Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10^–3 M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016±143 mol/l. The mean dose delivered was 13.2±2 g/m². The clearance was 49.1±11.7 ml min^–1 m^–2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with at _1/2 of 2.66±0.82 h and at _1/2 of 15.69±8.63 h. The volume of distribution was 0.32±0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%–21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. Thet _1/2 and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P<0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significantly different from those of the group of nonsensitive patients.     

An epidemiologic case-control study of breast cancer and exposure to hair dyes.

An epidemiologic case-control study of 1617 patients with a primary breast cancer and 1617 control subjects was conducted to test the hypothesis that use of hair dyes is related to breast cancer. No overall association was observed between breast cancer risk and "ever use" of hair dyes (odds ratio, 1.04; 95% confidence interval, 0.90 to 1.21), age when hair dye use started and age when it stopped, duration of hair dye use (years), types of hair dyes used, and estimated lifetime number of individual applications. The current data set also failed to show an increased risk for breast cancer in women who had been diagnosed with benign breast disease and were exposed to hair dyes.     

Individual patient data meta-analyses in head and neck carcinoma: what have we learnt?]

Carcinoma of the upper aerodigestive tract (oral cavity, oropharynx, hypopharynx, nasopharynx, larynx) are frequent tumors for which surgery and/or radiotherapy are the main therapeutic agents. The main results of meta-analyses based on the collection of individual patients data are reported: 1) The meta-analysis on chemotherapy, regrouping data of nearly 11,000 patients issued from 63 randomized trials showed an absolute benefit of 4% at five years in overall survival, in favor of chemotherapy (P<0.0001). Most of the benefit was seen with concomitant radiochemotherapy, however with a relatively large heterogeneity in this subgroup of trials. An update of this meta-analysis was performed including 24 additional trials, which confirmed the magnitude of the benefit due to concomitant chemotherapy (8% at 5 years). 2) The meta-analysis on larynx preservation, using induction chemotherapy in larynx and hypopharynx carcinomas. No significant difference was seen between the control arm with total laryngectomy and the larynx preservation approach. 3) The meta-analysis on chemotherapy in nasopharynx carcinomas, from the data of 11 randomized trials including 2722 patients, and comparing the radiotherapy to radio-chemotherapy (1979-2001). The results showed an absolute benefit of 6% at five years in overall survival, in favor of chemotherapy (P<0.0001). Most of the benefit was seen with concomitant radiochemotherapy. 4) Finally, a meta-analysis on altered fractionated RT, compared to conventional RT in 15 randomized trials regrouping 6515 patients. The results showed a small but significant improvement in favor of altered fractionated RT for overall survival and local control with an absolute benefit at five years of 3 and 6%, respectively.     

Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.     

Quantitative geometric analysis of rib, costal cartilage and sternum from childhood to teenagehood

Better understanding of the effects of growth on children’s bones and cartilage is necessary for clinical and biomechanical purposes. The aim of this study is to define the 3D geometry of children’s rib cages: including sternum, ribs and costal cartilage. Three-dimensional reconstructions of 960 ribs, 518 costal cartilages and 113 sternebrae were performed on thoracic CT scans of 48 children, aged 4 months to 15 years. The geometry of the sternum was detailed and nine parameters were used to describe the ribs and rib cages. A “costal index” was defined as the ratio between cartilage length and whole rib length to evaluate the cartilage ratio for each rib level. For all children, the costal index decreased from rib level 1 to 3 and increased from level 3 to 7. For all levels, the cartilage accounted for 45–60 % of the rib length, and was longer for the first years of life. The mean costal index decreased by 21 % for subjects over 3-year old compared to those under three (p < 10^?4). The volume of the sternebrae was found to be highly age dependent. Such data could be useful to define the standard geometry of the pediatric thorax and help to detect clinical abnormalities.     

Multicenter precision of cortical and trabecular bone quality measures assessed by high‐resolution peripheral quantitative computed tomography

High‐resolution peripheral quantitative computed tomography (HR‐pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technology to address important skeletal health questions requires translation to standardized multicenter data pools. Our goal was to evaluate the feasibility of pooling data in multicenter HR‐pQCT imaging trials. Reproducibility imaging experiments were performed using structure and composition‐realistic phantoms constructed from cadaveric radii. Single‐center precision was determined by repeat scanning over short‐term (<72 hours), intermediate‐term (3–5 months), and long‐term intervals (28 months). Multicenter precision was determined by imaging the phantoms at nine different HR‐pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters. Single‐center short‐term RMSCVs were <1% for all parameters except cortical thickness (Ct.Th) (1.1%), spatial variability in cortical thickness (Ct.Th.SD) (2.6%), standard deviation of trabecular separation (Tb.Sp.SD) (1.8%), and porosity measures (6% to 8%). Intermediate‐term RMSCVs were generally not statistically different from short‐term values. Long‐term variability was significantly greater for all density measures (0.7% to 2.0%; p < 0.05 versus short‐term) and several structure measures: cortical thickness (Ct.Th) (3.4%; p < 0.01 versus short‐term), cortical porosity (Ct.Po) (15.4%; p < 0.01 versus short‐term), and trabecular thickness (Tb.Th) (2.2%; p < 0.01 versus short‐term). Multicenter RMSCVs were also significantly higher than short‐term values: 2% to 4% for density and micro–finite element analysis (µFE) measures (p < 0.0001), 2.6% to 5.3% for morphometric measures (p < 0.001), whereas Ct.Po was 16.2% (p < 0.001). In the absence of subject motion, multicenter precision errors for HR‐pQCT parameters were generally less than 5%. Phantom‐based multicenter precision was comparable to previously reported in in vivo single‐center precision errors, although this was approximately two to five times worse than ex vivo short‐term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multicenter study designs. © 2013 American Society for Bone and Mineral Research.