Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer

BACKGROUND: Epidermal growth factor receptor (EGFR) represents a major target for current radiosensitizing strategies. We wished to ascertain whether a correlation exists between the expression of EGFR and treatment outcome in a group of patients with rectal adenocarcinoma who had undergone preoperative radiotherapy (RT). METHODS: Within a six-year period, 138 patients underwent preoperative radiotherapy and curative surgery for rectal cancer (UICC stages II-III) at our institute. Among them, 77 pretherapeutic tumor biopsies were available for semi-quantitative immunohistochemical investigation evaluating the intensity and the number (extent) of tumor stained cells. Statistical analyses included Cox regression for calculating risk ratios of survival endpoints and logistic regression for determining odds ratios for the development of loco-regional recurrences. RESULTS: Median age was 64 years (range: 30–88). Initial staging showed 75% and 25% stage II and III tumors, respectively. RT consisted of 44-Gy pelvic irradiation in 2-Gy fractions using 18-MV photons. In 25 very low-rectal-cancer patients the primary tumor received a boost dose of up to 16 Gy for a sphincter-preservation approach. Concomitant chemotherapy was used in 17% of the cases. All patients underwent complete total mesorectal resection. Positive staining (EGFR+) was observed in 43 patients (56%). Median follow-up was 36 months (range: 6–86). Locoregional recurrence rates were 7 and 20% for EGFR extent inferior and superior to 25%, respectively. The corresponding locoregional recurrence-free survival rate at two years was 94% (95% confidence interval, CI, 92–98%) and 84% (CI 95%, 58–95%), respectively (P = 0.06). Multivariate analyses showed a significant correlation between the rate of loco-regional recurrence and three parameters: EGFR extent superior to 25% (hazard ratio = 7.18, CI 95%, 1.17–46, P = 0.037), rectal resection with microscopic residue (hazard ratio = 6.92, CI 95%, 1.18–40.41, P = 0.032), and a total dose of 44 Gy (hazard ratio = 5.78, CI 95%, 1.04–32.05, P = 0.045). CONCLUSION: EGFR expression impacts on loco-regional recurrence. Knowledge of expression of EGFR in rectal cancer could contribute to the identification of patients with an increased risk of recurrences, and to the prediction of prognosis

Alpha2-Adrenoceptor Agonists and Stress-Induced Analgesia in Rats: Influence of Stressors and Methods of Analysis

The present experiments were de signed to investigate the role of housing and handling conditions during testing, as well as data analysis, on the outcome of antinociceptive testing of alpha(2)-adrenoceptor agonists, fentanyl, and a high dose of chlordiazepoxide in the tail withdrawal reaction test (TWR test) in rats. Dose-response curve data were obtained with fentanyl, clonidine, xylazine, dexmedetomidine, and 40.00 mg/kg chlordiazepoxide and were compared under normal TWR test conditions and during immobilization or immobilization with continuous painful stimulation. Data were analyzed in terms of ah-or-none criteria as well as percentage maximum possible effect (%MPE) analysis over the total measurement period or at any specific time point during testing. The results indicate that stress, induced by immobilization and immobilization with long-term-applied paw pressure, unmasked possible antinociceptive properties of the various alpha(2)-adrenoceptor agonists and potentiated the effects of fentanyl. Stress also unmasked the positive effects of benzodiazepines. The manner of data analysis was shown to significantly affect the outcome measured in stress and nonstress conditions. The MPE analysis, particularly at one time point, appeared much more sensitive than the ah-or-none criteria. The data indicate that the housing and handling conditions of animals during testing, together with data analysis, may affect the outcome of different classes of compounds in the TWR test, and this knowledge may help control for false positive results. (C) 1997 Elsevier Science Inc

Epidural clonidine or sufentanil for intraoperative and postoperative analgesia.

This study contrasts the efficacy and side effects of epidural clonidine and sufentanil in the perioperative period. Using a randomized, prospective, double-blind study design, 40 patients undergoing abdominal surgery under propofol/nitrous oxide anesthesia were enrolled. Before anesthesia, an epidural catheter was inserted at the L1-L2 interspace. At induction of anesthesia, the patients received epidurally either clonidine (4 micrograms/kg in 10 mL) infused in 20 min followed by a 2-micrograms.kg-1.h-1 infusion (5 mL/h) during 12 h (Group 1) or sufentanil (0.5 microgram/kg in 10 mL) in 20 min followed by a 0.25-microgram.kg-1.h-1 infusion (5 mL/h) during 12 h (Group 2). Intraoperatively, increases in arterial blood pressure and heart rate not responding to propofol bolus (0.5 mg/kg) were treated with a bolus of intravenous (IV) sufentanil 0.035 microgram/kg. Postoperatively, IV sufentanil boluses (5 micrograms) were given through a patient-controlled analgesia (PCA) device. Postoperative analgesia was assessed by recording the IV PCA sufentanil requirements and the patients' visual analog scale (VAS) at 3, 6, 12, 18, 24, 36, and 48 h. Sedation analog scales and side effects were also recorded. Plasma clonidine and sufentanil concentrations were measured after 20 min and 6, 12, and 24 h. The number of reinjections of propofol (n = 1.6 +/- 1.6 in Group 1 vs 6.5 +/- 4.0 in Group 2) and of IV sufentanil (n = 0.6 +/- 0.8 in Group 1 vs 3.8 +/- 3.7 in Group 2) was significantly reduced (P < 0.001) in the epidural clonidine group. In the early postoperative period, pain scores and rescue analgesic requirements were very low in both groups.(ABSTRACT TRUNCATED AT 250 WORDS

Digoxin enhances bupivacaine toxicity in rats.

The influence of digoxin on the systemic toxic effects of bupivacaine was studied in a rodent animal model. The experiment was undertaken with consideration to clinical situations such as pregnancy that are associated with the secretion of an endogenous digoxin-like factor. Twenty Wistar male rats, under barbiturate anesthesia and controlled ventilation, received either 5 micrograms/kg intravenous digoxin (n = 10) or saline (n = 10), blinded to the observer. Digoxin serum concentration was 1.8 +/- 0.24 ng/ml in the study group. Thirty minutes after digoxin or saline was administered, bupivacaine was infused at a constant rate of 2mg/kg/minute. The threshold doses of bupivacaine toxic effects (first ventricular arrhythmia, 25% fall of baseline heart rate, 25% fall of baseline mean arterial blood pressure, first seizure activity, isoelectric electroencephalogram, and asystole) were significantly lower in the digoxin group, as were the lethal bupivacaine serum concentrations. Digoxin, in hyperoxic nonacidotic rats, increases the cardiac and central nervous system toxicity of bupivacaine. Based on the known electrophysiologic actions of these two drugs, a synergistic toxic interaction is demonstrated

Clonidine pretreatment reduces the systemic toxicity of intravenous bupivacaine in rats.

BACKGROUND: Clonidine prolongs the duration of sensory and motor block induced by bupivacaine, and this association, in constant infusion by the epidural route, is used for postoperative analgesia. After a near-fatal intravenous bolus of bupivacaine in dogs, clonidine improves ventricular electrophysiologic parameters, but probably worsens bupivacaine-induced bradycardia and depression of the myocardial contractility. The current study, using a rodent animal model, evaluated the influence of clonidine pretreatment on the systemic toxic effects of bupivacaine overdose induced by a constant intravenous infusion. METHODS: Twenty Wistar male rats were anesthetized with thiopental, and controlled ventilation was started with an equal mixture of O2 and N2O. Electrocardiogram (ECG), electroencephalogram (EEG), and invasive arterial blood pressure were continuously recorded. Clonidine (5 micrograms/kg) or saline was injected intravenously in a randomized fashion. After 15 min, an intravenous infusion of bupivacaine was started at 2 mg.kg-1 x min-1. The time of occurrence of the bupivacaine-induced toxic events was recorded and the doses were calculated. Ten (five in each group) additional rats, pretreated according to the same protocol, were killed at the time of the first dysrhythmia, for blood sampling and plasma bupivacaine concentration measurement. RESULTS: Clonidine reduced heart rate and arterial blood pressure before bupivacaine infusion (P < 0.05). The threshold doses at the first QRS modification (11.3 +/- 5.6 vs. 2.1 +/- 0.9 mg/kg) and the first dysrhythmia (40.6 +/- 15.3 vs. 8.48 +/- 3.7 mg/kg), the increase in EEG total spectral power (33.3 +/- 21.9 vs. 8.2 +/- 5.1 mg/kg), the 25 and 50% reduction in baseline mean arterial pressure and heart rate, the isoelectric EEG (58.6 +/- 14 vs. 22 +/- 6.6 mg/kg), and the final systole (99 +/- 16 vs. 51.8 +/- 14.5 mg/kg) were significantly greater in the clonidine group than in the saline group (P < 0.01). The time between the first dysrhythmia and 50% reduction of baseline mean arterial blood pressure was not different between the groups. In the additional series, the first dysrhythmia occurred later (10.9 +/- 4.5 vs. 3.2 +/- 1.0 min, P < 0.01) and plasma bupivacaine levels were greater (18.7 +/- 8.0 vs. 7.8 +/- 3.2 micrograms/ml, P < 0.01) in the clonidine group than in the saline group. CONCLUSIONS: In this model, clonidine given prophylactically delays the toxic manifestations of bupivacaine overdose and does not accentuate the subsequent hypotension

La position de la SBAR à l'égard de la prémédication

peer reviewe

Pediatric liver transplantation: from the full-size liver graft to reduced, split, and living related liver transplantation.

Between 1984 and 1996, the authors performed 499 liver transplants in 416 children less than 15 years old. The overall patient survival at 10 years was 76.5%. It was 71.3% for the 209 children grafted in 1984-1990; 78.5% for biliary atresia (n = 286), 87.3% for metabolic diseases (n = 59), and 72.7% for acute liver failure (n = 22). The 5-year survival was 73.6% for the 209 children grafted in 1984-1990 and 85% for the 206 grafted in 1991-1996. Scarcity of size-matched donors led to the development of innovative techniques: 174 children who electively received a reduced liver as a first graft in our center had a 5-year survival of 76% while 168 who received a full-size graft had a survival of 85% (NS). Results of the European Split Liver Registry showed 6-month graft survival similar to results obtained with full-size grafts collected by the European Liver Transplant Registry. Extensive use of these techniques allowed the mortality while waiting to be reduced from 16.5% in 1984-1990 to 10% in 1991-1992. It rose again to 17% in 1993, leading the authors to develop a program of living related liver transplantation (LRLT). The legal and ethical aspects are analyzed. Between July 1993 and October 1997, the authors performed 53 LRLTs with 90% survival. In elective cases, a detailed analysis was made of the 45 children listed for LRLT between July 1993 and March 1997 and the 79 registered on the cadaveric waiting list during the same period. Mortality while waiting was 2% and 14.5% for the LRLT and cadaveric lists, respectively. The retransplantation rate was 4.6% and 16.1% for LRLT and cadaveric transplants, respectively. Overall post-transplant survival was 88% and 82% for children who received a LRLT or a cadaveric graft, respectively. Overall survival from the date of registration was 86% and 70% (P < 0.05) for LRLT or cadaveric LT respectively. The 2-year post-transplant survival in children less than 1 year of age at transplantation was 88.8% and 80. 3% with a LRLT or cadaveric graft, respectively; patient survival after 3 months post-transplant was 95.8% and 91.9% for stable children waiting at home, 93.7% and 93.7% in children hospitalized for complications of their disease, and 89.5% and 77.7% for children hospitalized in an intensive care unit at the time of transplantation for children who received a LRLT or cadaveric graft, respectively. It is concluded that LRLT seems to be justified for multidisciplinary teams having a large experience with reduced and split liver grafting