The effect of microscopic margin status on survival in adult retroperitoneal soft tissue sarcomas.

INTRODUCTION: Resection is the primary treatment for retroperitoneal (RP) soft tissue sarcomas (STS). Whether obtaining microscopically negative margins (R0) improves overall survival (OS) over microscopically positive margins (R1) remains unclear. METHODS: Using the National Cancer Data Base, we identified adult patients diagnosed with RP STS after R0 or R1 resection from 1998 to 2011. We used a multivariable logistic regression model to identify clinicopathologic factors associated with margin status, including radiotherapy receipt. To assess differences in OS, the log-rank test, Cox proportional hazards regression, and propensity score matching were used. RESULTS: We identified 4015 patients; 2593 (64.6%) underwent R0 resection and 1422 (35.4%) underwent R1 resection. The most common histology was liposarcoma (2,371, 59.1%), median age was 60 years, and median follow up was 67 months. Median OS for R0 vs. R1 patients was 92 and 70 months, respectively (log-rank p < .001). Pre-operative RT was associated with increased probability of R0 resection (68.0% vs. 57.2%, p = .012). Multivariable regression showed R0 vs. R1 resection (HR 0.70, 95% CI 0.60-0.81, p < .001) was associated with improved survival, a finding confirmed on propensity score matching. Other significant predictors of OS included low tumor grade, younger age, smaller tumor size, liposarcoma histology, and receipt of RT (HR 0.81, 95% CI 0.70-0.93, p = .016). CONCLUSIONS: Patients who undergo R0 resection for RP STS appear to experience superior OS compared with patients who had R1 resections.

Discrimination of gamma-hydroxybutyrate and ethanol administered separately and as a mixture in rats.

The physiological effects of gamma-hydroxybutyrate (GHB) are complex and not yet clearly defined. GHB has been labeled as a recreational drug and is reported to be frequently coabused with ethanol (ETH). Other studies have yielded discrepant results as to the interaction between GHB and ETH. Thus, the present study investigated extensively the discriminative stimulus of GHB and ETH and a mixture of the two compounds. Thirty male Long-Evans rats were divided into three groups and trained to discriminate doses of either 300 mg/kg GHB, 1000 mg/kg ETH, or a mixture (MIX: 150 mg/kg GHB+500 mg/kg ETH) from vehicle on a two-lever fixed-ratio (FR) 10 schedule of food reinforcement. Dose-response curves were attained in each group with its respective training drugs. GHB and ETH did not cross-generalize in the ETH- and GHB-trained rats, respectively. However, when the effects of the MIX were tested in the GHB- and ETH-trained rats, a greater than additive response was observed. Testing also revealed that the MIX-trained rats did not perceive a novel stimulus but a near-equal contribution from GHB and ETH. This study provides evidence of a complex relationship between GHB and ETH and opposes previous work reporting cross-generalization between GHB and ETH.

Human granulocyte CD11b expression as a pharmacodynamic biomarker of inflammation.

A method has been developed for the direct quantification of the CD11b integrin on granulocytes by flow cytometric analysis of whole blood specimens following either LTB(4) or lipopolysaccharide (LPS) stimulation. This method has utility in evaluating the pharmacodynamic action of either LTB(4) receptor antagonists or immune cell modulators in effecting CD11b integrin expression and granulocyte activation in human subjects administered such drugs. Previous studies using CD11b as a biomarker of granulocyte activation have faltered because of the difficulty in controlling the activation state of the granulocyte following removal of blood from subjects. The present study has made use of a newly validated method using either LTB(4) or LPS to stimulate CD11b expression on granulocytes and has been used, as one measure, in the evaluation of LPS activity when administered to normal human volunteers.

Hsp15: a ribosome-associated heat shock protein.

We are analyzing highly conserved heat shock genes of unknown or unclear function with the aim of determining their cellular role. Hsp15 has previously been shown to be an abundant nucleic acid-binding protein whose synthesis is induced massively at the RNA level upon temperature upshift. We have now identified that the in vivo target of Hsp15 action is the free 50S ribosomal subunit. Hsp15 binds with very high affinity (K(D) <5 nM) to this subunit, but only when 50S is free, not when it is part of the 70S ribosome. In addition, the binding of Hsp15 appears to correlate with a specific state of the mature, free 50S subunit, which contains bound nascent chain. This provides the first evidence for a so far unrecognized abortive event in translation. Hsp15 is suggested to be involved in the recycling of free 50S subunits that still carry a nascent chain. This gives Hsp15 a very different functional role from all other heat shock proteins and points to a new aspect of translation.

Alveolar oxygenation and mouth-to-mask ventilation: effects of oxygen insufflation.

The effect on alveolar oxygen fraction (FAO2) of insufflating oxygen under a mask (or through an inflow nipple provided in the mask) during simulated mouth-to-mask ventilation was investigated using a lung model. A variety of commercially produced masks were evaluated. Two patterns of artificial ventilation were applied: 1. 500 ml tidal volume at 20 breaths per minute, and 2. 900 ml tidal volume at 12 breaths per minute. The ventilating gas mixture was oxygen 16% in nitrous oxide, and oxygen was insufflated at flow rates of 2, 4, 6, 8, 10, 12 or 14 litres per minute. The rate of rise of FAO2 and the equilibrium FAO2 attained were greatest at high oxygen inflow rates. The relationship between oxygen flow and FAO2 was not linear however, and an oxygen flow rate of 10 l/min was adequate to generate FAO2's around 50% with either ventilatory pattern. The equilibrium FAO2 achieved was greater with smaller tidal volumes and with larger mask deadspace. We also found that several breaths were required for equilibration of FAO2 during each trial, supporting recommendations that several breaths should be given on commencement of artificial ventilation during cardiopulmonary resuscitation.

Performance of rats on the Maier three-table task following septal lesions occurring 24 hours after birth.

The purpose of this study was to determine whether behavioral sparing would be demonstrated when septal lesions occurred prior to the age at which the tested behavior first appears in normal rats. Rats given septal lesions at 1 day or 7 days after birth performed at approximately chance on the Maier three-table task when tested at 90 days of age. Rats that had control electrode insertions at the same ages performed at a level similar to normal animals. Animals given septal lesions at either age explored significantly more than did control animals. Results are discussed in terms of the constancy over time of the septal contribution to performance on the three-table task and the involvement of the septum and hippocampus in the processing of spatial information.

Influence of neonatal septal lesions on DRL performance in adulthood.

Two experiments are reported describing the influence of neonatal septal lesions on responding of rats trained on a differential-reinforcement-of-low-rate (DRL) schedule in adulthood. Rats given septal lesions at 1 day or at 7 days after birth emitted a significantly higher number of responses and earned fewer reinforcements than did animals given control electrode insertions. Thus, the inefficient performance on the DRL schedule, often observed after septal lesions in adulthood, does not depend upon the age of the animal at the time of the lesion. Furthermore, operant training given at an early age (25-45 days) to animals with neonatal septal damage did not facilitate performance when the animals were retrained in adulthood. In short, septal lesions at any age lead to permanent impairments of performance on a DRL 20-sec reinforcement schedule.

Cholinergic blockade, septal lesions, and DRL performance in the rat.

Four experiments describing the effects of cholinergic blockade produced by systemic injection of either atropine sulfate or atropine methyl nitrate on the differential reinforcement of low rate (DRL) responding of rats are reported. It was shown that atropine sulfate injected either chronically or at high dosage suppressed DRL responding. Injected acutely, atropine sulfate produced disinhibitory effects. When atropine was injected either chronically or acutely into animals with septal lesions, there was suppression of responding. It was suggested that the specific behavioral outcome resulting from cholinergic blockade depends on the balance resulting from the competing peripheral and central effects of such blockade.