The effects of pazopanib on doxorubicin pharmacokinetics in children and adults with non-rhabdomyosarcoma soft tissue sarcoma: a report from Children's Oncology Group and NRG Oncology study ARST1321.

PURPOSE: The use of tyrosine kinase inhibitors for the treatment for soft tissue sarcomas is increasing given promising signals of activity in a variety of tumor types. The recently completed study in non-rhabdomyosarcoma soft tissue sarcomas, ARST1321, demonstrated that the addition of pazopanib to neoadjuvant ifosfamide, doxorubicin, and radiation improved the pathological near complete response rate compared with chemoradiotherapy alone. Pharmacokinetic (PK) evaluation of doxorubicin with pazopanib has not been previously reported. As an exploratory aim, doxorubicin PK data were collected during the dose-finding phase of the study in patients receiving chemotherapy and pazopanib to assess the effect of pazopanib on doxorubicin PK parameters. METHODS: Blood samples were collected during cycle 2 (week 4) of chemotherapy at the following time points from doxorubicin administration: predose, 5, 30, and 60 min, and 2, 4, 8, 24 ± 3, and 48 ± 3 h after dosing. The population pharmacokinetic and individual post hoc estimates of doxorubicin and doxorubicinol were determined by nonlinear mixed-effects modeling. RESULTS: There were 52 doxorubicin and doxorubicinol samples from 7 individuals in this study (median age: 17 years; range 14-23). The doxorubicin clearance was 26.9 (16.1, 36.4, and 33.9) L/h/m2 (post hoc median and range) and 25.8 (23.3%) L/h/m2 [population estimate and IIV (CV%)]. The doxorubicinol apparent clearance was 67.5 (18.2, 1701) L/h/m2 (post hoc median and range) and 58.7 (63.7%) L/h/m2 [population estimate and IIV (CV%)]. CONCLUSION: The PK data of seven patients treated on ARST1321 is consistent with previously reported population and post hoc doxorubicin clearance and doxorubicinol apparent clearance estimates, showing that the addition of pazopanib does not significantly alter doxorubicin pharmacokinetics. These data support the safety of administration of pazopanib with doxorubicin-containing chemotherapy.

Non-invasive assessment of muscle oxygenation may aid in optimising transfusion threshold decisions in ambulatory paediatric patients.

OBJECTIVE: To assess the potential utility of a novel non-invasive muscle oxygen measurement to determine the presence of muscle hypoxia in patients with anaemia. BACKGROUND: Recent assessment of the risk/benefit ratio of blood transfusion has led to clinical strategies optimising transfusion decisions. These decisions are primarily based on haematocrit (Hct) but not oxygen delivery, the primary function of red blood cells (RBCs). We hypothesised that muscle oxygenation (MOx) would correlate with Hct in patients with anaemia and may be a physiologically relevant determinant of the transfusion threshold. METHODS/MATERIALS: MOx was non-invasively determined in children in the Cancer and Blood Disorders Center ambulatory clinic at Seattle Children's Hospital using a custom-designed optical probe and spectrometer. MOx was compared with contemporaneous Hct. In subjects receiving RBCs, MOx and Hct were also determined following transfusion. RESULTS: MOx ranged from 36·7 to 100%, and Hct ranged from 17·0 to 38·6% in 27 measurements from 16 patients. High MOx values were associated with high Hct. Mean MOx for patients with normal Hct for age (n = 5) was 95·9 ± 2·9%. RBC transfusion increased mean Hct from 19·1 ± 1·5% to 29·3 ± 2·0 and mean MOx from 67·9 ± 21·1% to 89·9 ± 9·8%. Among six transfusion episodes (in five patients) with initial Hct < 22, only three had a pre-transfusion MOx of <70%. Patients with the lowest pre-transfusion MOx had the largest increase in MOx after transfusion. CONCLUSIONS: These preliminary data suggest that MOx may aid in making transfusion decisions when used in combination with Hct.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study).

BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.

Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups.

BACKGROUND: Parameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004. PATIENTS AND METHODS: Clinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS). RESULTS: Ten-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%. CONCLUSIONS: While, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3-4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS.

Improved outcome for patients with middle ear rhabdomyosarcoma: a children's oncology group study.

PURPOSE: The goal of this study was to define the clinical features and optimal therapy for children and adolescents with middle ear (ME) rhabdomyosarcoma (RMS). PATIENTS AND METHODS: We reviewed demographic data, clinical features, therapy (including chemotherapy, surgery, and radiation), and outcome for the 179 eligible patients with ME RMS who were enrolled onto Intergroup Rhabdomyosarcoma Studies (IRS) I through IV or pilot studies between November 1972 and December 1997. RESULTS: Most patients were younger than 10 years old (90%), and 63% were male. Because of the parameningeal location, most tumors were not resected before chemotherapy (group I, < 1%; group II, 4%; group III, 84%; group IV, 12%). Although most tumors were locally invasive (T2, 89%), the majority were small (< or = 5 cm, 66%), lacked nodal metastases (N0, 86%), and had embryonal histology (85%). The 5-year failure-free survival (FFS) and overall survival (OS) estimates were 67% and 72%, respectively. Both FFS and OS improved significantly over the course of IRS I through IV (3-year FFS and OS: IRS-I, 42% and 42%; IRS-II, 70% and 74%; IRS-III, 65% and 72%; IRS-IV pilot, 81% and 96%; IRS-IV, 88% and 88%, P <.001). Lower clinical group or stage and smaller tumor size were associated with better outcome. Age, sex, tumor invasiveness, and nodal metastases were not predictive of outcome. CONCLUSION: Patients with ME RMS generally present with small, unresectable, invasive tumors at a site traditionally considered prognostically unfavorable. Nevertheless, such patients have benefited markedly from improvements in multimodal, risk-based therapy during the course of IRS I through IV, and with contemporary therapy, most are cured.

Stages of change and weight loss among rural African American women.

OBJECTIVE: Obesity is a prevalent public health problem in the United States, especially for rural African American women, and causes increased morbidity and mortality. The purpose of this analysis was to determine whether the transtheoretical stages of change model was generalizable to weight loss intention among overweight and obese rural African American women and to identify important predictors of the stages of change. RESEARCH METHODS AND PROCEDURES: The study was conducted in two rural counties in central Virginia. A population-based sample of 200 women under the age of 40 completed questionnaires concerning weight loss behavior and beliefs about weight. Ordinal logistic regression was used to predict stage of change. RESULTS: A total of 142 of the 200 women (71%) were overweight or obese (body mass index of > or =25) and were classified into a stage of change. Overall, 30% of respondents were in the precontemplation stage, 15% in the contemplation stage, 48% in the preparation stage, 4% in the action stage, and 3% in the maintenance stage. Education, what friends think about weight, body mass index, and a scale of the positive aspects of weight loss were significant predictors of the stage of change (p < 0.05). CONCLUSIONS: Several predictors of stage were the same as those found in studies of other health behaviors, and this research provides support for applying a stages of change model for weight loss intention among rural African American women. Two predictors in particular, significance of what friends think about weight and a scale of the positive aspects of weight loss, have implications for health education initiatives and social support in weight loss interventions.

The utility of skin biopsies in pediatric cancer patients: a single-institution, retrospective review.

Medical records of all patients who were diagnosed with a malignancy and who underwent a skin biopsy were reviewed to determine the clinical utility of skin biopsies in this population. Skill biopsies resulted in a change or refinement of the prebiopsy diagnosis in 44% of patients undergoing an initial evaluation for a malignancy, 57% of patients on therapy, and 17% of patients off therapy. Skin biopsies led to a change in therapy in 26%, 34%, and 17% of each respective group. Overall, the skin biopsy changed or refined the prebiopsy diagnosis in 45% of cases and altered therapy in 38%. Skin biopsy is a clinically useful tool in pediatric oncology patients for the evaluation of cutaneous findings that elude diagnosis by visual inspection.

Computed tomography in the evaluation of febrile neutropenic pediatric oncology patients.

AIM: To evaluate the diagnostic utility of computed tomography (CT) obtained during prolonged febrile neutropenia in pediatric oncology patients. METHODS: We evaluated the medical records of all patients with a malignant disease who had a CT examination during an episode of febrile neutropenia lasting for 4 days or more at Children's Hospital and Regional Medical Center in Seattle, WA, between January 1, 1997, and June 1, 1999. RESULTS: CT was performed on 83 patients to evaluate 109 episodes of prolonged febrile neutropenia. Sixty-eight (62%) of the initial CT scans demonstrated abnormalities, leading to changes in therapy in 42 (39%). The diagnostic and therapeutic utility of CT varied by anatomic site. Abdominal and head/neck CT detected abnormalities in only 19 and 8% of studies, respectively, resulting in therapy changes in 9 and 4%, respectively. Sinus CT demonstrated abnormalities in 41% of cases and altered therapy in 24%. Chest CT had the highest diagnostic utility, with 49% of cases demonstrating abnormalities, leading to therapy alteration in 30%. CT was rarely abnormal in the absence of localizing signs or symptoms. In 55 instances 1 or more follow-up scans were done. Thirteen follow-up CT scans showed abnormalities that led to a change in therapy. CONCLUSIONS: CT-detected abnormalities frequently lead to alterations in therapy, particularly sinus and thoracic CT. Most patients with CT-detected abnormalities have symptoms or signs referable to the site of abnormality. Asymptomatic febrile neutropenic children rarely have CT findings that lead to a change in therapy.

Successful dose-intensive treatment of desmoplastic small round cell tumor in three children.

Desmoplastic small round cell tumor (DSRCT) is a rare soft tissue tumor of primitive origin occurring primarily in children and young adults. Based on published reports in the literature, the response to conventional chemotherapy is poor. We report three pediatric patients successfully treated with dose-intensive, multimodal therapy. Between August 1994 and March 1998, we evaluated three consecutive patients with DSRCT at Children's Hospital and Regional Medical Center, Seattle, Washington. We established the diagnosis based on clinical presentation, radiologic staging, and pathologic review with immunohistochemical staining. All patients received a combined modality protocol including dose-intensive chemotherapy (two of them with peripheral blood stem cell [PBSC] support), second look surgery, and consolidative local irradiation. The patients remain in continuous remission at 66, 42, and 26 months after diagnosis, respectively. Two of our patients were younger than any previously reported patient, extending the age group for which DSRCT should be considered on diagnosis of small round cell tumors. The uniform survival achieved in our series indicates potential benefit for the combination of dose-intensive multiagent chemotherapy, local irradiation, and aggressive surgical approach in this disease.

Meningitis in pediatric cancer patients: a review of forty cases from a single institution.

BACKGROUND: Although the clinical features of bacterial meningitis in adult cancer patients and in healthy children have been described, no previous large series has described the clinical features of meningitis in pediatric cancer patients. We performed a retrospective review of bacterial or fungal meningitis in pediatric cancer patients to determine its clinical presentation, microbiology and outcome. METHOD: We reviewed the medical records of all patients younger than 18 years old with a diagnoses of any malignancy and bacterial or fungal meningitis at Children's Hospital and Regional Medical Center in Seattle, WA, from January, 1981, to June, 1998. RESULTS: During the study period there were 40 cases of bacterial or fungal meningitis in 36 pediatric cancer patients. Most patients (65%) had recent neurosurgery, a central nervous system device or cerebrospinal fluid leak. Neutropenia was present in 30% of patients. Fever and altered mental status were the most consistent signs at presentation. In addition at least one additional symptom or sign of meningitis (headache, neck pain or rigidity, seizures or photophobia) was present in 77% of cases. Staphylococcus aureus and Streptococcus pneumoniae were the most common microbiologic isolates. The five patients with fatal outcome were neutropenic. Neutropenia and seizures within 2 days of presentation were associated with long neurologic sequelae. CONCLUSIONS: Meningitis in pediatric cancer patients was associated with significant morbidity and mortality. Pediatric cancer patients with meningitis had clinical features and microbiology distinctly different from those of adult cancer patients and normal children with meningitis.

Spontaneous remission of congenital leukemia.

Most patients with congenital leukemia do not survive past infancy despite aggressive chemotherapy. We describe three patients with congenital leukemia who have undergone prolonged periods of spontaneous remission. Our experience suggests that some patients with congenital leukemia may benefit from initial conservative management without chemotherapy. We summarize the clinical presentations of these patients and review the literature.

Inactivation of p53 enhances sensitivity to multiple chemotherapeutic agents.

Many tumor types have p53 and/or RB mutations, and it is unclear what role the mutations of these tumor suppressor genes have on the efficacy of chemotherapeutic agents. The effect of p53 and RB inactivation on sensitivity to chemotherapeutic drugs was examined using a model system in which p53 or RB was inactivated in normal human foreskin fibroblasts (HFFs) by acute expression of human papillomavirus (HPV) 16E6 or 16E7. Cytotoxicity assays showed that HFFs expressing HPV 16E6 were 6- to 9-fold more sensitive to the DNA crosslinkers cisplatin and carboplatin and 7.8- to 11.5-fold more sensitive to the tubulin polymerizing agent paclitaxel than were LXSN-expressing cells. Analysis of mouse embryonal fibroblasts lacking p53 (p53-/-) compared with mouse embryonal fibroblasts homozygous (p53+/+) and heterozygous (p53+/-) for wild-type p53 confirmed the role of p53 in the enhanced sensitivity to cisplatin. Treatment with the alkylating agents melphalan and nitrogen mustard resulted in 3.8- to 7.3-fold greater sensitivity in HPV 16E6- or 16E7-expressing cells compared with LXSN-expressing cells. Enhanced sensitivity to cisplatin in cells lacking p53 function was explored by examination of its effects on cell cycle progression after exposure. When treated with cisplatin, HFFs expressing 16E6 showed delayed progression through S phase relative to HFFs expressing LXSN. The delay in S phase progression was coincident with the induction of p53 protein levels in LXSN-containing HFFs, suggesting a role for p53 in DNA repair of cisplatin-induced damage. These results indicate that the inactivation of p53 in the absence of other genetic alterations leads to enhanced sensitivity to multiple chemotherapeutic agents rather than to increased resistance.

Serum parathyroid hormone (PTH) in pregnant women determined by an immunoradiometric assay for intact PTH.

Most studies of circulating PTH levels using traditional RIAs have supported the concept of physiological hyperparathyroidism of pregnancy, with pregnant women having serum immunoreactive PTH levels significantly higher than those in nonpregnant subjects. However, such RIAs are insensitive and often detect inactive PTH fragments, so that the correlation between PTH immunoreactivity and bioactivity is poor. Employing a new intact PTH immunoradiometric assay (Allegro-Nichols), we reassessed the effects of pregnancy on parathyroid function. The mean serum PTH level in 81 pregnant women was 14.4 +/- 6.3 (+/- SD) compared to 24.8 +/- 9.0 ng/L in 11 normally cycling nonpregnant women (P less than 0.001). The mean serum total and ionized calcium levels in the 2 groups were similar. In 5 of the pregnant women, serum bioactive PTH, determined by cytochemical bioassay, was slightly lower (7.7 +/- 3.4 ng/L) than in normal individuals (11.1 +/- 1.9 ng/L). Our findings suggest, in contrast with the results of most previous studies, that serum intact PTH may decline during pregnancy.