Predictors of tolerance to chemotherapy in older cancer patients: a prospective pilot study

Few data are available to help predict which older cancer patient is at risk of developing chemotherapy-related toxicity. This study was a pilot for a project designing a predictive risk score. Chemotherapy patients aged 70 years and older were prospectively enrolled. Chemotherapies were adjusted for their published toxicity. 60 patients were enrolled, 59 were evaluable. Mean dose-intensity was 90.3%, range 33.3-129.0%. 47% of the patients experienced grade 4 haematological and/or grade 3-4 non-haematological toxicity. Published toxicity (MAX2), diastolic blood pressure, marrow invasion and lactate dehydrogenase (LDH) were all associated with toxicity (P<0.1); Body Mass Index, previous chemotherapy, red blood cells, platelets, polymedication with dose-intensity; and polymedication with FACT-G change. After adjustment for the published toxicity, the variables retained their significance, except for LDH and polymedication (for dose-intensity). Although the size of this pilot study imposes a cautious interpretation, patient-related and chemotherapy-related variables correlated independently with toxicity. Designing a composite predictive score to use in assessing the toxicity of multiple chemotherapy regimens therefore appears to be a valid undertaking.     

Determinants of prostate cancer-specific survival after radiation therapy for patients with clinically localized prostate cancer.

PURPOSE: Identifying pretreatment and posttreatment predictors of time to prostate cancer-specific death (PCSD) after external-beam radiation therapy (RT) was the subject of this study. PATIENTS AND METHODS: A Cox regression analysis was used to evaluate the ability of the pretreatment risk group to predict time to PCSD for 381 patients who underwent RT for clinically localized prostate cancer. Posttreatment factors analyzed for the 94 patients who experienced prostate-specific antigen (PSA) failure included the time to PSA failure, the posttreatment PSA doubling time (DT), and the timing of salvage hormonal therapy. RESULTS: Despite the median age of 73 years at diagnosis, 45% of patients with high-risk disease were estimated to die from prostate cancer within 10 years after RT compared with 0% (P =.004) and 6% (P =.05) for patients with low- or intermediate-risk disease, respectively. Predictors of time to PCSD after PSA failure included PSA DT (P =.01) and delayed use of hormonal therapy (P 相似文献   

Differential stimulation of the growth of lung-metastasizing tumor cells by lung (paracrine) growth factors: identification of transferrin-like mitogens in lung tissue-conditioned medium.

Certain metastatic tumor cells successfully form metastases at particular organ sites, and their organ colonization properties cannot be explained by mechanical or anatomic factors. These tumor cells possess the ability to colonize such sites through preferential adhesion to organ microvessel endothelial cells, preferential organ invasion by expression of particular degradative enzymes and response to organ motility factors, and preferential organ growth by response to growth factors present at relatively higher concentrations in the target organ. The likelihood that target organ-associated growth factors exist and are important in metastatic colonization has been approached by studying the mitogenic effects of target organ extracts, fragments, or conditioned media on poorly and highly metastatic tumor cells that show organ preference of metastasis. We previously described the isolation of a major organ-derived (paracrine) growth factor from lung tissue-conditioned medium. Characterization of this mitogen has demonstrated that it is a transferrin or a transferrin-like glycoprotein, and antibodies to transferrin can remove significant growth activity from lung tissue-conditioned medium. Further demonstration of the existence and characterization of metastasis-associated organ (paracrine) growth factors and their receptors will be helpful in understanding the organ preference of metastasis.     

Effect of infusion duration on valproate pharmacokinetics

The pharmacokinetics of intravenously administered valproic acid (VPA) were investigated in 16 healthy male volunteers in a single-dose, fasting, four-period, randomized, double-blind, placebo-controlled, parallel design study. Subjects were randomly assigned to be infused a single dose of sodium valproate equivalent to 1000 mg VPA or placebo over each of four different time periods. Valproate concentrations in plasma were determined using gas chromatography with flame ionization detection. The pharmacokinetic parameters were determined by both non-compartmental and model-dependent techniques. Analyses of variance (ANOVAs) were performed to detect any statistical differences among the regimens. Overall, the pharmacokinetics of valproate were similar after infusions of 5, 10, 30, and 60 min, with an average terminal-phase half-life of 15.9 h. There were modest differences in overall clearances among the regimens, with the 5 min infusion producing a mean area under the plasma concentration-time curve (AUC; 1877 μg·h ml^?1) that was significantly (13 to 16 per cent) higher than the means for the longer infusions (1614–1656 μg·h ml^?1). Differences in distribution were also noted as a function of infusion duration. The shortest duration produced a significantly smaller terminal volume of distribution (12.8 vs 14.2–15.1 l) and more rapid tissue equilibration. The α-phase rate constant declined from a mean of 5.1 h^?1 after the 5 min infusion to a mean of 0.9 h^?1 after the 60 min infusion. The distributional differences are almost certainly related to the saturable protein binding of valproate. However, the lower clearance after the 5 min infusion indicates that there may have also been partial saturation of one of the metabolic pathways of valproate during the distributive phase, and that the increase in f_u was smaller than the decrease in CL′_int, such that the product of f_u·CL′_int showed a net decrease.     

Outcome of renal transplants from pediatric donors <5 yr of age

AIM: Outcomes of single renal transplants from donors <5 yr old have traditionally been inferior to those from older donors. We retrospectively studied our experience with patients who received renal transplants, either individually or en bloc, from young donors (<5 yr of age) to determine the utility of these organs. We also compared the outcomes of these transplant patients maintained on either cyclosporine- (CyA) or tacrolimus-based (TRL) immunosuppression regimens. PATIENTS: Ninety-eight patients received transplants at our center from donors <5 yr of age between August 1993 and August 2003. They were followed-up from 12 months to 11 yr. Patients were divided into four groups based on whether they received single or en bloc transplants, and whether CyA or TRL was the base immunosuppressive agent. Patients in group I (n = 13) received single pediatric kidneys and were treated with CyA regimens; group II patients (n = 26) also received single pediatric kidneys, but were treated with TRL regimens; group III patients (n = 31) were transplanted en bloc and were treated with CyA; and group IV patients (n = 28) received en bloc transplants and were treated with TRL. RESULTS: One-year patient and death-censored graft survival was not significantly different between recipients of en bloc vs. single grafts (i.e. 88 and 85% vs. 90 and 87%, respectively), or between the four treatment groups (group I: 85 and 85%, group II: 92 and 88%, group III: 87 and 84%, and group IV: 89 and 86%, respectively). The overall 1-yr rejection rate was 30% (29 of 98), which was significantly higher in the CyA-treated patients 19 of 44; i.e. 43%, than in TRL-treated patients 10 of 54, i.e. 19%, p = 0.03). In the en bloc recipients, seven grafts (12%) were lost as a result of vascular thrombosis. Notably, none of the single kidneys were lost because of vascular thrombosis. At the end of follow-up the creatinine levels of both groups were comparable. CONCLUSIONS: Pediatric donor kidneys transplanted individually provide for equal patient and graft survival when compared with en bloc transplants. TRL can be used reduce the detrimental effect of acute rejection on graft growth and function when compared with CyA. Single use of such kidneys can safely and efficaciously be transplanted into adult recipients, greatly expanding the donor pool.     

Perioperative N-acetylcysteine to prevent renal dysfunction in high-risk patients undergoing cabg surgery: a randomized controlled trial

Context  Renal dysfunction is a complication of coronary artery bypass graft (CABG) surgery performed with cardiopulmonary bypass (CPB) that is associated with increased morbidity and mortality. N-acetylcysteine, an antioxidant and vasodilator, counteracts renal ischemia and hypoxia. Objective  To determine whether perioperative intravenous (IV) N-acetylcysteine preserves renal function in high-risk patients undergoing CABG surgery with CPB compared with placebo. Design, Setting, and Patients  Randomized, quadruple blind, placebo-controlled trial (October 2003-September 2004) in operating rooms and general intensive care units (ICUs) of 2 Ontario tertiary care centers. The 295 patients required elective or urgent CABG and had at least 1 of the following: preexisting renal dysfunction, at least 70 years old, diabetes mellitus, impaired left ventricular function, or undergoing concomitant valve or redo surgery. Interventions  Patients received 4 (2 intraoperative and 2 postoperative) doses of IV N-acetylcysteine (600 mg) (n = 148) or placebo (n = 147) over 24 hours. Main Outcome Measures  The primary outcome was the proportion of patients developing postoperative renal dysfunction, defined by an increase in serum creatinine level greater than 0.5 mg/dL (44 µmol/L) or a 25% increase from baseline within the first 5 postoperative days. Secondary outcomes included postoperative interventions and complications, the requirement for renal replacement therapy (RRT), adverse events, hospital mortality, and ICU and hospital length of stay. Results  There was no difference in the proportion of patients with postoperative renal dysfunction (29.7% vs 29.0%, P = .89; relative risk [RR], 1.03 [95% confidence interval {CI}, 0.72-1.46]) in the N-acetylcysteine and placebo groups, respectively. We noted nonsignificant differences in postoperative interventions and complications, the need for RRT (0.7% vs 2.1%; P = .37), total (6.1% vs 9.6%; P = .26) and serious adverse events, hospital mortality (3.4% vs 2.7%; P>.99), and ICU and hospital length of stay between the N-acetylcysteine and placebo groups. A post hoc subgroup analysis of patients (baseline creatinine level >1.4 mg/dL [120 µmol/L]) showed a nonsignificant trend toward fewer patients experiencing postoperative renal dysfunction in the N-acetylcysteine group compared with the placebo group (25.0% vs 37.1%; P = .29). Conclusions  N-acetylcysteine did not prevent postoperative renal dysfunction, interventions, complications, or mortality in high-risk patients undergoing CABG surgery with CPB. Further research is required to identify CABG patients at risk for postoperative renal events, valid markers of renal dysfunction, and to establish renal thresholds associated with important clinical outcomes.