Population pharmacokinetics of trabectedin in adolescent patients with cancer.

PURPOSE: To characterize the trabectedin population pharmacokinetics in children and adolescent patients with cancer and compare it with the trabectedin pharmacokinetics in adults. METHODS: Plasma concentrations from ten adolescent and three children with cancer (age range 4.0-17.0 years) treated with trabectedin at doses ranging from 1.1 to 1.7 mg/m2, administered as a 24-h continuous intravenous infusion every 3 weeks, were available for the analysis. An external model evaluation was performed to verify whether a previously developed adult population pharmacokinetic model was predictive of the pediatric plasma concentrations of trabectedin. The maximum a posteriori estimation of the individual pharmacokinetic parameters for pediatric patients was conducted, after successful completion of the external evaluation step. The relationships between pharmacokinetic parameters and body size were evaluated. RESULTS: External evaluation methods showed no major differences between the adult population and children and adolescent patients of this study. The mean ± standard deviation (SD) of the individual estimated clearance and central volume of distribution in these children/adolescent patients was 36.4 ± 16.1 L/h and 13.2 ± 6.54 L, respectively. These values were similar to the typical values reported for adult patients-37.6 L/h and 13.9 L (for females) and 16.1 L (for males). The median area under the plasma concentration versus time curve (AUC) in children/adolescent patients was 55.1 µg h/L, while in the adult population the median AUC was 61.3 µg h/L, both administered a 1.5 mg/m2 dose regimen with mean (range) BSA for adults = 1.86 (0.90-2.80) vs children/adolescent patients = 1.49 (0.66-2.54). CONCLUSIONS: The adult population pharmacokinetic model adequately described the trabectedin plasma concentrations and its variability in the pediatric population of patients involved in this assessment that mostly comprised adolescents. The trabectedin systemic exposure achieved in this population was comparable (within 12%) to the exposure obtained in adult population when the same dose, expressed in mg/m2, was administered.

Selective venous catheterization for the localization of phosphaturic mesenchymal tumors.

Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies.

Value of measuring subpopulations of T and B lymphocytes in patients with musculoskeletal tumours.

BACKGROUND: Aims of our study were to assess the clinical value of measuring subpopulations of T and B lymphocytes in patients with musculoskeletal tumours as an immunodiagnostic procedure in the primary diagnosis of tumours. METHODS: In this prospective study, blood samples were obtained from 145 patients aged 04-98 years with musculoskeletal tumours. CD3, CD4, CD8, Helper/Suppressor ratio and CD19 subpopulations of lymphocytes were measured in specimens of whole blood in EDTA, upon the principle of Ortho Cytoron Absolute flow cytometry. Histological tumour diagnosis was obtained by the histopathology investigation of biopsy sample and lymphocytes values allocated accordingly. RESULTS: Out of 145 patients, osteomyelitis was diagnosed in 15 (10.34%). Median values of subpopulations of lymphocytes were: CD3 2456, CD4 1479, CD8 929, Helper/Suppressor ratio 1.8 and CD19 560 and all were raised above normal values in patients with osteomyelitis. Results were also calculated for osteosarcomas, Ewing sarcomas, giant cell tumours, chondrosarcomas and other tumours. These causes had median values within normal reference levels. To confidently out rule or confirm diagnosis of osteomyelitis, we measured the cut off point values and they were: CD3 2420, CD4 1400, CD8 873 and CD19 550. CONCLUSIONS: The main clinical use of measuring subpopulations of lymphocytes is in establishing the correct diagnosis between suspected osteomyelitis and other musculoskeletal tumours. Levels of measured subpopulations of lymphocytes above the presented cut off values are important and accurate confirming factor for the clinical diagnosis of suspected osteomyelitis. LEVEL OF EVIDENCE: II.

Epithelioid hemangioendothelioma presenting with severe myelofibrosis and a high serum hyaluronan level.

Epithelioid hemangioendothelioma (EHE) is a rare tumor originating from the vascular endothelium; it has an intermediate malignant potential. EHEs affect all age groups and mostly originate from the soft tissues of the extremities, lungs, and liver. Spinal EHEs, especially those occurring in the bone marrow region, are extremely rare. We report a case of EHE with massive involvement of the liver, vertebrae, and cranial bones that caused severe myelofibrosis (MF) in a 67-yr-old-male patient. Hyaluronan deposits were diffusely observed in the tumor tissue biopsies obtained from both the liver and bone marrow. Furthermore, the serum hyaluronan level increased markedly along with rapid progression of the disease. To the best of our knowledge, this is the first report of MF occurring in an EHE; hyaluronan may have played an important role in the pathogenesis of fibrosis in this case.