M. Beth McCarville

Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy.

Purpose: Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy. However, increasing evidence suggests that vascular endothelial growth factor (VEGF) inhibition can effect transient “normalization” of the tumor vasculature, thereby improving tumor perfusion and, consequently, delivery of systemic chemotherapy. We sought to examine temporal changes in tumor vascular function in response to the anti-VEGF antibody, bevacizumab. Experimental Design: Established orthotopic neuroblastoma xenografts treated with bevacizumab were evaluated at serial time points for treatment-associated changes in intratumoral vascular physiology, penetration of systemically administered chemotherapy, and efficacy of combination therapy. Results: After a single bevacizumab dose, a progressive decrease in tumor microvessel density to <30% of control was observed within 7 days. Assessment of the tumor microenvironment revealed a rapid, sustained decrease in both tumor vessel permeability and tumor interstitial fluid pressure, whereas intratumoral perfusion, as assessed by contrast-enhanced ultrasonography, was improved, although this latter change abated by 1 week. Intratumoral drug delivery mirrored these changes; penetration of chemotherapy was improved by as much as 81% when given 1 to 3 days after bevacizumab, compared with when both drugs were given concomitantly, or 7 days apart. Finally, administering topotecan to tumor-bearing mice 3 days after bevacizumab resulted in greater tumor growth inhibition (36% of control size) than with monotherapy (88% bevacizumab, 54% topotecan) or concomitant administration of the two drugs (44%). Conclusions: Bevacizumab-mediated VEGF blockade effects alterations in tumor vessel physiology that allow improved delivery and efficacy of chemotherapy, although careful consideration of drug scheduling is required to optimize antitumor activity.

R2* magnetic resonance imaging of the liver in patients with iron overload

R2* magnetic resonance imaging (R2*-MRI) can quantify hepatic iron content (HIC) by noninvasive means but is not fully investigated. Patients with iron overload completed 1.5T R2*-MRI examination and liver biopsy within 30 days. Forty-three patients (sickle cell anemia, n = 32; beta-thalassemia major, n = 6; and bone marrow failure, n = 5) were analyzed: median age, 14 years, median transfusion duration, 15 months, average (+/-SD) serum ferritin 2718 plus or minus 1994 ng/mL, and average HIC 10.9 plus or minus 6.8 mg Fe/g dry weight liver. Regions of interest were drawn and analyzed by 3 independent reviewers with excellent agreement of their measurements (intraclass correlation coefficient = 0.98). Ferritin and R2*-MRI were weakly but significantly associated (range of correlation coefficients among the 3 reviewers, 0.41-0.48; all P < .01). R2*-MRI was strongly associated with HIC for all 3 reviewers (correlation coefficients, 0.96-0.98; all P < .001). This high correlation confirms prior reports, calibrates R2*-MRI measurements, and suggests its clinical utility for predicting HIC using R2*-MRI. This study was registered at www.clinicaltrials.gov as #NCT00675038.

Long-term Safety and Efficacy Following Systemic Administration of a Self-complementary AAV Vector Encoding Human FIX Pseudotyped With Serotype 5 and 8 Capsid Proteins

Adeno-associated virus vectors (AAV) show promise for liver-targeted gene therapy. In this study, we examined the long-term consequences of a single intravenous administration of a self-complementary AAV vector (scAAV2/ 8-LP1-hFIXco) encoding a codon optimized human factor IX (hFIX) gene in 24 nonhuman primates (NHPs). A dose-response relationship between vector titer and transgene expression was observed. Peak hFIX expression following the highest dose of vector (2 × 10(12) pcr-vector genomes (vg)/kg) was 21 ± 3 µg/ml (~420% of normal). Fluorescent in-situ hybridization demonstrated scAAV provirus in almost 100% of hepatocytes at that dose. No perturbations of clinical or laboratory parameters were noted and vector genomes were cleared from bodily fluids by 10 days. Macaques transduced with 2 × 10(11) pcr-vg/kg were followed for the longest period (~5 years), during which time expression of hFIX remained >10% of normal level, despite a gradual decline in transgene copy number and the proportion of transduced hepatocytes. All macaques developed serotype-specific antibodies but no capsid-specific cytotoxic T lymphocytes were detected. The liver was preferentially transduced with 300-fold more proviral copies than extrahepatic tissues. Long-term biochemical, ultrasound imaging, and histologic follow-up of this large cohort of NHP revealed no toxicity. These data support further evaluation of this vector in hemophilia B patients.

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma

Preclinical models show sequence‐dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion.

Phase I Trial of Temozolomide and Protracted Irinotecan in Pediatric Patients with Refractory Solid Tumors

Purpose: The purpose is to estimate the maximum-tolerated dose (MTD) of temozolomide and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with refractory solid tumors. Experimental Design: Twelve heavily pretreated patients received 56 courses of oral temozolomide at 100 mg/m2/day for 5 days combined with i.v. irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m2/day (n = 6) or 15 mg/m2/day (n = 6). We assessed toxicity, the pharmacokinetics of temozolomide and irinotecan, and the DNA repair phenotype in tumor samples. Results: Two patients experienced dose-limiting toxicity (DLT) at the higher dose level; one had grade 4 diarrhea, whereas the other had bacteremia with grade 2 neutropenia. In contrast, no patient receiving temozolomide and 10 mg/m2/day irinotecan experienced DLT. Myelosuppression was minimal and noncumulative. No pharmacokinetic interaction was observed. Drug metabolite exposures at the MTD were similar to exposures previously associated with single-agent antitumor activity. One complete response, two partial responses, and one minor response were observed in Ewing’s sarcoma and neuroblastoma patients previously treated with stem cell transplant. Responding patients had low or absent O6-methylguanine-DNA methyltransferase expression in tumor tissue. Conclusions: The MTD using this schedule was temozolomide (100 mg/m2/day) and irinotecan (10 mg/m2/day), with DLT being diarrhea and infection. Drug clearance was similar to single-agent values, and clinically relevant SN-38 lactone and MTIC exposures were achieved at the MTD. As predicted by xenograft models, this combination and schedule appears to be tolerable and active in pediatric solid tumors. Evaluation of a 21-day schedule is planned.

Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma

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.

Typhlitis in Childhood Cancer

Typhlitis is increasingly recognized in children undergoing chemotherapy but is poorly characterized. The authors investigated the demographic, clinical, and imaging (ultrasonography and computed tomography [CT] scans) variables related to the diagnosis, risk, and outcome of typhlitis.

Evaluation of a comprehensive transcranial doppler screening program for children with sickle cell anemia.

Although transcranial Doppler ultrasonography (TCD) screening is effective in identifying children with sickle cell anemia (SCA) who are at high risk of stroke, not all children are screened. In 2003, we instituted a comprehensive TCD screening program designed to screen all at‐risk children treated at our sickle cell center.

Metastatic osteosarcoma: Results of two consecutive therapeutic trials at St. Jude Children's Research Hospital

The outcome of patients with metastatic osteosarcoma treated in two consecutive trials from 1986 to 1997 was analyzed to evaluate the efficacy of carboplatin‐based multiagent chemotherapy and to identify prognostic factors. The initial study (OS‐86) used ifosfamide, cisplatin, doxorubicin, and high‐dose methotrexate, and the subsequent study (OS‐91) used the same agents at similar doses, but carboplatin was substituted for cisplatin.

Preservation of spleen and brain function in children with sickle cell anemia treated with hydroxyurea

Chronic organ damage is an insidious process in patients with sickle cell anemia (SCA). Although hydroxyurea prevents acute vaso‐occlusive events, its effects on the preservation of organ function remain undefined.