Laura J. Porro

Five-Year Outcomes after Oxandrolone Administration in Severely Burned Children: A Randomized Clinical Trial of Safety and Efficacy

BACKGROUND Oxandrolone, an anabolic agent, has been administered for 1 year post burn with beneficial effects in pediatric patients. However, the long-lasting effects of this treatment have not been studied. This single-center prospective trial determined the long-term effects of 1 year of oxandrolone administration in severely burned children; assessments were continued for up to 4 years post therapy. STUDY DESIGN Patients 0 to 18 years old with burns covering >30% of the total body surface area were randomized to receive placebo (n = 152) or oxandrolone, 0.1 mg/kg twice daily for 12 months (n = 70). At hospital discharge, patients were randomized to a 12-week exercise program or to standard of care. Resting energy expenditure, standing height, weight, lean body mass, muscle strength, bone mineral content (BMC), cardiac work, rate pressure product, sexual maturation, and concentrations of serum inflammatory cytokines, hormones, and liver enzymes were monitored. RESULTS Oxandrolone substantially decreased resting energy expenditure and rate pressure product, increased insulin-like growth factor-1 secretion during the first year after burn injury, and, in combination with exercise, increased lean body mass and muscle strength considerably. Oxandrolone-treated children exhibited improved height percentile and BMC content compared with controls. The maximal effect of oxandrolone was found in children aged 7 to 18 years. No deleterious side effects were attributed to long-term administration. CONCLUSIONS Administration of oxandrolone improves long-term recovery of severely burned children in height, BMC, cardiac work, and muscle strength; the increase in BMC is likely to occur by means of insulin-like growth factor-1. These benefits persist for up to 5 years post burn.

Exercise training after burn injury: A survey of practice

Exercise programs capable of contributing positively to the long-term rehabilitation of burn patients should be included in outpatient rehabilitation programs. However, the extent and intensity of the resistance and cardiopulmonary exercise prescribed are unclear. This study was conducted to investigate the existence, design, content, and prescription of outpatient cardiopulmonary and resistance exercise programs within outpatient burn rehabilitation. A survey was designed to gather information on existing exercise programs for burn survivors and to assess the extent to which these programs are included in overall outpatient rehabilitation programs. Three hundred and twenty-seven surveys were distributed in the licensed physical and occupational therapists part of the American Burn Association Physical Therapy/Occupational Therapy Special Interest Group. One hundred and three surveys were completed. Eighty-two percent of respondents indicated that their institutions offered outpatient therapy after discharge. The frequency of therapists’ contact with patients during this period varied greatly. Interestingly, 81% of therapists stated that no hospital-based cardiopulmonary endurance exercise programs were available. Patients’ physical function was infrequently determined through the use of cardiopulmonary parameters (oxygen consumption and heart rate) or muscle strength. Instead, more subjective parameters such as range of motion (75%), manual muscle testing (61%), and quality of life (61%) were used. Prescription and follow-up assessment of cardiopulmonary endurance training are inconsistent among institutions, underscoring the need for greater awareness of the importance of exercise in any burn rehabilitation program. Identification of cardiopulmonary and progressive resistance parameters for establishing and tracking exercise training is also needed to maximize exercise-induced benefits.

Apigenin inhibits pancreatic stellate cell activity in pancreatitis

BACKGROUND Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation, necrosis, and fibrosis. There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. MATERIALS AND METHODS Pancreatitis was induced in C57/BL6 mice using supraphysiologic doses of cerulein, and apigenin treatment (once daily, 50 μg per mouse by oral gavage) was initiated 1 wk into the recurrent acute pancreatitis (RAP) protocol. Pancreata were harvested after 4 wk of RAP. Immunostaining with fibronectin antibody was used to quantify the extent of pancreatic fibrosis. To assess how apigenin may decrease organ fibrosis, we evaluated the effect of apigenin on the proliferation and apoptosis of human pancreatic stellate cells (PSCs) in vitro. Finally, we assessed apigenins effect on the gene expression in PSCs stimulated with parathyroid hormone-related protein, a profibrotic and proinflammatory mediator of pancreatitis, using reverse transcription-polymerase chain reaction. RESULTS After 4 wk of RAP, apigenin significantly reduced the fibrotic response to injury while preserving acinar units. Apigenin inhibited viability and induced apoptosis of PSCs in a time- and dose-dependent manner. Finally, apigenin reduced parathyroid hormone-related protein-stimulated increases in the PSC messenger RNA expression levels of extracellular matrix proteins collagen 1A1 and fibronectin, proliferating cell nuclear antigen, transforming growth factor-beta, and interleukin-6. CONCLUSIONS These in vivo and in vitro studies provide novel insights regarding apigenins mechanism(s) of action in reducing the severity of RAP. Additional preclinical testing of apigenin analogs is warranted to develop a therapeutic agent for patients at risk for CP.

Prediction of maximal aerobic capacity in severely burned children.

INTRODUCTION Maximal oxygen uptake (VO₂ peak) is an indicator of cardiorespiratory fitness, but requires expensive equipment and a relatively high technical skill level. PURPOSE The aim of this study is to provide a formula for estimating VO₂ peak in burned children, using information obtained without expensive equipment. METHODS Children, with ≥ 40% total surface area burned (TBSA), underwent a modified Bruce treadmill test to assess VO(2) peak at 6 months after injury. We recorded gender, age, %TBSA, %3rd degree burn, height, weight, treadmill time, maximal speed, maximal grade, and peak heart rate, and applied McHenrys select algorithm to extract important independent variables and Robust multiple regression to establish prediction equations. RESULTS 42 children; 7-17 years old were tested. Robust multiple regression model provided the equation: VO₂ =10.33-0.62 × age (years)+1.88 × treadmill time (min)+2.3 (gender; females = 0, males = 1). The correlation between measured and estimated VO₂ peak was R = 0.80. We then validated the equation with a group of 33 burned children, which yielded a correlation between measured and estimated VO₂ peak of R = 0.79. CONCLUSIONS Using only a treadmill and easily gathered information, VO₂ peak can be estimated in children with burns.

Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression.

Objectives Patients with advanced pancreatic neuroendocrine tumors have limited therapeutic options. Everolimus (RAD001), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to increase progression-free survival, but not overall survival, indicating a need to identify additional therapeutic targets. Inhibition of mTOR complex 1 by RAD001 may induce upstream AKT upregulation. We hypothesized that dual inhibition of AKT along with mTOR will overcome the limited activity of RAD001 alone. Methods The BON cell line has been used as a model to study pancreatic neuroendocrine tumor cell biology. Western blots and cell growth assays were performed with mTOR inhibitor RAD001 (50 nM), mitogen-activated protein kinase inhibitor PD0325901 (50 nM), PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002 (25 &mgr;M), or vehicle control. Nude mice were treated daily for 6 weeks with RAD001 (oral gavage) and with LY29400 (subcutaneous) 1 week after intrasplenic injection of BON cells. Results Cellular proliferation was most attenuated with the combination therapy of LY29400 and RAD001. Similarly, the volume of liver metastasis was lowest in the group treated with both LY29400 (100 mg/kg per week, subcutaneous) and RAD001 (2.5 mg/kg per day) compared with that in the vehicle group (P = 0.04). Conclusion The combination therapy of LY29400 and RAD001 decreased the cell growth in vitro and progression of liver metastasis in vivo compared with vehicle or with single-drug therapy.

Triple Negative Breast Cancer: A Review of Clinicopathologic Characteristics And Treatment Options

Breast cancer is the second leading cause of cancer death in women. Approximately 15-20% are triple negative breast cancer (TNBC: no protein expression of estrogen receptor, progesterone receptor, nor human epidermal growth factor receptor 2), representing one of the most challenging molecular subtypes of breast cancer. TNBC encompasses a heterogenous group of breast cancers that are not generally responsive to targeted therapies for hormone and growth factor receptors. Compared to their hormone receptor-positive counterparts, TNBC cases are associated with poor prognosis, worse overall survival and earlier recurrence. The purpose of this review is to describe the clinicopathologic features, molecular variants, associations with the BRCA genes, and therapeutic approaches for TNBC. New TNBC-targeted drug therapies are currently under investigation and include poly-ADP-ribose polymerase (PARP) inhibitors, platinum-based drugs, anti-epidermal growth factor receptor (EGFR) inhibitors, and anti-vascular endothelial growth factor receptor (VEGF) inhibitors. Both clinical trials and basic research are needed to further our understanding of the best treatment options for patients with TNBC. Keyword: Triple negative breast cancer.