The Effects of Age And Chemotherapy on Gentamicin Pharmacokinetics and Dosing in Pediatric Oncology Patients

We attempted to determine the effects of prior antineoplastic chemotherapy and age on gentamicin pharmacokinetics in children (age 1–18 yrs) with cancer and in controls, and to establish a protocol for gentamicin dosing and monitoring to ensure rapid attainment of therapeutic serum concentrations in these patients. In a prospective controlled study, patients with fever who were receiving empiric gentamicin for confirmed or suspected infections were separated into three groups: 29 with cancer who were receiving a continuing chemotherapy protocol with nonnephrotoxic antineoplastic agents; 23 with cancer who were receiving a continuing chemotherapy protocol with nephrotoxic antineoplastic agents; and 25 control patients who did not have cancer. Three blood samples (one predose, two postdose concentrations), collected between the third and sixth gentamicin doses from each patient, were analyzed by the Emit assay. Pharmacokinetic parameters were calculated and gentamicin dosages recommended based on the Sawchuk-Zaske method of serum level interpretation. When normalized by body weight, there was no significant difference in clearance, volume of distribution, and half-life between the control group and either group of patients with cancer. However, when normalized by body surface area, patients receiving prior nephrotoxic chemotherapy appeared to have a lower mean clearance (98.2 ml/min/1.73 m²) than those exposed to nonnephrotoxic chemotherapy (117.4 ml/min/1.73 m²) and controls (113.3 ml/min/1.73 m²; ANCOVA p=0.033). When kinetic parameters were normalized by body weight, the effect of advancing age yielded a decrease in both clearance (p<0.001) and volume of distribution (p=0.02), and an increase in gentamicin half-life (p<0.001). When normalized by body surface area, age had no significant effect on clearance (p=0.579). There was no significant difference in gentamicin daily dose requirements (mg/kg) between the chemotherapy groups, which may be due to the lack of significant effects of chemotherapy on gentamicin's volume of distribution and clearance normalized by body weight. The final maintenance doses (mg/kg/day mean ± SD) for patients with cancer were 10.8 ± 1.8 for those age 1–5 years, 8.9 ± 1.1 for those age 6–12 years, and 7.9 ± 1.9 for those age 13–18 years. However, when normalized by body surface area, the age-dependent doses became remarkably similar for children in all three age groups (ANOVA p=0.932), approximately 250 mg/m²/day. We recommend that pediatric patients with cancer who require treatment for fever and neutropenia be given higher than standard gentamicin dosages to achieve therapeutic serum concentrations promptly. In particular, initial empiric doses of 10 mg/kg/day are appropriate for those age 1–5 years.     

College students' trait ratings of three age groups around the Pacific Rim

In this paper, the traits which younger adults associate with younger, middle-aged, and older adults in a number of Pacific Rim nations were assessed. Two dependent variables (personal vitality and benevolence) emerged from factor analyses of a series of trait adjectives. Cross cultural trends emerged which replicated patterns found in the US context. Main effects indicated declines in ratings of personal vitality and increases in ratings of benevolence with increasing target-age. However, interesting variations on this pattern emerged in different cultures. In particular, very negative evaluations of aging in Hong Kong, and a lack of differentiation between middle-aged and older adults in the Philippines and New Zealand were found. Little evidence emerged supporting the notion of particular positive evaluations of older adults in Asian cultures.     

Limitations of a convolution method for modeling geometric uncertainties in radiation therapy. II. The effect of a finite number of fractions

Convolution methods can be used to model the effect of geometric uncertainties on the planned dose distribution in radiation therapy. This requires several assumptions, including that the patient is treated with an infinite number of fractions, each delivering an infinitesimally small dose. The error resulting from this assumption has not been thoroughly quantified. This is investigated by comparing dose distributions calculated using the Convolution method with the result of Stochastic simulations of the treatment. Additionally, the dose calculated using the conventional Static method, a Corrected Convolution method, and a Direct Simulation are compared to the Stochastic result. This analysis is performed for single beam, parallel opposed pair, and four-field box techniques in a cubic water phantom. Treatment plans for a simple and a complex idealized anatomy were similarly analyzed. The average maximum error using the Static method for a 30 fraction simulation for the three techniques in phantoms was 23%, 11% for Convolution, 10% for Corrected Convolution, and 10% for Direct Simulation. In the two anatomical examples, the mean error in tumor control probability for Static and Convolution methods was 7% and 2%, respectively, of the result with no uncertainty, and 35% and 9%, respectively, for normal tissue complication probabilities. Convolution provides superior estimates of the delivered dose when compared to the Static method. In the range of fractions used clinically, considerable dosimetric variations will exist solely because of the random nature of the geometric uncertainties. However, the effect of finite fractionation appears to have a greater impact on the dose distribution than plan evaluation parameters.     

In vitro behavior of albumin-loaded carbonate hydroxyapatite gel

Hydroxyapatite (HA) powder, porous HA, plasma-sprayed HA, apatite cements, and sintered HA have all been investigated as delivery systems for compounds such as human growth hormone and vancomycin. However, many previous studies showed that the period of release was limited to 2-3 weeks. The concept of using a nanoporous matrix as a means of immobilizing proteins is well known but has largely been confined to silica-based systems. Carbonate hydroxyapatite (CHA) is more soluble in vivo than HA, and when formed as an aqueous precipitate, it is often formed as nanocrystals. This study investigated the release profiles of ovine albumin (OVA) from CHA gel stored in phosphate-buffered saline (PBS) and double distilled water (DDW) for times of up to 1 year. It was found that 7.9% OVA could be loaded onto apatitic gels by means of a purely aqueous process. This process provided a simple low-temperature method of protein adsorption on a high surface area apatitic matrix at physiological pH. The rate of short-term release of OVA was lower from CHA gels than from microcrystalline HA powder. However, the period of release from the CHA gel was short term and may have been associated with recrystallization of the gel. OVA loaded into CHA gel was found to remain undegraded in vitro at 37 degrees C for periods of up to 1 year.     

Cortical bone screw fixation in ionically modified apatite cements

Hydroxyapatite cements are used in reconstruction of the face; usually in well-defined cavities where the cement can be stabilized without the need for internal fixation. A hydroxyapatite cement that could enable screw fixation and some loading therefore has considerable potential in maxillofacial reconstruction. It has been demonstrated recently that water demand of calcium phosphate cements can be reduced by ionically modifying the liquid component. This study investigated the capacity of an ionically modified precompacted apatite cement to retain self-tapping cortical bone screws. Screw pullout forces were determined in the direction of the screw long axis and perpendicular to it, using cortical bone and polymethylmethacrylate cement as a control. In bending pullout tests, measured forces to remove screws from ionically modified precompacted cement were insignificantly different from cortical bone. However, pullout forces of bone screws from hydroxyapatite cement decreased with aging time in vitro.     

Cost-effectiveness of hepatitis A-B vaccine versus hepatitis B vaccine for healthcare and public safety workers in the western United States.

OBJECTIVE: To determine the cost-effectiveness of substituting hepatitis A-B vaccine for hepatitis B vaccine when healthcare and public safety workers in the western United States are immunized to protect against occupational exposures to hepatitis B. PARTICIPANTS: A cohort of 100,000 hypothetical healthcare and public safety workers from 11 western states with hepatitis A rates twice the national average. DESIGN: A Markov model of hepatitis A was developed using estimates from U.S. government databases, published literature, and an expert panel. Added costs of hepatitis A-B vaccine were compared with savings from reduced hepatitis A treatment and work loss. Cost-effectiveness was expressed as the ratio of net costs to quality-adjusted life-years (QALYs) gained. RESULTS: Substituting hepatitis A-B vaccine would prevent 29,796 work-loss-days, 222 hospitalizations, 6 premature deaths, and the loss of 214 QALYs. Added vaccination costs of $5.4 million would be more than offset by $1.9 million and $6.1 million reductions in hepatitis A treatment and work loss costs, respectively. Cost-effectiveness improves as the time horizon is extended, from $232,600 per QALY after 1 year to less than $0 per QALY within 11 years. Estimates are most sensitive to community-wide hepatitis A rates and the degree to which childhood vaccination may reduce future rates. CONCLUSION: For healthcare and public safety workers in western states, substituting hepatitis A-B vaccine for hepatitis B vaccine would reduce morbidity, mortality, and costs.     

Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers.

PURPOSE: These studies were designed to examine radiation-induced in-field and out-of-field DNA damage in rat lung as a function of dose and various volumes of irradiation. They also determined whether superoxide dismutase (SOD) and nitro-L-arginine methyl ester (L-NAME) protected against this damage. METHODS AND MATERIALS: The whole lung, or various volumes of the lower or upper lungs of Sprague-Dawley rats were exposed to doses up to 20 Gy of 60Co gamma rays. Radiation-induced DNA damage was quantified in fibroblasts obtained at 18 h after irradiation from both irradiated and shielded lung regions using a micronucleus assay. The radioprotective role of SOD (CuZnSOD: 10 mg/kg body weight; MnSOD: 50-100mg/kg body weight) and L-NAME (0.2 mg/kg body weight.) in vivo was determined by injecting them into rats 30 min before or immediately after a dose of 10 Gy. RESULTS: Micronucleus formation was approximately linear with dose up to 15 Gy. When 70% of the lung volume was irradiated with 10 Gy, irradiated lower lung gave similar numbers of micronuclei (MN)/binucleate cell (BN) to that observed following whole lung irradiation (0.91 MN/BN), whereas the irradiated upper lung gave only 0.66 MN/BN. Following lower lung irradiation, the shielded upper lung (30% of lung volume) showed substantial (out-of-field) damage (0.43 MN/BN). When 30% of the lung was given 10 Gy, irradiated upper or lower lung showed similar amounts of in-field damage (0.43 MN/BN) but this was smaller than that seen following irradiation of 70% of the lung volume. For 30% lower lung irradiation, the shielded upper lung showed only a small out-of-field effect (0.1 MN/BN). For both volumes of irradiation there was a similar or smaller effect in the shielded lower lung after upper lung irradiation. Injection of SOD before or L-NAME after 10 Gy to the lower 70% lung volume resulted in a reduction in DNA damage both in-field and out-of-field but the percentage was much greater for out-of-field damage (50-60%) than for in-field damage (10-30%). Following whole lung irradiation (10 Gy) significantly greater DNA damage was observed in fibroblasts from the left lung than from the right lung (0.93 MN/BN vs. 0.82 MN/BN). Following whole lung irradiation there was no significant difference in DNA damage observed in fibroblasts from the lower lung and the upper lung. CONCLUSIONS: With partial lung irradiation the lower lung sustains more in-field DNA damage following irradiation than the upper lung, whereas out-of-field effects are observed primarily in the upper lung (i.e. following lower lung irradiation). Following whole lung irradiation the left lung sustains more damage than the right lung but there is no difference between the upper and lower lung. The protective effects of SOD and L-NAME suggest that inflammatory cytokines induced by the irradiation may be involved in the initiation of a reaction resulting in the production of reactive oxyradicals and nitric oxide that cause indirect DNA damage both in and out of the radiation field.     

Investigating temporal fluctuations in tumor vasculature with combined carbogen and ultrasmall superparamagnetic iron oxide particle (CUSPIO) imaging

A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R₂* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ΔR₂*_carbogen followed by positive ΔR₂*_USPIO with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ΔR₂*_carbogen but no significant ΔR₂*_USPIO were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining ΔR₂*_carbogen and ΔR₂*_USPIO with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture. Magn Reson Med 66:227–234, 2011. © 2011 Wiley‐Liss, Inc.