Beth McCarville

Safety of contrast-enhanced ultrasound in children for non-cardiac applications: a review by the Society for Pediatric Radiology (SPR) and the International Contrast Ultrasound Society (ICUS)

The practice of contrast-enhanced ultrasound in children is in the setting of off-label use or research. The widespread practice of pediatric contrast-enhanced US is primarily in Europe. There is ongoing effort by the Society for Pediatric Radiology (SPR) and International Contrast Ultrasound Society (ICUS) to push for pediatric contrast-enhanced US in the United States. With this in mind, the main objective of this review is to describe the status of US contrast agent safety in non-cardiac applications in children. The five published studies using pediatric intravenous contrast-enhanced US comprise 110 children. There is no mention of adverse events in these studies. From a European survey 948 children can be added. In that survey six minor adverse events were reported in five children. The intravesical administration of US contrast agents for diagnosis of vesicoureteric reflux entails the use of a bladder catheter. Fifteen studies encompassing 2,951 children have evaluated the safety of intravesical US contrast agents in children. A European survey adds 4,131 children to this group. No adverse events could be attributed to the contrast agent. They were most likely related to the bladder catheterization. The existing data on US contrast agent safety in children are encouraging in promoting the widespread use of contrast-enhanced US.

Neural progenitor cell–mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis☆

PURPOSE Osteoprotegerin (OPG) inhibits osteoclast activation and reduces osteolysis in bone tumors. We hypothesized that tumor-tropic neural progenitor cells (NPCs) engineered to express OPG would reduce neuroblastoma disease burden in the bone. METHODS Stable expression of green fluorescent protein (NPC-GFP) and OPG (NPC-OPG) was established in human NPCs by lentivirus-mediated transduction. Bone disease was established by intrafemoral injection of luciferase-expressing human neuroblastoma (CHLA-255) cells into 20 SCID mice. Three weeks later, mice began receiving intravenous injection of 2 x 10(6) NPC-OPG or NPC-GFP (control) every 10 days x 3 doses. Disease was monitored with quantitative bioluminescence imaging and x-ray images, which were evaluated on a scale of 0 to 4. These studies were approved by the Institutional Animal Care and Use Committee. RESULTS Osteoprotegerin treatment in vitro produced no direct toxicity to tumor cells. Coculture of tumor cells with bone marrow significantly increased activation of bone marrow-derived osteoclasts as assessed by tartrate-resistant acid phosphatase staining (156 +/- 10.8 osteoclasts per well) compared to bone marrow culture alone (91.67 +/- 4.7, P = .005). This increase was abrogated by adding OPG-containing media (68.3 +/- 2.8, P = .001). NPC-OPG slowed tumor progression (108-fold increase from pretreatment) compared to mice treated with NPC-GFP (538-fold), as judged by bioluminescence imaging. X-rays subjectively demonstrated less bone disease in NPC-OPG-treated mice (2.27 +/- 0.25) compared to NPC-GFP-treated mice (3.25 +/- 0.22, P = .04). CONCLUSIONS Neural progenitor cell-mediated delivery of OPG slowed disease progression in a preclinical model of neuroblastoma bone metastasis. The decrease in bone disease was not from direct tumor cell toxicity but likely occurred indirectly through inhibition of osteoclast-directed bone resorption. Thus, targeted delivery of OPG by NPCs may be effective in the treatment of neuroblastoma bone metastasis.

Patients with osteosarcoma with a single pulmonary nodule on computed tomography: a single-institution experience

BACKGROUND/PURPOSE The purpose of this study is to determine if patients with osteosarcoma (OS) with metachronous metastatic pulmonary disease presenting with a single pulmonary nodule (SPN) on computed tomography (CT) were found to have other lesions at the time of thoracotomy. METHODS Data were collected retrospectively on consecutive patients with OS treated at our institution from 1982 to 2007. Patients with no evidence of disease at the end of initial therapy who subsequently relapsed in the lung were identified. RESULTS In our study, 16 (8%) of 198 patients with OS with metachronous metastatic pulmonary disease presented with a SPN on CT scan. In all patients, only 1 metastatic nodule for OS was found at the time of thoracotomy. The median time between diagnosis and first lung relapse was 23.8 months (range, 4-80 months). Eleven patients (68.7%) subsequently had a second lung relapse, but only 3 patients had involvement of the ipsilateral lung (mean time interval between first and second pulmonary relapses of 17 months; range, 2-44 months). Five-year overall survival from diagnosis was 56.2%. Seven patients (43.8%) died of disease progression. CONCLUSIONS In our experience, patients with OS with metachronous metastatic pulmonary disease presenting with a SPN on CT were not found to have additional malignant lesions at the time of thoracotomy. Consideration should be given in this group of selected patients to use a minimally invasive approach to nodule removal with image-guided localization, if needed, rather than open thoracotomy because ipsilateral metastases are not likely to be found.

IFN-β Restricts Tumor Growth and Sensitizes Alveolar Rhabdomyosarcoma to Ionizing Radiation

Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-β to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-β and ionizing radiation to assess synergistic effects in vitro and as orthotopic xenografts in CB17 severe combined immunodeficient mice. In addition to effects on tumor cell proliferation and xenograft growth, changes in the tumor microenvironment including interstitial fluid pressure, perfusion, oxygenation, and cellular histology were assessed. A nonlinear regression model and isobologram analysis indicated that IFN-β and ionizing radiation affected antitumor synergy in vitro in the Rh-30 cell line; the activity was additive in the Rh-41 cell line. In vivo continuous delivery of IFN-β affected normalization of the dysfunctional tumor vasculature of both Rh-30 and Rh-41 ARMS xenografts, decreasing tumor interstitial fluid pressure, increasing tumor perfusion (as assessed by contrast-enhanced ultrasonography), and increasing oxygenation. Tumors treated with both IFN-β and radiation were smaller than control tumors and those treated with radiation or IFN-β alone. Additionally, treatment with high-dose IFN-β followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-β. The combination of IFN-β and ionizing radiation showed synergy against ARMS by sensitizing tumor cells to the cytotoxic effects of ionizing radiation and by altering tumor vasculature, thereby improving oxygenation. Therefore, IFN-β and ionizing radiation may be an effective combination for treatment of ARMS. Mol Cancer Ther; 9(3); 761–71

The role of positron emission tomography in pediatric musculoskeletal oncology

F-fluorodeoxyglucose positron emission tomography (FDG PET) and PET-computed tomography (PET-CT) have emerged as powerful metabolic– anatomic imaging tools for the assessment of a wide variety of adult hematologic and solid malignancies. PET-CT offers an important advantage over PET alone, because the correlative CT images provide a method of accurately identifying the location of increased FDG activity and, in most cases, allow distinction of normal from pathologic processes and between pathologic processes. This fusion modality also aids in the detection of subtle anatomic abnormalities that may be less appreciable on diagnostic CT alone [1]. Although the value of PET and PET-CT in the assessment of adult cancers has been demonstrated, the appropriate role of these modalities in the management of pediatric cancers other than Hodgkin lymphoma has not been established. Osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT) are the most common childhood primary bone cancers in the United States. The survival of patients with these tumors has improved dramatically with the use of preoperative neoadjuvant therapy. A tumor’s histologic response to neoadjuvant therapy, i.e., the percent necrosis of the resected specimen, is predictive of prognosis. Magnetic resonance (MR) imaging, which is the conventional imaging method of monitoring these tumors’ response to therapy, has limited value because osseous tumors may respond well to therapy without a substantial change in size. Assessment of tumor necrosis by MR imaging is subjective unless dynamic contrast-enhanced MR imaging (DEMRI) is used to quantify the tumor’s dynamic vector magnitude and kep [2]. A reliable, non-invasive method of assessing tumor viability and response to therapy, such as PET, may permit the oncologist and surgeon to individualize the management of bone tumors, particularly those that are aggressive, respond poorly, or arise in sites that are surgically challenging. The FDG standardized uptake value (SUV) offers a semiquantitative measure of tumor metabolic activity. Because of tumor metabolic heterogeneity, the maximum SUVobtained from a region of interest (ROI) within the tumor is thought to provide the most reliable assessment of tumor metabolism [3]. Recently, Hawkins and colleagues investigated the value of the maximum SUV at diagnosis (SUV1) and after completion of neoadjuvant therapy (SUV2) in children and adults treated for ESFT. They found that patients with an SUV2 less than 2.5 were more likely than others to have a favorable histologic response (≤10% viable tumor) and to have 4-year progression-free survival [4]. Hawkins et al. and others have reported similar results of studies assessing the predictive value of the SUV before and after neoadjuvant therapy for primary OS [5]. Although the SUV is of value in assessing response to therapy of selected pediatric bone cancers, its accuracy in distinguishing benign from malignant bone tumors appears to be limited. In a study of 52 children and adults with benign (n=33) or malignant (n=19) bone B. McCarville (*) Department of Radiological Sciences, Division of Diagnostic Imaging, St. Jude Children’s Research Hospital, Mail Stop 210, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA e-mail: beth.mccarville@stjude.org

A Phase I Study of Gefitinib and irinotecan (IRN) in pediatric patients with refractory solid tumors

8521 Background: Gefitinib (Iressa), an oral Epidermal Growth Factor receptor (EGFR) inhibitor that has been well tolerated in adults, modulates intracellular drug effects through inhibition of efflux pumps (e.g., BCRP). In xenograft models of pediatric solid tumors it has additive/synergistic activity with IRN, which was independent of EGFR status. We are conducting a Phase I study of this combination in children with refractory solid tumors. METHODS Our objectives are to estimate the maximum tolerated dose and dose-limiting toxicities (DLT) of gefitinib administered daily × 21 days in combination with protracted intravenous IRN [day 1- 5, day 8 - 12]. Pharmacokinetic (PK) studies of IRN and metabolites were obtained with and without concurrent gefitinib. PK studies of gefitinib were obtained on days -1 and 8. Courses are repeated every 21 days in the absence of DLT or disease progression. RESULTS At present, 2 cohorts have been evaluated (age 3 -15 yrs, median 5 yrs). Cohort 1 (n = 5) received continuous daily gefitinib at 150 mg/m2/d and IRN at 15 mg/m2/d. Dose-limiting diarrhea was seen in 2 patients. In cohort 2 (n = 3), gefitinib was de-escalated to 112.5 mg/m2/d; DLTs were experienced by 2 patients (1 grade 4 anorexia, 1 grade 4 transaminitis). The onset of all DLTs was on day 10 or greater of the first 21 day course. Concomitant gefitinib administration was associated with decreased IRN lactone systemic clearance (P<0.05). Steady-state gefitinib concentrations approximates the IC50 for BCRP inhibition. One patient with Ewing sarcoma had a partial response, one with anaplastic Wilms tumor had a decrease in multiple (<1 cm each) pulmonary nodules, one with adrenocortical carcinoma had stable disease (SD) for 4 courses and one with neuroblastoma has SD for 3+ courses. Because of delayed onset of these DLTs, the study is being amended to administer gefitinib for the first 12 days of each course only. CONCLUSIONS Our data suggest a shorter schedule of gefitinib in combination with IRN may be better tolerated and will maintain the apparent synergy of these agents. This combination warrants further study in children with refractory solid tumors. [Table: see text].

Retrospective study of the surgical management and outcome of nonrhabdomyosarcoma soft tissue sarcomas of the groin and axilla in children

PURPOSE The incidence of pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) of the groin and axilla is unknown, and the optimal surgical approach to these patients is unclear. METHODS We conducted a retrospective study of patients treated at St Jude Childrens Research Hospital from January 1962 to March 2007 for NRSTSs of the groin and axilla. Demographic variables, tumor pathology, clinical management, and outcome were reviewed. RESULTS Of the 300 patients treated for NRSTSs, only 10 had tumors of the axilla or groin (6 of whom had synovial sarcoma). Surgical interventions included wide resection of the tumor (n = 7), marginal resection (n = 1), subtotal resection (n = 1), and biopsy only (n = 1). Six patients underwent lymph node sampling; all were negative for tumor. Short- and long-term surgical complications were rare. Four patients received adjuvant chemotherapy (n = 3) and/or radiotherapy (n = 2). At a median follow-up of 8.5 years, 7 of the 10 were surviving free of disease. Two of these patients died of tumor progression (1 with metastases at diagnosis and 1 with an unresectable tumor at diagnosis), and one patient who was free of NRSTS died of secondary breast carcinoma. CONCLUSIONS Pediatric NRSTSs of the axilla and groin are rare, but outcomes are similar to those of other patients with NRSTS. Wide local excision of the tumor with preservation of good limb function should be the surgical goal and may be sufficient therapy in some cases.

Pediatric bone and soft-tissue sarcomas

In this session I will review the clinical and imaging features of the most common pediatric bone and soft tissue sarcomas and several benign lesions that may mimic them. These malignancies often have unique features that can help narrow the differential diagnosis. The material will be presented in an informal manner and audience participation is encouraged. A review of the appropriate diagnostic work-up will also be presented, including the role of various imaging modalities to detect local-regional and distant metastatic disease. At the end of this session participants should be able to identify clinical features (age, race, etc.) and imaging features that are suggestive of the correct diagnosis.

The effect of topotecan in advanced intraocular retinoblastoma with manageable toxicity.

9540 Background: There is a need to identify new effective chemotherapeutic agents for the treatment of intraocular retinoblastoma (RB). METHODS An institutional protocol (RET5) for the study and treatment of patients with intraocular RB stratified patients into three groups according to laterality and stage of disease. The primary objective of RET5 was to estimate the response of window therapy for patients with bilateral RB in whom at least one eye was Reese-Ellsworth IV or V. Window therapy consisted of 2 courses of vincristine and topotecan (VT with G-CSF support). Patients with ≥ partial response received 3 more courses of VT alternating with 6 courses of vincristine and carboplatin. The topotecan dose started at 3 mg/m2/day, and was adjusted to attain a target systemic exposure of 140 ± 20 ng/ml*hr. Carboplatin was administered to achieve an area under the curve of 6.5 mg/ml/min. The dose of vincristine dose was 0.05 mg/kg if age at diagnosis < 12 months and 1.5mg/m2 if age at diagnosis > 12 months. RESULTS From 2/2005 until 6/2010, a total of 27 patients were treated VT window therapy. The median age at enrollment was 8.1 months (range, 0.7 to 22.1 months). Twenty-four of 27 patients (88.9%) responded to the VT window with a response rate 88.9% and a 95% Blyth-Still-Casella CI, 71.3%-96.9%. Hematologic toxicity in the form of grade 4 neutropenia (n=27), grade 3 anemia (n=19) and grade 3-4 thrombocytopenia (n=16) were observed during the VT window. Thirteen patients developed grade 3 non-hematologic toxicity. G-CSF support was added after treating 10 patients. Patients treated with GCSF (n=17) had a significant shorter duration of grade 4 neutropenia (median, 7 days) compared to patients without G-CSF (n=10) (median, 24 days) (Wilcoxon rank sum test p<0.0001). CONCLUSIONS Topotecan is an effective agent in the treatment of advanced intraocular RB. The use of GCSF alleviated toxicity, especially the duration of grade 4 neutropenia.