Merisa Piper

Functional Role of Suppressor of Cytokine Signaling 3 Upregulation in Hypothalamic Leptin Resistance and Long-Term Energy Homeostasis

OBJECTIVE Hypothalamic leptin resistance is found in most common forms of obesity, such as diet-induced obesity, and is associated with increased expression of suppressor of cytokine signaling 3 (Socs3) in the hypothalamus of diet-induced obese animals. This study aims to determine the functional consequence of Socs3 upregulation on leptin signaling and obesity, and to investigate whether Socs3 upregulation affects energy balance in a cell type–specific way. RESEARCH DESIGN AND METHODS We generated transgenic mice overexpressing Socs3 in either proopiomelanocortin (POMC) or leptin receptor–expressing neurons, at levels similar to what is observed in diet-induced obesity. RESULTS Upregulation of Socs3 in POMC neurons leads to impairment of STAT3 and mammalian target of rapamycin (mTOR)–S6K-S6 signaling, with subsequent leptin resistance, obesity, and glucose intolerance. Unexpectedly, Socs3 upregulation in leptin receptor neurons results in increased expression of STAT3 protein in mutant hypothalami, but does not lead to obesity. CONCLUSIONS Our study establishes that Socs3 upregulation alone in POMC neurons is sufficient to cause leptin resistance and obesity. Socs3 upregulation impairs both STAT3 and mTOR signaling before the onset of obesity. The lack of obesity in mice with upregulated Socs3 in leptin receptor neurons suggests that Socs3s effect on energy balance could be cell type specific. Our study indicates that POMC neurons are important mediators of Socs3s effect on leptin resistance and obesity, but that other cell types or alteration of other signaling regulators could contribute to the development of obesity.

Total skin-sparing mastectomy: a systematic review of oncologic outcomes and postoperative complications.

IntroductionDespite the potential aesthetic and psychological benefits of total skin-sparing mastectomy (TSSM) with preservation of the nipple-areolar complex (NAC) skin, there is still reluctance to use the technique due to concern for increased recurrence rates or higher postoperative complication rates. The rapidly expanding literature describing outcomes after TSSM enables a comprehensive review of recurrence rates and surgical complications. MethodsStudies describing nipple-sparing or TSSM were identified from the MEDLINE and Cochrane databases. Studies that reported oncologic outcomes and/or data on postoperative complications were included. ResultsTwenty-seven studies were identified that met inclusion criteria, representing a total of 3331 mastectomies. Review of oncologic outcomes in the 10 studies (representing 1148 mastectomies) with documented mean/median follow-up of 2 years demonstrated an overall local-regional recurrence rate of 2.8%. Ischemic complications involving the NAC were reported in 24 studies (representing 3091 mastectomies), with 9.1% of cases reported to have some degree of NAC necrosis and 2.0% of cases complicated by complete necrosis leading to NAC loss. Sixteen studies (representing 2213 mastectomies) reported rates of skin flap necrosis, which occurred in 9.5% of cases. Eighty-one percent of the total cases reviewed involved expander-implant reconstruction; in the 16 studies (representing 2343 reconstructions) that reported outcomes after expander-implant reconstruction, overall expander-implant loss was 3.4%. ConclusionsThere is now a significant body of literature demonstrating low rates of early local-regional recurrence and postoperative complications after TSSM. These data support the use of TSSM techniques, which improve psychological and aesthetic outcomes without compromising therapeutic efficacy.

Retraction Notice to: Impairment of Central Leptin-Mediated PI3K Signaling Manifested as Hepatic Steatosis Independent of Hyperphagia and Obesity

Hepatic steatosis is generally thought to develop via peripheral mechanisms associated with obesity. We show that chronic central infusion of leptin suppresses hepatic lipogenic gene expression and reduces triglyceride content via stimulation of hepatic sympathetic activity. This leptin function is independent of feeding and body weight but requires phosphatidylinositol 3-kinase (PI3K) signaling. Attenuation of leptin-induced PI3K signaling, brought about by transgenic expression of phosphatase and tensin homolog (PTEN) in leptin receptor neurons, leads to decreased hepatic sympathetic tone and increased triglyceride levels without affecting adiposity or hepatic insulin signaling. Central leptins effects on hepatic norepinephrine levels and triglyceride content are blunted in these mutant mice. Simultaneous downregulation of PI3K and signal transducer and activator of transcription-3 (Stat3) in leptin receptor neurons does not exacerbate obesity but causes more severe hepatic steatosis. Together, our results indicate that central cellular leptin resistance in PI3K signaling manifests as hepatic steatosis without causing obesity.

Functional Role of c-Jun-N-Terminal Kinase in Feeding Regulation

c-Jun-N-terminal kinase (JNK) is a signaling molecule that is activated by proinflammatory signals, endoplasmic reticulum (ER) stress, and other environmental stressors. Although JNK has diverse effects on immunological responses and insulin resistance in peripheral tissues, a functional role for JNK in feeding regulation has not been established. In this study, we show that central inhibition of JNK activity potentiates the stimulatory effects of glucocorticoids on food intake and that this effect is abolished in mice whose agouti-related peptide (AgRP) neurons are degenerated. JNK1-deficient mice feed more upon central administration of glucocorticoids, and glucocorticoid receptor nuclear immunoreactivity is enhanced in the AgRP neurons. JNK inhibition in hypothalamic explants stimulates Agrp expression, and JNK1-deficient mice exhibit increased Agrp expression, heightened hyperphagia, and weight gain during refeeding. Our study shows that JNK1 is a novel regulator of feeding by antagonizing glucocorticoid function in AgRP neurons. Paradoxically, JNK1 mutant mice feed less and lose more weight upon central administration of insulin, suggesting that JNK1 antagonizes insulin function in the brain. Thus, JNK may integrate diverse metabolic signals and differentially regulate feeding under distinct physiological conditions.

Oncoplastic breast surgery: current strategies

The surgical management of breast cancer has dramatically evolved over the past 20 years, with oncoplastic surgery gaining increased popularity. This field of breast surgery allows for complete resection of tumor, preservation of normal parenchyma tissue, and the use of local or regional tissue for immediate breast reconstruction at the time of partial mastectomy. These techniques extend the options for breast conservation surgery, improve aesthetic outcomes, have high patient satisfaction and result in better control of tumor margins. This article will detail the approach to evaluating and treating patients undergoing oncoplastic reconstruction. Different oncoplastic approaches will be described and applied to an oncoplastic reconstructive algorithm. Surgical complications, oncologic outcomes and aesthetic outcomes are reviewed.

Outcomes Following Oncoplastic Reduction Mammoplasty: A Systematic Review.

BackgroundReconstruction of partial mastectomy defects with oncoplastic approaches has become increasingly popular as a strategy for improving aesthetic outcomes and extending the option of breast conservation therapy. However, interpretation of reported oncologic outcomes and postoperative complications has been challenging because of limited data and significant variability in surgical technique and degree of tissue rearrangement. MethodsStudies describing oncoplastic mammoplasty or partial mastectomy reconstruction were identified from the MEDLINE and Cochrane databases. Only studies reporting the use of oncoplastic reduction mammoplasty techniques with significant breast parenchymal rearrangement were included for analysis. Primary outcomes assessed were postoperative complications and oncologic outcomes, including local recurrence rates and need for re-excision or completion mastectomy. ResultsSeventeen articles met the inclusion criteria, representing 1324 oncoplastic cases. Reported follow-up ranged from 20 to 73 months. Of the 12 studies with at least 2 years’ mean/median follow-up, the pooled local-regional recurrence rate was 3.1%. Fifteen articles reported re-excision and completion mastectomy rates (3.5% and 3.7%, respectively). Twelve articles reported postoperative complications. Overall, 4.6% of patients had wound dehiscence, 4.3% developed fat necrosis, 2.8% developed an infection, 0.9% had either partial or total nipple necrosis, and 0.6% had seromas. ConclusionsPartial mastectomy reconstruction with oncoplastic reduction techniques is associated with high rates of successful breast conservation and low rates of required re-excisions, likely due to the ability to take wide tumor margins without compromising aesthetic outcome. Future studies should consistently report complications, recurrences, and patient-reported outcomes to improve our ability to evaluate the use of this technique.

Axillary Web Syndrome: Current Understanding and New Directions for Treatment.

BackgroundAxillary web syndrome (AWS) is a poorly understood but common cause of significant morbidity after axillary lymph node dissection for breast cancer. It is characterized by painful scar tissue formation and contracture extending from the axilla down the medial arm which limits shoulder and arm mobility. We sought to gain a better understanding of its pathophysiology and available treatments. Additionally, we present our preliminary experience with 2 novel treatment methods: (1) percutaneous needle cord disruption with fat grafting, (2) Xiaflex injection to the cording. MethodsIn order to gain better understanding of current treatment modalities, we performed a literature search to identify articles that described axillary cording after axillary dissection exclusively for breast cancer. We performed operative percutaneous cord disruption and immediate autologous fat grafting in 18 patients. Xiaflex injection was performed in one patient. Details from the 2 new treatment modalities are described. ResultsDescribed treatments in the literature include physical therapy, nonsteroidal anti-inflammatories, moist heat, and 1 case of Ascueven Forte. Typically, symptoms lasted from 1 week to 2 years, and most cases resolved by 3 months postoperatively with return to preoperative functionality. We found our 2 new treatment modalities markedly improved arm and shoulder range of motion, overall daily functioning, and pain. Aesthetic outcomes were also improved with softening of the cords. ConclusionsAxillary web syndrome remains an incompletely understood postoperative phenomenon, which warrants further research. Those patients who develop severe cording often do not respond to traditional therapy and may require more aggressive treatment. Our 2 novel techniques provide alternative options for treating this condition.

Do Prolonged Prophylactic Antibiotics Reduce the Incidence of Surgical-Site Infections in Immediate Prosthetic Breast Reconstruction?

Background: Approximately 50,000 women in the United States undergo mastectomy and immediate prosthetic breast reconstruction annually, and most receive postoperative prophylactic antibiotics. The effect of these antibiotics on the risk of surgical-site infections remains unclear. Methods: The authors searched the Medline, Embase, and Cochrane Library databases for studies that compared less than 24 hours and greater than 24 hours of antibiotics following immediate prosthetic breast reconstruction. Primary outcomes were surgical-site infections and implant loss. Conservative random effects models were used to obtain pooled relative risk estimates. Results: The authors identified 927 studies, but only four cohort studies and one randomized controlled trial met their inclusion criteria. Unadjusted incidences of surgical-site infections were 14 percent with more than 24 hours of antibiotics, 19 percent with less than 24 hours of antibiotics, and 16 percent overall. Unadjusted incidences of implant loss were 8 percent with more than 24 hours of antibiotics, 10 percent with less than 24 hours of antibiotics, and 9 percent overall. The pooled relative risk of implant loss was 1.17 (95 percent CI, 0.39 to 3.6) with less than 24 hours of antibiotics, which was not statistically significant. Conclusions: Prolonged antibiotic use did not have a statistically significant effect on reducing surgical-site infections or implant loss. There was significant heterogeneity between studies, and prolonged antibiotics may have increased the risk of implant loss in the randomized controlled trial. Definitive evidence may only be obtained with data from more prospective randomized controlled trials.

The Novel Application of Genomic Profiling Assays to Shorten Inactive Status for Potential Kidney Transplant Recipients With Breast Cancer.

The concern about cancer recurrence has traditionally resulted in delaying kidney transplantation for 2–5 years after a cancer diagnosis in patients who are otherwise eligible for transplant. This period of inactive status to observe the tumor biology can result in significant morbidity and decreased quality of life for patients with end‐stage renal disease (ESRD). We reported the novel application of genomic profiling assays in breast cancer to identify low‐risk cancers in two patients with ESRD who were able to have the mandatory inactive status eliminated prior to kidney transplantation.

Pediatric lower extremity sarcoma reconstruction: A review of limb salvage procedures and outcomes

BACKGROUND In recent years, dramatic advances in the multidisciplinary treatment of pediatric sarcoma have resulted in significant improvement in the long-term survival of the patient. Thus, following tumor resection, significant effort has gone into limb salvage and improving functional outcomes. Plastic surgeons, in conjunction with orthopedic surgeons, are using techniques in microvascular free-tissue transfer and rotational flap surgery to preserve limb length. This study presents a review of the current reconstructive strategies and the oncologic, surgical, and functional outcomes in this population. METHODS Using the Pubmed and Cochrane Library databases, studies describing lower extremity plastic surgical reconstruction were identified following pediatric lower extremity sarcoma resection. This study included those studies which described reconstructive techniques, oncologic and functional outcomes, and surgical complications. RESULTS A total of nine articles were identified, yielding 96 pediatric patients. The most common procedures performed were free fibular flaps (53 patients) followed by pedicled muscle flaps (31 patients). A total of 72 of 96 patients (75%) achieved independent ambulation, and an additional 19 patients (20%) ambulated with assistance. There were only three (3%) amputations. A total of 13 patients died from metastatic disease (14%). CONCLUSIONS Plastic surgery procedures play an increasingly important role in pediatric lower extremity sarcoma reconstruction and functional limb salvage. Published series are limited in number and case volume; to date, no systematic review has been published. The existing data emphasize the role of microvascular free-fibula transfer as well as local muscle flap coverage in preserving limb length and function, with minimal risk of local recurrence and need for amputation.