABSTRACT

Extracorporeal membrane oxygenation (ECMO) supports infants and children with severe cardiopulmonary compromise. Nutritional support for these children includes provision of medium- and long-chain fatty acids (FAs). However, ECMO induces a stress response, which could limit the capacity for FA oxidation. Metabolic impairment could induce new or exacerbate existing myocardial dysfunction. Using a clinically relevant piglet model, we tested the hypothesis that ECMO maintains the myocardial capacity for FA oxidation and preserves myocardial energy state. Provision of 13-Carbon labeled medium-chain FA (octanoate), long-chain free FAs (LCFAs), and lactate into systemic circulation showed that ECMO promoted relative increases in myocardial LCFA oxidation while inhibiting lactate oxidation. Loading of these labeled substrates at high dose into the left coronary artery demonstrated metabolic flexibility as the heart preferentially oxidized octanoate. ECMO preserved this octanoate metabolic response, but also promoted LCFA oxidation and inhibited lactate utilization. Rapid upregulation of pyruvate dehydrogenase kinase-4 (PDK4) protein appeared to participate in this metabolic shift during ECMO. ECMO also increased relative flux from lactate to alanine further supporting the role for pyruvate dehydrogenase inhibition by PDK4. High dose substrate loading during ECMO also elevated the myocardial energy state indexed by phosphocreatine to ATP ratio. ECMO promotes LCFA oxidation in immature hearts, while maintaining myocardial energy state. These data support the appropriateness of FA provision during ECMO support for the immature heart.


Subject(s)
Extracorporeal Membrane Oxygenation , Fatty Acids/metabolism , Myocardium/metabolism , Animals , Heart , Hemodynamics , Immunoblotting , Magnetic Resonance Spectroscopy , Male , Oxidation-Reduction , Swine
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