Outcomes of SARS-CoV-2 infection in 126 children and adolescents with central nervous system tumors.

BACKGROUND: The Global Registry of COVID-19 in Childhood Cancer (GRCCC) seeks to describe the natural history of SARS-CoV-2 in children with cancer across the world. Here, we report the disease course and management of coronavirus disease 2019 (COVID-19) infection in the subset of children and adolescents with central nervous system (CNS) tumors who were included in the GRCCC until February 2021, the first data freeze. PROCEDURE: The GRCCC is a deidentified web-based registry of patients less than 19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30 and 60 days post infection. RESULTS: The GRCCC included 1500 cases from 45 countries, including 126 children with CNS tumors (8.4%). Sixty percent of the cases were from middle-income countries, while no cases were reported from low-income countries. Low-grade gliomas, high-grade gliomas, and CNS embryonal tumors were the most common CNS cancer diagnoses (67%, 84/126). Follow-up at 30 days was available for 107 (85%) patients. Based on the composite measure of severity, 53.3% (57/107) of reported SARS-CoV-2 infections were asymptomatic, 39.3% (42/107) were mild/moderate, and 6.5% (7/107) were severe or critical. One patient died from SARS-CoV-2 infection. There was a significant association between infection severity and absolute neutrophil count less than 500 (p = .04). Of 107 patients with follow-up available, 40 patients (37.4%) were not receiving cancer-directed therapy. Thirty-four patients (50.7%) had a modification to their treatment due to withholding of chemotherapy or delays in radiotherapy or surgery. CONCLUSION: In this cohort of patients with CNS tumors and COVID-19, the frequency of severe infection appears to be low, although severe disease and death do occur. We found that greater severity was seen in patients with severe neutropenia, although treatment modifications were not associated with infection severity or cytopenias. Additional analyses are needed to further describe this unique group of patients.

Impact of Neoadjuvant Chemotherapy on Image-Defined Risk Factors in High-Risk Neuroblastoma.

PURPOSE: Image-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection (GTR) of locoregional disease in patients with high-risk neuroblastoma. METHODS: We retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined. RESULTS: Eighty-eight patients were included. There were 438 IDRFs (average 5.0 ± 3.1 per patient) at diagnosis and 198 (average 2.3 ± 1.9 per patient) after neoadjuvant chemotherapy (p < 0.01). A reduction in IDRFs was seen in 81.8% of patients with average decrease of 2.9 ± 2.5 per patient. The average percent reduction in tumor volume was 89.8 ± 18.9% and correlated with the number of IDRFs present after chemotherapy (p < 0.01). Three or fewer IDRFs prior to surgery was associated with the highest odds ratio for > 90% GTR at 9.33 [95% confidence interval 3.14-31.5]. CONCLUSION: Neoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection.

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study.

BACKGROUND: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. METHODS: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. FINDINGS: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8-8·8]; p<0·0001) and upper-middle-income (1·6 [1·2-2·2]; p=0·0024) country status; age 15-18 years (1·6 [1·1-2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8-3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3-2·4]; p=0·0001), and intensive treatment (1·8 [1·3-2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3-0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3-0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3-2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1-2·3]; p=0·020). INTERPRETATION: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. FUNDING: American Lebanese Syrian Associated Charities and the National Cancer Institute.

Role of implicit bias in pediatric cancer clinical trials and enrollment recommendations among pediatric oncology providers.

BACKGROUND: Provider implicit bias can negatively affect clinician-patient communication. In the current study, the authors measured implicit bias training among pediatric oncology providers and exposure to implicit association tests (IATs). They then assessed associations between IATs for race and socioeconomic status (SES) and recommendations for clinical trial enrollment. METHODS: A prospective multisite study was performed to measure implicit bias among oncology providers at St. Jude Children's Research Hospital and affiliate clinics. An IAT was used to assess bias in the domains of race and SES. Case vignettes were used to determine an association between bias and provider recommendation for trial enrollment. Data were analyzed using Student t tests or Wilcoxon tests for comparisons and Jonckheere-Terpstra tests were used for association. RESULTS: Of the 105 total participants, 95 (90%) had not taken an IAT and 97 (92%) had no prior implicit bias training. A large effect was found for (bias toward) high SES (Cohen d, 1.93) and European American race (Cohen d, 0.96). The majority of participants (90%) had a vignette score of 3 or 4, indicating recommendation for trial enrollment for most or all vignettes. IAT and vignette scores did not significantly differ between providers at St. Jude Children's Research Hospital or affiliate clinics. No association was found between IAT and vignette scores for race (P = .58) or SES (P = .82). CONCLUSIONS: The authors noted a paucity of prior exposure to implicit bias self-assessments and training. Although these providers demonstrated preferences for high SES and European American race, this did not appear to affect recommendations for clinical trial enrollment as assessed by vignettes.

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors.

BACKGROUND: The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors. METHODS: In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients. RESULTS: Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline. CONCLUSIONS: The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4-week cycle for children with recurrent solid tumors.

Increased aridity drives post-fire recovery of Mediterranean forests towards open shrublands.

Recent observations suggest that repeated fires could drive Mediterranean forests to shrublands, hosting flammable vegetation that regrows quickly after fire. This feedback supposedly favours shrubland persistence and may be strengthened in the future by predicted increased aridity. An assessment was made of how fires and aridity in combination modulated the dynamics of Mediterranean ecosystems and whether the feedback could be strong enough to maintain shrubland as an alternative stable state to forest. A model was developed for vegetation dynamics, including stochastic fires and different plant fire-responses. Parameters were calibrated using observational data from a period up to 100 yr ago, from 77 sites with and without fires in Southeast Spain and Southern France. The forest state was resilient to the separate impact of fires and increased aridity. However, water stress could convert forests into open shrublands by hampering post-fire recovery, with a possible tipping point at intermediate aridity. Projected increases in aridity may reduce the resilience of Mediterranean forests against fires and drive post-fire ecosystem dynamics toward open shrubland. The main effect of increased aridity is the limitation of post-fire recovery. Including plant fire-responses is thus fundamental when modelling the fate of Mediterranean-type vegetation under climate-change scenarios.

Barriers and facilitators of clinical trial enrollment in a network of community-based pediatric oncology clinics.

INTRODUCTION: Major advances in the field of pediatric oncology have resulted from rigorous, prospective clinical oncology research trials. Optimizing access for all children and adolescents to clinical research trials is an important goal. Barriers to clinical trial enrollment are numerous, involving the health care system, research infrastructure, access to care, providers, and participants. The perspectives of pediatric oncologists may provide insight into the barriers of clinical trial enrollment for this unique population. METHODS AND MATERIALS: We conducted qualitative structured interviews over two months of pediatric oncologists in a community-based clinical network as part of a quality improvement project aimed at increasing enrollment rates at St. Jude Affiliate Clinics. We assessed barriers and facilitators to clinical trial opportunities for racial and ethnic minority pediatric participants. In the same fiscal year of the interviews, we tracked clinical trial enrollment by race and ethnicity of the participant over 12 months. RESULTS: The major barriers to clinical trial enrollment for pediatric cancer minority participants included language discordance, travel difficulties, and complex trial designs. In contrast, the major facilitators included building trust with participants and their parents, and education on the merits of clinical research studies. We did not observe any disparities in clinical trial enrollment among the racial and ethnic minority participants of the clinical trials conducted across our network of pediatric oncology clinics. CONCLUSIONS: Identifying barriers and facilitators may improve clinical trial enrollment for underrepresented participant groups.

Biochemical testing for neuroblastoma using plasma free 3-O-methyldopa, 3-methoxytyramine, and normetanephrine.

BACKGROUND: Neuroblastoma, the most common extracranial solid tumor of childhood, produces catecholamines that are metabolized within tumor cells. Homovanillic acid (HVA) and vanillylmandelic acid (VMA), the end products of catecholamine metabolism, have limited accuracy for testing of the tumors. This study assessed whether metabolites produced in earlier steps of catecholamine metabolism might offer improved diagnostic accuracy over urinary HVA and VMA. PROCEDURE: Plasma concentrations of 3-methoxytyramine, normetanephrine, and metanephrine were measured in two pediatric cohorts: (i) 96 children with confirmed neuroblastoma and (ii) 41 children with signs and symptoms of a catecholamine-producing tumor or other neoplasms and in whom neuroblastoma was excluded. Additional measurements of plasma 3-O-methyldopa and relationships of metabolites to MYCN amplification were examined in patient subgroups. RESULTS: Overall, 94 of the 96 patients with neuroblastoma had concentrations of 3-methoxytyramine or normetanephrine above age-specific upper limits of reference intervals, providing a diagnostic sensitivity of 97.9% that was higher (P < 0.0001) than that of 82.2% for HVA and VMA. One of the two patients with normal plasma results showed an elevation of plasma 3-O-methyldopa. Diagnostic specificities were, respectively, 95.1% and 84.8%. Areas under receiver-operating characteristic curves confirmed the superior diagnostic power of the plasma than the urinary test (0.994 vs 0.945; P = 0.0095). Ratios of plasma 3-methoxytyramine to normetanephrine were 7.2-fold higher (P < 0.0001) for patients who had neuroblastomas with MYCN amplification than without MYCN amplification. CONCLUSIONS: Measurements of plasma 3-methoxytyramine and normetanephrine provide a highly accurate diagnostic test for neuroblastoma and also offer potential for prognostic risk stratification.

Determining success rates of the current pharmacokinetically guided dosing approach of topotecan in pediatric oncology patients.

BACKGROUND: Topotecan is a chemotherapeutic agent that is active against many pediatric tumors. Although its effect is related to systemic exposure, the interpatient variability in systemic clearance makes it challenging to achieve desired topotecan targets. This study aims to evaluate the success of the pharmacokinetically (PK) guided dosing process, which was used to achieve a target topotecan area under the concentration-time curve (AUC). METHODS: Patients received an empiric topotecan dosage on the first day; the topotecan lactone AUC was determined, and based upon these values the topotecan dosage was adjusted. The success rates of both the empiric and PK-guided strategies were calculated. Patient-specific covariates were collected to explain variability observed in the empiric and PK-guided results. A simulation study was performed to assess the differences in cumulative topotecan dosage and systemic exposure between a PK-guided and standard dosing approach. RESULTS: Data were collected from nine clinical trials open from 1996 to 2016 (n = 232 patients). The empiric dosing success rate was 35.5%, while the PK-guided rate was 64.4%. A difference in mean serum creatinine was observed between successful empiric studies and those above the AUC target. Compared to a standard dosing approach, the PK-guided group had a higher average cumulative dosage and systemic exposure. CONCLUSION: The low empiric dosing success rate indicates that additional studies are needed to refine the initial topotecan dosage. The role of renal function, measured as serum creatinine, remains to be elucidated. However, the PK-guided targeting success rate highlighted the need to account for variable topotecan systemic clearance.

Managing local-regional failure in children with high-risk neuroblastoma: A single institution experience.

BACKGROUND: Intensification of systemic therapy for high-risk neuroblastoma (HRNB) has resulted in improved local control and overall survival (OS) leaving potential for de-escalation of primary site radiotherapy. The utility of primary site de-escalation should be evaluated in the context of potential for successful local-regional salvage. We evaluated salvage strategies and outcomes in patients with HRNB with local-regional recurrence as a component of first failure. METHODS: Twenty of 89 patients with HRNB experienced local-regional recurrence as a component of first relapse after chemotherapy, radiotherapy, surgery, and stem cell transplant from 1997 to 2013. We reviewed salvage therapy strategies and disease control, and report on the impact of local therapy as salvage for local-regional relapse. RESULTS: Six of 20 patients with local-regional failure (LRF) were alive after a median follow-up of 13 years (range, 0.9-25.2 years). Median OS was 4.6 years (95% CI, 0.6 to not reached) versus 0.6 years (95% CI, 0.05-2.6) after LRF with and without distant failure, respectively (P = 0.03). OS in patients receiving salvage radiotherapy was comparable to those receiving initial adjuvant but no salvage radiotherapy. Time to first failure and death was significantly impacted by the intensity of frontline systemic therapy (P = 0.03). Salvage radiotherapy reduced the hazard for subsequent LRF (hazard ratio 0.3, 95% CI 0.1-0.9, P = 0.04) but not OS (P = 0.07). CONCLUSIONS: Our study highlights the potential of local control strategies at first failure in patients with LRF when primary site radiotherapy was initially omitted, and delineates potential selection factors which may further improve the therapeutic ratio.

Redirecting fire-prone Mediterranean ecosystems toward more resilient and less flammable communities.

The extensive abandonment of agricultural lands in the Mediterranean basin has led to large landscapes being dominated by early-successional species, characterized by high flammability and an increasing fire risk. This fact promotes fire occurrence and places ecosystems in a state of arrested succession. In this work, we assessed the effectiveness of several restoration actions in redirecting these ecosystems toward more resilient communities dominated by resprouting species. These actions included the mechanical clearing of early-successional species, the plantation of resprouting species, and the combination of both treatments. For 13 years, we assessed shifts in the successional trajectory and ecosystem flammability by changes in: species composition, species richness, ecosystem evenness, the natural colonization of resprouting species, total biomass and proportion of dead biomass. We observed that the plantation and clearing combination was a suitable strategy to promote resilience. Species richness increased as well as the presence of the resprouting species introduced by planting. The natural colonization of the resprouting species was also enhanced. These changes in the successional trajectory were accompanied by a possible reduction of fire risk by reducing dead fuel proportion. These findings are relevant for the management of Mediterranean basin areas, but also suggest new tools for redirecting systems in fire-prone areas worldwide.

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma 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 two 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.

NCCN Guidelines Insights: Bone Cancer, Version 2.2017.

The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.

Safety and diagnostic accuracy of tumor biopsies in children with cancer.

BACKGROUND: Tumor biopsies are central to the diagnosis and management of cancer and are critical to efforts in personalized medicine and targeted therapeutics. In the current study, the authors sought to evaluate the safety and accuracy of biopsies in children with cancer. METHODS: All biopsies performed in children at the study institution with a suspected or established diagnosis of cancer from 2003 through 2012 were reviewed retrospectively. Patient characteristics and disease-related and procedure-related factors were correlated with procedure-related complications and diagnostic accuracy using logistic regression analysis. RESULTS: A total of 1073 biopsies were performed in 808 patients. Of 1025 biopsies with adequate follow-up, 79 (7.7%) were associated with an adverse event, 35 (3.4%) of which were minor (grade 1-2) and 32 (3.1%) of which were major (grade 3-4) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The most common major adverse events were blood transfusion (>10 mL/kg; 24 cases) and infection requiring intravenous antibiotics (6 cases). Eleven deaths (1.4%) occurred within 30 days after the procedure, but the procedure may have contributed to the outcome in only 2 cases. A total of 926 biopsies (90.3%) provided definitive histologic diagnoses. Using multivariable analysis, biopsy site, preprocedure hematocrit level, and body mass index were found to be associated with the risk of postprocedural complications (P<.0001, P<.0001, and P =.0029, respectively). Excisional biopsy and biopsy site were found to be independently associated with obtaining a diagnostic result (P =.0002 and P =.0008, respectively). CONCLUSIONS: Tumor biopsies in children with cancer are associated with a low incidence of complications and a high rate of diagnostic accuracy. The predictive factors identified for adverse outcomes may aid in risk assessment and preprocedural counseling.

Comparison of pain outcomes between two anti-GD2 antibodies in patients with neuroblastoma.

BACKGROUND: Addition of anti-GD2 antibody ch14.18 to the treatment of neuroblastoma has improved outcomes. The most common side effect of ch14.18 is neuropathic pain, which may in part be complement-mediated. Hu14.18K322A is a humanized anti-GD2 antibody designed to diminish complement activation and induce less pain. We compare the pain outcomes in patients treated with ch14.18 and those treated with hu14.18K322A, and explore dose-dependent relationships between pain scores, opioid requirements, and complement levels in patients treated with hu14.18K322A. PROCEDURE: Opioid (morphine equivalent mg/kg) and anxiolytic requirements during course 1 (4 days) in patients treated with hu14.18K322A and ch14.18 were reviewed. Correlations between antibody dose and pain scores, opioid requirements, and complement levels were examined for patients receiving hu14.18K322A. RESULTS: Patients treated with hu14.18K322A (n = 19) had lower opioid requirements than those who received ch14.18 (n = 9). The differences in median opioid requirements (mg/kg) were statistically significant for the overall course (1.57 vs. 2.41, P = 0.019) as well as for Days 3 (0.34 vs. 0.65, P = 0.005), and 4 (0.32 vs. 0.64, P = 0.010). No difference in anxiolytic use was observed between the two groups. In the group treated with hu14.18K322A, we found a positive correlation between antibody dose administered and pain scores, but no correlation between antibody dose and opioid requirements or changes in complement levels. CONCLUSIONS: In this retrospective analysis, hu14.18K322A induced less pain than ch14.18 based on opioid requirements. Pediatr Blood Cancer 2015;62:224-228. © 2014 Wiley Periodicals, Inc.

Phase I clinical trial of ifosfamide, oxaliplatin, and etoposide (IOE) in pediatric patients with refractory solid tumors.

Oxaliplatin, although related to cisplatin and carboplatin, has a more favorable toxicity profile and may offer advantages in combination regimens. We combined oxaliplatin, ifosfamide, and etoposide (IOE) and estimated the regimen's maximum tolerated dose (MTD) in children with refractory solid tumors. Dose-limiting toxicity (DLT) and MTD were assessed at 3 dose levels in a 21-day regimen: day 1, oxaliplatin 130 mg/m (consistent dose); days 1 to 3, ifosfamide 1200 mg/m/d (level 0) or 1500 mg/m/d (levels 1 and 2) and etoposide 75 mg/m/d (levels 0 and 1) or 100 mg/m/d (level 2). Course 1 filgrastim/pegfilgrastim was permitted after initial DLT determination, if neutropenia was dose limiting. Seventeen patients received 59 courses. Without filgrastim (n=9), DLT was neutropenia in 2 patients at dose level 1. No DLT was observed after adding filgrastim (n=8). There was no ototoxicity, nephrotoxicity >grade 1, or neurotoxicity >grade 2. One patient experienced a partial response and 9 had stable disease after 2 courses. In conclusion, the IOE regimen was well tolerated. Without filgrastim, neutropenia was dose limiting with MTD at ifosfamide 1200 mg/m/d and etoposide 75 mg/m/d. The MTD with filgrastim was not defined due to early study closure. Filgrastim allowed ifosfamide and etoposide dose escalation and should be included in future studies.

Subsequent malignant neoplasms in pediatric patients initially diagnosed with neuroblastoma.

BACKGROUND: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. METHODS: Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. RESULTS: Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. CONCLUSIONS: Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.

Adaptive functioning of childhood brain tumor survivors following conformal radiation therapy.

Adaptive functioning is not often examined in childhood brain tumor (BT) survivors, with the few existing investigations relying on examiner interviews. Parent questionnaires may provide similar information with decreased burden. The purpose of this study was: (1) to examine adaptive behaviors in BT survivors relative to healthy peer and cancer survivor groups, and (2) to explore the validity of a parent questionnaire in relation to an examiner administered interview. Participants (age 13.11 ± 2.98 years) were BT survivors treated with conformal radiation therapy (n = 50), healthy siblings of BT survivors (n = 39) and solid tumor (ST) survivors who did not receive CNS-directed therapy (n = 40). Parents completed the Adaptive Behavior Assessment System­2nd Edition (ABAS-II). For a subset of the BT cohort (n = 32), examiners interviewed the parents using the Vineland Adaptive Behavior Scales (VABS) within 12 months. Groups differed significantly on each of the ABAS-II indices and the general adaptive composite, with the BT group scoring lower than the sibling and ST groups across indices. Executive functioning, but not IQ, was associated with adaptive skills; no clear pattern of clinical and demographic predictors was established. VABS scores were correlated with ABAS-II scores on nearly all indices. BT survivors showed significantly lower adaptive functioning when compared to healthy and cancer controls. The ABAS-II proved sensitive to these behavioral limitations and was consistent with scores on the VABS. The use of a parent questionnaire to assess adaptive functioning enhances survivorship investigations by increasing flexibility of assessment and decreasing examiner burden.

Flammability properties of British heathland and moorland vegetation: models for predicting fire ignition.

Temperate ecosystems, for example British heathlands and moorlands, are predicted to experience an increase in severe summer drought and wildfire frequency over the next few decades. The development of fire ignition probability models is fundamental for developing fire-danger rating systems and predicting wildfire outbreaks. This work assessed the flammability properties of the fuel complex of British moorlands as a function of their moisture content under laboratory conditions. Specifically, we aimed to develop: (1) models of the probability of fire ignition in peat/litter fuel-beds (litter of four different plant species, Sphagnum moss and peat); (2) flammability properties in terms of ignitability, sustainability, consumability and combustibility of these peat/litter fuel-beds; (3) the probability of ignition in a canopy-layer of Calluna vulgaris (the most dominant heath/moor species in Britain) as a function of its dead-fuel proportion and moisture content; (4) the efficacy of standardized smouldering and flaming ignition sources in developing sustained ignitions. For this, a series of laboratory experiments simulating the fuel structure of moor vegetation were performed. The flammability properties in peat/litter fuel-beds were influenced strongly by the fuel moisture content. There were small differences in moisture thresholds for experiencing initial flaming ignitions (35-59%), however, the threshold for sustained ignitions (i.e. spreading a fixed distance from the ignition point) varied across a much wider range (19-55%). Litter/peat fuel-beds were classified into three groups: fuel-beds with high ignitability and combustibility, fuel-beds with high levels of sustainability, and fuel-beds with low levels in all flammability descriptors. The probability of ignition in the upper Calluna-vegetation layer was influenced by both the proportion of dead fuels and their moisture content, ranging from 19% to 35% of moisture as dead fuel proportion increased. Smouldering sources were more efficient in igniting peat/litter fuel-beds but in the Calluna-vegetation layer flaming sources performed better. This work can assist in improving the predictions of fire-rating systems implemented in British moorlands, by providing better warnings based on critical moisture thresholds for various fuel types.