BackgroundWnt signaling is implicated in many developmental decisions, including stem cell control, as well as in cancer. There are relatively few target genes known of the Wnt pathway.ResultsWe have identified target genes of Wnt signaling using microarray technology and human embryonic carcinoma cells stimulated with active Wnt protein. The ~50 genes upregulated early after Wnt addition include the previously known Wnt targets Cyclin D1, MYC, ID2 and βTRCP. The newly identified targets, which include MSX1, MSX2, Nucleophosmin, Follistatin, TLE/Groucho, Ubc4/5E2, CBP/P300, Frizzled and REST/NRSF, have important implications for understanding the roles of Wnts in development and cancer. The protein synthesis inhibitor cycloheximide blocks induction by Wnt, consistent with a requirement for newly synthesized β-catenin protein prior to target gene activation. The promoters of nearly all the target genes we identified have putative TCF binding sites, and we show that the TCF binding site is required for induction of Follistatin. Several of the target genes have a cooperative response to a combination of Wnt and BMP.ConclusionsWnt signaling activates genes that promote stem cell fate and inhibit cellular differentiation and regulates a remarkable number of genes involved in its own signaling system.

BACKGROUND. The combination of gemcitabine and docetaxel has demonstrated promise in sarcomas diagnosed in adults. In the current study, the toxicity and efficacy of this combination were evaluated in pediatric sarcomas. METHODS. A retrospective case review of 22 patients with recurrent or refractory bone or soft‐tissue sarcomas who received gemcitabine (at a dose of 675 mg/m2 intravenously on Days 1 and 8) and docetaxel (at a dose of 75–100 mg/m2 intravenously on Day 8) was undertaken. RESULTS. The patients (ages 8–23 years) received a total of 109 courses of chemotherapy (median, 4 courses; range, 1–13 courses). Seventeen patients had osteosarcoma, 2 patients had Ewing sarcoma family of tumors (ESFT), 1 patient had a malignant fibrous histiocytoma (MFH), 1 patient had a chondrosarcoma, and 1 patient had an undifferentiated sarcoma. Of the 14 patients evaluable for response, the patient with an MFH achieved a complete response (CR), 3 patients with osteosarcoma achieved a partial response (PR), and 2 patients (1 with ESFT and 1 with osteosarcoma) had stable disease (SD). The overall objective response (CR + PR) rate was 29%. Median duration of response (CR + PR + SD) was 4.8 months (range, 1.6‐13 months). The toxicity was manageable and consisted primarily of thrombocytopenia and neutropenia. CONCLUSIONS. In the current study, gemcitabine in combination with docetaxel was found to be well tolerated and demonstrated antitumor activity in children and adolescents with recurrent or refractory osteosarcoma and MFH. Further evaluation of this drug combination is warranted in these patients. Cancer 2008. © 2008 American Cancer Society.

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Fungi from the Zygomycetes class are increasingly recognized causes of infection in immunosuppressed children, but no comprehensive literature review and few case series have been published on the topic. A case series of 6 pediatric oncology patients with Zygomycetes infections cared for at our institution was constructed, and a concurrent search of the English language literature for Zygomycetes infections in children with oncologic disorders was undertaken. Our case series described 6 patients (5 male) between the ages of 2.5 and 19.5 years. One patient was diagnosed with rhinocerebral disease, 2 with rhinosinusitis, 2 with pulmonary involvement, and 1 with a gastrointestinal presentation. Five patients survived. Our literature review identified 82 cases from 61 studies. The mean subject age was 10.8 years (1.4 to 21.0 y). About 92.7% of all patients suffered from some form of leukemia, with 70.7% suffering from acute lymphoblastic leukemia. Overall, 58.5% of reported patients survived, with individuals with disseminated disease showing the worst prognosis (68.2% mortality) and those with cutaneous disease the best (14.3% mortality). Survival is increasingly reported in the literature, perhaps as a result of improved diagnostic capabilities, increased physician awareness and increased reliance on adjunctive surgical therapy.

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received 2 courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria, or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2–4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5%±10.0% and 83.4%±7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (< 5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.

Purpose To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design Prior to tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age 12.2 years) enrolled on a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space,49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure as body mass index percentile was significantly (p<0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure prior to primary tumor resection was associated with increased risk of major wound healing complications after surgery (p<0.05). Conclusion A population pharmacokinetic model for bevacizumab was developed which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications.

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