Use of water-equivalent plastic scintillator for intravascular brachytherapy dosimetry.

Beta irradiation has recently been investigated as a possible technique for the prevention of restenosis in intravascular brachytherapy after balloon dilatation or stent implantation. Present methods of beta radiation dosimetry are primarily conducted using radiochromic film. These film dosimeters exhibit limited sensitivity and their characteristics differ from those of tissue, therefore the dose measurement readings require correction factors to be applied. In this work a novel, mini-size (2 mm diameter by 5 mm long) dosimeter element fabricated from Organic Plastic Scintillator (OPS) material was employed. Scintillation photon detection is accomplished using a precision photodiode and innovative signal amplification and processing techniques, rather than traditional photomultiplier tube methods. A significant improvement in signal to noise ratio, dynamic range and stability is achieved using this set-up. In addition, use of the non-saturating organic plastic scintillator material as the detector enables the dosimeter to measure beta radiation at very close distances to the source. In this work the plastic scintillators have been used to measure beta radiation dose at distances of less than 1 mm from an Sr-90 cardiovascular brachytherapy source having an activity of about 2.1 GBq beta radiation levels for both depth-distance and longitudinal profile of the source pellet chain, both in air and in liquid water, are measured using this system. The data obtained is compared with results from Monte Carlo simulation technique (MCNP 4B). Plastic scintillator dosimeter elements, when used in conjunction with photodiode detectors may prove to be useful dosimeters for cardiovascular brachytherapy beta sources, or other applications where precise near-source field dosimetry is required. The system described is particularly useful where measurement of actual dose rate in real time, a high level of stability and repeatability, portability, and immediate access to results are prime requirements.

Therapeutic effect of dimethyl sulfoxide on ICAM-1 gene expression and activation of NF-kappaB and AP-1 in septic rats.

BACKGROUND: Dimethyl sulfoxide (DMSO) is a potent antioxidant which protects against endotoxemia and septic shock in animal models. We investigated the therapeutic effect of DMSO on intercellular adhesion molecule 1 (ICAM-1) gene expression and activation of nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) in a rat model of peritonitis sepsis. This postchallenge model simulates the clinical treatment of ruptured viscus peritonitis. MATERIALS AND METHODS: Peritonitis was produced by subjecting rats to laparotomy, followed by a 1-cm cecal incision (CI) to produce fecal soilage of the peritoneum. Rats were subjected to laparotomy only for the sham-operated group. For the protection study, DMSO (6 ml/kg) was injected ip at 30, 60, or 90 min post-CI surgery. The levels of ICAM-1 mRNA expression and activation of NF-kappaB and AP-1 in livers were determined at 3 and 6 h post-CI. RESULTS: At 3 h post-CI surgery (early sepsis), DMSO treatment at 30 and 60 min post-CI surgery significantly inhibited sepsis-induced ICAM-1 mRNA expression and activation of NF-kappaB and AP-1. DMSO has no effect on ICAM-1 gene expression and activation of NF-kappaB and AP-1 when administered at 90 min post-CI surgery. At 6 h post-CI surgery (late sepsis), DMSO administered at 30, 60, or 90 min post-CI surgery significantly inhibited ICAM-1 mRNA expression and NF-kappaB activation but not AP-1 activation. CONCLUSIONS: Therapeutic treatment of DMSO inhibited sepsis-induced activation of NF-kappaB and AP-1, resulting in the suppression of ICAM-1 gene expression in the livers of peritonitis septic rats. This finding suggests that reactive oxidants are involved in the signal transduction pathways for activation of NF-kappaB and AP-1. Thus, antioxidants which inhibit NF-kappaB and AP-1 activation may be beneficial in treating sepsis and septic shock.

Dosimetry errors in endovascular high-dose-rate brachytherapy.

Monte Carlo data were used to demonstrate the dosimetry of the microSelectron high-dose-rate (HDR) iridium 192 (192Ir) stepping source. These data were used to assess the accuracy of the Nucletron brachytherapy planning system (BPS version 13) for peripheral vessel endovascular brachytherapy. Dose rates from the high-dose-rate (HDR) source are calculated using the Monte Carlo code MCNP4A. Calculations are made at 0.25-cm intervals in the longitudinal direction on sleeves of radii of 1 and 0.25 cm. The Monte Carlo data are summed and weighted to simulate the longitudinal dose distribution at a distance of 1 and 0.25 cm from an 192Ir source stepping through a straight pathway. A comparison is made between the simulated Monte Carlo dosimetry and the Nucletron brachytherapy planning system's dosimetry. This study illustrates and quantifies the dosimetric errors at small distances associated with a point source dose calculation algorithm. The effects of step size, dwell time optimization, and active length on the accuracy of BPS v.13 for HDR endovascular brachytherapy are demonstrated.

Verification of brachytherapy dosimetry with radiochromic film.

The aim of this work is to empirically validate the optimized dose distribution calculated by the Nucletron Brachytherapy Planning System (v. 13.3) at a distance of 1.0 cm from a stepping source of high-dose-rate-iridium 192 (192Ir). The longitudinal dose distribution at 1.0 cm from a straight pathway of multiple-source positions is measured using radiochromic film and compared with the planning system's calculated results. The optical density of the exposed films was determined with a modified Scanditronix film scanner, and the film was calibrated with 192Ir using manually calculated exposure times. A calibration equation was used to convert scanner output to dose. Our results illustrate the significance of exacting geometry in the experimental setup due to the inverse square law and the small distances involved. The dose distribution calculated by the Nucletron Brachytherapy Planning System (v. 13.3), at a distance of 1.0 cm, is validated to within +/-4% of the measured dose distribution. The advantages and limitations of radiochromic film as a dosimetry tool are also addressed in this work.

Inhibitory effect of dimethyl sulfoxide on nuclear factor-kappa B activation and intercellular adhesion molecule 1 gene expression in septic rats.

Antioxidants are potent radical scavengers that protect against endotoxemia and septic shock in animal models. Using a rat model of peritonitis sepsis induced by cecal incision we studied the effect of the free radical scavenger dimethyl sulfoxide (DMSO) on hepatic nuclear factor kappa B (NF-kappa B) activation, hepatic intercellular adhesion molecule 1 (ICAM-1) gene expression, serum tumor necrosis factor alpha (TNF) formation, and serum glucose concentration. Five groups of rats (N = 5) were treated as follows: (1) untreated control (Untreated), (2) sham operated with laparotomies (Sham), (3) pretreated with 6 ml/kg DMSO followed by sham operation (DMSO/Sham), (4) cecal incision (Sepsis), and (5) pretreated with DMSO followed by cecal incision (DMSO/Sepsis). In the DMSO/Sham group, DMSO did not affect NF-kappa B activation, ICAM-1 gene expression, and TNF formation. At 3 h postcecal incision, DMSO inhibited sepsis-induced hepatic NF-kappa B activation and hepatic ICAM-1 gene expression to control levels and suppressed serum TNF by 75%. In the late (6 h) septic phase, DMSO inhibited NF-kappa B activation (32%), ICAM-1 gene expression (27%), and TNF formation (71%). These findings suggest that the protective mechanism of antioxidants in septic rats may be partly due to the inhibition of NF-kappa B activation and NF-kappa B-mediated events.

Dose errors in the near field of an HDR brachytherapy stepping source.

The dose rate at point P at 0.25 cm in water from the transverse bisector of a straight catheter with an active stepping source (Nucletron microSelectron HDR source) with a dwell length of 2 cm was calculated using Monte Carlo code MCNP 4.A. The source step sizes were 1 cm and 0.25 cm. The Monte Carlo (MC) results were used for comparison with the results calculated with the Nucletron brachytherapy planning system (BPS) formalism, first with BPS variants and then with its respective MC calculated radial dose function and anisotropy function. The dose differences at point P calculated using the BPS formalism and variants are +15.4% and +3.1% for the source step size of 1 cm and 0.25 cm respectively. This reduction in dose difference is caused by the increased importance of errors in the anisotropy function with the smaller step size, which counter the errors in the radial dose function. Using the MC calculated radial dose function and anisotropy function with the BPS formalism. 1% dose calculation accuracy can be achieved, even in the near field, with negligible extra demand on computation time.

Standard linear plans in single channel high dose rate brachytherapy: a dosimetric analysis.

The use of standard linear plans is proposed for single channel intraluminal High Dose Rate brachytherapy. This technique employs the optimized dwell times derived from a straight line within a curved geometry. Such standardization of the planning procedure ensures expedient delivery of treatment. The 3-D dose distribution resulting from the use of standard linear plans within various curved geometries is investigated. In this study a comparison is made between the dose delivered to the perimeter of the target volume from both standard linear plans and individually optimized plans. Our results demonstrate that the use of a standard linear plan is acceptable in curved geometries, given the current practice of dose and volume specification for high dose rate intraluminal brachytherapy.

The contribution of 18F-fluoro-2-deoxy-glucose positron emission tomographic imaging to radiotherapy planning in lung cancer.

A retrospective analysis was performed to determine whether coronal thoracic [18F]fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) scans, if viewed at the time of radiotherapy (RT) planning, would have influenced the anterior-posterior (AP) RT volumes that were administered to a group of unoperated lung cancer patients. Viewing of PET and diagnostic images enabled a qualitative assessment of whether abnormal thoracic PET activity was present in areas regarded as normal by diagnostic imaging; this would, therefore, have influenced the RT volume if done prospectively. Additionally a method of graphical co-registration was devised to quantitate the adequacy of coverage of each patient's abnormal PET activity by his/her actual RT field. Of 15 patients analyzed, 26.7% (four patients) would have had their RT volume influenced by PET findings, highlighting the potential value of PET in treatment planning.

Effect of dexamethasone on NF-kB activation, tumor necrosis factor formation, and glucose dyshomeostasis in septic rats.

Glucocorticoids are potent anti-inflammatory and immunosuppressive therapeutic agents. The protective effect of dexamethasone (DEX) on hepatic phosphoenolpyruvate carboxykinase (PEPCK) transcript level, hepatic NF-kB (nuclear factor-kB) activation, and serum tumor necrosis factor alpha (TNF) formation was investigated in peritoneal sepsis induced by cecal incision in rats. For the control the rats were sham-operated with laparotomies only. Each group (N = 6) was pretreated with either normal saline (NS) or DEX before surgery (NS/Sham, NS/Sepsis, DEX/Sham, and DEX/Sepsis). At 3 hr post cecal incision, DEX treatment inhibited sepsis-induced hepatic NF-kB activation by 23%, suppressed circulating TNF by 50%, reduced serum glucose by 36%, reduced hepatic glycogen depletion by 76%, and attenuated PEPCK mRNA level. These findings suggested that DEX treatment was beneficial in attenuating glucose dyshomeostasis and significantly inhibited two sepsis-induced inflammatory mediators, NF-kB and TNF, in the early phase of peritoneal sepsis. However, in the late (6 hr) septic phase, DEX treatment inhibited serum TNF by 69%, but had no effect on NF-kB activation, glycogen depletion, and PEPCK mRNA level suggesting liver function failure injury.

Efficacy of anti-tumor necrosis factor polyclonal antibody on phosphoenolpyruvate carboxykinase expression in septic and endotoxemic rats.

We studied the protective effect of anti-tumor necrosis factor-alpha (anti-TNF) polyclonal antibody on phosphoenolpyruvate carboxykinase (PEPCK) expression in lipopolysaccharide-induced endotoxemia and peritonitis sepsis induced by cecal incision. At 3 h after intraperitoneal lipopolysaccharide injection, levels of serum glucose, liver glycogen, and PEPCK expression were decreased and serum TNF was elevated. In contrast, 3 h after cecal incision, levels of serum glucose, serum TNF, and PEPCK expression were elevated. At 6 h after cecal incision (terminal sepsis), serum TNF remained elevated and levels of serum glucose, liver glycogen, and PEPCK expression were decreased. Circulating TNF was not detected in septic and endotoxemic rats pretreated with anti-TNF. Passive immunization with rat anti-TNF antibody restored PEPCK expression in early endotoxemia and sepsis (3 h), but not in terminal sepsis (6 h). Anti-TNF failed to reverse sepsis-induced hypoglycemia and hyperglycemia, suggesting that besides TNF, some other mediators are involved in glucose dyshomeostasis.

The utility of the Philips SRI-100 Real Time Portal Imaging Device in a case of postoperative irradiation for prevention of heterotopic bone formation following total hip replacement.

The new Radiation Oncology Department at the Heidelberg Repatriation Hospital in Melbourne, Australia commenced operation in June 1992. As part of quality control the Philips SL-15 linear accelerator was fitted with the Philips SRI-100 Real Time Portal Imaging Device (RTPID), the first such apparatus in Australia. One of its major advantages over older systems is its ability to provide a permanent hard copy of the image of the field treated. The computer image can be immediately manipulated and enhanced on the screen (with respect to such qualities as brightness and contrast) prior to the printing of the hard copy. This is a significant improvement over the more cumbersome older port films that required developing time, without any pre-assessment of the image quality. The utility of the Philips SRI-100 RTPID is demonstrated in the case of a patient irradiated soon after total hip replacement, as prophylaxis against heterotopic bone formation (HBF). The rapidity and quality of image production is a major advantage in these patients where post-operative pain may result in positional change between film exposure and image production. Extremely accurate shielding block position is essential to shield the prosthesis (and allow bone ingrowth for fixation) whilst avoiding inadvertent shielding of the areas at risk for HBF. A review of the literature is provided.

Altered levels of mRNA encoding enzymes of hepatic glucose metabolism in septic rats.

We investigated whether the multiple pathophysiological signals generated in a peritonitis septic model alter the mRNA levels of glycolytic and gluconeogenic enzymes, and whether these alterations are associated with glucose dyshomeostasis. Rats were sham-operated in the control group, and peritonitis sepsis was produced by a 1 cm cecal incision in the septic group. At 2, 4, and 6 hr post-surgery, total cellular RNAs were isolated from livers, and Northern blots performed to measure mRNA levels of aldolase B (ADL), lactate dehydrogenase (LDH), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), and glucokinase (GK). Hepatic PEPCK enzymatic activity was measured by condensing 14CO2 with phosphoenolpyruvate (PEP) to form malate. Serum glucose concentrations were also measured. We found the following: At 2 hr of peritonitis sepsis, serum glucose concentrations, mRNA levels of all enzymes, and PEPCK enzymatic activity increased over control levels. At 4 hr of peritonitis sepsis, serum glucose concentrations and mRNA levels of GK and PK continued to increase; mRNA levels of all other enzymes, as well as PEPCK enzymatic activity decreased to or below control levels. At 6 hr of peritonitis sepsis, serum glucose concentrations, mRNA levels of all enzymes, and PEPCK enzymatic activity decreased to or below control levels. We concluded that sepsis affects mRNA levels of glycolytic and gluconeogenic enzymes at the transcriptional level, and that these alterations are associated with glucose dyshomeostasis.

Alterations in the activities of DNA topoisomerase enzymes and O6-methylguanine-DNA-methyltransferase in septic rat liver.

To understand the genomic changes contributing to the various metabolic derangements in sepsis and septic shock, we measured the activities of the following liver enzymes intimately associated with DNA function: (1) DNA topoisomerases I and II (topo I and topo II) controlling DNA conformation in mammalian nuclei, and (2) O6-methylguanine-DNA-methyltransferase (MT) capable of removing the methyl groups from the O6-position of guanine in DNA. We found that in septic rat livers the specific activities (units/mg protein) of topo II and MT were elevated by 1.4- and 1.6-fold, respectively, over the sham-operated controls (P less than 0.001). There was no significant difference in topo I activity. We believe that peritonitis sepsis alters topo II levels modulating the selective pretranscriptional changes in chromatin and that MT functions as a cellular stress protein.

Lung and muscle water after crystalloid and colloid infusion in septic rats: effect on oxygen delivery and metabolism.

We compared the effect of crystalloid infusion with that of colloid infusion on extravascular lung water and muscle water in septic rats. We also examined the relationship of lung and muscle edema to arterial oxygenation and muscle energy metabolism during sepsis. Cecal ligation and perforation were used to induce sepsis. Five animals served as sham-operated controls. Five animals were infused with 0.9% saline solution and five with 10% low molecular weight hydroxyethyl starch (hetastarch). Thermodilution cardiac output, plasma colloid osmotic pressure, and arterial blood gases were sequentially measured over a 6-hour interval. At 6 hours, a biopsy specimen was taken from the rectus femoris and the lungs and adductor magnus muscle harvested for gravimetric analysis (wet-dry/dry weight ratio). The colloid osmotic pressure was 16.1 +/- 1.2 mm Hg in the control animals, 9.3 +/- 0.5 mm Hg in the saline solution-infused animals, and 21.6 +/- 0.5 mm Hg in the hetastarch-infused animals at 6 hours (p less than 0.05 saline vs control, hetastarch). The lung wet-dry/dry weight ratio was 3.46 +/- 0.11 in the control animals, 3.74 +/- 0.13 in the saline group, and 3.64 +/- 0.11 in the hetastarch group (difference not significant). Arterial oxygenation was not significantly different in the three groups. Muscle wet-dry/dry weight ratio was 3.11 +/- 0.16 in the control animals, 2.75 +/- 0.12 in the hetastarch-infused animals, and 3.06 +/- 0.08 in the saline-infused group (not significant). There were no significant differences in skeletal muscle energy production or lactate/pyruvate ratio between the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Early impairment of oxidative metabolism and energy production in severe sepsis.

We investigated the relationship of systemic blood flow to skeletal muscle tissue oxygenation, lactate production, and energy production during rat peritonitis established by cecal ligation and perforation. The study included five sham rats, five septic rats, and five septic rats infused with 5% albumin. Thermodilution cardiac output and skeletal muscle tissue oxygen tension were sequentially measured over a 6 hr interval. At 6 hr the rectus femoris was biopsied. In sham rats, there was no change in cardiac output or tissue oxygen tension. Skeletal muscle lactate/pyruvate ratio was 10.4 +/- 0.6, ATP was 5.39 +/- 0.23 mumol/g and total tissue adenine nucleotides were 6.41 +/- 0.21 mumol/g. In septic rats, significant decreases in cardiac output and tissue oxygen tension were associated with a lactate/pyruvate ratio of 25.7 +/- 3.7, an ATP level of 4.38 +/- 0.08 mumol/g and tissue adenine nucleotides of 5.59 +/- 0.08 mumol/g (P less than 0.01 vs. sham). In albumin infused septic rats, cardiac output and tissue oxygen tension were maintained at control levels. Skeletal muscle lactate/pyruvate ratio was 14.8 +/- 1.0, ATP was 4.70 +/- 0.12 mumol/g and tissue adenine nucleotides were 5.80 +/- 0.12 mumol/g (P less than 0.05 vs. sham). Despite the maintenance of systemic blood flow and tissue oxygenation in albumin infused septic rats, the increase in lactate/pyruvate ratio and decrease in high energy phosphates suggest impaired oxidative metabolism and energy production early in the course of severe sepsis.

Liver gluconeogenic metabolites in young and old rats during septic shock.

Aged individuals have diminished resistance to severe sepsis and septic shock. Previous studies in young animals showed that the liver's gluconeogenic capacity was an important determinant of survival in shock states. This study compared hepatic carbohydrate intermediates from young rats and old rats to correlate changes during peritonitis septic shock with known differences in survival times. Old control rats had glucose 6-phosphate (G6P) concentrations two-fold higher than young controls, 354 +/- 49 nanomole/g wet liver vs 180 +/- 41, suggesting a reduced ability to convert hexose monophosphate precursor into blood sugar. There was a 53% increase in G6P levels in the peritonitis livers, to 540 +/- 155 nanomole/g liver while in young septic rats the G6P decreased 33 per cent. These opposite, highly significant changes in shock (P = 0.01) show the reduced ability of old animals to mobilize gluconeogenic precursors. Fructose 1,6-biphosphate (FBP) in old control liver was 14 +/- 3 nanomole/g liver and did not change in shock; in young rats, FBP was 7.0 +/- 3 nanomole and increased 230 per cent in shock, showing a different metabolic response in young and old animals. These data suggest older animals may be more vulnerable to shock because of lower gluconeogenic potential.

Effect of aging on hepatic carbohydrate metabolism in septic rats.

Aged individuals have diminished resistance to severe sepsis and septic shock. Past work with animals suggested that an important determinant of survival was the ability of the liver to supply glucose. In this study, young adult (3 to 4 months) and old (24 months) Fischer 344 rats were fasted and subjected to cecal incisions producing a rapidly lethal peritonitis. We then determined gluconeogenic intermediates in the liver. In the old rats with peritonitis, hexosemonophosphates (HMP) increased 50% relative to control liver, whereas in the young animals with peritonitis, the substrate decreased 50%. The accumulation of HMP in the old rat liver cells indicates a failure to dephosphorylate glucose-6-phosphate (G6P). This increase in HMP is associated with a decline in hepatic glucose-6-phosphatase (G6Pase), the final enzyme in the gluconeogenic pathway, and is reflected in a significant reduction in serum glucose in old Fischer 344 rats when compared to young Fischer rats.