Tiebin Liu

The pediatric preclinical testing program: description of models and early testing results.

The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide.

Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies.

Advances in systemic and local therapies have improved outcomes for patients with the Ewing sarcoma family of tumors (ESFT). As new treatments are developed, a critical review of data from past treatment eras is needed to identify clinically relevant risk groups.

Improved survival for patients with recurrent Wilms tumor: The experience at St. Jude Children's Research Hospital

Background Reported estimates of survival for patients with recurrent Wilms tumor are 24% to 43%. Because published survival data are more than a decade old and do not reflect advances in therapy, the authors reviewed their experience in treating recurrent Wilms tumor to determine whether the probability of survival has increased. Patients and Methods The authors reviewed the cases of 54 patients with recurrent Wilms tumor who were treated on one of six consecutive clinical trials at St. Jude Childrens Research Hospital between 1969 and 2000. Results Five-year overall survival estimates after relapse were 63.6 ± 15.7% for patients treated during or after 1984 (n = 20) and 20.6 ± 6.5% for patients treated before 1984 (n = 34) (P = 0.002). When the analysis was restricted to patients with high-risk clinical features, 5-year overall survival estimates were 47.6 ± 15.7% for those treated in the modern era (n = 16) and 11.1 ± 5.2% for those treated in the earlier era (n = 25) (P = 0.005). Only three patients received high-dose chemotherapy with autologous stem cell rescue; one survived. No patients with recurrent anaplastic histology disease survived. Conclusions Significant progress has been achieved in the treatment of recurrent favorable-histology Wilms tumor using multimodality salvage regimens with conventional doses of chemotherapy. Novel therapeutic strategies will be necessary to cure patients with recurrent anaplastic Wilms tumor.

High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma

High‐dose methotrexate (HDMTX) is used frequently in combination regimens that include nephrotoxic chemotherapy. The authors evaluated the impact of factors such as age and prior nephrotoxic agents on MTX pharmacokinetics in children and young adults with osteosarcoma and examined whether MTX pharmacokinetic parameters were associated with outcome.

UGT1A1 Promoter Genotype Correlates With SN-38 Pharmacokinetics, but Not Severe Toxicity in Patients Receiving Low-Dose Irinotecan

PURPOSE To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). PATIENTS AND METHODS Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy. RESULTS The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios. CONCLUSION Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.

Clinical and Diagnostic Imaging Findings Predict Anesthetic Complications in Children Presenting with Malignant Mediastinal Masses

Background:  The presence of a mediastinal mass in a child poses significant anesthesia‐related risks including death. To optimize outcome clinicians must be able to predict which patients are at highest risk of anesthetic complications.

Tumor size as a predictor of outcome in pediatric non-metastatic osteosarcoma of the extremity.

Better predictors of outcome would allow improved risk‐adapted therapy for pediatric nonmetastatic osteosarcoma of the extremity. We investigated the predictive value of MR imaging‐based measures of absolute and relative tumor size and volume at the time of diagnosis. We also assessed the relation of tumor size to age and histologic response.

Bone mineral density deficits in pediatric patients treated for sarcoma.

Children treated for sarcoma are at risk of treatment‐associated deficits in bone mineral density (BMD). We investigated the severity of risk factors for BMD deficits in this patient population.

Second cancers in patients with the Ewing sarcoma family of tumours

BACKGROUND Patients are at risk of second malignancies (SM) after treatment for Ewing sarcoma family of tumours (ESFT). METHODS We performed a retrospective review of 237 patients with ESFT treated at our institution from September 1979 through to February 2004. Cumulative incidence (CI) of SM by the type of malignancy and treatment was estimated. RESULTS Twelve patients with SM were identified. Secondary leukaemia (SL) developed in 8 patients (2 ALL, 6 MDS/AML), a median 2.6 years (range 1.4-19.6 years) after diagnosis of ESFT. Four patients had secondary solid tumours, a median 8.0 years (range 7.4-9.4 years) after the ESFT diagnosis. Five- and 10-year estimates of the CI of SM were 3.0+/-1.1% and 4.7+/-1.5%, respectively. Patients treated on recent protocols with higher cumulative doses or an increased dose intensity of alkylators and epipodophyllotoxins and the use of G-CSF had a higher estimated CI of SL than those in earlier studies (5-year CI 6.4+/-2.4% versus 0.0+/-0.0%, respectively, P=0.004). CONCLUSIONS Patients with ESFT are at risk for SM after treatment. The cumulative incidence of SM is higher with the current treatment protocols and may be related to the intensification of chemotherapeutic agents.

Pulmonary nodules discovered during the initial evaluation of pediatric patients with bone and soft-tissue sarcoma

Recent technical advances in CT imaging and data processing have improved the ability to detect small pulmonary nodules in children with bone and soft‐tissue sarcoma undergoing radiologic imaging of the chest.