Elevation of circulating big endothelin-1: an independent prognostic factor for tumor recurrence and survival in patients with esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Endothelin(ET) axis plays a key role in many tumor progression and metastasis via various mechanisms such as angiogenesis, mediating extracellular matrix degradation and inhibition of apoptosis. However, there is limited information regarding the clinical significance of plasma big ET-1 levels in esophageal cancer patients. Circulating plasma big ET-1 levels were measured in patients with esophageal squamous cell carcinoma(ESCC) to evaluate the value of ET-1 as a biomarker for predicting tumor recurrence and patients survival.</p> <p>Methods</p> <p>Preoperative plasma big ET-1 concentrations were measured by an enzyme linked immunosorbent assay(ELISA) in 108 ESCC patients before surgery, and then again at 1,2,3,10 and 30 days after curative radical resection for ESCC. The association between preoperative plasma big ET-1 levels and clinicopathological features, tumor recurrence and patient survival, and their changes following surgery were evaluated.</p> <p>Results</p> <p>The preoperative plasma big ET-1 levels in ESCC patients were significantly higher than those in controls. And there was a significant association between plasma big ET-1 levels and disease stage, as well as invasion depth of the tumor and lymph node status. Furthermore, plasma big ET-1 levels decreased significantly after radical resection of the primary tumor and patients with postoperative recurrence had significantly higher plasma big ET-1 levels than that of patients without recurrence. Finally, the survival rate of patients with higher plasma big ET-1 concentrations (>4.3 pg/ml) was significantly lower than that of patients with lower level (≤ 4.3 pg/ml). Multivariate regression analysis showed that plasma big ET-1 level is an independent prognostic factor for survival in patients with ESCC.</p> <p>Conclusion</p> <p>Plasma big ET-1 level in ESCC patients may reflect malignancy and predict tumor recurrence and patient survival. Therefore, the preoperative plasma big ET-1 levels may be a clinically useful biomarker for choice of multimodality therapy in ESCC patients.</p

Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects?

Endothelin-1 (ET-1) is an endothelium-derived peptide that also possesses potent mitogenic activity. There is also a suggestion the ET-1 is a neuropeptide, based mainly on its histological identification in both the central and peripheral nervous system in a number of species, including man. A neuropeptide role for ET-1 is supported by studies showing a variety of effects caused following its administration into different regions of the brain and by application to peripheral nerves. In addition there are studies proposing that ET-1 is implicated in a number of neural circuits where its transmitter affects range from a role in pain and temperature control to its action on the hypothalamo-neurosecretory system. While the effect of ET-1 on nerve tissue is beyond doubt, its action on nerve blood flow is often ignored. Here, we review data generated in a number of species and using a variety of experimental models. Studies range from those showing the distribution of ET-1 and its receptors in nerve tissue to those describing numerous neurally-mediated effects of ET-1

The pharmacokinetics and safety of an intraoperative bupivacaine-collagen implant (XaraColl&amp;reg;) for postoperative analgesia in women following total abdominal hysterectomy

Susan L Cusack,1 Philip Reginald,2 Lisa Hemsen,3 Emmanuel Umerah21Cusack Pharmaceutical Consulting, Burlington, NJ, USA; 2Departments of Gynaecology and Anaesthetics, Wexham Park Hospital, Slough, SL2 4HL, UK; 3Innocoll Technologies, Athlone, IrelandBackground: XaraColl&amp;reg;, a collagen-based intraoperative implant that delivers bupivacaine to the site of surgical trauma, is under development for postoperative analgesia. We examined the pharmacokinetics, safety and efficacy of XaraColl following implantation in women undergoing total abdominal hysterectomy.Methods: Three XaraColl implants, each containing 50 mg bupivacaine hydrochloride, were implanted in 12 women undergoing total abdominal hysterectomy for a benign condition. Serum samples were obtained through 96 hours for pharmacokinetic analysis. Patients received acetaminophen 1000 mg every 6 hours, diclofenac 50 mg every 8 hours, and were given access to intravenous morphine for breakthrough pain via patient-controlled analgesia during the first 24 hours. Pain intensity was assessed at regular intervals using a 100 mm visual analog scale. Safety was assessed through 30 days.Results: The pharmacokinetic profile displayed a double peak in bupivacaine concentration with the second peak occurring up to 24 hours after the first and at a generally higher concentration. The time to maximum concentration (tmax) varied from 0.5 to 24 hours (median 12 hours) according to which peak predominated. The mean maximum concentration (Cmax) was 0.22 &amp;micro;g/mL and the maximum individual Cmax was 0.44 &amp;micro;g/mL, which are well below the established systemic toxicity threshold. Morphine use was generally low (mean 16.8 mg; median 6.5 mg) and compared favorably with institutional experience. At 6 hours post-surgery, 11 patients recorded pain scores &amp;le; 20 mm, 6 recorded &amp;le; 10 mm, and 2 reported no pain. Scores continued to decline throughout the study. The product was considered safe and well tolerated.Conclusion: XaraColl exhibits a biphasic and sustained release profile that may provide a significant advance over standard wound infiltration. Considering the encouraging results from this study alongside those from other randomized controlled efficacy trials, XaraColl should be further evaluated as a postoperative analgesic in large, double-blind efficacy trialsKeywords: pain, opioid use, analgesia, anestheti

Clinical evaluation of XaraColl&amp;reg;, a bupivacaine-collagen implant, for postoperative analgesia in two multicenter, randomized, double-blind, placebo-controlled pilot studies

Susan L Cusack,1 Mark Jaros,2 Michael Kuss,3 Harold S Minkowitz,4 Peter Winkle,5 Lisa Hemsen61Cusack Pharmaceutical Consulting, Burlington, NJ, 2Summit Analytical, Denver, CO, USA; 3Premier Research Group, Austin, TX, USA; 4Memorial Hermann Memorial City Medical Center, Houston, TX, USA; 5Advanced Clinical Research Institute, Anaheim, CA, USA; 6Innocoll Technologies, Athlone, IrelandBackground: XaraColl&amp;reg;, a collagen-based implant that delivers bupivacaine to the site of surgical trauma, is under development for postoperative analgesia. Because of differing patient attitudes to postoperative pain control and the inability to assess baseline pain, standard clinical methods for evaluating analgesic efficacy are compromised and justify application of novel integrated approaches.Methods: We conducted two independent, multicenter, double-blind, placebo-controlled studies in men undergoing unilateral inguinal hernioplasty by open laparotomy to evaluate the safety and efficacy of XaraColl at different doses (100 mg and 200 mg of bupivacaine hydrochloride; study 1 and 2, respectively). Enrolled patients (50 in study 1 and 53 in study 2) were randomized to receive active or placebo implants in a 1:1 ratio. Postoperative pain intensity and use of supplementary opioid medication were recorded through 72 hours. Safety was assessed through 30 days. The principal efficacy variables were the summed pain intensity (SPI), total use of opioid analgesia (TOpA), and an integrated endpoint (I-SPI-TOpA). Each variable was analyzed at 24, 48, and 72 hours after implantation. A pooled analysis of both studies was also performed retrospectively.Results: Through 24 and 48 hours, XaraColl-treated patients experienced significantly less pain in study 1 (P &amp;lt; 0.001 and P = 0.012, respectively) whereas they took significantly less opioid analgesia in study 2 (P = 0.004 and P = 0.042, respectively). Over the same time intervals in the pooled analysis, treated patients experienced both significantly less pain (P &amp;lt; 0.001 and P = 0.006, respectively) and took significantly less opioid analgesia (P = 0.001 and P = 0.024, respectively). The I-SPI-TOpA endpoint that combined both SPI and TOpA demonstrated a significant treatment effect through 72 hours in the pooled analysis (P = 0.021).Conclusion: XaraColl offers great potential for improving the management of postoperative pain and warrants further investigation in definitive clinical trials.Keywords: pain, opioid use, herniorrhaphy, hernioplasty&amp;nbsp

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively