Cost-effectiveness of posttreatment surveillance after radiation therapy for early stage seminoma.

BACKGROUND: This study evaluated the cost-effectiveness of posttreatment surveillance after radiation therapy for early stage seminoma. METHODS: From 1988-1995, 47 patients with Stage I, and 11 patients with Stage II seminoma (based on the Royal Marsden staging system) received paraaortic and pelvic lymph node radiation after radical orchiectomy. Patient records were reviewed and patients surveyed to determine the tests ordered for posttreatment surveillance. RESULTS: With a median follow-up of 55 months, there were 2 recurrences among the 58 patients. Eight-year actuarial disease free survival was 93%, with 100% overall survival. Information concerning follow-up screening was available for 56 patients. The follow-up tests ordered included 842 physical examinations, 815 chest X-rays, 839 serum markers, 250 computerized tomography scans, and 112 abdominal plain films. The total cost of these examinations according to 1996 private sector charges and 1996 Medicare reimbursement rates, respectively, was $602,673.01 (average $10,762.02 per patient) and $282,746.52 (average $5049.05 per patient). The two patients who experienced recurrence were diagnosed independently of their posttreatment screening program. One patient recurred 7.5 months after his original diagnosis with an isolated spinal cord compression. The second patient had a mediastinum recurrence > 6 years after treatment. At last follow-up, both patients were disease free after salvage treatment. CONCLUSIONS: Patients with early stage seminoma treated with orchiectomy and radiation have excellent disease free survival rates. The cost of the surveillance program studied does not appear to be justifiable.

Vomiting and recovery after outpatient tonsillectomy and adenoidectomy in children. Comparison of four anesthetic techniques using nitrous oxide with halothane or propofol.

BACKGROUND: The authors' purpose in this study was to compare prospectively four different anesthetic induction and maintenance techniques using nitrous oxide with halothane and/or propofol for vomiting and recovery after outpatient tonsillectomy and adenoidectomy procedures in children. METHODS: Eighty unpremedicated children, aged 3-10 yr, were assigned randomly to four groups: group H/H, 0.5-2% halothane induction/halothane maintenance; group P/P, 3-5 mg.kg-1 propofol induction and 0.1-0.3 mg.kg-1.min-1 propofol maintenance; group H/P, 0.1-0.3 mg.kg-1.min-1 halothane induction/propofol maintenance; and group P/H, 3-5 mg.kg-1 propofol induction and 0.5-2% halothane maintenance. Nitrous oxide (67%) and oxygen (33%) were administered in all the groups. Other treatments and procedures were standardized intra- and postoperatively. Results of postoperative vomiting and recovery were analyzed in the first 6 h and beyond 6 h. RESULTS: Logistic regression showed that vomiting occurred 3.5 times as often when halothane was used for maintenance of anesthesia (groups H/H and P/H) compared with the use of propofol (groups P/P and H/P; Odds Ratio 3.5; 95% confidence interval 1.3 and 9.4, respectively; P = 0.012). A significant association between vomiting ( < 6 h: yes/no) and discharge times ( > 6 h: yes/no) (Odd's Ratio = 3.6; 95% confidence interval: 1.02, 12.4, respectively) (P = 0.046) was shown. However, no significant differences among the groups in the incidence of vomiting beyond 6 h, recurrent vomiting, or hospital discharge times were shown. CONCLUSIONS: After tonsillectomy and adenoidectomy procedures, despite reduced postoperative vomiting with use of propofol rather than halothane, along with nitrous oxide for anesthetic maintenance, the authors found no differences in "true" endpoints such as unplanned admissions or discharge times. Among the groups, the main factor that delayed hospital discharge beyond 6 h was vomiting within the first 6 h.

Radioprotection by 16,16 dimethyl prostaglandin E2 is equally effective in male and female mice.

Pretreatment with 16,16 dimethyl prostaglandin E2 (DiPGE2) provides effective protection against radiation and chemical injury. Cytoprotection against chemical injury is known to be influenced by sex factors, and is more effective in females than males. Since prostaglandin metabolism and biological responses to prostaglandin may vary between sexes, studies were conducted to compare DiPGE2-induced radioprotection in male and female mice. Pretreatment with 400 micrograms DiPGE2/kg body wt substantially enhanced 30-day survival in males and females. There was no significant difference in the LD50/30 of male and female mice receiving vehicle alone prior to irradiation, 8.34 Gy versus 8.46 Gy, respectively. DiPGE2 treatment increased the LD50/30 in males to 12.1 Gy, providing a dose modification factor (DMF) of 1.45. Similar increases were observed in females, with a LD50/30 of 11.6 and a DMF of 1.37. The reported difference in DiPGE2-induced cytoprotection between males and females exposed to ethanol injury, and the lack of variation in the present radioprotection study suggests that separate mechanisms are involved in two processes.

Effects of heat and amino acid supplementation on the uptake of arginine and its incorporation into proteins in Escherichia coli.

Hyperthermic treatment reduces protein synthesis and modifies amino acid transport in Escherichia coli. The present study examined the role of nutrient availability on these processes. Cultures of E. coli in log phase were aliquoted into growth medium with or without complete amino acid supplementation and exposed to 37, 44, or 48 degrees C for 10 min. Amino acid supplementation increased radiolabelled arginine uptake at 48 degrees C when compared with unsupplemented cells. Exposure to 48 degrees C also reduced protein synthesis in both groups by at least 50% as reflected by labelled arginine incorporation. Two-dimensional gel electrophoresis indicated that this heat-related decrement in synthesis was most apparent in basic proteins. Total density analysis of the fluorographs demonstrated reductions in basic proteins of 15% at 44 degrees C and 89% at 48 degrees C, while acidic proteins only showed an 80% reduction at 48 degrees C. Amino acid supplementation appears to raise the baseline, but not to modify the final results of hyperthermia-induced inhibition of protein synthesis. The sensitivity of basic protein synthesis seems to be a key event in this process.

Proteinuria of B700, a 67 kD albumin-like melanoma-specific antigen.

B700 is a murine melanoma antigen that is closely related to, but distinct from, serum albumin. The present study examined the metabolic fate and anatomic distribution of radioiodinated B700 and mouse serum albumin (MSA) administered s.c. to mice. In blood, both proteins were associated with the plasma fraction where the halflife of B700, a glycoprotein, was 0.5 days, compared to 2.7 days for MSA. Of particular interest was the observation that B700, a 67 kD anionic protein, was excreted primarily in urine. The selective B700-proteinuria did not alter urinary volumes or produce hematuria or edema. SDS-polyacrylamide gel electrophoresis and western blot analysis using the H-2-3-3 B700-specific monoclonal antibody revealed that B700 proteinuria occurred in B-16 murine melanoma bearing animals but not in control mice. These studies demonstrate that the tumor-bearing host readily distinguishes between very similar normal protein (MSA) and tumor-associated antigen (B700) molecules and processes them differently.

Leukotriene C4-induced radioprotection: the role of hypoxia.

Pretreatment of mice with leukotriene C4 (LTC4), a biological mediator that can cause marked contraction of vascular, tracheal, and bronchial smooth muscles, enhances radiation survival. Optimal protection is observed with 10 micrograms LTC4 per mouse (400 micrograms/kg body wt) administered subcutaneously 5 to 10 min prior to irradiation. Pretreatment with 10 micrograms LTC4 increases the LD50/30 from 8.36 Gy in mice receiving saline to 15.7 Gy, providing a dose reduction factor of 1.9. Enhanced survival of mice was observed with doses of 50 micrograms LTD4/mouse, but not with LTE4. Fifteen minutes after administration of 10 micrograms LTC4, the breathing rate is reduced by 33%, the blood paO2 by 20%, the paCO2 by 29%, and the HCO3- by 43%. Whole blood lactate increased by 288% at this same time. The period over which the elevation in blood lactate occurs is similar to the times for optimal radioprotection. These data coupled with the finding that protection was eliminated when irradiation occurred in an enriched oxygen atmosphere indicate that hypoxia plays a role in leukotriene C4-induced animal radiation survival. High-performance liquid chromatography and tissue distribution analyses support a role for an indirect mechanism since the highest levels of LTC4 in the tissues do not correlate with the peak time for radioprotection.

The first radiation accident in America: a centennial account of the x-ray photograph made in 1890.

On February 22, 1890, Dr Arthur Goodspeed and William Jennings made the first x-ray photograph, in the physical lecture room of the University of Pennsylvania. On that evening, Goodspeed and Jennings had been making brush electrographs of coins and brass weights. After they finished their experiments, Jennings stacked all of the photographic plates; two coins--either left from the experiments or Jennings' trolley fare--were placed on top of the plates. Goodspeed then demonstrated to Jennings the university's collection of Crookes tubes, with the idea of photographing the glow from the tube. While the two men were talking, however, the Crookes tube was emitting x radiation that affected the nearby plates. After the plates were developed, Jennings noted that one had the shawdow(s) of a disk(s) on it; neither man could explain the image. On hearing of Roentgen's work in 1896, Goodspeed and Jennigns retrieved the original plate and reproduced their "accident." The glass plate was subsequently lost among library archives.

Serologic demonstration of the albuminoid nature of the B700 murine melanoma antigen.

Limited available evidence indicates that the B700 murine melanoma antigen is related to serum albumin, but potential relationships to other members of the serum albumin protein family have not yet been established. Using specific antibodies raised against each of the members of the albumin family, we have studied cross-reactivity by solid phase enzyme-linked immunosorbent assay and Western immunoblotting. We demonstrate that B700 is serologically cross-reactive to members of the serum albumin family, which includes alpha-fetoprotein and vitamin D binding protein. Therefore, B700 is part of the serum albumin family of proteins, although the mechanism underlying its specific expression by transformed melanocytes remains unknown.

Effect of diet on hyperthermia-induced cell lethality and prostaglandin release.

Hyperthermia-induced cell lethality is thought to be mediated through injury to the cell membrane. Membrane perturbation results in the release of prostaglandins (PG) and leukotrienes (LT). These compounds are potent biological mediators and may modify the tumor microenvironment and therapeutic efficacy. Membrane composition and PG/LT release are influenced by the dietary fatty acids. The relationship between these variables and response to hyperthermia was examined in vitro using murine P388 leukemia cells grown as an ascites in mice provided either saturated fatty acid diet (SFA; 16% beef tallow) or unsaturated fatty acid diet (UFA; 16% safflower oil). Cells were harvested and exposed in vitro to either 37 degrees C or 43.5 degrees C for periods up to 2 hours. Hyperthermic exposure for 2 hours resulted in 40% cell lethality in SFA cells and 55% in UFA cells. The phospholipid and total cholesterol content was higher (33% and 50% respectively) in the UFA versus the SFA cells. Hyperthermia produced a six-fold increase in prostaglandin E2 PGE2 release by SFA cells and a 4.5-fold increase by UFA cells. No LTC4 was detected. Alteration of dietary fat affects cell lethality and PG release following hyperthermic treatment. The increase in phospholipid and cholesterol content of UFA cells may be a response to reduced membrane fluidity.

The influence of exogenous eicosanoids on the radiation response of cultured bovine aortic endothelial cells.

The radioprotection by several eicosanoids was investigated in cultures of bovine aortic endothelial cells. One hour before irradiation (0-500 cGy, 137Cs gamma rays) 10 micrograms/ml of PGD2, PGE1, PGI2, misoprostol (PGE1-analog), 16,16-dimethyl PGE2, PGA2, or 1 microgram/ml LTC4 was added. Radiation decreased incorporation of [3H]thymidine at 4 h, cell number/culture at 24 h, and cell survival as measured by colony formation. Under these conditions the eicosanoids were not radioprotective. Two eicosanoids, PGD2 and PGA2, appeared to be toxic. Because receptors might mediate eicosanoid-induced radioprotection, radioligand binding of PGE2 and LTC4 and levels of adenosine 3',5'-cyclic monophosphate (cAMP) were measured. Evidence for a receptor was equivocal; there was nonspecific binding and metabolism of LTC4. The level of cAMP was elevated by 16-16-dimethyl-PGE2 in the presence of isobutyl methylxanthine; however, this combination of the prostaglandin and the methylxanthine was not radioprotective. These investigations suggest that an elevated cAMP level alone does not lead to eicosanoid-induced radioprotection of bovine aortic endothelial cell monolayers in vitro.

B700, an albumin-like melanoma-specific antigen, is a vitamin D binding protein.

B700, a murine melanoma-specific antigen, is a member of the serum albumin protein family. Other members include serum albumin and vitamin D binding protein. The primary structure and biochemical functions of B700, as well as its in vivo metabolic fate, are largely unknown. We compared murine albumin, vitamin D binding protein and B700 for their ability to specifically bind [3H]-1,25-dihydroxy-vitamin D3. Scatchard analysis revealed a single binding site for B700 with a Ka of 51,000 mol/l and a Bmax of 4.51 x 10(-7) mol/l. There was no significant difference in the Ka and Bmax among the albuminoid proteins. However, differences in the binding sites could be distinguished by competition experiments where vitamin D3, vitamin D2 or 7-dehydrocholesterol competed for the specific binding of 1.25-dihydroxyvitamin D3 to a greater extent by B700 than by vitamin D binding protein. The albumin binding site more closely resembles vitamin D binding protein than B700, but the data indicate that the binding function of the albuminoid proteins is conserved in B700.

Comparison of the metabolic fate and tissue distribution of B700, an albumin-like melanoma-specific antigen with serum albumin in normal and tumor-bearing mice.

1. B700, a murine melanoma antigen, is a member of the serum albumin protein family, being closely related to murine serum albumin (MSA). 2. We have studied and compared the metabolic fate and anatomic distribution of radioiodinated B700 and MSA administered to semisyngeneic naive and tumor-bearing mice. 3. Labelled material from both proteins is excreted primarily into urine. 4. The rate of excretion of the two proteins is markedly different, with B700 having a shorter half-life in the body. 5. Despite their similar molecular weights, intact B700 represents approx. 30% of the radioactivity in the urine but only 4% of the MSA in the urine is intact. 6. These studies demonstrate that the host can readily distinguish between very similar normal (MSA) and tumor-associated (B700) molecules and process them differently. 7. Similar findings of differential fate and distribution have been reported in comparing other albuminoid molecules [Dueland S., Blomhoff R. and Pedersen J. I. (1990) Biochem. J. 267, 721-725].

Interaction of leukotriene C4 and Chinese hamster lung fibroblasts (V79A03 cells). 1. Characterization of binding.

A novel, specific, and potent biological action of leukotriene C4 (LTC4) was demonstrated in the Chinese hamster lung fibroblast cell line V79A03 (V79 cells), namely the confirment of protection against subsequent gamma-irradiation. Consequently, studies were conducted to determine whether LTC4-conferred radioprotection could be attributed to a receptor-mediated phenomenon. Specific binding sites for leukotriene C4 (LTC4) were identified and characterized using intact V79 cells incubated at 4 degrees C in the presence of serine-borate, during which time conversion of LTC4 to LTD4 or LTE4 was undetectable. Binding was maximal in a broad region between pH 6.2 and 8.8. Ca2+, Mg2+, and Na+ were not required for binding, and binding was not altered by GTP, ATP, or cAMP, by leukotrienes B4, D4, or E4, or by the leukotriene end point antagonists LY 171883, FPL 55712, or Revlon 5901-5. Scatchard analyses and kinetic experiments indicated the presence of high-affinity [Kd = 2.5 +/- 0.63 nM, approximately 9.9 x 10(5) sites/cell] and low-affinity [Kd = 350 +/- 211 nM, approximately 2.7 x 10(6) sites/cell] binding sites. The observed binding characteristics of LTC4 to V79 cells are consistent with a receptor-mediated phenomenon. In a companion communication which follows this report, we report the subcellular distribution of LTC4 binding to V79 cells and demonstrate that this binding is unlikely to be attributed principally to interaction with glutathione-S-transferase.

Interaction of leukotriene C4 and Chinese hamster lung fibroblasts (V79A03 cells). 2. Subcellular distribution of binding and unlikely role of glutathione-S-transferase.

It was reported previously that radiation-induced cytotoxicity in V79A03 (V79) cells was attenuated by pretreatment of cells with leukotriene C4 (LTC4), leading us to determine that V79 cells possessed specific binding sites, with characteristics of receptors, for LTC4 (see the preceding, companion communication). Additional studies were conducted to determine the subcellular distribution and the chemical nature of the LTC4 binding site in V79 cells. Trypsin treatment of cells before LTC4 binding assays resulted in a 74% reduction in high-affinity binding. In tests to examine the subcellular location of LTC4 binding, plasma membrane and nuclear fractions were obtained from V79 cells. In contrast to Scatchard analyses of LTC4 binding to intact cells which were curvilinear, Scatchard analyses of nuclear and plasma membrane fractions were linear, indicative of the presence in these cellular substituents of low and high-affinity binding, respectively. To examine the nature of the high-affinity LTC4 binding sites, intact V79 cells were photolyzed with [3H]-LTC4 rendered photoactive by preincubation with N-hydroxysuccinimidyl-4-azidobenzoate. The cell-bound radioactivity migrated during sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with an apparent molecular weight of approximately 40 kdal. Five different commercial preparations of glutathione-S-transferase (GST), which has been implicated as a source of LTC4 "specific binding" in other cells, migrated in the same SDS-PAGE system with an apparent molecular weight of 20-24 kdal. Furthermore, preincubations of V79 cells with three antisera generated against GST had minimal effects upon subsequent LTC4 binding to intact cells. These data, taken together with the data from the preceding companion communication, suggest that the radioprotective effect of LTC4 upon V79 cells may be attributable to a receptor-mediated phenomenon which appears distinct from leukotriene binding to GST.

Behavioral and physiological effects of leukotriene C4.

Leukotriene C4 (LTC4), a lipoxygenase metabolite of arachidonic acid, is a biological mediator of vasoregulation, pulmonary activity, shock, and inflammation, that has been demonstrated to have radioprotective efficacy. The effects of LTC4 on locomotor activity, rectal temperature and hematocrit were examined. Subcutaneous administration of doses of 1.0 micrograms LTC4/mouse or less did not affect locomotor activity. Doses of 5 or 10 micrograms LTC4/mouse, however, resulted in almost complete cessation of locomotion within 12-14 min following treatment. At these doses, activity was suppressed for 2 h with complete recovery by 3 h postinjection. While a dose as high as 10 micrograms LTC4 did not affect rectal temperature, 5 and 10 micrograms LTC4 resulted in hematocrit increases of 10% and 40% respectively. Hematocrit returned to baseline within 1 h after a 5 micrograms pretreatment of LTC4, and by 3 h following a 10 micrograms pretreatment. The duration of LTC4-induced locomotor suppression did not correlate with previously determined durations of LTC4-induced radioprotection.

The effects of theophylline and nifedipine on corticotropin-stimulated cortisol secretion.

The adrenal cortisol response to corticotropin appears to involve both calcium and cyclic adenosine 3',5'-monophosphate (cAMP) as intracellular mediators. In 10 healthy male volunteers, the short-term administration of theophylline, which affects both intracellular calcium and cAMP, lowered basal cortisol levels but augmented the in vivo cortisol response to short-term corticotropin stimulation. Short-term administration of nifedipine, a calcium channel antagonist, had no effect on basal or peak cortisol levels but reduced the incremental cortisol response to corticotropin. The effects of both theophylline and nifedipine, although statistically significant, were modest and of questionable clinical significance but should be considered in the interpretation of the clinical corticotropin stimulation test. They may also provide some insight into the post-receptor actions of corticotropin.

Advances in radioprotection through the use of combined agent regimens.

The most effective radioprotective agents exhibit toxicities that can limit their usefulness. It may be possible to use combinations of agents with different radioprotective mechanisms of action at less toxic doses, or to reduce the toxicity of the major protective compound by adding another agent. With regard to the latter possibility, improved radioprotection and reduced lethal toxicity of the phosphorothioate WR-2721 was observed when it was administered in combination with metals (selenium, zinc or copper). The known mechanisms of action of potential radioprotective agents and varying effects of different doses and times of administration in relation to radiation exposure must be considered when using combined-agent regimens. A number of receptor-mediated protectors and other biological compounds, including endotoxin, eicosanoids and cytokines, have at least an additive effect when administered with thiol protectors. Eicosanoids and other bioactive lipids must be administered before radiation exposure, whereas some immunomodulators have activity when administered either before or after radiation exposure. For example, the cytokine interleukin-1 administered simultaneously with WR-2721 before irradiation or after irradiation enhances the radioprotective efficacy of WR-2721. The most effective single agents or combinations of protectors result in a decrement in locomotor activity, an index of behavioral toxicity. Recent evidence indicates that administration of the CNS stimulant caffeine mitigates the behavioral toxicity of an effective radioprotective dose of the phosphorothioate WR-3689 without altering its radioprotective efficacy. These examples indicate that the use of combinations of agents is a promising approach for maximizing radioprotection with minimal adverse effects.

Alterations in rat cardiac myosin isozymes induced by whole-body irradiation are prevented by 3,5,3'-L-triiodothyronine.

Changes in cardiac myosin isozymes and serum thyroid hormone levels were investigated in rats following 10 Gy whole-body gamma irradiation. The percent beta-myosin heavy chain increased from 21.3 +/- 1.8 to 28.1 +/- 6.8 (NS) at 3-day postirradiation, 37.7 +/- 1.9 (P less than .001) at 6-day postirradiation, and 43.8 +/- 3.3 (P less than .001) at 9-day postirradiation. Along with the change in myosin isozymes was a significant 53% decrease (P less than .001) in the serum thyroxine (T4) level by day 3 postirradiation, remaining depressed through day 9 postirradiation. The serum 3,5,3'-triiodothyronine (T3) level, however, was normal until day 9, when significant depression was also observed. In contrast, the thyroid-stimulating hormone (TSH) level was significantly increased by fourfold at day 3, returning to near normal values by day 9 postirradiation. Daily injections of physiological doses of T3 (0.3 microgram/100 g body weight) prevented the change in the myosin isozymes following whole-body irradiation. Daily pharmacological injections of T3 (3.0 micrograms/100 g body weight) to the irradiated rats produced a further decrease in the percent beta-myosin heavy chain (below control values) indicating tissue hyperthyroidism. Thus, this study suggests that the change in myosin isozymes following whole-body irradiation is caused by an alteration in thyroid hormone activity.

B700, a melanoma-specific antigen, catalyzes metabolism of prostaglandin E2.

B700 is an albumin-like mouse-melanoma-specific antigen of unknown primary structure and biochemical function. The ability of mouse serum albumin to catalyze weak degradation of prostaglandin E2 has been utilized to compare functional similarities between B700 and mouse serum albumin. Both proteins catalyze the degradation of prostaglandin E2 to prostaglandin A2 and prostaglandin B2. This catalytic ability is related to the amino acid composition of the two proteins within the functional region rather than the 3-dimensional configuration, the activity is not altered upon boiling. The primary prostaglandin E2 metabolite in the presence of mouse serum albumin is prostaglandin B2, while prostaglandin A2 predominates in B700 catalyzed degradations. An additional product, presently unidentified, is produced during B700 catalyzed degradation of prostaglandin E2. Our studies indicate that the B700 protein has weak enzymatic activity for prostaglandin E2 similar to that of albumin. To our knowledge, B700 is the only melanoma antigen for which enzymatic activity has been demonstrated.