Radioactive seed localization compared to wire localization in breast-conserving surgery: initial 6-month experience.

BACKGROUND: Wire localization (WL) of nonpalpable breast cancers on the day of surgery is uncomfortable for patients and impacts operating room efficiency. Radioactive seed localization (RSL) before the day of surgery avoids these disadvantages. In this study we compare outcomes of our initial 6-month experience with RSL to those with WL in the preceding 6 months. METHODS: Lumpectomies for invasive or intraductal cancers localized with a single (125)iodine seed (January-June 2012) were compared with those using 1 wire (July-December 2011). Surgeons and radiologists did not change. Positive and close margins were defined as tumor on ink and tumor ≤1 mm from ink, respectively. Demographic and clinical characteristics and outcomes were compared between RSL and WL patients. RESULTS: There were 431 RSL and 256 WL lumpectomies performed. Clinicopathologic characteristics did not differ between groups. Most seeds (90 %) were placed before the day of surgery. Positive margins were present in 7.7 % of RSL versus 5.5 % of WL patients, and 16.9 % of RSL versus 19.9 % of WL had close margins (p = 0.38). The median operative time was longer for lumpectomy and sentinel lymph node biopsy (SLNB) in the RSL group (55 vs. 48 min, p < 0.0001). There was no significant difference in the volume of tissue excised between groups. CONCLUSIONS: In the first 6 months of RSL, operative scheduling was simplified, while rates of positive and close margins were similar to those seen after many years of experience with WL. Operative time was slightly longer for RSL lumpectomy and SLNB; we anticipate this will decrease with experience.

Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). METHODS: C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PFT or DMSO (vehicle) was administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western blot, real-time PCR, and biochemical assays. RESULTS: PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells. CONCLUSIONS: The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the ß-oxidation of fatty acids.

Early growth response-1 transcription factor promotes hepatic fibrosis and steatosis in long-term ethanol-fed Long-Evans rats.

BACKGROUND: Previous studies demonstrated that the Long-Evans (LE) rats exhibited liver injury and lipid metabolic abnormalities after 8 weeks of ethanol feeding. AIMS: The goal of this study was to investigate if the LE rats develop more advanced hepatic abnormalities (e.g., fibrosis) after long-term feeding with an ethanol-containing Lieber-DeCarli diet. In addition, the contribution of early growth response-1 (EGR1) transcription factor to these pathological changes was assessed. METHODS: Long-Evans rats were fed an ethanol-containing or isocaloric control liquid diet for 18 months. Livers were processed for histological analyses, studies of fibrosis-related gene expression, cell fractionation and triglyceride measurement. Serum alanine aminotransferase (ALT) levels were assessed. DNA binding activities of p53 and the sterol regulatory element-binding protein-1c (SREBP1c) were analysed. The abundance of EGR1 and enzymes involved in fatty acid synthesis were determined. Chromatin immunoprecipitation was employed to study EGR1 binding to the SREBP1c promoter region. RESULTS: Ethanol feeding generated steatosis, chicken wire fibrosis and ALT elevations in the LE rats. Fibrosis was associated with the upregulation of EGR1 and its downstream target genes. EGR1 upregulation was associated with enhanced p53 activity and an increase in the cellular p66(shc) abundance. Steatosis was linked to the activation of SREBP1c. Importantly, EGR1 upregulation paralleled the expression and transcriptional activity of SREBP1c. Finally, EGR1 was shown to bind to the SREBP1c promoter region. CONCLUSIONS: Long-term ethanol feeding promoted steatosis and fibrosis in LE rats via EGR1 activation. The highly abundant EGR1 bound to the SREBP1c promoter and contributed to the steatosis observed in the LE rat model.

Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease.

BACKGROUND & AIMS: Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of PTEN. We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but also promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. METHODS: Fischer (F), Sprague-Dawley (SD) and LE rats were fed ethanol-containing or control liquid diet for 8 weeks. Histopathological and biochemical changes were assessed. RESULTS: Here, we demonstrate that chronic ethanol feeding in rats promotes p53 activation, hepatic steatosis, oxidative stress, PUMA, and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2,6-bisphosphate (Fru-2,6-P2) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. CONCLUSIONS: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P2) levels it promotes insulin resistance and therefore, contributes to the metabolic abnormalities associated with hepatic steatosis.